Patent Application
20240383842
The disclosed invention is generally in the field of chiral amino acids.
Organic synthesis often uses active methylene compounds to build complex structures. When located between two electron-withdrawing groups, methylene bridges can be easily deprotonated and doubly substituted. These substitution reactions, when coupled with further derivatization of the tetrasubstituted carbon, can rapidly provide polyfunctionalized structures. Malonic ester synthesis is an example of such a paradigm that has been implemented for more than a century to forge α-substituted carboxylic acids via a sequence of substitution, hydrolysis, and decarboxylation (J. Wislicenus, Liebigs Ann. Chem. 186, 161-228 (1877); A. C. Cope, et al., Org. React. 107-331 (1957); and H. O. House, Modern Synthetic 2nd ed W. A. Benjamin, inc., 1972, pp. 492-623). When combined with phthalimide-based Gabriel amine synthesis (S. Gabriel, Ber. 20, 2224-2236 (1887); M. S. Gibson and R. W. Bradshaw, Angew. Chem., Int. Ed. Engl. 7, 919-930 (1968)), this synthetic protocol is further empowered to produce α-amino acids (S. K. Mitra, J. Ind. Chem. Soc. 7, 799-802 (1930)). While the malonate-based approach to this family of biomolecules has the advantages of facile substrate preparation and high modularity, its capability of accessing these acids stereoselectively is limited.
Asymmetric malonic ester synthesis needs a fast and stereoselective decarboxylation pathway that can outcompete self-decarboxylation reaction to racemic acids, to deliver a small proton precisely to one face of the enol intermediate after CO2 extrusion. These challenges may be addressed by enzymatic catalysis with arylmalonate decarboxylase (AMDase, EC 4.1.1.76, K. Miyamoto and Kourist, R., Appl. Microbiol. Biotechnol. 100, 8621-8631 (2016); M. Wilding, et al., Comprehensive Chirality, H. Yamamoto, & E. M. Carreira, Eds. (Elsevier, 2012) pp. 402-409). In a basic medium, diacid substrates are deprotonated to their conjugate bases that have an inhibited self-decarboxylation and can fit into the active site of AMDase containing two polar pockets of contrasting sizes and a dioxyanion hole (W. H. Richardson and H. E. O'Neal, Comprehensive Chemical Kinetics: Decomposition and Isomerization of Organic Compounds, C. H. Bamford & C. F. H. Tipper Eds. (Elsevier, 1972) pp. 381-565). The anion hole is composed of four residues with six hydrogen bond donors that lower the barrier of decarboxylation by stabilizing negative charges. Subsequently, a nearby cysteine protonates the fixed dianion in a stereoinversive fashion. The enzymatic approach is particularly selective in decarboxylating malonic acids with an aryl and a small alkyl group. However, amino acids (i.e., compounds 10a and 10b in K. Okrasa, et al., Angew. Chem. Int. Ed. 48, 7691-7694 (2009)) obtained using this method are only moderately enantioenriched (i.e., an enantiomeric excess of up to 61%).
The asymmetric decarboxylation was also attempted by chemical catalysis (J. Blanchet, et al., Eur. J. Org. Chem. 5493-5506 (2008)). Early study of malonic acids revealed a higher rate of decarboxylation in basic solvents, such as tertiary amines and pyridines, indicative of possible base catalysis (W. H. Richardson and H. E. O'Neal, Comprehensive Chemical Kinetics: Decomposition and Isomerization of Organic Compounds, C. H. Bamford & C. F. H. Tipper Eds. (Elsevier, 1972) pp. 381-565). As a result, organic bases, particularly cinchona alkaloids, have been heavily studied. However, these only result in limited enantioinduction and thus low ee. For example, the best result of organic base-catalyzed decarboxylation of aminomalonic acids was found in H. Brunner and M. A. Baur, Eur. J. Org. Chem. 2854-2862 (2003), where malonic acid 4 gave the amino acid in 8.1 and 11.9% ee.
There remains a need to develop improved methods of preparing chiral amino acids, such as high enantiomeric excess (ee).
Therefore, it is an object of the present invention to provide methods of preparing chiral amino acids with high enantiomeric excess (ee).
It is a further object of the present invention to provide methods of preparing chiral amino acids that have a variety of side chains.
It is a further object of the present invention to provide chiral amino acids having a variety of side chains.
Methods for preparing chiral α-amino acids using chiral phosphoric acids as catalysts have been developed. The disclosed methods can use amino-malonic acids as substrates to generate chiral amino acids with a variety of side chains in high optical purity (such as an ee value of at least 70%) and with a high yield (i.e., a yield of at least 80%, such as in a range from about 80% to about 99%), via an asymmetric decarboxylation reaction. The decarboxylation reaction of the methods is catalyzed by chiral phosphoric acids that can achieve a selective protonation during decarboxylation, which is considered one of the most difficult processes in asymmetric catalysis. In some forms, the catalyst can be a chiral phosphoric acid loaded on a suitable support.
Generally, the method for producing chiral amino acids includes (i) maintaining a first reaction mixture at a first temperature for a first period of time sufficient to form a product containing a chiral amino acid. The first reaction mixture contains a substrate, a catalyst, and a solvent. The solvent is preferably an ether, such as cyclopentylmethylether (CPME). The catalyst is typically a chiral phosphoric acid. In some forms, the catalyst is a chiral phosphoric acid loaded on a support. Generally, the catalyst is present in the first reaction mixture in an amount ranging from about 1 mol % to about 20 mol %, from about 1 mol % to about 10 mol %, from about 2 mol % to about 20 mol %, from about 2 mol % to about 10 mol %, or from about 2.5 mol % to about 10 mol %, such as about 10 mol % or about 2.5 mol %.
Generally, the first reaction mixture can be maintained at a temperature ranging from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., such as about 80° C., for a period of time ranging from about 1 hour to about 12 hours, from about 1 hour to about 10 hours, from about 1 hour to about 8 hours, from about 1 hour to about 5 hours, or from about 1 hour to about 3 hours, such as about 2 hours, to produce the product containing chiral amino acids.
Typically, the substrate is a malonic acid. In some forms, the malonic acid can have the structure of Formula I or Formula I′:
In some forms, the disclosed method also includes: (ii) adding an alkylation reactant (such as a methylation reactant, e.g., trimethylsilyldiazomethane, or ethylation reactant) or an acid (such as HCl) to the product to form a second reaction mixture, and (iii) maintaining the second reaction mixture at a second temperature for a second period of time sufficient to form an alkylation product (such as a methylation or ethylation product) or hydrolysis product. The alkylation product or hydrolysis product contains an alkylated chiral amino acid or hydrolyzed chiral amino acid. In some forms, the alkylated chiral amino acid can have the structure of Formula VIII or Formula VIII′, and the hydrolyzed chiral amino acid can have the structure of Formula V or Formula V′:
In some forms, the second reaction mixture undergoes a methylation reaction. In these forms, the second reaction mixture can be maintained at a temperature ranging from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., for a period of time ranging from about 30 minutes to about 2 hours or from about 30 minutes to about 1 hour, to produce methylated chiral amino acid; or can be maintained at a temperature ranging from about 90° C. to about 120° C. or from about 90° C. to about 110° C., for a period of time ranging from about 12 hours to about 36 hours or from about 12 hours to about 24 hours, to produce hydrolyzed chiral amino acid. In some forms, after step (i), the product can be cooled to room temperature or about 0° C. before adding the methylation reactant or the acid.
In some forms, P1 can be
where L1 can be
R2 can be hydrogen, hydroxyl, halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, alkoxy, thiol, amino, amido, carbonyl, cyano, isocyano, nitro, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl; R3-R10 can be independently hydrogen or a substituted or unsubstituted alkyl (such as unsubstituted alkyl, for example, C1-C10 unsubstituted alkyl, C1-C8 unsubstituted alkyl, C1-C6 unsubstituted alkyl, or C1-C4 unsubstituted alkyl); and the substituents, when present, can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl.
In some forms, L1 can be
In some forms, R2 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, alkoxy, thiol, amino, amido, or carbonyl.
In some forms, R2 can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted aralkyl. In some forms, R2 can be
where R11-R15 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl. In some forms, R11-R15 can be independently hydrogen, halide, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted phenyl, unsubstituted haloalkyl, unsubstituted aralkyl, cyano, isocyano, nitro,
where R16-R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted phenyl, unsubstituted haloalkyl, or unsubstituted aralkyl, and R′18 can an unsubstituted alkyl.
In some forms, R2 can be
where R12-R14 can be independently halide (such as F, Cl, or I), unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), cyano, isocyano, nitro,
and R16 and R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), and R′18 can an unsubstituted alkyl.
In some forms, R2 can be
where R12 can be
R13 can be halide (such as F, Cl, or I), unsubstituted alkyl, unsubstituted haloalkyl (such as —CF3), cyano, isocyano, nitro,
and R16 and R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), R′18 can an unsubstituted alkyl. In some form, R13 can be nitro.
In some forms, R1 can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, where the substituents, when present, can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, azido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl. In some forms, the substituents, when present, can be independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, azido, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, or nitro. In some forms, the substituents, when present, can be independently a biomolecule moiety.
In some forms, one or more carbons, one or more nitrogen, and/or one or more hydrogens of the substrate can be in the form of 13C, 14C, 15N, and/or D.
In some forms, the chiral phosphoric acid can be a Binol phosphoric acid or derivative thereof, an H8 Binol phosphoric acid or derivative thereof, a Spinol phosphoric acid or derivative thereof, a Biphenol phosphoric acid or derivative thereof, a dithiophosphoric acid or derivative thereof, a Taddol phosphoric acid or derivative thereof, a paracyclophane or derivative thereof, a TiPSY phosphoric acid or derivative thereof, or a TRIP phosphoric acid or derivative thereof. In some forms, the chiral phosphoric acid can have the structure of Formula III or Formula III′:
and R25 can be substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), substituted or unsubstituted aryl (such as phenyl), or substituted or unsubstituted aralkyl (such as benzyl).
In some forms, at least one of R19 and R20 and at least one of R′19 and R′20 can be independently a substituted aryl or substituted polyaryl, and optionally wherein the substituted aryl or polyaryl has three or more substituents (such as 2,4,6-substituted phenyl). In some forms, the chiral phosphoric acid can have the structure of:
In some forms, the disclosed method can further includes one or more of the following steps: purifying the product after step (i) and/or the alkylation or hydrolysis product after step (iii); preparing the substrate prior to step (i); recycling an amino protecting agent and the catalyst after step (i) and/or step (iii); and derivatizing the chiral amino acid or alkylated or hydrolyzed chiral amino acid to a derivatized compound after step (i) and/or step (iii), such as a cyclic amino acid, a drug-amino acid conjugate, or a DNA gyrase inhibitor.
In some forms, the derivatization step can be performed via an oxidation reaction, a coupling reaction (such as click reaction), a nucleophilic/electrophilic substitution, or a metathesis reaction, or a combination thereof.
In some forms, the substrate can be prepared using a commercially available malonic ester as a starting compound, such as one having the structure of Formula VI; the starting material be converted to an amino protected compound of Formula VII:
It is to be understood that the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only and is not intended to be limiting.
“Substituted,” as used herein, refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, an amino acid. Such a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, and an amino acid can be further substituted.
Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
“Alkyl,” as used herein, refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl, and cycloalkyl (alicyclic). In some forms, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 15 or fewer, or 10 or fewer. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Likewise, a cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in their ring structure, and have 5, 6 or 7 carbons in the ring structure. Cycloalkyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkyl rings”). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, etc.
“Substituted alkyl” refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen (such as fluorine, chlorine, bromine, or iodine), hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), aryl, alkoxyl, aralkyl, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, an aromatic or heteroaromatic moiety. —NRR′, wherein R and R′ are independently hydrogen, alkyl, or aryl, and wherein the nitrogen atom is optionally quaternized; —SR, wherein R is a phosphonyl, a sulfinyl, a silyl a hydrogen, an alkyl, or an aryl; —CN; —NO2; —COOH; carboxylate; —COR, —COOR, or —CON(R)2, wherein R is hydrogen, alkyl, or aryl; imino, silyl, ether, haloalkyl (such as —CF3, —CH2—CF3, —CCl3); —CN; —NCOCOCH2CH2; —NCOCOCHCH; and —NCS; and combinations thereof.
It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, aralkyl, azido, imino, amido, phosphonium, phosphanyl, phosphoryl (including phosphonate and phosphinate), oxo, sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), haloalkyls, —CN and the like. Cycloalkyls can be substituted in the same manner.
Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
“Heteroalkyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkyl radicals, or combinations thereof, containing at least one heteroatom on the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond. Alkenyl groups include straight-chain alkenyl groups, branched-chain alkenyl, and cycloalkenyl. A cycloalkenyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon double bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkenyl rings”) and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C′D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbol C. The term “alkenyl” as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkenyls” and “substituted alkenyls,” the latter of which refers to alkenyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkenyl” also includes “heteroalkenyl.”
The term “substituted alkenyl” refers to alkenyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.
“Heteroalkenyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkenyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkenyl group” is a cycloalkenyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
The term “alkynyl group” as used herein is a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups include straight-chain alkynyl groups, branched-chain alkynyl, and cycloalkynyl. A cycloalkynyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon triple bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkynyl rings”) and contain at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C≡C(C″D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkyne is present, or it may be explicitly indicated by the bond symbol C. The term “alkynyl” as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkynyls” and “substituted alkynyls,” the latter of which refers to alkynyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkynyl” also includes “heteroalkynyl.”
The term “substituted alkynyl” refers to alkynyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.
“Heteroalkynyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkynyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkynyl group” is a cycloalkynyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
“Aryl,” as used herein, refers to C5-C26-membered aromatic or fused aromatic ring systems. Examples of aromatic groups are benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, etc.
The term “substituted aryl” refers to an aryl group, wherein one or more hydrogen atoms on one or more aromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, —CH2—CF3, —CCl3), —CN, aryl, heteroaryl, and combinations thereof.
“Heterocycle” and “heterocyclyl” are used interchangeably, and refer to a cyclic radical attached via a ring carbon or nitrogen atom of a non-aromatic monocyclic or polycyclic ring containing 3-30 ring atoms, 3-20 ring atoms, 3-10 ring atoms, or 5-6 ring atoms, where each ring contains carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, C1-C10 alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Heterocyclyl are distinguished from heteroaryl by definition. Heterocycles can be a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, etc, such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl. Heterocyclic groups can optionally be substituted with one or more substituents as defined above for alkyl and aryl.
The term “heteroaryl” refers to C5-C26-membered aromatic or fused aromatic ring systems, in which one or more carbon atoms on one or more aromatic ring structures have been substituted with a heteroatom. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Examples of heteroaryl groups pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined below for “substituted heteroaryl.”
The term “substituted heteroaryl” refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, —CH2—CF3, —CCl3), —CN, aryl, heteroaryl, and combinations thereof.
The term “polyaryl” refers to a chemical moiety that includes two or more fused aryl groups. When two or more fused heteroaryl groups are involved, the chemical moiety can be referred to as a “polyheteroaryl.”
The term “substituted polyaryl” refers to a polyaryl in which one or more of the aryls are substituted, with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof. When a polyheteroaryl is involved, the chemical moiety can be referred to as a “substituted polyheteroaryl.”
The term “cyclic ring” or “cyclic group” refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as those formed from single or fused ring systems), such as a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, or a substituted or unsubstituted heterocyclyl, that have from three to 30 carbon atoms, as geometric constraints permit. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls, and heterocyclyls are substituted as defined above for the alkyls, alkenyls, alkynyls, and heterocyclyls, respectively.
The term “aralkyl” as used herein is an aryl group or a heteroaryl group having an alkyl, alkynyl, or alkenyl group as defined above attached to the aromatic group, such as an aryl, a heteroaryl, a polyaryl, or a polyheteroaryl. An example of an aralkyl group is a benzyl group.
The terms “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generally describe compounds represented by the formula —ORv, wherein Rv includes, but is not limited to, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted alkylheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, and an amino. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. A “lower alkoxy” group is an alkoxy group containing from one to six carbon atoms. An “ether” is two functional groups covalently linked by an oxygen as defined below. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O— aralkyl, —O-aryl, —O-heteroaryl, —O-polyaryl, —O-polyheteroaryl, —O-heterocyclyl, etc.
The term “substituted alkoxy” refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, oxo, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.
The term “ether” as used herein is represented by the formula A2OA1, where A2 and A1 can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above.
The term “polyether” as used herein is represented by the formula:
where A3 can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above; g can be a positive integer from 1 to 30.
The term “phenoxy” is art recognized and refers to a compound of the formula —ORv wherein Rv is C6H5 (i.e., —O—C6H5). One of skill in the art recognizes that a phenoxy is a species of the aroxy genus.
The term “substituted phenoxy” refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.
The terms “aroxy” and “aryloxy,” as used interchangeably herein, are represented by —O-aryl or —O-heteroaryl, wherein aryl and heteroaryl are as defined herein.
The terms “substituted aroxy” and “substituted aryloxy,” as used interchangeably herein, represent —O-aryl or —O-heteroaryl, having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl, as defined herein. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.
The term “amino” as used herein includes the group
The terms “amide” or “amido” are used interchangeably, refer to both “unsubstituted amido” and “substituted amido” and are represented by the general formula:
“Carbonyl,” as used herein, is art-recognized and includes such moieties as can be represented by the general formula:
wherein X is a bond, or represents an oxygen or a sulfur, and R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or —(CH2)m—R″, or a pharmaceutical acceptable salt; E″ is absent, or E″ is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl; R′ represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or —(CH2)m—R″; R″ represents a hydroxyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E″ groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl). Where X is oxygen and R is defined as above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a “carboxylic acid.” Where X is oxygen and R′ is hydrogen, the formula represents a “formate.” Where X is oxygen and R or R′ is not hydrogen, the formula represents an “ester.” In general, where the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a “thiocarbonyl” group. Where X is sulfur and R or R′ is not hydrogen, the formula represents a “thioester.” Where X is sulfur and R is hydrogen, the formula represents a “thiocarboxylic acid.” Where X is sulfur and R′ is hydrogen, the formula represents a “thioformate.” Where X is a bond and R is not hydrogen, the above formula represents a “ketone.” Where X is a bond and R is hydrogen, the above formula represents an “aldehyde.”
The term “phosphanyl” is represented by the formula
The term “phosphonium” is represented by the formula
The term “phosphonyl” is represented by the formula
The term “phosphoryl” defines a phosphonyl in which E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and independently of E, Rvi and Rvii are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the phosphoryl cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. When E, Rvi and Rvii are substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).
The term “sulfinyl” is represented by the formula
The term “sulfonyl” is represented by the formula
The term “sulfonic acid” refers to a sulfonyl, as defined above, wherein R is hydroxyl, and E is absent, or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).
The term “sulfate” refers to a sulfonyl, as defined above, wherein E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the sulfate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).
The term “sulfonate” refers to a sulfonyl, as defined above, wherein E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, —(CH2)m—R′″, R′″ represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amido, an amino, or a polycycle; and m is zero or an integer ranging from 1 to 8. When E is oxygen, sulfonate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).
The term “sulfamoyl” refers to a sulfonamide or sulfonamide represented by the formula
wherein E is absent, or E is substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted cycloalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, R and R′ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or —(CH2)m—R′″, or R and R′ taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R′″ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).
The term “silyl group” as used herein is represented by the formula —SiRR′R,″ where R, R′, and R″ can be, independently, a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a thiol, an amido, an amino, an alkoxy, or an oxo, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.
The terms “thiol” are used interchangeably and are represented by —SR, where R can be a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, an amido, an amino, an alkoxy, an oxo, a phosphonyl, a sulfinyl, or a silyl, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.
The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
The compounds and substituents can be substituted, independently, with the substituents described above in the definition of “substituted.”
The numerical ranges disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein. For example, in a given range carbon range of C3-C9, the range also discloses C3, C4, C5, C6, C7, C8, and C9, as well as any subrange between these numbers (for example, C4-C6), and any possible combination of ranges possible between these values. In yet another example, a given temperature range may be from about 25° C. to 30° C., where the range also discloses temperatures that can be selected independently from about 25, 26, 27, 28, 29, and 30° C., as well as any range between these numbers (for example, 26 to 28° C.), and any possible combination of ranges between these values.
Use of the term “about” is intended to describe values either above or below the stated value, which the term “about” modifies, to be within a range of approximately +/−10%. When the term “about” is used before a range of numbers (i.e., about 1-5) or before a series of numbers (i.e., about 1, 2, 3, 4, etc.) it is intended to modify both ends of the range of numbers and/or each of the numbers recited in the entire series, unless specified otherwise.
The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
The compounds and substituents can be substituted with, independently, with the substituents described above in the definition of “substituted.”
The full names of certain abbreviations as used herein is provided in the following table:
Methods for preparing chiral α-amino acids using chiral phosphoric acids as catalysts have been developed. The chiral α-amino acids produced using the disclosed methods can be natural or unnatural, and have diverse side chains and functionality.
The disclosed methods can use amino-malonic acids as substrates to generate chiral amino acids with a variety of side chains in high optional purity (such as an ee value of at least 70%) via an asymmetric decarboxylation reaction. The decarboxylation reaction of the methods is catalyzed by chiral phosphoric acids that can achieve a selective protonation during decarboxylation (see, e.g.,
Without being bound to any theories, it is believed that the selective protonation achieved using chiral phosphoric acids in the methods not only lies in the high acidity of the chiral phosphoric acids that can rapidly protonate, but also in the chiral phosphoric acids' capability to impose stereocontrol by forming a rich network of hydrogen bonds within their pockets, particularly with heteroatom-rich substrates or intermediates (see, e.g., 8 and 9 in
In some forms, the amino-malonic acid substrates (also referred to herein as “substrates”) used in the disclosed methods are prepared using commercially available malonic acids/esters as starting material. The starting material can be converted by attaching a suitable functional group or biomolecule moiety to the methylene carbon of the malonic acid/ester via, for example, a substitution reaction between the starting material and an alkyl halide (see, e.g., Scheme 2), which is then hydrolyzed to provide the substrates (see, e.g., Scheme 3). The amino-malonic acid substrate can then be directly converted to a corresponding chiral amino acid via asymmetric decarboxylation reaction using chiral phosphoric acid as catalyst (see, e.g., Scheme 10). As such, the functional group or biomolecule moiety introduced during the preparation of the substrate becomes the side chain or part of the side chain of the chiral amino acid produced therefrom. Using the disclosed methods, a large panel of side chains of different shapes and with distinct functional groups can be attached to and eventually incorporated in the final chiral amino acid products via the decarboxylation reaction. Thus, the disclosed methods provide a general, selective, and efficient approach to provide chiral α-amino acids with diverse side chains and functionality, natural or unnatural, that is currently lacking using existing methods.
Generally, the disclosed method for producing chiral amino acids includes: (i) maintaining a first reaction mixture at a first temperature for a first period of time sufficient to form a product, where the product contains a chiral amino acid. The first reaction mixture contains a substrate, a catalyst, and a solvent. The catalyst is preferably a chiral phosphoric acid. Typically, in step (i), the chiral amino acid is produced via an asymmetric decarboxylation of the substrate catalyzed by the chiral phosphoric acid.
In some forms, the chiral amino acid in the product formed in step (i) further reacts with a reactant to produce an alkylated chiral amino acid or hydrolyzed amino acid. In these forms, the disclosed method also includes: (ii) adding an alkylation reactant (such as a methylation or ethylation reactant) or an acid to the product to form a second reaction mixture, and (iii) maintaining the second reaction mixture at a second temperature for a second period of time sufficient to form an alkylation product (such as a methylation or ethylation product) or hydrolysis product. The alkylation product or hydrolysis product contains an alkylated chiral amino acid (such as a methylated or ethylated chiral amino acid) or hydrolyzed chiral amino acid.
In some forms, the disclosed method further includes: purifying the product after step (i) and/or the alkylation or hydrolysis product after step (iii); preparing the substrate prior to step (i); recycling an amino protecting agent and the catalyst after step (i) and/or step (iii); and/or derivatizing the chiral amino acid or alkylated or hydrolyzed chiral amino acid to a derivatized compound after step (i) and/or step (iii).
Generally, a first reaction mixture containing a substrate and a catalyst, preferably a chiral phosphoric acid, in a suitable solvent is maintained at a suitable temperature for a period of time sufficient to form a product containing a chiral amino acid formed by asymmetric decarboxylation of the substrate. Typically, the reaction conditions for performing the reaction are simple. For example, the temperature for performing the asymmetric decarboxylation reaction can range from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., such as about 80° C., at 1 atm; and the time period for performing the reaction at any of the temperature ranges described above can range from about 1 hour to about 12 hours, from about 1 hour to about 10 hours, from about 1 hour to about 8 hours, from about 1 hour to about 5 hours, or from about 1 hour to about 3 hours, such as about 2 hours.
The first reaction mixture can be formed by mixing the substrate and the chiral phosphoric acid in the solvent prior to reaction. Examples of solvents suitable for use in step (i) of the disclosed method include, but are not limited to, ethyl acetate, tBuOMe, THF, 2-MeTHF, 1,4-dioxane, cyclopentylmethylether (CPME), and (MeOCH2CH2)2O, and a combination thereof. In preferred forms, the solvent forming the first reaction mixture in step (i) is an ether, such as CPME.
In step (i) of the disclosed method, the catalyst catalyzes an asymmetric decarboxylation reaction of the substrate to produce the chiral amino acid. Typically, the substrate is a malonic acid substrate. In some forms, the malonic acid substrate has the structure of Formula I or Formula I′:
In some forms, the amino protecting group P1 can be
where L1 can be
R2 can be hydrogen, hydroxyl, halide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, alkoxy, thiol, amino, amido, carbonyl, cyano, isocyano, nitro, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl; R3-R10 can be independently hydrogen or a substituted or unsubstituted alkyl (such as unsubstituted alkyl, for example, C1-C10 unsubstituted alkyl, C1-C8 unsubstituted alkyl, C1-C6 unsubstituted alkyl, or C1-C4 unsubstituted alkyl); and the substituents, when present, can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl.
In preferred forms, L1 is
In some forms, R2 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, alkoxy, thiol, amino, amido, or carbonyl. In some forms, R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted aralkyl.
In some forms, R2 can be
where R11-R15 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl (such as aldehyde, ketone, carboxylic acid, ester, etc.), alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl.
In some forms, R11-R15 can be independently hydrogen, halide, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted phenyl, unsubstituted haloalkyl unsubstituted aralkyl, cyano, isocyano, nitro,
where R16-R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted phenyl, unsubstituted haloalkyl, or unsubstituted aralkyl, where R′18 is an unsubstituted alkyl.
In some forms, R2 can be
where R12-R14 can be independently halide (such as F, Cl, or I), unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), cyano, isocyano, nitro,
and R16 and R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), where R′18 can be an unsubstituted alkyl.
In some forms, R2 can be
where R12 can be
R13 can be halide (such as F, Cl, or I), unsubstituted alkyl, unsubstituted haloalkyl (such as —CF3), cyano, isocyano, nitro,
and R16 and R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), where R′18 can be unsubstituted alkyl. In some forms, R13 can be nitro.
In some forms, the functional group or biomolecule moiety R1 attached to the methylene carbon of the malonic ester substrate can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, where the substituents, when present, can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, azido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl. In some forms, the substituents, when present, can be independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, azido, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, or nitro. In some forms, the substituents, when present, are independently a biomolecule moiety, such as a cholic acid moiety (see, e.g., (+)-39 in
In some forms, the substrate, such as the malonic acid substrate of Formula I or I′, contains one or more isotopes. For example, one or more carbons, one or more nitrogen, and/or one or more hydrogens of the substrate, such as the malonic acid substrate of Formula I or I′, can be in the form of 13C, 14C, 15N, and/or D.
For any forms of the substrate described above, the alkyl, when present, can be a linear alkyl, a branched alkyl, or a cyclic alkyl (either monocyclic or polycyclic). The terms “cyclic alkyl” and “cycloalkyl” are used interchangeably herein. Exemplary alkyl include a linear C1-C30 alkyl, a branched C4-C30 alkyl, a cyclic C3-C30 alkyl, a linear C1-C20 alkyl, a branched C4-C20 alkyl, a cyclic C3-C20 alkyl, a linear C1-C10 alkyl, a branched C4-C10 alkyl, a cyclic C3-C10 alkyl, a linear C1-C6 alkyl, a branched C4-C6 alkyl, a cyclic C3-C6 alkyl, a linear C1-C4 alkyl, cyclic C3-C4 alkyl, such as a linear C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 alkyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 alkyl group. The cyclic alkyl can be a monocyclic or polycyclic alkyl, such as a C4-C30, C4-C25, C4-C20, C4-C18, C4-C16, C4-C15, C4-C14, C4-C13, C4-C12, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 monocyclic or polycyclic alkyl group.
For any forms of the substrate described above, the alkenyl, when present, can be a linear alkenyl, a branched alkenyl, or a cyclic alkenyl (either monocyclic or polycyclic). The terms “cyclic alkenyl” and “cycloalkenyl” are used interchangeably herein. Exemplary alkenyl include a linear C2-C30 alkenyl, a branched C4-C30 alkenyl, a cyclic C3-C30 alkenyl, a linear C2-C20 alkenyl, a branched C4-C20 alkenyl, a cyclic C3-C20 alkenyl, a linear C2-C10 alkenyl, a branched C4-C10 alkenyl, a cyclic C3-C10 alkenyl, a linear C2-C6 alkenyl, a branched C4-C6 alkenyl, a cyclic C3-C6 alkenyl, a linear C2-C4 alkenyl, cyclic C3-C4 alkenyl, such as a linear C2-C10, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkenyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl group. The cyclic alkenyl can be a monocyclic or polycyclic alkenyl, such as a C4-C30, C4-C25, C4-C20, C4-C18, C4-C16, C4-C15, C4-C14, C4-C13, C4-C12, C4-C10, C4-C9, C4- C8, C4-C7, C4-C6, or C4-C5 monocyclic or polycyclic alkenyl group.
For any forms of the substrate described above, the alkynyl can be a linear alkynyl, a branched alkynyl, or a cyclic alkynyl (either monocyclic or polycyclic). The terms “cyclic alkynyl” and “cycloalkynyl” are used interchangeably herein. Exemplary alkynyl include a linear C2-C30 alkynyl, a branched C4-C30 alkynyl, a cyclic C3-C30 alkynyl, a linear C2-C20 alkynyl, a branched C4-C20 alkynyl, a cyclic C3-C20 alkynyl, a linear C2-C10 alkynyl, a branched C4-C10 alkynyl, a cyclic C3-C10 alkynyl, a linear C2-C6 alkynyl, a branched C4-C6 alkynyl, a cyclic C3-C6 alkynyl, a linear C2-C4 alkynyl, cyclic C3-C4 alkynyl, such as a linear C2-C10, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkynyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl group. The cyclic alkynyl can be a monocyclic or polycyclic alkynyl, such as a C4-C30, C4-C25, C4-C20, C4-C18, C4-C16, C4-C15, C4-C14, C4-C13, C4-C12, C4-C10, C4-C9, C4-C8, C4- C7, C4-C6, or C4-C5 monocyclic or polycyclic alkynyl group.
It is understood that any of the exemplary alkyl, alkenyl, and alkynyl groups can be heteroalkyl, heteroalkenyl, and heteroalkynyl, respectively.
For any forms of the substrate described above, the aryl group can be a C5-C30 aryl, a C5-C20 aryl, a C5-C12 aryl, a C5-C11 aryl, a C5-C9 aryl, a C6-C20 aryl, a C6-C12 aryl, a C6-C11 aryl, or a C6-C9 aryl. It is understood that the aryl can be a heteroaryl, such as a C5-C30 heteroaryl, a C5-C20 heteroaryl, a C5-C12 heteroaryl, a C5-C11 heteroaryl, a C5-C9 heteroaryl, a C6-C30 heteroaryl, a C6-C20 heteroaryl, a C6-C12 heteroaryl, a C6-C11 heteroaryl, or a C6-C9 heteroaryl.
For any forms of the substrate described above, the polyaryl group can be a C10-C30 polyaryl, a C10-C20 polyaryl, a C10-C12 polyaryl, a C10-C11 polyaryl, or a C12-C20 polyaryl. It is understood that the aryl can be a polyheteroaryl, such as a C10-C30 polyheteroaryl, a C10-C20 polyheteroaryl, a C10-C12 polyheteroaryl, a C10-C11 polyheteroaryl, or a C12-C20 polyheteroaryl.
The catalyst in the first reaction mixture of step (i) for catalyzing asymmetric decarboxylation of the substrate to produce chiral amino acids is preferably a chiral phosphoric acid. Without being bound to any theories, it is believed that the selective protonation achieved using chiral phosphoric acids in the methods not only lies in the high acidity of the chiral phosphoric acids that can rapidly protonate, but also in the chiral phosphoric acids' capability to impose stereocontrol by forming a rich network of hydrogen bonds within their pockets, particularly with heteroatom-rich substrates or intermediates (see, e.g., 8 and 9 in
Any suitable chiral phosphoric acids ((R)- and (S)-chiral phosphoric acids), such as those that are commercially available, can be used in the disclosed method. Examples of chiral phosphoric acid suitable for use in step (i) of the disclosed method include, but are not limited to, Binol phosphoric acids and derivatives thereof, H8 Binol phosphoric acids and derivatives thereof, Spinol phosphoric acids and derivatives thereof, Biphenol phosphoric acids and derivatives thereof, dithiophosphoric acids and derivatives thereof, Taddol phosphoric acids and derivatives thereof, paracyclophane and derivatives thereof, TiPSY phosphoric acids and derivatives thereof, and TRIP phosphoric acids and derivatives thereof. Exemplary structures of chiral phosphoric acids are disclosed on https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/reaction-design-and-optimization/chiral-phosphoric and website daicelchiraltech.cn/en/reagents/list02.aspx?pid=72621643502977024&cid=72620543991349248&sid=72626041549488128.
In some forms, the catalyst can be chiral phosphoric acid loaded on a support to facilitate recycling following the asymmetric decarboxylation and/or a subsequent alkylation reaction or hydrolysis. The support can be any material suitable for loading the chiral phosphoric acid that do not interfere with the asymmetric decarboxylation reaction, such as polystyrene, metal-organic frameworks, covalent organic framework, etc.
In some forms, the chiral phosphoric acid used in the first reaction mixture for catalyzing asymmetric decarboxylation of the substrate to produce chiral amino acids can have the structure of Formula III or Formula III′:
and R25 can be substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), substituted or unsubstituted aryl (such as phenyl), or substituted or unsubstituted aralkyl (such as benzyl).
In some forms, at least one of R19 and R20 and at least one of R′19 and R′20 can be independently a substituted aryl or substituted polyaryl, and optionally wherein the substituted aryl or polyaryl has three or more substituents (such as 2,4,6-substituted phenyl). In some forms, both R19 and R20 and both R′19 and R′20 can be independently a substituted aryl or substituted polyaryl, and optionally the substituted aryl or polyaryl has three or more substituents (such as 2,4,6-substituted phenyl).
In some forms, the substituents on the aryl or polyaryl of R19, R20, R′19, and R′20 can be unsubstituted alkyl (such as methyl, ethyl, isopropyl, n-propyl, etc.), unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or an alkoxy (such as methoxy, ethoxy, aryloxy, benzoether, etc.). In some forms, the substituents on the aryl or polyaryl of R19, R20, R′19, and R′20 can be unsubstituted alkyl (such as methyl, ethyl, isopropyl, n-propyl, etc.).
In some forms, the chiral phosphoric acid can have the structure of:
Generally, the catalyst is present in the first reaction mixture in an amount ranging from about 1 mol % to about 20 mol %, from about 1 mol % to about 10 mol %, from about 2 mol % to about 20 mol %, from about 2 mol % to about 10 mol %, or from about 2.5 mol % to about 10 mol %, such as about 10 mol % or about 2.5 mol %.
The product formed in step (i) contains a chiral amino acid, which is produced by asymmetric decarboxylation of the substrate. As such, the functional group or biomolecule moiety (besides the protected amino group) that attaches to the methylene carbon of a malonic acid substrate becomes the side chain or part of the side chain of the chiral amino acid produced therefrom.
In some forms, when the substrate is a malonic acid substrate of Formula I or Formula I′, the chiral amino acid produced therefrom has the structure of Formula II or Formula II′:
When the chiral amino acid produced in step (i), such as the chiral amino acid of Formula II or Formula II′, is further reacted with an alkylation reactant (such as a methylation or ethylation reactant), the carboxyl group of the chiral amino acid is alkylated to produce an alkylated chiral amino acid (such as a methylated chiral amino acid or an ethylated amino acid). In some forms, the alkylated chiral amino acid can have the structure of Formula VIII or Formula VIII′:
In some forms, the alkylated chiral amino acid can be a methylated chiral amino acid having the structure of Formula IV or Formula IV′:
In some forms, P1 of Formula VIII, VIII′, IV, and IV′ can be
where R12 can be
R13 can be cyano, isocyano, nitro, or
and R16 and R18 can be independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), where R′18 can be unsubstituted alkyl. In some forms, R13 can be nitro and R12 can be
where R16 can be an unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3). In some forms, R13 can be nitro and R12 can be
where R16 can be —CH2—CH2—CF3, —CH2—CF2—CF3, or —CH2—CF2—CF2—CF3.
In some forms, the functional group or biomolecule moiety R1 of Formula VIII, VIII′, IV, and IV′ can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, where the substituents, when present, can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, azido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl. In some forms, the substituents, when present, can be independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, azido, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, or nitro. In some forms, the substituents, when present, are independently a biomolecule moiety, such as a cholic acid moiety (see, e.g., (+)-39 in
In some forms, the alkylated chiral amino acid produced using the disclosed method can have the structure of any one of the following:
When the chiral amino acid produced in step (i), such as the chiral amino acid of Formula II or Formula II′, is further reacted with an acid, the protected amino group of the chiral amino acid is hydrolyzed to produce a hydrolyzed chiral amino acid. In some forms, the hydrolyzed chiral amino acid can have the structure of Formula V or Formula V′:
Generally, the chiral amino acid in the product formed from the asymmetric decarboxylation reaction using the disclosed methods can have an enantiomeric excess (“ee”) of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in a range from about 70% to 100%, from about 75% to 100%, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 75% to 99%, from about 80% to 99%, from about 85% to 99%, or from about 90% to 99%, as determined by chiral HPLC. The ee of chiral amino acid in the product can be calculated using the formula: ee=[(moles of enantiomer−moles of another enantiomer)/total moles of both enantiomers]×100%. The ee of the chiral amino acid can be determined using known methods, such as using chiral HPLC or a polarimeter. In some forms, the ee of the chiral amino acid is determined using chiral HPLC.
In some forms, the chiral amino acid of Formula II, the alkylated chiral amino acid of Formula VIII, the methylated chiral amino acid of Formula IV, or the hydrolyzed chiral amino acid of Formula V in the product formed from the asymmetric decarboxylation reactions catalyzed by a chiral phosphoric acid (such as a chiral phosphoric acid of Formula III or CPA-8) using the disclosed methods can have an ee of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in a range from about 70% to 100%, from about 75% to 100%, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 75% to 99%, from about 80% to 99%, from about 85% to 99%, or from about 90% to 99%, as determined by chiral HPLC.
In some forms, the chiral amino acid of Formula II′, the alkylated chiral amino acid of Formula VIII′, the methylated chiral amino acid of Formula IV′, or the hydrolyzed chiral amino acid of Formula V′ in the product formed from the asymmetric decarboxylation reactions catalyzed by a chiral phosphoric acid (such as a chiral phosphoric acid of Formula III′) using the disclosed methods can have an ee of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in a range from about 70% to 100%, from about 75% to 100%, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 75% to 99%, from about 80% to 99%, from about 85% to 99%, or from about 90% to 99%, as determined by chiral HPLC.
b. Yield
Generally, the chiral amino acid in the product formed from the asymmetric decarboxylation reaction using the disclosed methods can have a yield of at least 80%, such as in a range from about 80% to about 99%. The yield of the chiral amino acid in the product can be calculated using the formula: chiral amino acid yield=(experimentally obtained total no. of mole of chiral amino acid)/(theoretical total no. of mole of chiral amino acid)×100%. The experimentally obtained total no. of mole of the chiral amino acid can be determined using known methods, such as using NMR (e.g. 1H NMR, 19F NMR, and/or 31P NMR) spectroscopy with an internal standard of known quantity, such as using a known quantity of PhTMS as the internal standard.
In some forms, the chiral amino acid of Formula II, the alkylated chiral amino acid of Formula VIII, the methylated chiral amino acid of Formula IV, or the hydrolyzed chiral amino acid of Formula V in the product formed from the asymmetric decarboxylation reactions catalyzed by a chiral phosphoric acid (such as a chiral phosphoric acid of Formula III or CPA-8) using the disclosed methods can have a yield of at least 80%, such as in a range from about 80% to about 99%.
In some forms, the chiral amino acid of Formula II′, the alkylated chiral amino acid of Formula VIII′, the methylated chiral amino acid of Formula IV′, or the hydrolyzed chiral amino acid of Formula V′ in the product formed from the asymmetric decarboxylation reactions catalyzed by a chiral phosphoric acid (such as a chiral phosphoric acid of Formula III′) using the disclosed methods can have a yield of at least 80%, such as in a range from about 80% to about 99%.
The disclosed methods can include one or more optional steps, such as (ii) adding an alkylation reactant (such as a methylation or ethylation reactant) or an acid to the product to form a second reaction mixture, and (iii) maintaining the second reaction mixture at a second temperature for a second period of time sufficient to form an alkylation product (such as a methylation or ethylation product) or hydrolysis product; purifying the product after step (i) and/or the alkylation or hydrolysis product after step (iii); preparing the substrate prior to step (i); recycling an amino protecting agent and the catalyst after step (i) and/or step (iii); and/or derivatizing the chiral amino acid or alkylated or hydrolyzed chiral amino acid to a derivatized compound after step (i) and/or step (iii).
In some forms, the disclosed method includes a step of purifying the product to remove impurities, such as the catalyst, the undesired isomer(s), and/or unreacted substrates, in the product, and thereby obtain purified chiral amino acid, subsequent to the asymmetric decarboxylation reaction (i.e., step (i)). The product can be purified by known methods, such as using column chromatography on silica gel or recrystallization in a suitable solvent.
In some forms, the catalyst and/or an amino protecting agent can be recycled from the product, subsequent to the asymmetric decarboxylation reaction (i.e., step (i)), and/or subsequent to the alkylation/hydrolysis reaction (i.e., step (ii)). For example, the catalyst and an amino protecting agent can be recycled using extraction subsequent to hydrolysis of the chiral amino acid produced in an asymmetric decarboxylation reaction.
In some forms, subsequent to the asymmetric decarboxylation reaction (i.e., step (i)), the chiral amino acid produced in the asymmetric decarboxylation reaction is further treated with an alkylation reactant (such as a methylation or ethylation reactant) or an acid to form an alkylated chiral amino acid (such as a methylated or ethylated chiral amino acid) or hydrolyzed chiral amino acid. Alkylation reactants and reaction conditions for converting carboxylic acid group to esters are known, see, for example, those described in Matsumoto et al., “Recent Advances in the Synthesis of Carboxylic Acid Esters” DOI: 10.5772/intechopen.74543.
For example, the chiral amino acid of Formula II or Formula II′ (as described above) is reacted with a methylation reactant to form a methylated chiral amino acid of Formula IV or Formula IV′ (as described above) via a methylation reaction. The methylation reactant can be any suitable chemical that can react with the chiral amino acid and convert its carboxyl group to an ester. Examples of methylation reactant suitable for use in the methylation reaction include, but are not limited to, trimethylsilyldiazomethane, iodomethane, dimethyl sulfate, dimethyl carbonate, or tetramethylammonium chloride, methyl triflate, diazomethane, and methyl fluorosulfonate. In preferred forms, the methylation reactant used in the methylation reaction to form the methylated chiral amino acid is trimethylsilyldiazomethane. Generally, the methylation reaction is performed at a temperature ranging from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., for a period of time ranging from about 30 minutes to about 2 hours or from about 30 minutes to about 1 hour.
For example, the chiral amino acid of Formula II or Formula II′ (as described above) is reacted with an acid to form a hydrolyzed chiral amino acid of Formula V or Formula V′ (as described above) via hydrolysis. The acid can be any suitable acid having an acidity that can deprotect the protected amino group of the chiral amino acid, such as any one of those described above for A1. In preferred forms, the acid used in the hydrolysis reaction to deprotect the protected amino group and form the hydrolyzed chiral amino acid is HCl. Generally, the hydrolysis reaction is performed at a temperature ranging from about 90° C. to about 120° C. or from about 90° C. to about 110° C., for a period of time ranging from about 12 hours to about 36 hours or from about 12 hours to about 24 hours.
For example, the chiral amino acid of Formula II or Formula II′ (as described above) is reacted with an ethylation reactant to form an ethylated chiral amino acid via an ethylation reaction (such as reaction between the chiral amino acid of Formula II or II′ and thionyl chloride in ethanol).
In some forms, prior to addition of the alkylation reactant (such as a methylation or ethylation reactant) or acid (i.e., step (ii)), the product containing chiral amino acid is cooled to room temperature or about 0° C., following which the alkylation reactant (such as a methylation or ethylation reactant) or acid is added into the cooled product at room temperature (such as for methylation reaction) or 0° C. (for hydrolysis) before heating the reaction mixture to a suitable temperature (such as those described above) for reaction.
In some forms, prior to the asymmetric decarboxylation reaction (i.e., step (i)), the substrate is prepared by converting a starting material to the substrate using known reactions, such as substitution reaction and hydrolysis. Typically, the starting material is readily available, such as commercially available malonic acids or esters.
In some forms, the starting material is a commercially available malonic ester having the structure of Formula VI:
In these forms, the starting material can react with an amino protecting agent P1X1 via a substitution reaction to form an amino-protected malonic ester having the structure of Formula VII:
The amino protected malonic ester of Formula VII can then undergo a substitution reaction and hydrolysis to form the substrate of Formula I or Formula I′ described above. For example, the amino protected malonic ester of Formula VII reacts with a substitution reactant R1X2, where X2 is a halide (such as fluoride, chloride, iodide, etc.) and R1 is a functional or biomolecule moiety (such as any one of those described above for the substrate), to attach R1 to the methylene carbon of the malonic ester, which is then hydrolyzed to form the malonic acid substrate of Formula I or Formula I′. In some forms, the substitution reaction and hydrolysis can occur simultaneously, i.e., the substitution reaction to attach R1 and hydrolysis of the ester groups to form carboxyl groups are achieved in a single step.
Because of the various functionalities introduced through a sidechain in the chiral amino acids, the chiral amino acids can be used for further derivatization to generate a multitude of useful compounds, such as cyclic amino acids, drug-amino acid conjugates, DNA gyrase inhibitors, etc.
Further derivatization of the chiral amino acids can be performed using any known reactions, such as oxidation reactions, coupling reactions (such as click reaction), nucleophilic/electrophilic substitutions, and metathesis reactions, and combinations thereof.
For example, the chiral amino acids produced using the disclosed method containing a p-methoxybenzyl group in the sidechain can be derived to form a cyclic amino acid via a series of substitution and oxidation reactions (see, e.g.,
Specific exemplary substrates, chiral phosphoric acids, chiral amino acids, alkylated chiral amino acids (such as methylated chiral amino acids), hydrolyzed chiral amino acids, chiral amino acids with further derivatization, and their corresponding yields and enantiomeric ratios, are described in the Examples below.
The disclosed methods and compositions can be further understood through the following numbered paragraphs.
1. A method for producing chiral amino acids, comprising:
2. The method of paragraph 1, wherein the substrate is a malonic acid.
3. The method of paragraph 2, wherein the malonic acid has the structure of Formula I or Formula I′:
4. The method of any one of paragraphs 1-3, further comprising:
5. The method of paragraph 4, wherein the alkylated chiral amino acid has the structure of Formula VIII or Formula VIII′, and the hydrolyzed chiral amino acid has the structure of Formula V or Formula V′:
6. The method of paragraph 4 or 5, wherein the alkylation reactant in the second reaction mixture is a methylation reactant (such as trimethylsilyldiazomethane) and the acid in the second reaction mixture is HCl.
7. The method of any one of paragraphs 3-6, wherein P1 is
and wherein:
8. The method of paragraph 7, wherein L1 is
9. The method of paragraph 7 or 8, wherein R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, alkoxy, thiol, amino, amido, or carbonyl.
10. The method of any one of paragraphs 7-9, wherein R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted aralkyl.
11. The method of any one of paragraphs 7-10, wherein R2 is
and wherein R11-R15 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, nitro, amino, amido, oxo, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, or phosphonyl.
12. The method of paragraph 11, wherein R11-R15 are independently hydrogen, halide, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted phenyl, unsubstituted haloalkyl, unsubstituted aralkyl, cyano, isocyano, nitro,
and wherein R16-R18 are independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted phenyl, unsubstituted haloalkyl, or unsubstituted aralkyl, and R′18 is unsubstituted alkyl.
13. The method of any one of paragraphs 7-12, wherein R2 is:
and
and wherein R16 and R18 are independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), and R′18 is unsubstituted alkyl.
14. The method of any one of paragraphs 7-13, wherein R2 is
and wherein R12 is
R13 is halide (such as F, Cl, or I), unsubstituted alkyl, unsubstituted haloalkyl (such as —CF3), cyano, isocyano, nitro,
and R16 and R18 are independently hydrogen, hydroxyl, —OR′18, unsubstituted alkyl, unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), or unsubstituted aralkyl (such as benzyl), and R′18 is unsubstituted alkyl.
15. The method of paragraph 14, wherein R13 is nitro.
16. The method of any one of paragraphs 3-15, wherein R1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, and
17. The method of paragraph 16, wherein the substituents, when present, are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, azido, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, or nitro.
18. The method of paragraph 16 or 17, wherein the substituents, when present, are independently a biomolecule moiety.
19. The method of any one of paragraphs 1-18, wherein one or more carbons, one or more nitrogen, and/or one or more hydrogens of the substrate are in the form of 13C, 14C, 15N, and/or D.
20. The method of any one of paragraphs 1-19, wherein the chiral phosphoric acid is a Binol phosphoric acid or derivative thereof, an H8 Binol phosphoric acid or derivative thereof, a Spinol phosphoric acid or derivative thereof, a Biphenol phosphoric acid or derivative thereof, a dithiophosphoric acid or derivative thereof, a Taddol phosphoric acid or derivative thereof, a paracyclophane or derivative thereof, a TiPSY phosphoric acid or derivative thereof, or a TRIP phosphoric acid or derivative thereof.
21. The method of any one of paragraphs 1-20, wherein the chiral phosphoric acid has the structure of Formula III or Formula III′:
22. The method of paragraph 21, wherein at least one of R19 and R20 and at least one of R′19 and R′20 is independently a substituted aryl or substituted polyaryl, and optionally wherein the substituted aryl or polyaryl has three or more substituents (such as 2,4,6-substituted phenyl).
23. The method of any one of paragraphs 1-22, wherein the chiral phosphoric acid has the structure of
24. The method of any one of paragraphs 1-23, wherein the catalyst is present in the first reaction mixture in an amount ranging from about 1 mol % to about 20 mol %, from about 1 mol % to about 10 mol %, from about 2 mol % to about 20 mol %, from about 2 mol % to about 10 mol %, or from about 2.5 mol % to about 10 mol %, such as about 10 mol % or about 2.5 mol %.
25. The method of any one of paragraphs 1-24, wherein the solvent is an ether.
26. The method of paragraph 25, wherein the ether is ethyl acetate, tBuOMe, THF, 2-MeTHF, 1,4-dioxane, cyclopentylmethylether (CPME), or (MeOCH2CH2)2O, or a combination thereof.
27. The method of any one of paragraphs 1-26, wherein the first reaction mixture is maintained at a temperature ranging from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., such as about 80° C., for a period of time ranging from about 1 hour to about 12 hours, from about 1 hour to about 10 hours, from about 1 hour to about 8 hours, from about 1 hour to about 5 hours, or from about 1 hour to about 3 hours, such as about 2 hours.
28. The method of any one of paragraphs 4-27, wherein the second reaction mixture (such as for methylation reaction) is maintained at a temperature ranging from about 50° C. to about 100° C., from about 60° C. to about 100° C., or from about 70° C. to about 100° C., for a period of time ranging from about 30 minutes to about 2 hours or from about 30 minutes to about 1 hour, or
29. The method of any one of paragraphs 4-28, wherein after step (i), the product is cooled to room temperature or about 0° C. before adding the alkylation reactant (such as the methylation reactant) or the acid.
30. The method of any one of paragraphs 1-29, wherein the chiral amino acid has a yield of at least 80% or in a range from about 80% to about 99%.
31. The method of any one of paragraphs 1-30, wherein the chiral amino acid has an enantiometric excess (ee) of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in a range from about 70% to 100%, from about 75% to 100%, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 75% to 99%, from about 80% to 99%, from about 85% to 99%, or from about 90% to 99%, as determined by chiral HPLC.
32. The method of any one of paragraphs 1-31, further comprising purifying the product after step (i) and/or the alkylation or hydrolysis product after step (iii); preparing the substrate prior to step (i); recycling an amino protecting agent and the catalyst after step (i) and/or step (iii); and/or derivatizing the chiral amino acid or alkylated or hydrolyzed chiral amino acid to a derivatized compound after step (i) and/or step (iii).
33. The method of paragraph 32, wherein the derivatization step is performed via an oxidation reaction, a coupling reaction (such as click reaction), a nucleophilic/electrophilic substitution, or a metathesis reaction, or a combination thereof.
34. The method of paragraph 32 or 33, wherein the derivatized compound is a cyclic amino acid, a drug-amino acid conjugate, or a DNA gyrase inhibitor.
35. The method of any one of paragraphs 32-34, wherein the substrate is prepared by:
36. A chiral amino acid having the structure of Formula VIII or Formula VIII′:
37. The chiral amino acid of paragraph 36, wherein R26 is methyl or ethyl; R13 is nitro; and R12 is
and R16 is an unsubstituted haloalkyl (such as fluoride substituted C1-C6 haloalkyl, e.g., —CF3, —CH2—CF3, —CH2—CH2—CF3, —CH2—CF2—CF3, —CH2—CF2—CF2—CF3), optionally wherein R16 is —CH2—CH2—CF3, —CH2—CF2—CF3, or —CH2—CF2—CF2—CF3.
38. The chiral amino acid of paragraph 36 or 37, wherein the substituents, when present, are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl, azido, carbonyl, alkoxy, halide, hydroxyl, thiol, cyano, isocyano, or nitro.
39. The chiral amino acid of any one of paragraphs 36-38, wherein the substituents, when present, are independently a biomolecule moiety (such as a cholic acid moiety, estrone moiety, etc.).
40. The chiral amino acid of any one of paragraphs 36-39, wherein R26 is methyl; R13 is nitro; and R12 is
and R16 is —CH2—CF2—CF3.
41. The chiral amino acid of any one of paragraphs 36-40, having any one of the structure of:
Unless otherwise noted, all reactions were run under nitrogen atmosphere. (R)- or (S)-chiral phosphoric acids (CPAs) (>98% purity) were purchased from Daicel Chiral Technologies (China) Co., Ltd., and used as received. Cyclopentyl methyl ether (CPME) was purchased from Shanghai Macklin Biochemical Co., Ltd. and used as received. Thin layer chromatography (TLC) was run on silica gel plates purchased from Yantai Huanghai Silica gel Development Co., Ltd.
1H NMR, 13C NMR, and 19F NMR spectra were obtained on a Bruker 400, 500, or 600 spectrometer (400/500/600 MHz for 1H, 100/125/150 MHz for 13C, 376/471 MHz for 19F). 15N NMR spectra were obtained on a Bruker 400 spectrometer (40 MHz for 15N). All 1H NMR experiments were measured with tetramethylsilane (0 ppm) in CDCl3, using the signal of residual DMSO (2.50 ppm) in DMSO-d6, the signal of residual CH3OH (3.31 ppm) in CD3OD, or the signal of residual CH3CN (1.94 ppm) in CD3CN as internal reference. All 13C NMR experiments were measured in relative to the signal of CDCl3 (77.0 ppm), the signal of DMSO-d6 (39.52 ppm), the signal of CD3OD (49.00 ppm), or the signal of CD3CN (1.32, 118.3 ppm). Data for 1H NMR, 13C NMR, and 19F NMR were presented as follows: chemical shifts (δ, ppm), multiplicity (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, hept=heptet, dd=doublet of doublets, tt=triplet of triplets, td=triplet of doublets, m=multiplet), coupling constant (Hz), and integration. Chiral HPLC spectra were measured on an Agilent 1260 Infinity II. The [α]D was recorded using INESA SGW-531 Automatic Polarimeter. Infrared absorption spectra were recorded on a PerkinElmer UATR two FT-IR and the data were presented as per centimeter (cm−1). High-resolution EI mass spectra were recorded on a Thermo Scientific DFS high resolution magnetic sector MS. High-resolution ESI-MS measurements were performed on a Bruker impact II high-resolution LC-QTOF mass spectrometer. Accurate masses from high-resolution mass spectra were reported for the molecular ion [M+H]+.
Step I: To a suspension of NaH (32.4 g, 810 mmol, 311 mol %, 60% dispersion in mineral oil) in THF (600 mL), 2,2,3,3,3-pentafluoropropan-1-ol (58.5 g, 390 mmol, 150 mol %) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 min and then 3-fluoro-4-nitrobenzoic acid (60.0 g, 324 mmol, 125 mol %) was added in small batches. The mixture was stirred at room temperature for 4 h, monitored by TLC. When the acid starting material was fully consumed, 1 M HCl (500 mL) aqueous solution was added slowly to the reaction mixture. The organic phase (THF) was separated, concentrated under vacuum, and redissolved in EtOAc. The aqueous phase was extracted with EtOAc (100 mL×3). The organics were combined, washed with water and brine, dried with Na2SO4, filtered, and concentrated to give 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid that was directly used for the next step without further purification.
Step II: To a solution of crude 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid synthesized above in DCM (600 mL), oxalyl chloride (33.4 mL, 390 mmol, 150 mol %) was added at room temperature. 2 mL DMF was added dropwise and slowly to the reaction mixture. The reaction mixture was stirred at room temperature until all the solid was dissolved and the mixture became clear. The reaction mixture was concentrated under vacuum to give acid chloride that was directly used for the next step without purification.
Step III: To a solution of diethyl aminomalonate hydrochloride (55.1 g, 260 mmol, 100 mol %) in DCM (600 mL), triethylamine (150 mL) was added at 0° C. under vigorous stirring. The above-synthesized 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoyl chloride in 200 mL DCM was then added dropwise to the reaction mixture. The reaction mixture was stirred under the same temperature for 1 h, monitored by TLC. After completion, the mixture was poured into 500 mL water and vigorously stirred for 5 mins. The organic phase was separated and washed with water (500 mL×3). The organic solution was concentrated under vacuum to around 200 mL. The precipitation was collected by filtration and washed with hexane (200 mL×3). The solid was dried under vacuum to give 16 (109.69 g, 89% Yield) as a light-yellow solid that can be used for the next step without further purification.
To a solution of 16 (100 mol %) in CH3CN (0.1 M), Cs2CO3 (200 mol %) and RI or RBr (150 mol %) were added at room temperature. The resulting mixture was stirred at room temperature to full conversion, as monitored by TLC. CH3CN was then removed under vacuum, and aqueous 1 M HCl solution (0.1 M as to 16) was added to the residue. The mixture was stirred for 5 mins and extracted with EtOAc. The combined organic solvents were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane/ethyl acetate) to give the disubstituted malonic ester.
To a solution of disubstituted diethyl 2-(4-nitro-3-(2,2,3,3,3-pentafluoropropoxy)benzamide) malonate (100 mol %) in 1,4-dioxane (0.5 M), 2 M NaOH aqueous solution (400 mol %) was added dropwise at 0° C. After the resulting mixture was warmed to room temperature, it was stirred at 40° C. until hydrolysis finished, as monitored by TLC. 1,4-dioxane was removed under vacuum, and the aqueous layer was acidified by 1 M HCl aqueous solution to pH 6-7 and washed with diethyl ether to remove the unreacted malonic acid half esters and 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid until only malonic acid remained in aqueous, as monitored by TLC. Then the aqueous phase was acidified by 1 M HCl aqueous to pH 2-3 and extracted with diethyl ether for three times. The organic phase was washed with brine, dried over MgSO4, and filtered and evaporated under vacuum without further purification to give aminomalonic acid.
Step a: Diethyl malonate-2-13C (1.0 g, 6.3 mmol) was dissolved in a mixture of water (2.0 mL) and acetic acid (1.5 mL), and cooled to 0° C. Sodium nitrite (2.20 g, 31.5 mmol, 500 mol %) was added portion wise to the reaction mixture. The mixture was stirred at room temperature overnight. After reaction completion as indicated by TLC, the reaction mixture was poured into 30 mL water and extracted with diethyl ether (30 mL×3). The combined organic phase was treated with saturated sodium bicarbonate solution carefully and stirred until the aqueous layer became lightly yellow. The organic layer was separated (retention factor (“Rf”)=0.4 (hexane/EtOAc 5:1)), washed with brine, dried with Na2SO4, filtered, and concentrated to give corresponding oxime (1.2267 g, quantitative yield). The oxime was used directly in the next step without further purification.
Step b: The above-synthesized oxime and Pd/C (10%, 100 mg) was mixed in a 50 mL round bottom flask. The flask was sealed with a rubber septum and purged with nitrogen for 10 mins. 15 mL methanol was added into the reaction mixture under a nitrogen balloon. The reaction mixture was purged with hydrogen for 15 mins and stirred at room temperature overnight under hydrogen. The reaction mixture was filtered through a plug of Celite, and eluted with EtOAc. The filtrate was concentrated to give diethyl aminomalonate-2-13C (0.9067 g, 82% Yield). The amine was used directly in the next step without further purification. Rf=0.2 (hexane/EtOAc 1:1).
Step c: The above-synthesized aminomalonic ester (0.9067 g, 5.2 mmol) and triethylamine (2.0 mL, 14 mmol, 270 mol %) were dissolved in 50 mL DCM. Bz7Cl (prepared from 7.3 mmol Bz7OH as described in the general procedure) in 20 mL DCM was added to the reaction mixture dropwise at 0° C. The reaction mixture was stirred at 0° C., and monitored by TLC. Once completed, the mixture was poured into 50 mL water and extracted with DCM (25 mL×3). The combined organics were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give α-13C-16 (1.7428 g, 71% Yield) as colorless oil. Rf=0.2 (hexane/EtOAc 4:1).
Step d: To a solution of α-13C-16 (1.7428 g, 3.7 mmol) in 50 mL CH3CN, Cs2CO3 (2.41 g, 7.4 mmol, 200 mol %) and iodomethane (781 mg, 5.5 mmol, 150 mol %) were added at room temperature. The resulting mixture was stirred at room temperature to full conversion, as monitored by TLC. The CH3CN was then removed under vacuum, and aqueous 1 M HCl solution (50 mL) was added to the residue. The mixture was stirred for 5 mins and extracted with EtOAc (25 mL×3). The combined organic solvents were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was submitted to flash column chromatography to give diester of α-13C-68 (1.3762 g, 77% Yield) as colorless oil. Rf=0.5 (hexane/EtOAc 3:1).
α-13C-68 was obtained from the above diester using the general hydrolysis procedure (2.5 mmol scale of hydrolysis, 0.8426 g, 78% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1).
Step a: Diethyl malonate (1.0 g, 6.3 mmol) was dissolved in a mixture of water (2.0 mL) and acetic acid (1.5 mL), and cooled to 0° C. Sodium nitrite-15N (2.0 g, 28.6 mmol, 450 mol %) was added portion wise to the reaction mixture. The mixture was stirred at room temperature overnight. After reaction completion as indicated by TLC, the reaction mixture was poured into 30 mL water and extracted with diethyl ether (30 mL×3). The combined organic phase was treated with saturated sodium bicarbonate solution carefully and stirred until the aqueous layer became lightly yellow. The organic layer was separated, washed with brine, dried with Na2SO4, filtered, and concentrated to give corresponding oxime (1.1771 g, 99% Yield). The oxime was used directly in the next step without further purification. Rf=0.4 (hexane/EtOAc 5:1).
Step b: The above-synthesized oxime and Pd/C (10%, 100 mg) were mixed in a 50 mL round bottom flask. The flask was sealed with a rubber septum and purged with nitrogen for 10 mins. 15 mL methanol was added under a nitrogen balloon. The reaction mixture was purged with hydrogen for 15 mins and stirred at room temperature overnight under hydrogen. The reaction mixture was filtered through a plug of Celite, and eluted with EtOAc. The filtrate was concentrated to give diethyl aminomalonate-15N (0.8805 g, 80% Yield). The amine was used directly in the next step without further purification. Rf=0.2 (hexane/EtOAc 1:1).
Step c: The above-synthesized aminomalonic ester (0.8805 g, 5.0 mmol) and triethylamine (2.0 mL, 14 mmol, 270 mol %) were dissolved in 50 mL DCM. Bz7Cl (prepared from 7.3 mmol Bz7OH as described in the general procedure) in 20 mL DCM was added to the reaction mixture dropwise at 0° C. The reaction mixture was stirred at 0° C., and monitored by TLC. Once completed, the mixture was poured into 50 mL water and extracted with DCM (25 mL×3). The combined organics were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give 15N-16 (1.4331 g, 61% Yield) as colorless oil. Rf=0.2 (hexane/EtOAc 4:1).
Step d: To a solution of α-13C-16 (1.4331 g, 3.0 mmol) in 40 mL CH3CN, Cs2CO3 (1.96 g, 6.0 mmol, 200 mol %) and iodomethane (639 mg, 4.5 mmol, 150 mol %) were added at room temperature. The resulting mixture was stirred at room temperature to full conversion, as monitored by TLC. The CH3CN was then removed under vacuum, and aqueous 1 M HCl solution (50 mL) was added to the residue. The mixture was stirred for 5 mins and extracted with EtOAc (25 mL×3). The combined organic solvents were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was submitted to flash column chromatography to give diester of 15N-68 (897.3 mg, 61% Yield) as colorless oil. Rf=0.5 (hexane/EtOAc 3:1).
Step I: To a solution of Lamivudine (2.2972 g, 10 mmol, 100 mol %) and TBSCl (tert-butyldimethylsilyl chloride) (1.8097 g, 12 mmol, 120 mol %) in DCM (80 mL), imidazole (1.0332 g, 15 mmol, 150 mol %) was added. The reaction mixture was stirred at room temperature for 12 h and monitored by TLC. After reaction completion, the mixture was poured into 100 mL water, and the aqueous phase was extracted with DCM (50 mL×3). The combined organic phase was washed with brine, dried over MgSO4, and filtered, and evaporated under vacuum without further purification to give S73-SM-1 as a light-yellow oil that can be used for the next step without further purification. Rf=0.7 (DCM/MeOH 5:1).
Step II: To a solution of all S73-SM-1 from step I in DCM (50 mL), triethylamine (2.8 mL, 20 mmol, 200 mol %) was added at 0° C. under vigorous stirring. BzCl (1.4 mL, 12 mmol, 120 mol %) was added dropwise to the reaction mixture. The reaction was warmed to the room temperature and stirred for 2 h, and monitored by TLC. After reaction completion, the mixture was poured into 50 mL water, and the aqueous phase was extracted with DCM (50 mL×3). The combined organic phase was washed with brine, dried over MgSO4, and filtered, and evaporated under vacuum without further purification to afford S73-SM-2 as a light-yellow oil that can be used for the next step without further purification. Rf=0.2 (Hexane/EtOAc 1:1).
Step III: To a solution of all S73-SM-2 from step II in THF (20 mL), TBAF (tetrabutylammonium fluoride) (20 mL, 1.0 M in THF) was added dropwise within 10 min at 0° C. under argon. The resulting mixture was stirred at rt for 18 h, monitored by TLC. and concentrated under reduced pressure to give S73-SM-3 as a light-yellow oil that can be used for the next step without further purification.
Step IV: To a solution of all S73-SM-3 from step III in DMF (50 mL), NaH (0.6005 g, 15 mmol, 150 mol % (60%, disperse in mineral oil)) was added at 0° C. under vigorous stirring. The reaction mixture was warmed to the room temperature and stirred for 0.5 h. 3-bromopropyne (1.3 mL, 15 mmol, 150 mol %) was added dropwise to the reaction mixture at 0° C. The reaction mixture was warmed to the room temperature and stirred for 2 h, and monitored by TLC. After reaction completion, the mixture was quenched by 10 mL saturated NH4Cl aqueous and extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum without further purification to give S73 as a light-yellow oil.
To a solution of S17-diesters (1.4592 g, 3 mmol, 100 mol %) in 1,4-dioxane (0.5 M), 2 M NaOH aqueous solution (2.25 mL, 4.5 mmol, 150 mol %) was added dropwise at 0° C. After the resulting mixture was warmed to room temperature, it was stirred at 40° C. until hydrolysis finished, as monitored by TLC. 1,4-dioxane was removed under vacuum. The aqueous layer was washed three times with diethyl ether to remove the unreacted starting material, acidified by 1 M HCl aqueous to pH=6-7, and washed with diethyl ether to remove 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid until only malonic acid remained in aqueous phase as monitored by TLC. Then the aqueous phase was acidified by 1 M HCl aqueous to pH=3-4 and extracted with diethyl ether for three times. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum without further purification to afford (±)-80.
To a solution of 16 (0.9966 g, 2.1 mmol, 100 mol %) in CH3CN (0.1 M), Cs2CO3 (2.6125 g, 8.0 mmol, 400 mol %) and Mel (0.5 mL, 8.0 mmol, 400 mol %) were added at room temperature. The resulting mixture was stirred at room temperature to full conversion, as monitored by TLC. CH3CN was then removed under vacuum, and aqueous 1 M HCl solution (0.1 M as to 16) was added to the residue. The mixture was stirred for 5 mins and extracted with EtOAc. The combined organic solvents were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was submitted to flash column chromatography (hexane/ethyl acetate) to afford the disubstituted malonic ester 84-SM (1.0012 g, 95% Yield). Rf=0.5 (Hexane/EtOAc 2:1).
To a solution of 84-SM (1.0012 g, 2 mmol, 100 mol %) in 1,4-dioxane (0.5 M), 2 M NaOH aqueous solution (4 mL, 8 mmol, 400 mol %) was added dropwise at 0° C. After the resulting mixture was warmed to room temperature, it was stirred at 40° C. until hydrolysis finished, as monitored by TLC. 1,4-dioxane was removed under vacuum, and the aqueous layer was acidified by 1 M HCl aqueous to pH=6-7 and washed with diethyl ether to remove the unreacted malonic acid half esters and 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid until only malonic acid remained in aqueous phase as monitored by TLC. Then the aqueous phase was acidified by 1 M HCl aqueous to pH=2-3 and extracted with diethyl ether for three times. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum without further purification to afford 84.
To a solution of 16 (7.0845 g, 15 mmol, 100 mol %) in CH3CN (0.1 M), Cs2CO3 (9.7850 g, 30 mmol, 200 mol %) and 1,3-dibromopropane (3 mL, 30 mmol, 200 mol %) were added at room temperature. The resulting mixture was stirred at room temperature to full conversion, as monitored by TLC. The CH3CN was then removed under vacuum, and aqueous 1 M HCl solution (0.1 M as to 16) was added to the residue. The mixture was stirred for 5 mins and extracted with EtOAc. The combined organic solvents were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane/ethyl acetate) to give the disubstituted malonic ester 85-SM (6.5103 g, 73% Yield). Rf=0.7 (Hexane/EtOAc 2:1).
To a solution of 85-SM (2.1522 g, 3.6 mmol, 100 mol %) in 1,4-dioxane (0.5 M), 2 M NaOH aqueous solution (7.2 mL, 14.4 mmol, 400 mol %) was added dropwise at 0° C. After the resulting mixture was warmed to room temperature, it was stirred at 40° C. until hydrolysis was finished, as monitored by TLC. 1,4-dioxane was removed under vacuum, and the aqueous layer was acidified by 1 M HCl aqueous to pH=6-7 and washed with diethyl ether to remove the unreacted malonic acid half esters and 4-nitro-3-(2,2,3,3,3-pentafluoropropoxy) benzoic acid until only malonic acid remained in aqueous phase as monitored by TLC. Then the aqueous phase was acidified by 1 M HCl aqueous to pH=2-3 and extracted with diethyl ether for three times. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum without further purification to afford 85.
Malonic acid (0.2 mmol, 100 mol %) and (R)-CPA-8 (11.0 mg, 0.02 mmol, 10 mol %) were added into an oven-dried 25 mL Schlenk tube. The tube was sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 4 mL CPME was added to the tube via syringe under nitrogen atmosphere, and the reaction mixture was stirred at 80° C. for 5-20 h. After the reaction mixture was cooled to room temperature, 0.8 mL MeOH and 0.8 mL 2 M TMSCHN2 (800 mol %) were added to the reaction mixture, and the reaction mixture was stirred for an additional hour. The solvent was removed under vacuum and the filtrate was purified by flash column chromatography (hexanes/ethyl acetate) to obtain the decarboxylation product.
To an oven-dried 100 mL round bottom flask, (R)-CPA-8 (41.8 mg, 0.075 mmol, 2.5 mol %) was added. The flask was sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 12 mL of CPME was added to the flask via syringe under nitrogen atmosphere, which was then stirred at 80° C. in an oil bath.
S17 (3.0 mmol, 1.2912 g, 100 mol %) was dissolved in 48 mL CPME and added to the reaction mixture dropwise using a syringe pump for 24 h, and the reaction mixture was stirred at the same temperature for another 12 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was directly used in the next step.
The residue was dissolved in 1,4-dioxane (6 mL). 6 M HCl (20 mL, 4000 mol %) was added to the reaction mixture at 0° C. The mixture was warmed to room temperature and then stirred at 100° C. for 24 h. The reaction mixture was cooled to room temperature and washed with diethyl ether (10 mL×3). The aqueous phase was concentrated under vacuum to give amino acid hydrochloride (+)-1858 as a solid (0.3136 g, 83% Yield). Rf=0.2 (DCM/MeOH 1:1).
To an oven-dried 25 mL Schlenk tube, (+)-41 (226.0 mg, 0.4 mmol, 91% e.e., 100 mol %) was added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 2 mL DCM was added to the tube via syringe under nitrogen atmosphere. The reaction mixture was cooled to 0° C., then DDQ (273.2 mg, 1.2 mmol, 300 mol %) was added and the reaction mixture was stirred at room temperature for 10 h. Then 1 mL saturated NaHCO3 aqueous was added to quench the reaction, which was then extracted with DCM (5 mL×6), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to give (+)-42 (151.5 mg, 85% Yield) as colorless oil. Rf=0.2 (Hexane/EtOAc 1:1).
To an oven-dried 25 mL Schlenk tube, (+)-42 (88.6 mg, 0.2 mmol, 91% e.e., 100 mol %), PPh3 (63.2 mg, 0.24 mmol, 120 mol %), imidazole (16.4 mg, 0.24 mmol, 120 mol %), were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 1 mL DCM was added to the tube via syringe under nitrogen atmosphere. The reaction mixture was cooled to 0° C., then I2 (60.8 mg, 0.24 mmol, 120 mol %) was added and the reaction mixture was stirred at room temperature for 16 h. Then 1 mL saturated Na2S2O3 aqueous solution was added to quench the reaction, which was extracted with DCM (5 mL×6), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to afford the (+)-43 (96.6 mg, 87% Yield) as white solid. Rf=0.6 (Hexane/EtOAc 1:1).
To an oven-dried 25 mL Schlenk tube, (+)-43 (110.5 mg, 0.2 mmol, 91% e.e., 100 mol %), was added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 1 mL DMF was added to the tube via syringe under nitrogen atmosphere. The reaction mixture was cooled to 0° C., then Cs2CO3 (130.8 mg, 0.4 mmol, 200 mol %) was added and the reaction mixture was stirred at room temperature for 2 h. Then 1 mL H2O was added to quench the reaction, which was extracted with ethyl acetate (5 mL×3), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to give the (−)-44 (75.2 mg, 88% Yield) as white solid. Rf=0.3 (Hexane/EtOAc 2:1).
To an oven-dried 25 mL Schlenk tube, (+)-29 (63.7 mg, 0.15 mmol, 98% e.e., 100 mol %) and Zidovudine (54.1 mg, 0.225 mmol, 150 mol %) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 3 mL DCM was added to the tube via syringe under nitrogen atmosphere. Sodium ascorbate (9 mg dissolved in 1.5 mL H2O, 0.045 mmol, 30 mol %) and CuSO4·5H2O (3.8 mg dissolved in 1.5 mL H2O, 0.015 mmol, 10 mol %) were added to the reaction sequentially. The reaction mixture was stirred at 30° C. for 40 h, extracted with DCM (5 mL×3), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to give (+)-72 (95.4 mg, 92% Yield) as colorless oil. The d.r. was determined as >20:1 using 1H NMR analysis of crude product with CH2Br2 (10.5 μL) as the internal standard. Rf=0.3 (EtOAc 100%).
To an oven-dried 25 mL Schlenk tube, (+)-57 (77.6 mg, 0.15 mmol, 97% e.e., 100 mol %) and Lamivudine derived terminal alkyne (67.5 mg, 0.18 mmol, 120 mol %) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 1.5 mL DCM was added to the tube via syringe under nitrogen atmosphere. Sodium ascorbate (9.1 mg dissolved in 0.75 mL H2O, 0.045 mmol, 30 mol %) and CuSO4·H2O (3.9 mg dissolved in 0.75 mL H2O, 0.015 mmol, 10 mol %) were added to the reaction sequentially. The reaction mixture was stirred at room temperature for 24 h, extracted with DCM (5 mL×3), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to afford the (+)-73 (115.3 mg, 86% Yield) as colorless oil. The d.r. was determined as >20:1 using 1H NMR analysis of crude product with CH2Br2 (10.5 μL) as the internal standard. Rf=0.4 (Hexane/EtOAc 1:3).
To an oven-dried 25 mL Schlenk tube, (+)-57 (77.5 mg, 0.15 mmol, 97% e.e., 100 mol %) and diacetone-D-glucose derived terminal alkyne (53.5 mg, 0.18 mmol, 120 mol %) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 1.5 mL of DCM was added to the tube via syringe under nitrogen atmosphere. Sodium ascorbate (9 mg dissolved in 0.75 mL H2O, 0.045 mmol, 30 mol %) and CuSO4·H2O (3.8 mg dissolved in 0.75 mL H2O, 0.015 mmol, 10 mol %) were added to the reaction sequentially. The reaction mixture was stirred at room temperature for 12 h, extracted with DCM (5 mL×3), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to give (+)-74 (114.9 mg, 94% Yield) as a colorless oil. The d.r. was determined as >20:1 using 1H NMR analysis of crude product with CH2Br2 (10.5 μL) as the internal standard. Rf=0.2 (Hexane/EtOAc 2:1).
Step I: To an oven-dried 100 mL flask, (−)-77 (232.5 mg, 0.75 mmol, 94% e.e.) and Pd/C dry powder (10%, 50 mg) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 40 mL of MeOH was added to the flask via syringe under nitrogen atmosphere. The reaction mixture was purged by H2 for 5 min with a H2 balloon, then sealed and stirred under H2 atmosphere with a H2 balloon. After stirred at room temperature for 12 h, the reaction mixture was filtrated with Celite and the filtrate was concentrated under vacuum and purified by flash column chromatography to afford 78 (176.2 mg, 84% Yield) as a colorless oil, which was directly use in next step. Rf=0.3 (Hexane/EtOAc 1:1).
Step II: To an oven-dried 100 mL flask, 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (116.7 mg, 0.6 mmol, 100 mol %) and dry DCM (18 mL) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. Oxalyl chloride (254 μL dissolved in 4 mL dry DCM, 3 mmol, 500 mol %) was added to the flask via syringe under nitrogen atmosphere. 5 drops of DMF were added carefully into the reaction mixture, which was stirred at room temperature for 24 h. After that, the solvent was removed under vacuum, and the residue (79-SM-1) was redissolved in 4 mL DCM, which was directly use in next step without further purification.
Step III: To an oven-dried 50 mL flask, 78 (168.2 mg, 0.6 mmol, 100 mol %) and dry DCM (4 mL) were added and sealed with a rubber septum and evacuated/refilled with nitrogen for three times. 79-SM-1 (dissolved in 4 mL dry DCM, from step II) and anhydrous pyridine (4 mL) were added to the flask sequentially under nitrogen atmosphere. After stirred at room temperature for 24 h, the reaction mixture was concentrated under vacuum, then redissolved in DCM (50 mL), washed with 1 M HCl, brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to give 79-SM-2 (72.7 mg, 27% Yield) as a yellow oil, which was directly use in next step. Rf=0.5 (Hexane/EtOAc 1:1).
Step IV: To a stirred solution of 79-SM-2 (60.0 mg, 0.13 mmol, 100 mol %) in THF/H2O (1.2 mL 4:1 mixture), LiOH·H2O (11.5 mg, 0.26 mmol, 200 mol %) was added. After stirred at room temperature for 3 h, the reaction mixture was concentrated under vacuum to remove THF, then redissolved in H2O (5 mL), and washed with diethyl ether (5 mL×3). The aqueous layer was acidified by 1 M HCl aqueous to pH=2-3 and extracted with diethyl ether (5 mL×3). The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by flash column chromatography to afford the (−)-79 (41.1 mg, 71% Yield) as white solid. Rf=0.3 (DCM/MeOH 5:1).
16 (260 mmol scale, 109.69 g, 89% Yield) light-yellow solid. Rf=0.4 (Hexane/EtOAc 2:1). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 5.30 (d, J=6.4 Hz, 1H), 4.61 (t, J=11.8 Hz, 2H), 4.46-4.20 (m, 4H), 1.34 (t, J=6.8 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 166.0, 164.3, 150.2, 142.4, 138.1, 126.0, 120.7, 115.1, 66.2 (t, J=28.5 Hz), 63.0, 56.9, 13.9. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3293, 2992, 1748, 1530, 1190. HRMS (ESI) calcd C17H18F5N2O8+ [M+H]+: 473.0978. Found: 473.0977.
S17-diester (13.0 mmol scale, 5.4544 g, 88% Yield) white solid. Rf=0.6 (Hexane/EtOAc 2:1). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.4 Hz, 1H), 7.75-7.60 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 4.62 (t, J=11.8 Hz, 2H), 4.30 (q, J=7.1 Hz, 4H), 1.87 (s, 3H), 1.29 (t, J=7.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 168.3, 163.2, 150.3, 142.3, 138.7, 126.1, 120.4, 115.0, 66.2 (t, J=28.2 Hz), 63.4, 62.9, 20.5, 13.9. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=12.4 Hz). IR (neat, cm−1) 3405, 2987, 1743, 1534, 1190. HRMS (ESI) calcd C10H20F5N2O8+ [M+H]+: 487.1134. Found: 487.1135.
S17 (11.2 mmol scale of hydrolysis, 3.8477 g, 80% Yield) as white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J=8.4 Hz, Hz, 1H), 5.19 (t, J=13.0 Hz, 2H), 1.69 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 170.0, 163.7, 149.0, 141.4, 138.7, 125.3, 121.7, 118.4 (qt, J1=284.6 Hz, J2=34.8 Hz), 115.0, 112.7 (tq, J1=252.8 Hz, J2=37.4 Hz), 65.1 (t, J=27.5 Hz), 63.2, 21.0. 19F NMR (376 MHz, CDCl3) δ −82.7, −122.5 (t, J=11.7 Hz). IR (neat, cm−1) 3460 (br), 3414, 1693, 1520, 1196. HRMS (ESI) calcd C14H12F5N2O8+ [M+H]+: 431.0508. Found: 431.0506.
S19 (5.9 mmol scale of hydrolysis, 1.8778 g, 73% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 2.30 (q, J=7.1 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H). 13C NMR (100 MHz, CD3CN) δ 170.6, 165.6, 150.6, 143.2, 139.2, 126.6, 122.4, 115.8, 67.6, 66.7 (t, J=27.8 Hz), 27.4, 8.4. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=13.2 Hz). IR (neat, cm−1) 3384, 3091, 1733, 1516, 1149. HRMS (ESI) calcd C15H14F5N2O8+ [M+H]+: 445.0665. Found: 445.0668.
S20 (5.3 mmol scale of hydrolysis, 1.6774 g, 69% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 2.23 (t, J=8.2 Hz, 2H), 1.38-1.25 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). 13C NMR (100 MHz, CD3CN) δ 170.8, 165.6, 150.6, 143.1, 139.2, 126.6, 122.3, 115.8, 67.1, 66.7 (t, J=28.2 Hz), 36.1, 18.0, 14.1. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3395, 2977, 1739, 1530, 1194. HRMS (ESI) calcd C16H16F5N2O8+ [M+H]+: 459.0821. Found: 459.0819.
S21 (9.3 mmol scale of hydrolysis, 3.4190 g, 78% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (500 MHz, CD3CN) δ 7.92 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 4.84 (t, J=12.5 Hz, 2H), 2.26 (t, J=8.0 Hz, 2H), 1.41-1.20 (m, 4H), 0.88 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CD3CN) δ 170.7, 165.5, 150.7, 143.2, 139.2, 126.6, 122.4, 115.8, 67.1, 66.7 (t, J=27.5 Hz), 33.7, 26.6, 23.2, 14.1. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3312, 2973 1756, 1538, 1207. HRMS (ESI) calcd C17H18F5N2O8+ [M+H]+: 473.0978. Found: 473.0976.
S22 (8.3 mmol scale of hydrolysis, 2.3683 g, 54% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 2.37-2.12 (m, 2H), 1.37-1.16 (m, 12H), 0.85 (t, J=6.6 Hz, 3H). 13C NMR (100 MHz, CD3CN) δ 170.7, 165.5, 150.6, 143.2, 139.2, 126.6, 122.3, 115.8, 67.1, 66.7 (t, J=27.8 Hz), 33.9, 32.5, 30.0, 29.9, 29.8, 24.4, 23.3, 14.4. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3316, 2929, 1760, 1541 1203. HRMS (ESI) calcd C21H26F5N2O8[M+H]+: 529.1604. Found: 529.1604.
S23 (3.9 mmol scale of hydrolysis, 0.7891 g, 43% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.05-7.84 (m, 2H), 7.69 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 2.21 (d, J=7.2 Hz, 2H), 0.76-0.62 (m, 1H), 0.44 (q, J=6.0 Hz, 2H), 0.11 (q, J=4.9 Hz, 2H). 13C NMR (100 MHz, CD3CN) δ 171.0, 165.4, 150.6, 143.1, 139.3, 126.6, 122.3, 115.8, 67.0, 66.7 (t, J=28.9 Hz), 38.6, 6.5, 4.4. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3400, 3116, 1731, 1531, 1193. HRMS (ESI) calcd C17H16F5N2O8+ [M+H]+: 471.0821. Found: 471.0819.
S24 (10.9 mmol scale of hydrolysis, 1.0992 g, 22% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.71-7.61 (m, 2H), 4.83 (t, J=12.4 Hz, 2H), 2.64-2.46 (m, 1H), 1.09 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CD3CN) δ 171.8, 166.7, 150.6, 143.1, 138.9, 126.6, 122.5, 115.8, 69.7, 66.7 (t, J=27.5 Hz), 34.6, 18.2. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3274, 2977, 1734, 1534, 1199. HRMS (ESI) calcd C16H16F5N2O8+ [M+H]+: 459.0821. Found: 459.0818.
S25 (19.2 mmol scale of hydrolysis, 5.4429 g, 62% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.91 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 5.79-5.68 (m, 1H), 5.21-5.11 (m, 2H), 4.83 (t, J=12.6 Hz, 2H), 3.05 (d, J=7.6 Hz, 2H). 13C NMR (100 MHz, CD3CN) δ 169.5, 165.4, 150.6, 143.2, 139.3, 132.1, 126.6, 122.3, 120.8, 115.8, 67.0, 66.7 (t, J=27.8 Hz), 38.0. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3383, 2951, 1730, 1524, 1195. HRMS (ESI) calcd C16H14F5N2O8+ [M+H]+: 457.0665. Found: 457.0664.
S26 (4.9 mmol scale of hydrolysis, 1.8927 g, 73% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 2H), 7.29 (t, J=7.4 Hz, 2H), 7.23 (t, J=7.0 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.20-6.10 (m, 1H), 4.77 (t, J=12.6 Hz, 2H), 3.21 (d, J=7.2 Hz, 2H). 13C NMR (100 MHz, CD3CN) δ 169.5, 165.6, 150.6, 143.1, 139.4, 137.9, 135.7, 129.6, 128.7, 127.2, 126.6, 123.5, 122.4, 115.8, 67.3, 66.7 (t, J=27.8 Hz), 37.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3379, 2979, 1729, 1529, 1193. HRMS (ESI) calcd C22H18F5N2O8+ [M+H]+: 533.0978. Found: 533.0975.
S27 (19.7 mmol scale of hydrolysis, 3.3933 g, 32% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.91 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 5.69 (s, 1H), 5.60 (s, 1H), 4.84 (t, J=12.6 Hz, 2H), 3.57 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.4, 165.3, 150.6, 143.2, 139.4, 126.9, 126.6, 123.7, 122.3, 115.8, 66.8, 66.7 (t, J=27.8 Hz), 43.3. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3390, 2992, 1734, 1530, 1199. HRMS (ESI) calcd C16H13F5N2O879Br+ [M+H]+: 534.9770. Found: 534.9766.
S28 (7.2 mmol scale of hydrolysis, 2.8503 g, 82% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.91 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.05 (t, J=7.4 Hz, 1H), 4.83 (t, J=12.6 Hz, 2H), 3.02 (d, J=7.6 Hz, 2H), 1.69 (s, 3H), 1.55 (s, 3H). 13C NMR (100 MHz, CD3CN) δ 170.0, 165.5, 150.7, 143.2, 139.3, 138.8, 126.6, 122.3, 116.9, 115.8, 66.8, 66.7 (t, J=27.8 Hz), 32.7, 26.0, 18.1. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3392, 2978, 1729, 1529, 1193. HRMS (ESI) calcd C18H18F5N2O8+ [M+H]+: 485.0978. Found: 485.0977.
S29 (17.3 mmol scale of hydrolysis, 5.3877 g, 69% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.99-7.82 (m, 2H), 7.69 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 3.01 (d, J=1.6 Hz, 2H), 2.32 (s, 1H). 13C NMR (100 MHz, CD3CN) δ 168.0, 165.4, 150.7, 143.3, 139.0, 126.7, 122.3, 115.8, 78.7, 73.4, 66.7 (t, J=27.8 Hz), 66.2, 24.3. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3391, 3293, 1953, 1733, 1521, 1198. HRMS (ESI) calcd C16H12F5N2O8+ [M+H]+: 455.0510. Found: 455.0508.
S30 (7.4 mmol scale of hydrolysis, 2.6497 g, 67% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.39-7.25 (m, 5H), 4.80 (t, J=12.4 Hz, 2H), 3.53 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.3, 165.4, 150.7, 143.2, 139.2, 132.5, 129.51, 129.46, 126.7, 123.7, 122.3, 115.8, 84.5, 84.4, 66.7 (t, J=27.9 Hz), 66.6, 25.3. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3405, 2924, 1739, 1530, 1199. HRMS (ESI) calcd C22H16F5N2O8+ [M+H]+: 531.0821. Found: 531.0823.
S31 (5.8 mmol scale of hydrolysis, 1.9438 g, 60% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.90 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 5.12-4.97 (m, 2H), 4.83 (t, J=12.6 Hz, 2H), 3.03 (d, J=7.6 Hz, 2H), 2.06-1.94 (m, 4H), 1.63 (s, 3H), 1.55 (s, 6H). 13C NMR (100 MHz, CD3CN) δ 170.1, 165.6, 150.7, 143.2, 142.4, 139.2, 132.5, 126.6, 124.9, 122.2, 116.9, 115.8, 66.8, 66.7 (t, J=27.8 Hz), 40.5, 32.6, 27.2, 25.8, 17.8, 16.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.4 Hz). IR (neat, cm−1) 3383, 2951, 1731, 1525, 1195. HRMS (ESI) calcd C23H26F5N2O8+ [M+H]+: 553.1604. Found: 553.1606.
S32 (4.0 mmol scale of hydrolysis, 0.7862 g, 35% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.82 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.32-7.17 (m, 3H), 7.11 (d, J=7.2 Hz, 2H), 5.55 (s, 1H), 5.42 (s, 1H), 4.66 (t, J=12.4 Hz, 2H), 3.34 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.7, 164.9, 150.5, 143.0, 139.0, 132.1, 129.5, 129.3, 127.4, 126.5, 126.4, 123.4, 122.3, 115.7, 90.7, 90.2, 67.3, 66.5 (t, J=27.8 Hz), 39.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3396, 2928, 2157, 1737, 1530, 1195. HRMS (ESI) calcd C24H18F5N2O8+ [M+H]+: 557.0978. Found: 557.0979.
S33 (8.3 mmol scale of hydrolysis, 2.5487 g, 57% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.91 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.32-7.22 (m, 2H), 7.21-7.08 (m, 3H), 4.83 (t, J=12.6 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 2.27 (t, J=7.8 Hz, 2H), 1.71-1.48 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 170.4, 165.5, 150.6, 143.1, 142.7, 139.1, 129.4, 126.9, 126.6, 122.4, 115.8, 67.0, 66.7 (t, J=27.8 Hz), 35.8, 33.4, 26.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3385, 2936, 1729, 1531, 1193. HRMS (ESI) calcd C22H20F5N2O8+ [M+H]+: 535.1134. Found: 535.1131.
S34 (1.2 mmol scale of hydrolysis, 0.4657 g, 68% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.83 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.4 Hz, 1H), 6.92 (s, 1H), 4.77 (t, J=12.6 Hz, 2H), 3.62 (s, 3H), 2.81-2.74 (m, 2H), 2.74-2.66 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 170.1, 165.2, 150.5, 143.0, 138.9, 138.1, 128.4, 127.6, 126.4, 122.3, 121.9, 119.51, 119.47, 115.5, 113.8, 110.3, 67.3, 66.6 (t, J=27.8 Hz), 33.9, 32.8, 20.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.4 Hz). IR (neat, cm−1) 3405, 2929, 1736, 1534, 1199. HRMS (ESI) calcd C24H21F5N3O8+ [M+H]+: 574.1243. Found: 574.1246.
S35 (1.8 mmol scale of hydrolysis, 0.5831 g, 55% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.58 (s, 1H), 7.90-7.84 (m, 2H), 7.71-7.66 (m, 1H), 7.59-7.49 (m, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.32-7.23 (m, 1H), 4.79 (t, J=12.2 Hz, 2H), 3.49-3.33 (m, 2H), 2.66-2.52 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 172.0, 170.0, 168.3, 166.2, 150.6, 143.0, 138.9, 138.1, 133.2, 131.3, 131.0, 130.1, 128.7, 126.6, 122.5, 115.8, 66.6 (t, J=27.8 Hz), 66.2, 36.2, 33.4. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.0 (t, J=12.4 Hz). IR (neat, cm−1) 3347, 2943, 1714, 1534, 1199. HRMS (ESI) calcd C23H17F5N3O10+ [M+H]+: 590.0829. Found: 590.0833.
S36 (9.5 mmol scale of hydrolysis, 2.9939 g, 60% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 2.60-2.16 (m, 4H), 1.75-1.45 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 169.5, 165.5, 150.6, 143.2, 139.2, 126.6, 122.4, 120.8, 115.8, 66.9, 66.7 (t, J=27.5 Hz), 32.5, 21.0, 17.3. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3395, 2982, 2190, 1738, 1520, 1194. HRMS (ESI) calcd C17H15F5N3O8+ [M+H]+: 484.0774. Found: 484.0774.
S37 (9.7 mmol scale of hydrolysis, 3.8063 g, 76% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ7.97-7.86 (m, 2H), 7.70 (d, J=1.2 Hz, 1H), 7.62 (dd, J1=8.2, J1=1.4 Hz, 1H), 4.92-4.75 (m, 3H), 3.95-3.84 (m, 2H), 3.83-3.71 (m, 2H), 2.44-2.30 (m, 2H), 1.69-1.54 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 170.0, 165.6, 150.6, 143.2, 139.1, 126.6, 122.3, 115.8, 104.0, 66.8, 66.7 (t, J=27.5 Hz), 65.8, 28.8, 28.0. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=13.2 Hz). IR (neat, cm−1) 3395, 2290, 1739, 1534, 1194. HRMS (ESI) calcd C18H18F5N2O10+ [M+H]+: 517.0876. Found: 517.0878.
S38 (2.0 mmol scale of hydrolysis, 0.4997 g, 50% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.91 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.84 (t, J=12.4 Hz, 2H), 3.33 (t, J=6.6 Hz, 2H), 2.51-2.21 (m, 2H), 1.63-1.42 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 170.0, 165.5, 150.6, 143.1, 139.2, 126.6, 122.4, 115.8, 67.0, 66.7 (t, J=27.8 Hz), 51.6, 30.9, 24.2. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3390, 2943, 2098, 1739, 1534, 1199. HRMS (ESI) calcd C16H15F5N5O8+ [M+H]+: 500.0835. Found: 500.0837.
S39 (0.46 mmol scale of hydrolysis, 0.2571 g, 68% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.93 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 4.84 (t, J=12.6 Hz, 2H), 3.37 (s, 1H), 3.27 (s, 3H), 3.22 (s, 3H), 3.19 (s, 3H), 3.14 (s, 1H), 3.04-3.93 (m, 1H), 2.36-2.08 (m, 2H), 2.02-1.94 (m, 3H), 1.88-0.96 (m, 21H), 0.91-0.82 (m, 6H), 0.64 (s, 3H). 13C NMR (100 MHz, CD3CN) δ 170.7, 170.6, 165.4, 150.7, 143.2, 139.2, 126.6, 122.3, 115.8, 83.0, 81.4, 78.2, 67.1, 66.7 (t, J=27.8 Hz), 56.2, 56.0, 55.5, 47.7, 46.9, 43.5, 42.7, 40.4, 36.4, 36.1, 35.8, 35.6, 35.5, 34.3, 28.6, 28.5, 28.2, 27.7, 23.9, 23.2, 22.7, 21.1, 18.2, 12.8. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3395, 2934, 1739, 1530, 1199. HRMS (ESI) calcd C40H56F5N2O11+ [M+H]+: 835.3799. Found: 835.3795.
S40 (1.7 mmol scale of hydrolysis, 0.7305 g, 57% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.61 (d, J=7.2 Hz, 1H), 6.54 (s, 1H), 5.20 (t, J=12.8 Hz, 2H), 3.87-3.84 (m, 2H), 2.75 (s, 2H), 2.46-2.38 (m, 1H), 2.36-2.22 (m, 3H), 2.16-2.02 (m, 2H), 1.98-1.86 (m, 2H), 1.78-1.62 (m, 3H), 1.56-1.26 (m, 8H), 0.81 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 219.7, 169.3, 163.4, 156.5, 148.9, 141.4, 138.4, 137.4, 131.7, 126.2, 125.2, 121.7, 115.0, 114.3, 112.1, 67.0, 66.7, 65.1 (t, J=28.3 Hz), 49.6, 47.4, 43.4, 37.9, 35.4, 32.0, 31.4, 29.1, 28.7, 26.1, 25.5, 21.2, 20.3, 13.5. 19F NMR (376 MHz, DMSO-d6) δ −82.5 (s), −122.4 (t, J=12.6 Hz). IR (neat, cm−1) 3400, 2939, 1743, 1539, 1199. HRMS (ESI) calcd C35H38F5N2O10+ [M+H]+: 741.2441. Found: 741.2444.
S41 (6.0 mmol scale of hydrolysis, 2.6009 g, 73% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.01 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.20 (d, J=7.2 Hz, 2H), 6.83 (d, J=7.2 Hz, 2H), 4.80 (t, J=12.2 Hz, 2H), 4.37 (s, 2H), 3.74 (s, 3H), 3.53-3.42 (m, 2H), 3.45-3.23 (m, 2H), 1.70-1.50 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 170.5, 165.7, 160.2, 150.6, 143.1, 139.2, 131.5, 130.4, 126.6, 122.3, 115.8, 114.6, 73.1, 70.1, 66.9, 66.7 (t, J=27.9 Hz), 55.8, 31.3, 24.8. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3395, 2934, 1743, 1515, 1194. HRMS (ESI) calcd C24H24F5N2O10+ [M+H]+: 595.1346. Found: 595.1349.
S45 (6.1 mmol scale of hydrolysis, 1.9894 g, 64% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.0 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.45 (dd, J1=8.2, J2=1.4 Hz, 1H), 7.30-7.22 (m, 3H), 7.15-7.04 (m, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.65 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.2, 165.6, 150.6, 143.1, 139.4, 135.9, 131.0, 129.4, 128.4, 126.7, 122.1, 115.8, 68.1, 66.7 (t, J=27.8 Hz), 38.6. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.4 Hz). IR (neat, cm−1) 3382, 2983, 1729, 1525, 1195. HRMS (ESI) calcd C20H16F5N2O8+ [M+H]+: 507.0821. Found: 507.0819.
S46 (5.0 mmol scale of hydrolysis, 1.9277 g, 75% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.52-7.45 (m, 2H), 7.14-7.07 (m, 2H), 7.04-6.96 (m, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.64 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.0, 165.5, 163.2 (d, J=241.9 Hz), 150.6, 143.2, 139.4, 132.8 (d, J=8.0 Hz), 132.0 (d, J=2.9 Hz), 126.6, 122.2, 116.2, 115.9 (d, J=19.5 Hz), 68.1, 66.7 (t, J=27.5 Hz), 37.7. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −117.0-−117.1 (m), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3387, 2953, 1730, 1510, 1193. HRMS (ESI) calcd C20H15F6N2O8+ [M+H]+: 525.0727. Found: 525.0726.
S47 (4.8 mmol scale of hydrolysis, 1.7392 g, 67% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.52-7.43 (m, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.64 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.8, 165.5, 150.6, 143.2, 139.4, 134.9, 133.8, 132.7, 129.4, 126.6, 122.3, 115.8, 68.0, 66.7 (t, J=27.8 Hz), 37.8. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3389, 2926, 1729, 1526, 1193. HRMS (ESI) calcd C20H15F5N2O835Cl+ [M+H]+: 541.0432. Found: 541.0437.
S48 (5.6 mmol scale of hydrolysis, 2.0157 g, 62% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.52-7.45 (m, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.62 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.8, 165.5, 150.6, 143.2, 139.3, 135.4, 133.0, 132.4, 126.6, 122.3, 121.9, 115.8, 67.9, 66.7 (t, J=27.8 Hz), 37.9. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=13.2 Hz). IR (neat, cm−1) 3386, 2927, 1730, 1526, 1194. HRMS (ESI) calcd C20H15F5N2O879Br+ [M+H]+: 584.9926. Found: 584.9923.
S49 (4.2 mmol scale of hydrolysis, 1.4281 g, 64% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.52-7.40 (m, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.81 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.74 (s, 3H), 3.57 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.3, 165.4, 160.1, 150.6, 143.1, 139.5, 132.1, 127.6, 126.7, 122.2, 115.8, 114.7, 68.1, 66.7 (t, J=27.8 Hz), 55.8, 37.9. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=11.8 Hz). IR (neat, cm−1) 3366, 2964, 1733, 1511, 1202. HRMS (ESI) calcd C21H18F5N2O9+ [M+H]+: 537.0927. Found: 537.0928.
S50 (5.2 mmol scale of hydrolysis, 2.1458 g, 67% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.56-7.26 (m, 7H), 7.02 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 5.03 (s, 2H), 4.82 (t, J=12.4 Hz, 2H), 3.59 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.3, 165.4, 159.2, 150.6, 143.1, 139.5, 138.3, 132.1, 129.5, 128.9, 128.7, 128.0, 126.7, 122.1, 115.8, 115.7, 70.6, 68.1, 66.7 (t, J=27.8 Hz), 37.8. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), -124.0 (t, J=12.4 Hz). IR (neat, cm−1) 3390, 2939, 1739, 1515, 1199. HRMS (ESI) calcd C27H22F5N2O9+ [M+H]+: 613.1240. Found: 613.1241.
S51 (6.5 mmol scale of hydrolysis, 2.0763 g, 56% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.03 (d, J=7.2 Hz, 2H), 4.86 (t, J=12.0 Hz, 2H), 3.69 (s, 2H), 2.08 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 171.6, 170.4, 166.6, 151.0, 143.5, 140.1, 139.0, 132.5, 131.4, 126.7, 122.3, 121.1, 115.8, 69.1, 66.8 (t, J=27.5 Hz), 38.1, 23.7. 19F NMR (376 MHz, CD3OD) δ −84.8 (s), −124.7 (t, J=12.4 Hz). IR (neat, cm−1) 3313, 2929, 1763, 1515, 1209. HRMS (ESI) calcd C22H19F5N3O9+ [M+H]+: 564.1036. Found: 564.1034.
S52 (4.3 mmol scale of hydrolysis, 1.3536 g, 57% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.09 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.52-7.43 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.4 Hz, 2H), 3.79 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.5, 165.6, 150.6, 148.5, 144.1, 143.2, 139.3, 132.2, 126.6, 124.4, 122.3, 115.8, 67.9, 66.7 (t, J=27.8 Hz), 38.2. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=13.2 Hz). IR (neat, cm−1) 3356, 2977, 1749, 1521, 1349, 1199. HRMS (ESI) calcd C20H15F5N3O10+ [M+H]+: 552.0672. Found: 552.0675.
S53 (4.0 mmol scale of hydrolysis, 0.7493 g, 32% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.6 Hz, 2H), 7.62 (s, 1H), 7.53-7.44 (m, 2H), 7.33 (d, J=7.6 Hz, 2H), 4.82 (t, J=12.4 Hz, 2H), 3.77 (s, 2H), 3.03 (s, 3H). 13C NMR (100 MHz, CD3CN) δ 168.7, 165.5, 150.6, 143.2, 142.6, 141.0, 139.3, 132.0, 128.2, 126.6, 122.3, 115.8, 68.0, 66.7 (t, J=27.8 Hz), 44.5, 38.3. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=13.2 Hz). IR (neat, cm−1) 3390, 2934, 1734, 1539, 1204. HRMS (ESI) calcd C21H18F5N2O10S+ [M+H]+: 585.0597. Found: 585.0596.
S54 (4.7 mmol scale of hydrolysis, 1.5121 g, 56% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.4 Hz, 1H), 7.63-7.55 (m, 3H), 7.51-7.46 (m, 2H), 7.28 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.74 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.7, 165.6, 150.6, 143.2, 140.8, 139.3, 131.8, 129.9 (q, J=32.0 Hz), 126.6, 126.2 (q, J=3.8 Hz), 125.5 (q, J=269.6 Hz), 122.3, 115.8, 68.0, 66.7 (t, J=27.8 Hz), 38.2. 19F NMR (376 MHz, CD3CN) δ −63.0 (s), −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3389, 2957, 1730, 1530, 1195. HRMS (ESI) calcd C21H15F8N2O8+ [M+H]+: 575.0695. Found: 575.0697.
S55 (6.6 mmol scale of hydrolysis, 1.7377 g, 48% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92-7.80 (m, 3H), 7.62 (s, 1H), 7.53-7.42 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.73 (s, 2H), 2.52 (s, 3H). 13C NMR (100 MHz, CD3CN) δ 198.9, 168.8, 165.6, 150.6, 143.2, 141.6, 139.4, 137.3, 131.3, 129.3, 126.6, 122.2, 115.8, 67.9, 66.7 (t, J=27.8 Hz), 38.4, 27.0. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3395, 2934, 1739, 1534, 1194. HRMS (ESI) calcd C22H18F5N2O9+ [M+H]+: 549.0927. Found: 549.0928.
S56 (4.0 mmol scale of hydrolysis, 1.4263 g, 61% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.60-7.43 (m, 5H), 7.43-7.33 (m, 2H), 7.33-7.24 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.85 (t, J=12.2 Hz, 2H), 3.78 (s, 2H). 13C NMR (100 MHz, CD3OD) δ 170.4, 166.6, 151.0, 143.6, 141.8, 141.4, 140.1, 136.0, 131.6, 129.8, 128.3, 127.9, 127.8, 126.8, 122.3, 115.8, 69.1, 66.8 (t, J=28.6 Hz), 38.3. 19F NMR (376 MHz, CD3OD) δ −84.8 (s), −124.6 (t, J=11.8 Hz). IR (neat, cm−1) 3385, 3074, 1760, 1510, 1193. HRMS (ESI) calcd C26H20F5N2O8+ [M+H]+: 583.1134. Found: 583.1138.
S57 (6.0 mmol scale of hydrolysis, 2.0061 g, 61% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.52-7.42 (m, 2H), 7.10 (d, J=7.6 Hz, 2H), 6.96 (d, J=7.6 Hz, 2H), 4.81 (t, J=12.2 Hz, 2H), 3.63 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.0, 165.5, 150.6, 143.2, 140.3, 139.4, 132.7, 132.5, 126.6, 122.2, 120.0, 115.8, 68.0, 66.7 (t, J=27.8 Hz), 37.9. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3381, 2929, 2117, 1734, 1510, 1209. HRMS (ESI) calcd C20H15F5N5O8+ [M+H]+: 548.0835. Found: 548.0832.
S58 (4.0 mmol scale of hydrolysis, 1.3662 g, 56% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.87 (d, J=8.0 Hz, 1H), 7.77-7.59 (m, 6H), 7.57-7.43 (m, 4H), 7.24 (d, J=6.8 Hz, 2H), 4.80 (t, J=12.0 Hz, 2H), 3.77 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 197.1, 168.8, 165.6, 150.6, 143.2, 141.1, 139.4, 138.5, 137.6, 133.5, 131.1, 130.9, 130.7, 129.4, 126.6, 122.3, 115.8, 68.0, 66.7 (t, J=27.8 Hz), 38.4. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3400, 3056, 1735, 1528, 1195. HRMS (ESI) calcd C27H20F5N2O9+ [M+H]+: 611.1083. Found: 611.1084.
S59 (4.7 mmol scale of hydrolysis, 1.0209 g, 41% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.4 Hz, 1H), 7.68-7.56 (m, 3H), 7.51-7.42 (m, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.73 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.6, 165.5, 150.6, 143.2, 141.9, 139.3, 133.2, 132.0, 126.6, 122.3, 119.6, 115.8, 112.0, 67.9, 66.7 (t, J=27.5 Hz), 38.5. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3380, 2959, 1730, 1531, 1199. HRMS (ESI) calcd C21H15F5N3O8+ [M+H]+: 532.0774. Found: 532.0773.
S60 (8.3 mmol scale of hydrolysis, 2.8275 g, 65% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.43 (m, 2H), 7.37 (d, J=7.6 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 4.81 (t, J=12.6 Hz, 2H), 3.66 (s, 2H), 3.37 (s, 1H). 13C NMR (100 MHz, CD3CN) δ 168.9, 165.5, 150.6, 143.2, 139.4, 137.2, 132.9, 131.3, 126.6, 122.2, 122.0, 115.7, 83.8, 79.2, 68.0, 66.7 (t, J=27.8 Hz), 38.3. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3298, 2939, 1743, 1534, 1199. HRMS (ESI) calcd C22H16F5N2O8+ [M+H]+: 531.0821. Found: 531.0824.
S61 (5.1 mmol scale of hydrolysis, 1.5484 g, 46% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.88 (d, J=7.6 Hz, 1H), 7.78-7.62 (m, 7H), 7.62-7.54 (m, 3H), 7.52-7.42 (m, 3H), 7.41-7.33 (m, 1H), 7.19 (d, J=6.4 Hz, 2H), 4.80 (t, J=12.2 Hz, 2H), 3.72 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.1, 165.5, 150.6, 143.2, 141.2, 140.9, 140.23, 140.20, 139.5, 135.3, 131.7, 129.9, 128.5, 128.4, 128.2, 127.8, 127.7, 126.7, 122.2, 115.8, 68.1, 66.7 (t, J=27.8 Hz), 38.3. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3385, 2924, 1739, 1530, 1204. HRMS (ESI) calcd C32H24F5N2O8+ [M+H]+: 659.1447. Found: 659.1443.
S62 (5.0 mmol scale of hydrolysis, 1.6554 g, 61% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.55-7.43 (m, 2H), 7.19-7.11 (m, 1H), 6.99 (t, J=8.6 Hz, 1H), 6.89 (s, 1H), 4.81 (t, J=12.2 Hz, 2H), 3.63 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.7, 165.5, 150.7 (ddd, J1=244.1, J2=19.9, J3=12.6 Hz), 150.6, 143.2, 139.3, 133.6 (dd, J1=5.5, J2=4.0 Hz), 127.7 (dd, J1=6.2, J2=3.3 Hz), 126.6, 122.3, 119.0 (dd, J1=156.0, J2=16.6 Hz), 115.8, 68.0, 66.7 (t, J=27.8 Hz), 37.7. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz), −140.1-−140.3 (m), −142.0-−142.2 (m). IR (neat, cm−1) 3381, 2987, 1743, 15225 1204. HRMS (ESI) calcd C20H14F7N2O8+ [M+H]+: 543.0633. Found: 543.0634.
S63 (4.8 mmol scale of hydrolysis, 0.9836 g, 33% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92-7.80 (m, 2H), 7.66 (s, 1H), 7.56 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 4.81 (t, J=12.6 Hz, 2H), 3.83 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.0, 165.5, 150.6, 143.1, 141.2, 139.5, 139.4, 132.0, 130.2, 129.4, 126.5, 122.4, 116.0, 102.5, 67.6, 66.7 (t, J=27.8 Hz), 42.5. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3394, 2926, 1729, 1525, 1193. HRMS (ESI) calcd C20H15F5N2O8+ [M+H]+: 632.9788. Found: 632.9789.
S64 (4.7 mmol scale of hydrolysis, 1.5007 g, 57% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89-7.82 (m, 2H), 7.80-7.72 (m, 2H), 7.59 (d, J=13.2 Hz, 2H), 7.53-7.41 (m, 4H), 7.23 (d, J=8.0 Hz, 1H), 4.72 (t, J=12.2 Hz, 2H), 3.83 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.0, 165.6, 150.6, 143.1, 139.5, 134.3, 133.7, 133.6, 129.9, 129.1, 128.9, 128.53, 128.48, 127.3, 127.0, 126.6, 122.3, 115.7, 68.2, 66.6 (t, J=27.8 Hz), 38.7. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.0 (t, J=12.6 Hz). IR (neat, cm−1) 3411, 3061, 1729, 1512, 1193. HRMS (ESI) calcd C24H18F5N2O8+ [M+H]+: 557.0978. Found: 557.0980.
S65 (4.3 mmol scale of hydrolysis, 0.8075 g, 34% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.82 (d, J=8.4 Hz, 1H), 7.88-7.75 (m, 3H), 7.43-7.30 (m, 6H), 7.25 (d, J=8.0 Hz, 1H), 4.68 (t, J=12.6 Hz, 2H), 4.17 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.2, 166.0, 150.4, 143.0, 139.4, 134.8, 134.0, 132.5, 129.6, 129.5, 129.1, 127.1, 126.6, 126.5, 126.3, 124.8, 122.2, 115.6, 68.3, 66.6 (t, J=27.5 Hz), 34.7. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3385, 2945, 1738, 1526, 1197. HRMS (ESI) calcd C24H18F5N2O8+ [M+H]+: 557.0978. Found: 557.0979.
S66 (5.1 mmol scale of hydrolysis, 1.8568 g, 71% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 7.85 (d, J=4.8 Hz, 1H), 4.82 (t, J=12.4 Hz, 2H), 3.70 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 169.1, 165.5, 150.6, 143.2, 139.4, 135.9, 130.0, 126.9, 126.7, 125.2, 122.2, 115.8, 67.8, 66.7 (t, J=27.8 Hz), 33.3. 19F NMR (376 MHz, CD3CN) δ −84.1 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3385, 3062, 1730, 1527, 1193. HRMS (ESI) calcd C18H14F5N2O8S+ [M+H]+: 513.0386. Found: 513.0387.
S67 (6.8 mmol scale of hydrolysis, 2.2831 g, 68% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.89 (d, J=8.0 Hz, 1H), 7.68-7.57 (m, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 6.31 (s, 1H), 6.13 (d, J=2.0 Hz, 1H), 4.82 (t, J=12.6 Hz, 2H), 3.73 (s, 2H). 13C NMR (100 MHz, CD3CN) δ 168.8, 165.5, 150.65, 150.60, 143.7, 143.1, 139.5, 126.7, 122.2, 115.7, 111.5, 109.9, 66.9, 66.7 (t, J=27.5 Hz), 31.9. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3392, 3075, 1731, 1530, 1194. HRMS (ESI) calcd C18H14F5N2O9+ [M+H]+: 497.0614. Found: 497.0617.
1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 5.19 (t, J=12.6 Hz, 2H), 1.69 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.0 (d, J=57.8 Hz), 163.7, 149.0, 141.4, 138.6, 125.3, 121.7, 115.0, 65.1 (t, J=27.8 Hz), 63.2, 21.0 (d, J=36.9 Hz). 19F NMR (376 MHz, DMSO-d6) δ −82.6 (s), −122.5 (t, J=13.2 Hz). IR (neat, cm−1) 3385, 2977, 1743, 1534, 1199. HRMS (ESI) calcd C1313CH12F5N2O8+ [M+H]+: 432.0542. Found: 432.0546.
15N-68 (1.6 mmol scale of hydrolysis, 0.6461 g, 91% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.92 (d, J=8.4 Hz, 1H), 7.91 (d, J=93.2 Hz, 1H), 7.70 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 4.83 (t, J=12.4 Hz, 2H), 1.79 (s, 3H). 13C NMR (100 MHz, CD3CN) δ 171.0, 165.8 (d, J=15.9 Hz), 150.6, 143.1, 139.1 (d, J=8.6 Hz), 126.6, 122.3, 115.8, 66.7 (t, J=27.8 Hz), 63.5 (d, J=12.3 Hz), 21.7. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). 15N NMR (40 MHz, CD3CN) δ 121.9. IR (neat, cm−1) 3390, 2943, 1739, 1539, 1194. HRMS (ESI) calcd C14H12F5N15NO8+ [M+H]+: 432.0479. Found: 432.0477.
S71 (4.0 mmol scale of hydrolysis, 1.5972 g, 92% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 8.01-7.84 (m, 2H), 7.70 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 4.83 (t, J=12.6 Hz, 2H). 13C NMR (150 MHz, CD3CN) δ 171.0, 165.8, 150.6, 143.1, 139.1, 126.6, 122.3, 119.6 (qt, J1=283.9 Hz, J2=34.6 Hz), 115.8, 113.6 (tq, J1=253.1 Hz, J2=37.8 Hz), 66.7 (t, J=27.5 Hz), 63.4, 20.9 (hept, J=19.7 Hz). 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.4 Hz). IR (neat, cm−1) 3395, 2987, 1734, 1530, 1194. HRMS (ESI) calcd C14H9D3F5N2O8+ [M+H]+: 434.0697. Found: 434.0693.
S73 (10.0 mmol scale of hydrolysis, 2.5373 g, 68% Yield, 4 steps) white solid. Rf=0.7 (DCM/MeOH 5:1). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.2 Hz, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 1H), 7.47-7.34 (m, 2H), 6.41 (d, J=8.0 Hz, 1H), 6.37-6.26 (m, 1H), 5.26 (s, 1H), 4.92 (s, 2H), 4.09-3.94 (m, 1H), 3.92-3.77 (m, 1H), 3.57-3.38 (m, 2H), 3.13 (dd, J1=12.0, J2=3.6 Hz, 1H), 2.28 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 177.4, 153.9, 149.3, 136.4, 135.4, 132.7, 129.8, 128.2, 98.0, 87.1, 86.6, 78.0, 71.0, 63.1, 37.6, 32.2. IR (neat, cm−1) 3417, 3289, 2927, 2248, 1646, 1555, 1250, 1263. HRMS (ESI) calcd C18H18N3O4S+ [M+H]+: 372.1013. Found: 372.1009.
76 (9.3 mmol scale of hydrolysis, 2.9922 g, 94% Yield) was obtained as white solid from the general procedure by using isopropyl alcohol instead of 2,2,3,3,3-pentafluoropropan-1-ol. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 9.38 (br, 2H), 7.98 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.90-4.71 (m, 1H), 1.77 (s, 3H), 1.28 (d, J=6.0 Hz, 6H). 13C NMR (100 MHz, CD3CN) δ 171.2, 167.0, 151.5, 144.1, 138.4, 126.0, 120.0, 116.4, 74.0, 63.6, 22.0, 21.6. IR (neat, cm−1) 3395, 2977, 1734, 1525, 1253. HRMS (ESI) calcd C14H17N2O8+ [M+H]+: 341.0979. Found: 341.0981.
(±)-80 (3.0 mmol scale of hydrolysis, 0.3556 g, 26% Yield) white solid. Rf=0.3 (DCM/MeOH 5:1). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 5.19 (t, J=12.8 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 1.70 (s, 3H), 1.16 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.7, 168.2, 163.9, 148.9, 141.4, 138.4, 125.2, 121.7, 115.0, 65.1 (t, J=27.8 Hz), 63.3, 61.5, 21.1, 13.9. 19F NMR (376 MHz, DMSO-d6) δ −82.6 (s), −122.5 (t, J=12.4 Hz). IR (neat, cm−1) 3400, 2924, 1739, 1539, 1194. HRMS (ESI) calcd C16H16F5N2O8+ [M+H]+: 459.0821. Found: 459.0824.
83 (8.5 mmol scale of hydrolysis, 1.4693 g, 89% Yield) was prepared according to a reported procedure as white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3OD) δ 7.43 (d, J=8.0 Hz, 2H), 7.37-7.23 (m, 3H), 5.08 (br, 2H), 1.83 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 175.3, 140.4, 129.0, 128.6, 128.4, 59.9, 23.0.
84 (2.0 mmol scale of hydrolysis, 0.2127 g, 24% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (500 MHz, DMSO-d6) δ 8.02 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.17 (t, J=13.0 Hz, 2H), 2.88 (s, 3H), 1.71 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 170.0, 169.1, 149.3, 141.7, 140.2, 125.6, 120.9, 114.3, 68.0, 65.0 (t, J=27.6 Hz), 35.1, 20.4. 19F NMR (376 MHz, DMSO-d6) δ −82.6 (s), -122.5 (t, J=13.2 Hz). IR (neat, cm−1) 2929, 1748, 1593, 1530, 1199. HRMS (ESI) calcd C15H14F5N2O8+ [M+H]+: 445.0665. Found: 445.0664.
85 (3.6 mmol scale of hydrolysis, 1.2227 g, 74% Yield) white solid. Rf=0.1 (DCM/MeOH 5:1). 1H NMR (400 MHz, CD3CN) δ 7.93 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.80 (t, J=12.6 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 2.09-1.99 (m, 2H). 13C NMR (100 MHz, CD3CN) δ 171.7, 169.7, 150.7, 142.2, 141.2, 126.9, 121.9, 115.2, 72.5, 66.7 (t, J=27.5 Hz), 52.2, 36.9, 25.6. 19F NMR (376 MHz, CD3CN) δ −84.2 (s), −124.1 (t, J=12.6 Hz). IR (neat, cm−1) 3463, 2977, 1753, 1530, 1442, 1194. HRMS (ESI) calcd C16H14F5N2O8+ [M+H]+: 457.0665. Found: 457.0664.
(+)-17 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S17 (86.1 mg, 0.2 mmol) for 10 h using the general procedure (71.9 mg, 90% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.59 min, tr (major)=11.56 min) gave the isomeric composition of the product: 94% e.e., [□]17 D=+21.7 (c=1.05, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.4 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.49 (dd, J1=8.4, J2=1.6 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 4.86-4.71 (m, 1H), 4.61 (t, J=11.8, 2H), 3.83 (s, 3H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 173.8, 164.2, 149.9, 141.9, 138.6, 125.7, 120.5, 118.3 (qt, J1=284.3 Hz, J2=34.3 Hz), 114.4, 111.8 (tq, J1=254.6 Hz, J2=37.8 Hz), 65.9 (t, J=28.7 Hz), 52.7, 48.8, 17.7. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3373, 2964, 1711, 1529, 1193. HRMS (ESI) calcd C14H14F5N2O6+ [M+H]+: 401.0767. Found: 401.0768.
(−)-17 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S17 (86.2 mg, 0.2 mmol) for 10 h using the general procedure with (S)-CPA-8 as catalyst (73.1 mg, 91% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (major)=8.54 min, tr(minor)=11.80 min) gave the isomeric composition of the product: 93% e.e., [α]D19=−18.7 (c=1.13, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.32 (d, J=6.8 Hz, 1H), 4.85-4.72 (m, 1H), 4.59 (t, J=12.0 Hz, 2H), 3.83 (s, 3H), 1.54 (d, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.0, 164.1, 150.0, 142.0, 138.6, 125.7, 120.5, 114.5, 66.0 (t, J=28.2 Hz), 52.8, 48.8, 17.9. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.3 (t, J=11.8 Hz). IR (neat, cm−1) 3332, 2968, 1739, 1530, 1199. HRMS (ESI) calcd C14H14F5N2O6+ [M+H]+: 401.0767. Found: 401.0766.
HPLC analysis of derivatized (+)-18 shown above (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.17 min, tr (major)=8.01 min) gave the isomeric composition of the product: 97% e.e., [α]D19=+12.9 (amino acid hydrochloride (+)-18, c=1.00, MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (br, 2 H), 3.92 (q, J=7.1 Hz, 1H), 1.40 (d, J=7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 171.6, 47.8, 15.8. IR (neat, cm−1) 3356, 2929, 1734, 1623, 1121. HRMS (ESI) calcd C3H8NO2+ [M+H]+: 90.0550. Found: 90.0551.
(+)-19 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S19 (88.9 mg, 0.2 mmol) for 10 h using the general procedure (71.7 mg, 86% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.02 min, tr (major)=11.44 min) gave the isomeric composition of the product: 93% e.e., [α]D23=+22.4 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=8.4, 1H), 6.96 (d, J=7.2 Hz, 1H), 4.83-4.71 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 2.12-1.97 (m, 1H), 1.93-1.78 (m, 1H), 0.99 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.2, 164.4, 150.1, 142.0, 138.8, 125.8, 120.4, 114.7, 66.1 (t, J=28.6 Hz), 54.1, 52.7, 25.3, 9.7. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3312, 2974, 1737, 1531, 1199. HRMS (ESI) calcd C15H16F5N2O6+[M+H]+: 415.0923. Found: 415.0926.
(+)-20 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S20 (91.8 mg, 0.2 mmol) for 8 h using the general procedure (72.5 mg, 85% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.47 min, tr (major)=11.24 min) gave the isomeric composition of the product: 93% e.e., [α]D19=+20.9 (c=1.04, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.48 (d, J=8.4, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.87-4.74 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 2.03-1.87 (m, 1H), 1.85-1.71 (m, 1H), 1.51-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.4, 164.3, 150.2, 142.1, 138.8, 125.9, 120.4, 114.8, 66.2 (t, J=28.5 Hz), 52.8, 52.7, 34.3, 18.7, 13.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3303, 2968, 1748, 1539, 1194. HRMS (ESI) calcd C16H18F5N2O6+ [M+H]+: 429.1080. Found: 429.1079.
(+)-21 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S21 (94.6 mg, 0.2 mmol) for 8 h using the general procedure (72.8 mg, 82% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.56 min, tr (major)=10.98 min) gave the isomeric composition of the product: 91% e.e., [α]D22=+18.5 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.49 (d, J=8.4, 1H), 6.90 (d, J=7.2 Hz, 1H), 4.84-4.75 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 2.04-1.91 (m, 1H), 1.87-1.74 (m, 1H), 1.45-1.27 (m, 4H), 0.91 (t, J=6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.1, 164.3, 150.3, 142.2, 139.1, 126.0, 120.3, 115.1, 66.3 (t, J=28.6 Hz), 53.0, 52.7, 32.1, 27.4, 22.2, 13.8. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3393, 2959, 1742, 1532, 1195. HRMS (ESI) calcd C17H20F5N2O6+ [M+H]+: 443.1236. Found: 443.1234.
(+)-22 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S22 (158.5 mg, 0.3 mmol) for 8 h using the general procedure (120.3 mg, 80% Yield). Rf=0.6 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.10 min, tr (major)=8.92 min) gave the isomeric composition of the product: 92% e.e., [α]D22=+19.6 (c=0.92, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.85-4.75 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 2.03-1.92 (m, 1H), 1.85-1.75 (m, 1H), 1.42-1.21 (m, 12H), 0.87 (t, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.6, 164.3, 150.1, 142.1, 138.7, 125.8, 120.4, 114.7, 66.1 (t, J=28.2 Hz), 53.0, 52.7, 32.1, 31.7, 29.3, 29.11, 29.09, 25.4, 22.6, 14.0. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=12.6 Hz). IR (neat, cm−1) 3260, 2928, 1744, 1533, 1196. HRMS (ESI) calcd C21H28F5N2O6+ [M+H]+: 499.1862. Found: 499.1860.
(+)-23 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S23 (94.0 mg, 0.2 mmol) for 14 h using the general procedure (75.9 mg, 86% Yield). Rf=0.6 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.94 min, tr (major)=13.33 min) gave the isomeric composition of the product: 91% e.e., [α]D20=+27.4 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 4.95-4.81 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 1.96-1.74 (m, 2H), 0.80-0.66 (m, 1H), 0.60-0.44 (m, 2H), 0.18-0.06 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 173.0, 164.1, 150.2, 142.1, 139.0, 125.9, 120.3, 114.9, 66.2 (t, J=28.5 Hz), 53.4, 52.6, 36.8, 6.9, 4.2, 4.1. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3233, 3050, 1750, 1538, 1197. HRMS (ESI) calcd C17H18F5N2O6+[M+H]+: 441.1080. Found: 441.1081.
(+)-24 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S24 (91.6 mg, 0.2 mmol) for 8 h using the general procedure (74.8 mg, 87% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.57 min, tr (major)=11.69 min) gave the isomeric composition of the product: 84% e.e., [α]D19=+21.4 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.82-4.71 (m, 1H), 4.62 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 2.38-2.23 (m, 1H), 1.02 (d, J=7.2 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 172.4, 164.6, 150.3, 142.2, 139.3, 126.0, 120.2, 115.2, 66.3 (t, J=28.0 Hz), 57.9, 52.5, 31.5, 18.9, 17.9. 19F NMR (471 MHz, CDCl3) δ −83.3 (s), -123.2 (t, J=11.3 Hz). IR (neat, cm−1) 3369, 2968, 1743, 1530, 1199. HRMS (ESI) calcd C16H18F5N2O6+ [M+H]+: 429.1080. Found: 429.1078.
(+)-25 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S25 (91.5 mg, 0.2 mmol) for 6 h using the general procedure (71.5 mg, 84% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.41 min, tr (major)=14.32 min) gave the isomeric composition of the product: 92% e.e., [α]D22=+23.5 (c=1.05, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.4 Hz, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.46 (dd, J1=8.2, J2=1.4 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 5.84-5.63 (m, 1H), 5.25-5.10 (m, 2H), 4.94-4.78 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 2.83-2.55 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.0, 164.2, 150.3, 142.2, 139.1, 131.8, 126.0, 120.3, 119.8, 115.1, 66.3 (t, J=28.2 Hz), 52.7, 52.3, 36.3. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3228, 2961, 1748, 1641, 1534, 1195. HRMS (ESI) calcd C16H16F5N2O6+ [M+H]+: 427.0923. Found: 427.0921.
(+)-26 was obtained as yellow oil from the asymmetric decarboxylation reaction of malonic acid S26 (106.7 mg, 0.2 mmol) for 10 h using the general procedure (90.9 mg, 90% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=16.08 min, tr (major)=16.67 min) gave the isomeric composition of the product: 93% e.e., [□]21 D=+44.0 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.36-7.28 (m, 4H), 7.27-7.22 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.48 (d, J=16.0 Hz, 1H), 6.17-6.01 (m, 1H), 5.01-4.87 (m, 1H), 4.51 (t, J=11.8 Hz, 2H), 3.84 (s, 3H), 2.97-2.86 (m, 1H), 2.84-2.74 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 172.1, 164.4, 150.2, 142.1, 139.1, 136.5, 134.6, 128.6, 127.9, 126.2, 126.0, 123.0, 120.3, 114.8, 66.1 (t, J=28.6 Hz), 52.8, 52.6, 35.7. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3225, 2961, 1750, 1642, 1538, 1197. HRMS (ESI) calcd C22H20F5N2O6+ [M+H]+: 503.1236. Found: 503.1235.
(+)-27 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S27 (107.2 mg, 0.2 mmol) for 15 h using the general procedure (83.7 mg, 83% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=9.89 min, tr (major)=17.82 min) gave the isomeric composition of the product: 93% e.e., [α]D19=+37.7 (c=1.02, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=8.5 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.50 (dd, J1=8.5, J2=1.5 Hz, 1H), 6.96 (d, J=7.0 Hz, 1H), 5.69 (s, 1H), 5.59 (d, J=1.5 Hz, 1H), 5.06-5.92 (m, 1H), 4.61 (t, J=12.0 Hz, 2H), 3.84 (s, 3H), 3.20 (dd, J1=14.5, J2=5.0 Hz, 1H), 3.08 (dd, J1=14.8, J2=6.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 171.5, 164.4, 150.2, 142.2, 138.6, 127.2, 125.9, 121.3, 120.4, 114.9, 66.2 (t, J=28.4 Hz), 52.9, 51.8, 42.8. 19F NMR (471 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=12.0 Hz). IR (neat, cm−1) 3240, 3065, 1753, 1540, 1194. HRMS (ESI) calcd C16H15F5N2O679Br+ [M+H]+: 505.0028. Found: 505.0027.
(+)-28 was obtained as yellow oil from the asymmetric decarboxylation reaction of malonic acid S28 (96.9 mg, 0.2 mmol) for 10 h using the general procedure (80.3 mg, 88% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=7.88 min, tr (major)=12.60 min) gave the isomeric composition of the product: 91% e.e., [α]D21=+37.1 (c=1.02, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J=6.5 Hz, 1H), 6.80 (d, J=7.0 Hz, 1H), 5.06 (t, J=7.5 Hz, 1H), 4.87-4.76 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 2.78-2.67 (m, 1H), 2.64-2.54 (m, 1H), 1.72 (s, 3H), 1.62 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 172.3, 164.2, 150.4, 142.2, 139.3, 137.2, 126.1, 120.2, 116.9, 115.2, 66.3 (t, J=27.9 Hz), 52.8, 52.7, 30.5, 25.8, 17.9. 19F NMR (471 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=12.0 Hz). IR (neat, cm−1) 3251, 3051, 1748, 1647, 1534, 1194. HRMS (ESI) calcd C18H20F5N2O6+ [M+H]+: 455.1236. Found: 455.1237.
(+)-29 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S29 (91.2 mg, 0.2 mmol) for 6 h using the general procedure (72.4 mg, 85% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=12.33 min, tr (major)=24.54 min) gave the isomeric composition of the product: 92% e.e., [α]D22=+64.7 (c=1.09, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 4.98-4.86 (m, 1H), 4.62 (t, J=11.8 Hz, 2H), 3.87 (s, 3H), 3.04-2.81 (m, 2H), 2.09 (t, J=2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 170.6, 164.4, 150.3, 142.3, 138.8, 126.0, 120.5, 115.2, 77.9, 72.1, 66.2 (t, J=28.5 Hz), 53.1, 51.3, 22.2. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3306, 2973, 1732, 1524, 1198. HRMS (ESI) calcd C16H14F5N2O6+ [M+H]+: 425.0767. Found: 425.0771.
(+)-30 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S30 (106.3 mg, 0.2 mmol) for 5 h using the general procedure (88.5 mg, 88% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (major)=12.71 min, tr (minor)=14.87 min) gave the isomeric composition of the product: 90% e.e., [α]D19=+108.4 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.40-7.25 (m, 5H), 7.11 (d, J=7.2 Hz, 1H), 5.05-4.92 (m, 1H), 4.57 (t, J=11.8 Hz, 2H), 3.88 (s, 3H), 3.25-3.03 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 170.7, 164.3, 150.3, 142.3, 139.1, 131.6, 128.5, 128.4, 126.1, 122.5, 120.5, 115.2, 84.2, 83.0, 66.3 (t, J=28.2 Hz), 53.1, 51.6, 23.4. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3313, 2953, 1753, 1534, 1199. HRMS (ESI) calcd C22H18F5N2O6+ [M+H]+: 501.1080. Found: 501.1076.
(+)-31 was obtained as yellow oil from the asymmetric decarboxylation reaction of malonic acid S31 (110.4 mg, 0.2 mmol) for 8 h using the general procedure (66.5 mg, 64% Yield). Rf=0.6 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=6.62 min, tr (major)=10.41 min) gave the isomeric composition of the product: 88% e.e., [α]D20=+40.0 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.15-4.96 (m, 2H), 4.89-4.78 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 2.81-2.68 (m, 1H), 2.66-2.55 (m, 1H), 2.12-1.95 (m, 4H), 1.65 (s, 3H), 1.62 (s, 3H), 1.58 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.4, 164.1, 150.3, 142.1, 140.6, 139.1, 131.8, 126.0, 123.6, 120.2, 117.0, 115.0, 66.2 (t, J=28.2 Hz), 52.8, 52.6, 39.7, 30.3, 26.4, 25.6, 17.6, 16.1. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3224, 2961, 1750, 1643, 1538, 1196. HRMS (ESI) calcd C23H28F5N2O6+ [M+H]+: 523.1862. Found: 523.1859.
(+)-32 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S32 (111.2 mg, 0.2 mmol) for 12 h using the general procedure (85.7 mg, 81% Yield). Rf=0.6 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=9.12 min, tr (major)=19.17 min) gave the isomeric composition of the product: 93% e.e., [α]D16=+44.2 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.35-7.27 (m, 5H), 7.10 (d, J=7.2 Hz, 1H), 5.59 (s, 1H), 5.40 (s, 1H), 5.09-4.98 (m, 1H), 4.46 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.01 (dd, J1=14.0, J2=4.8 Hz, 1H), 2.89 (dd, J1=14.0, J2=5.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.5, 164.2, 150.1, 142.1, 138.9, 131.4, 128.8, 128.4, 125.8, 125.73, 125.67, 122.2, 120.3, 114.8, 90.7, 88.8, 66.0 (t, J=28.6 Hz), 52.8, 52.6, 38.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3230, 3056, 2960, 2150, 1746, 1531, 1199. HRMS (ESI) calcd C24H20F5N2O6+ [M+H]+: 527.1236. Found: 527.1238.
(+)-33 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S33 (107.0 mg, 0.2 mmol) for 8 h using the general procedure (91.4 mg, 91% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=11.72 min, tr (major)=13.77 min) gave the isomeric composition of the product: 92% e.e., [α]D18=+25.2 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 2H), 7.24-7.06 (m, 3H), 6.80 (d, J=7.6 Hz, 1H), 4.90-4.75 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.79 (s, 3H), 2.76-2.56 (m, 2H), 2.08-1.93 (m, 1H), 1.90-1.64 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 173.2, 164.3, 150.1, 142.1, 141.3, 138.7, 128.4, 128.3, 126.1, 125.8, 120.4, 114.8, 66.1 (t, J=28.6 Hz), 52.8, 52.7, 35.2, 31.7, 27.2. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3338, 2956, 1741, 1531, 1194. HRMS (ESI) calcd C22H22F5N2O6+ [M+H]+: 505.1393. Found: 505.1394.
(+)-34 was obtained as yellow oil from the asymmetric decarboxylation reaction of malonic acid S34 (114.2 mg, 0.2 mmol) for 12 h using the general procedure (89.7 mg, 83% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=14.09 min, tr (major)=18.80 min) gave the isomeric composition of the product: 90% e.e., [α]D19=+15.9 (c=1.05, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 2H), 7.14-7.06 (m, 1H), 6.86 (s, 1H), 6.85-6.71 (m, 2H), 4.95-4.78 (m, 1H), 4.49 (t, J=12.0 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 2.99-2.80 (m, 2H), 2.49-2.38 (m, 1H), 2.32-2.21 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 172.8, 164.0, 150.0, 141.9, 138.7, 137.2, 127.2, 126.8, 125.6, 121.9, 119.9, 119.1, 118.8, 114.6, 112.9, 109.4, 66.1 (t, J=28.6 Hz), 53.3, 52.6, 32.5, 31.8, 21.5. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3342, 2963, 1748, 1530, 1199. HRMS (ESI) calcd C24H23F5N3O6+ [M+H]+: 544.1502. Found: 544.1500.
(+)-35 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S35 (117.8 mg, 0.2 mmol) for 12 h using the general procedure (87.5 mg, 78% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak ID-3, hexane/iPrOH=70/30, 0.8 mL/min, 230 nm; tr (minor)=49.50 min, tr (major)=136.27 min) gave the isomeric composition of the product: 72% e.e., (57% Yield, 99% e.e., single recrystallized from DCM/hexane, Chiralpak IB-3, hexane/PrOH=70/30, 0.8 mL/min, 254 nm; tr (major)=28.09 min, tr (minor)=32.20 min), [α]D19=+124.8 (c=0.97, CHCl3 (99% e.e.)). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.4 Hz, 1H), 7.91-7.81 (m, 3H), 7.81-7.68 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 4.99-4.89 (m, 1H), 4.75 (t, J=12.2 Hz, 2H), 3.97-3.76 (m, 2H), 3.49 (s, 3H), 2.64-2.48 (m, 1H), 2.40-2.31 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 171.8, 168.6, 164.3, 150.2, 142.0, 138.9, 134.5, 131.7, 126.2, 123.4, 121.2, 114.4, 66.1 (t, J=28.2 Hz), 52.6, 50.1, 33.5, 29.2. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3245, 3065, 1714, 1534, 1204. HRMS (ESI) calcd C23H19F5N3O8+ [M+H]+: 560.1087. Found: 560.1083.
(+)-36 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S36 (96.7 mg, 0.2 mmol) for 18 h using the general procedure (77.9 mg, 86% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak ID-3, hexane/iPrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=12.48 min, tr (major)=21.42 min) gave the isomeric composition of the product: 91% e.e., [α]D19=+23.0 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 4.89-4.76 (m, 1H), 4.62 (t, J=11.8 Hz, 2H), 3.84 (s, 3H), 2.46 (t, J=7.0 Hz, 2H), 2.24-2.10 (m, 1H), 2.02-1.90 (m, 1H), 1.88-1.75 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.4, 164.6, 150.1, 142.2, 138.5, 125.9, 120.5, 119.1, 114.8, 66.1 (t, J=28.2 Hz), 53.0, 52.2, 31.2, 21.7, 16.8. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3337, 2958, 2180, 1743, 1530, 1199. HRMS (ESI) calcd C17H17F5N3O6+ [M+H]+: 454.1032. Found: 454.1036.
(+)-37 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S37 (103.5 mg, 0.2 mmol) for 18 h using the general procedure (85.9 mg, 88% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=25.48 min, tr (major)=33.43 min) gave the isomeric composition of the product: 90% e.e., [α]D18=+8.2 (c=1.03, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.61-7.47 (m, 2H), 4.98-4.89 (m, 1H), 4.80-4.69 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 4.05-3.75 (m, 7H), 2.17-1.80 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 172.6, 164.5, 150.2, 142.1, 139.0, 125.9, 120.4, 115.0, 103.3, 66.2 (t, J=28.6 Hz), 65.0, 52.8, 52.6, 29.0, 25.1. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3314, 2968, 1743, 1534, 1194. HRMS (ESI) calcd C18H20F5N2O8+ [M+H]+: 487.1134. Found: 487.1132.
(+)-38 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S38 (99.9 mg, 0.2 mmol) for 12 h using the general procedure (84.3 mg, 90% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=14.33 min, tr (major)=16.43 min) gave the isomeric composition of the product: 92% e.e., [α]D19=+19.1 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 4.90-4.76 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.84 (s, 3H), 3.45-3.28 (m, 2H), 2.16-2.03 (m, 1H), 1.97-1.84 (m, 1H), 1.77-1.66 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.8, 164.5, 150.1, 142.1, 138.6, 125.9, 120.4, 114.8, 66.1 (t, J=28.2 Hz), 52.9, 52.5, 50.6, 29.4, 24.9. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=12.6 Hz). IR (neat, cm−1) 3245, 2968, 2103, 1739, 1534, 1194. HRMS (ESI) calcd C16H17F5N6O6+ [M+H]+: 470.1094. Found: 470.1093.
(+)-39 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S39 (167.0 mg, 0.2 mmol) for 15 h using the general procedure (137.0 mg, 86% Yield). >20:1 d.r., as determined by 1H NMR analysis of crude product with CH2Br2 (14 μL) as the internal standard. Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak ID-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=11.35 min, tr (major)=18.56 min) gave the isomeric composition of the product: 91% e.e., [α]D19=+33.6 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 4.82-4.71 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 3.39-3.28 (m, 4H), 3.24 (s, 3H), 3.20 (s, 3H), 3.14 (s, 1H), 3.05-2.93 (m, 1H), 2.24-1.64 (m, 13H), 1.63-1.56 (m, 1H), 1.55-1.38 (m, 4H), 1.32-0.96 (m, 8H), 0.92-0.84 (m, 6H), 0.64 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.6, 164.3, 150.1, 142.1, 138.8, 125.8, 120.4, 114.8, 82.0, 80.7, 76.9, 66.1 (t, J=28.3 Hz), 55.8, 55.6, 55.3, 53.2, 52.6, 46.4, 46.0, 42.7, 41.9, 39.5, 35.4, 35.3, 35.2, 34.8, 34.4, 32.6, 27.9, 27.7, 27.5, 26.7, 23.1, 22.8, 22.0, 21.9, 17.6, 12.4. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 2939, 2866, 1739, 1539, 1194, 1102. HRMS (ESI) calcd C40H58F5N2O9+ [M+H]+: 805.4057. Found: 805.4055.
(+)-40 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S40 (148.0 mg, 0.2 mmol) for 15 h using the general procedure (120.4 mg, 85% Yield). >20:1 d.r., as determined by 1H NMR analysis of crude product with CH2Br2 (14 μL) as the internal standard. Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=29.47 min, tr (major)=37.40 min) gave the isomeric composition of the product: 94% e.e., [α]D18=+72.1 (c=1.08, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.24-7.10 (m, 2H), 6.67 (d, J=8.8 Hz, 1H), 6.60 (s, 1H), 4.89-4.76 (m, 1H), 4.58 (t, J=11.8 Hz, 2H), 3.94 (t, J=5.8 Hz, 2H), 3.81 (s, 3H), 2.94-2.79 (m, 2H), 2.55-2.45 (m, 1H), 2.43-2.33 (m, 1H), 2.28-1.78 (m, 10H), 1.67-1.42 (m, 7H), 0.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 221.0, 173.1, 164.4, 156.8, 150.1, 142.0, 138.8, 137.8, 132.1, 126.3, 125.8, 120.5, 114.8, 114.4, 111.9, 67.2, 66.1 (t, J=28.3 Hz), 52.9, 52.7, 50.3, 47.9, 43.9, 38.3, 35.8, 31.7, 31.5, 29.6, 28.6, 26.4, 25.8, 22.2, 21.5, 13.7. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3351, 2943, 1729, 1534, 1194. HRMS (ESI) calcd C35H40F5N2O8+ [M+H]+: 711.2699. Found: 711.2700.
(+)-41 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S41 (118.9 mg, 0.2 mmol) for 5 h using the general procedure (104.4 mg, 92% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=16.08 min, tr (major)=22.40 min) gave the isomeric composition of the product: 91% e.e., [α]D19=+14.7 (c=1.05, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.78-7.63 (m, 2H), 7.55 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 6.81 (d, J=8.0 Hz, 2H), 4.77-4.67 (m, 1H), 4.54 (t, J=11.8 Hz, 2H), 4.47 (d, J=11.0 Hz, 1H), 4.40 (d, J=11.5 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.56 (t, J=5.3 Hz, 2H), 2.06 (q, J=6.5 Hz, 2H), 1.80-1.68 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 172.6, 164.6, 159.4, 150.0, 141.8, 139.0, 129.6, 129.5, 125.8, 120.4, 114.9, 113.8, 73.0, 69.7, 66.1 (t, J=28.4 Hz), 55.2, 52.8, 52.5, 28.9, 25.2. 19F NMR (471 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=12.0 Hz). IR (neat, cm−1) 3356, 2929, 1661, 1632, 1277. HRMS (ESI) calcd C24H26F5N2O8+ [M+H]+: 565.1604. Found: 565.1606.
HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr(minor)=12.82 min, tr (major)=22.73 min) gave the isomeric composition of the product: 91% e.e., [α]D24=+9.6 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=6.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 4.76-4.67 (m, 1H), 4.62 (t, J=12.0 Hz, 2H), 3.88-3.60 (m, 5H), 2.87 (br, 1H), 2.12-1.94 (m, 2H), 1.77-1.59 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.8, 164.8, 150.0, 141.8, 138.9, 125.8, 120.6, 114.7, 66.0 (t, J=28.6 Hz), 61.9, 52.8, 52.6, 28.7, 27.9. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.3 (t, J=12.6 Hz). IR (neat, cm−1) 3308, 2943, 1743, 1539, 1194. HRMS (ESI) calcd C16H18F5N2O7+ [M+H]+: 445.1029. Found: 445.1031.
HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr(minor)=13.92 min, tr (major)=15.77 min) gave the isomeric composition of the product: 91% e.e., [α]D22=+10.1 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.87-4.76 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.84 (s, 3H), 3.30-3.15 (m, 2H), 2.20-2.05 (m, 1H), 2.03-1.84 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 172.6, 164.4, 150.2, 142.2, 138.7, 126.0, 120.3, 115.0, 66.2 (t, J=28.2 Hz), 52.9, 52.1, 33.2, 29.2, 5.1. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3393, 2958, 1748, 1530, 1199. HRMS (ESI) calcd C16H17F5N2O6I+ [M+H]+: 555.0046. Found: 555.0048.
HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr(major)=14.90 min, tr (minor)=17.46 min) gave the isomeric composition of the product: 91% e.e., [α]D19=−41.1 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.98-7.84 (m, 1H), 7.42-7.29 and 7.21-7.13 (m, 2H), 4.73-4.48 (m, 3H), 3.80 (s, 3H), 3.68-3.58 (m, 1H), 3.55-3.40 (m, 1H), 2.44-2.24 (m, 1H), 2.15-1.89 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 172.1, 166.6, 150.2, 141.8, 141.1, 126.0, 125.9, 121.2, 120.6, 115.0, 114.7, 66.4 (t, J=28.6 Hz), 61.1, 59.2, 52.5, 52.4, 49.8, 46.7, 31.3, 29.2, 25.2, 22.4. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 2958, 1743, 1632, 1531, 1437, 1194. HRMS (ESI) calcd C16H16F5N2O6+ [M+H]+: 427.0923. Found: 427.0926.
(+)-45 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S45 (101.3 mg, 0.2 mmol) for 8 h using the general procedure (83.4 mg, 87% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=12.37 min, tr (major)=20.38 min) gave the isomeric composition of the product: 92% e.e., [α]D21=+65.5 (c=0.96, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.37-7.26 (m, 4H), 7.12 (d, J=7.6 Hz, 2H), 6.69 (d, J=7.6 Hz, 1H), 5.13-5.00 (m, 1H), 4.58 (t, J=12.0 Hz, 2H), 3.82 (s, 3H), 3.32 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.23 (dd, J1=13.8, J2=5.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.8, 164.1, 150.3, 142.2, 139.1, 135.4, 129.2, 128.8, 127.5, 126.1, 120.3, 115.0, 66.3 (t, J=28.2 Hz), 53.7, 52.7, 37.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3230, 2973, 1748, 1535, 1195. HRMS (ESI) calcd C20H18F5N2O6+ [M+H]+: 477.1080. Found: 477.1082.
(+)-46 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S46 (104.7 mg, 0.2 mmol) for 8 h using the general procedure (88.9 mg, 90% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=19.09 min, tr (major)=23.31 min) gave the isomeric composition of the product: 92% e.e., [α]D23=+60.1 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.15-7.05 (m, 2H), 7.04-6.95 (m, 2H), 6.86 (d, J=6.4 Hz, 1H), 5.11-4.95 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.29 (dd, J1=14.2, J2=5.8 Hz, 1H), 3.18 (dd, J1=14.0, J2=6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.8, 164.2, 162.1 (d, J=244.9 Hz), 150.2, 142.2, 138.8, 131.2 (d, J=3.6 Hz), 130.7 (d, J=8.0 Hz), 126.0, 120.2, 115.6 (d, J=21.7 Hz), 115.0, 66.2 (t, J=28.5 Hz), 53.9, 52.7, 36.8. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −114.9-−114.0 (m), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3227, 2963, 1748, 1536, 1194. HRMS (ESI) calcd C20H17F6N2O6+ [M+H]+: 495.0985. Found: 495.0988.
(+)-47 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S47 (108.0 mg, 0.2 mmol) for 8 h using the general procedure (90.1 mg, 88% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=70/30, 0.8 mL/min, 254 nm; tr (major)=15.82 min, tr (minor)=20.62 min) gave the isomeric composition of the product: 91% e.e., [α]D23=+66.8 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.86 (d, J=6.8 Hz, 1H), 5.10-4.97 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.29 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.18 (dd, J1=14.0, J2=6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.1, 164.1, 150.2, 142.2, 138.8, 134.0, 133.4, 130.5, 128.9, 126.0, 120.2, 115.0, 66.2 (t, J=28.6 Hz), 53.7, 52.8, 37.0. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=12.4 Hz). IR (neat, cm−1) 3226, 2963, 1748, 1536, 1195. HRMS (ESI) calcd C20H17F5N2O635Cl+ [M+H]+: 511.0690. Found: 511.0688.
(+)-48 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S48 (117.1 mg, 0.2 mmol) for 8 h using the general procedure (104.2 mg, 94% Yield). Rf=0.3 (Hexane/EtOAc 4:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.8 mL/min, 254 nm; tr (major)=16.95 min, tr (minor)=24.54 min) gave the isomeric composition of the product: 93% e.e., [α]D23=+65.1 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.87 (d, J=7.6 Hz, 1H), 5.12-4.95 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.28 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.16 (dd, J1=14.0, J2=6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.7, 164.2, 150.2, 142.2, 138.7, 134.5, 131.8, 130.8, 126.0, 121.4, 120.2, 114.9, 66.2 (t, J=28.5 Hz), 53.7, 52.8, 37.0. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=12.6 Hz). IR (neat, cm−1) 3222, 2964, 1750, 1538, 1195. HRMS (ESI) calcd C20H17F5N2O679Br+ [M+H]+: 555.0185. Found: 555.0181.
(+)-49 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S49 (107.3 mg, 0.2 mmol) for 12 h using the general procedure (92.9 mg, 92% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=19.69 min, tr (major)=26.99 min) gave the isomeric composition of the product: 92% e.e., [α]D23=+73.3 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.35 (dd, J1=8.4, J2=1.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.88 (d, J=6.8 Hz, 1H), 5.07-4.97 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.25 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.17 (dd, J1=14.0, J2=5.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 172.0, 164.1, 158.9, 150.2, 142.1, 139.0, 130.2, 127.2, 126.0, 120.3, 114.9, 114.1, 66.2 (t, J=28.2 Hz), 55.2, 53.9, 52.7, 36.7. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3222, 3049, 1751, 1539, 1197. HRMS (ESI) calcd C21H20F5N2O7+ [M+H]+: 507.1185. Found: 507.1182.
(+)-50 was obtained as colorless oil from the asymmetric decarboxylation reaction of malonic acid S50 (122.7 mg, 0.2 mmol) for 14 h using the general procedure (102.5 mg, 88% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=24.25 min, tr (major)=38.49 min) gave the isomeric composition of the product: 94% e.e., [α]D19=+48.8 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.50-7.27 (m, 6H), 7.02 (d, J=8.0 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.62 (d, J=6.8 Hz, 1H), 5.16-4.91 (m, 3H), 4.59 (t, J=11.6 Hz, 2H), 3.81 (s, 3H), 3.31-3.12 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.0, 164.1, 158.1, 150.2, 142.1, 138.9, 136.7, 130.2, 128.6, 128.0, 127.6, 127.4, 125.9, 120.2, 115.1, 114.9, 69.9, 66.1 (t, J=28.2 Hz), 53.9, 52.7, 36.7. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3230, 3060, 1748, 1539, 1199. HRMS (ESI) calcd C27H24F5N2O7+ [M+H]+: 583.1498. Found: 583.1497.
(+)-51 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S51 (112.8 mg, 0.2 mmol) for 20 h using the general procedure with 1,4-dioxane as solvent (94.3 mg, 88% Yield). Rf=0.4 (Hexane/EtOAc 1:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.9 mL/min, 254 nm; tr (minor)=17.07 min, tr(major)=21.99 min) gave the isomeric composition of the product: 90% e.e., [α]D19=+64.7 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.05 (d, J=8.0 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 5.11-4.94 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.28 (dd, J1=13.8, J2=5.4 Hz, 1H), 3.18 (dd, J1=14.2, J2=5.4 Hz, 1H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.7, 168.5, 164.3, 150.2, 142.1, 139.0, 137.1, 131.4, 129.7, 126.0, 120.3, 120.2, 114.9, 66.2 (t, J=28.2 Hz), 53.8, 52.7, 37.0, 24.4. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3264, 3065, 1743, 1530, 1194. HRMS (ESI) calcd C22H21F5N3O7+ [M+H]+: 534.1294. Found: 534.1296.
(+)-52 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S52 (110.1 mg, 0.2 mmol) for 12 h using the general procedure (94.9 mg, 91% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.9 mL/min, 254 nm; tr (major)=18.83 min, tr (minor)=51.69 min) gave the isomeric composition of the product: 95% e.e., [α]D20=+65.6 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 6.80 (d, J=6.8 Hz, 1H), 5.16-5.04 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.83 (s, 3H), 3.45 (dd, J1=14.0, J2=6.0 Hz, 1H), 3.32 (dd, J1=13.6, J2=5.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.3, 164.2, 150.4, 147.3, 143.4, 142.4, 138.5, 130.1, 126.1, 123.8, 120.2, 115.2, 66.3 (t, J=28.6 Hz), 53.6, 53.0, 37.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3225, 2962, 1751, 1539, 1197. HRMS (ESI) calcd C20H17F5N3O8+ [M+H]+: 522.0930. Found: 522.0932.
(+)-53 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S53 (116.7 mg, 0.2 mmol) for 15 h using the general procedure (102.9 mg, 93% Yield). Rf=0.2 (Hexane/EtOAc 1:1). HPLC analysis (Chiralpak IC-3, hexane/iPrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=57.51 min, tr (major)=63.89 min) gave the isomeric composition of the product: 90% e.e., [α]D18=+53.8 (c=1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.92-7.76 (m, 3H), 7.59 (s, 1H), 7.44-7.32 (m, 3H), 7.03 (d, J=7.5 Hz, 1H), 5.14-5.03 (m, 1H), 4.61 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.43 (dd, J1=14.0, J2=5.5 Hz, 1H), 3.30 (dd, J1=14.0, J2=6.5 Hz, 1H), 3.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.3, 164.4, 150.2, 142.4, 142.2, 139.4, 138.6, 130.2, 127.6, 126.0, 120.3, 115.0, 66.2 (t, J=28.6 Hz), 53.6, 52.9, 44.3, 37.4. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3351, 2962, 1748, 1530, 1151. HRMS (ESI) calcd C21H20F5N2O8+ [M+H]+: 555.0855. Found: 555.0857.
(+)-54 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S54 (115.0 mg, 0.2 mmol) for 10 h using the general procedure (96.4 mg, 88% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (major)=24.44 min, tr (minor)=32.15 min) gave the isomeric composition of the product: 92% e.e., [α]D23=+57.6 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.85 (d, J=7.2 Hz, 1H), 5.17-5.01 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 3.39 (dd, J1=13.6, J2=5.6 Hz, 1H), 3.27 (dd, J1=13.8, J2=5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.5, 164.2, 150.3, 142.3, 139.7, 138.7, 129.7 (q, J=32.3 Hz), 129.6, 126.1, 125.6 (q, J=3.6 Hz), 124.0 (q, J=270.4 Hz), 120.2, 115.0, 66.3 (t, J=28.6 Hz), 53.6, 52.9, 37.4. 19F NMR (376 MHz, CDCl3) δ −62.6 (s), −83.4 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3223, 3049, 1751, 1539, 1197. HRMS (ESI) calcd C21H17F8N2O6+ [M+H]+: 545.0953. Found: 545.0956.
(+)-55 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S55 (109.7 mg, 0.2 mmol) for 15 h using the general procedure (92.9 mg, 90% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (major)=36.17 min, tr (minor)=57.45 min) gave the isomeric composition of the product: 95% e.e., [α]D19=+74.7 (c=1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.06 (d, J=7.6 Hz, 1H), 5.14-5.02 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 3.39 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.26 (dd, J1=14.0, J2=6.4 Hz, 1H), 2.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.7, 171.6, 164.2, 150.2, 142.1, 141.2, 138.7, 136.2, 129.4, 128.7, 125.9, 120.3, 115.0, 66.2 (t, J=28.5 Hz), 53.7, 52.8, 37.6, 26.5. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.7 Hz). IR (neat, cm−1) 3240, 3060, 1753, 1534, 1194. HRMS (ESI) calcd C22H20F5N2O7+ [M+H]+: 519.1185. Found: 519.1186.
(+)-56 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S56 (116.4 mg, 0.2 mmol) for 12 h using the general procedure (99.7 mg, 90% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=11.38 min, tr (major)=16.59 min) gave the isomeric composition of the product: 94% e.e., [α]D23=+81.9 (c=1.03, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.63-7.50 (m, 5H), 7.44 (t, J=7.4 Hz, 2H), 7.40-7.32 (m, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.71 (d, J=7.2 Hz, 1H), 5.16-5.04 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.84 (s, 3H), 3.36 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.28 (dd, J1=14.0, J2=5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.9, 164.2, 150.2, 142.2, 140.30, 140.26, 138.9, 134.4, 129.6, 128.8, 127.5, 127.4, 126.9, 126.0, 120.3, 115.0, 66.2 (t, J=28.2 Hz), 53.8, 52.7, 37.2. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3222, 2962, 1751, 1539, 1197. HRMS (ESI) calcd C26H22F5N2O6+ [M+H]+: 553.1393. Found: 553.1390.
(+)-57 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S57 (109.7 mg, 0.2 mmol) for 18 h using the general procedure (95.7 mg, 92% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak ID-3, hexane/iPrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=9.16 min, tr (major)=10.78 min) gave the isomeric composition of the product: 94% e.e., [α]D19=+82.2 (c=1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.12 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H), 6.88 (d, J=7.2 Hz, 1H), 5.12-4.96 (m, 1H), 4.59 (t, J=12.0 Hz, 2H), 3.82 (s, 3H), 3.30 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.18 (dd, J1=14.0, J2=6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.8, 164.1, 150.2, 142.2, 139.3, 138.8, 132.1, 130.5, 126.0, 120.2, 119.3, 115.0, 66.2 (t, J=28.2 Hz), 53.9, 52.7, 37.0. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3235, 3035, 2122, 1748, 1534, 1199. HRMS (ESI) calcd C20H17F5N5O6+ [M+H]+: 518.1094. Found: 518.1093.
(+)-58 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S58 (122.3 mg, 0.2 mmol) for 12 h using the general procedure (107.4 mg, 92% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=16.01 min, tr (major)=28.66 min) gave the isomeric composition of the product: 93% e.e., [α]D23=+61.3 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89-7.81 (m, 1H), 7.81-7.66 (m, 4H), 7.65-7.53 (m, 2H), 7.47 (t, J=7.4 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.04-6.87 (m, 1H), 5.19-5.02 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 3.42 (dd, J1=13.6, J2=5.6 Hz, 1H), 3.30 (dd, J1=13.8, J2=5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.3, 171.6, 164.2, 150.2, 142.2, 140.5, 138.7, 137.3, 136.6, 132.6, 130.5, 129.9, 129.2, 128.3, 126.0, 120.2, 115.0, 66.2 (t, J=28.5 Hz), 53.7, 52.8, 37.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3223, 3049, 1750, 1539, 1197. HRMS (ESI) calcd C27H22F5N2O7+ [M+H]+: 581.1342. Found: 581.1343.
(+)-59 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S59 (106.2 mg, 0.2 mmol) for 12 h using the general procedure (82.5 mg, 82% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.8 mL/min, 254 nm; tr (major)=17.91 min, tr (minor)=30.23 min) gave the isomeric composition of the product: 94% e.e., [α]D20=+24.8 (c=1.01, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=8.5 Hz, 1H), 7.66-7.53 (m, 3H), 7.39 (dd, J1=8.5, J2=1.5 Hz, 1H), 7.26 (d, J=7.5 Hz, 2H), 6.91-6.80 (m, 1H), 5.12-5.03 (m, 1H), 4.61 (t, J=12.0 Hz, 2H), 3.82 (s, 3H), 3.39 (dd, J1=14.0, J2=6.0 Hz, 1H), 3.27 (dd, J1=13.8, J2=5.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 171.3, 164.1, 150.4, 142.4, 141.3, 138.6, 132.4, 130.0, 126.1, 120.2, 118.4, 115.2, 111.4, 66.3 (t, J=28.0 Hz), 53.6, 52.9, 37.9. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3224, 2962, 1751, 1539, 1197. HRMS (ESI) calcd C21H17F5N3O6+ [M+H]+: 502.1032. Found: 502.1031.
(+)-60 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S60 (106.1 mg, 0.2 mmol) for 15 h using the general procedure (90.8 mg, 91% Yield). Rf=0.6 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=18.46 min, tr (major)=29.46 min) gave the isomeric composition of the product: 93% e.e., [α]D19=+88.1 (c=1.03, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.42 (d, J=7.6 Hz, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.83 (d, J=7.6 Hz, 1H), 5.12-4.98 (m, 1H), 4.58 (t, J=12.0 Hz, 2H), 3.81 (s, 3H), 3.32 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.20 (dd, J1=13.6, J2=6.0 Hz, 1H), 3.09 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 171.7, 164.2, 150.2, 142.2, 138.8, 136.3, 132.4, 129.2, 126.0, 121.3, 120.2, 114.9, 83.0, 77.8, 66.2 (t, J=28.6 Hz), 53.7, 52.8, 37.5. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3303, 3055, 1753, 1355, 1199. HRMS (ESI) calcd C22H18F5N2O6+ [M+H]+: 501.1080. Found: 501.1078.
(+)-61 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S61 (131.8 mg, 0.2 mmol) for 15 h using the general procedure (120.3 mg, 96% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=25.60 min, tr (major)=33.12 min) gave the isomeric composition of the product: 93% e.e., [α]D18=+81.8 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.72-7.53 (m, 9H), 7.46 (t, J=7.4 Hz, 2H), 7.37 (d, J=7.2 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 5.17-5.04 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.85 (s, 3H), 3.37 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.29 (dd, J1=13.8, J2=5.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.8, 164.2, 150.3, 142.2, 140.5, 140.3, 139.8, 139.1, 139.0, 134.5, 129.7, 128.8, 127.5, 127.4, 127.3, 127.2, 127.0, 126.1, 120.3, 115.1, 66.3 (t, J=28.5 Hz), 53.8, 52.7, 37.3. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3070, 1748, 1530, 1267, 1204. HRMS (ESI) calcd C32H26F5N2O6+ [M+H]+: 629.1706. Found: 629.1707.
(+)-62 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S62 (108.4 mg, 0.2 mmol) for 15 h using the general procedure (96.6 mg, 94% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=18.66 min, tr (major)=20.58 min) gave the isomeric composition of the product: 95% e.e., [α]D18=+62.8 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.15-6.94 (m, 3H), 6.92-6.83 (m, 1H), 5.11-4.93 (m, 1H), 4.59 (t, J=12.0 Hz, 2H), 3.82 (s, 3H), 3.28 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.15 (dd, J1=14.0, J2=6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.7, 164.3, 150.2, 149.9 (ddd, J1=247.2, J2=54.6, J3=12.7 Hz), 142.1, 138.6, 132.6 (dd, J1=5.0, J2=4.4 Hz), 125.9, 125.2 (dd, J1=6.3, J2=3.3 Hz), 120.2, 117.7 (dd, J1=54.9, J2=17.4 Hz), 114.8, 66.1 (t, J=28.5 Hz), 53.8, 52.8, 36.8. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=11.8 Hz), −137.0-−137.3 (m), −139.4-−137.6 (m). IR (neat, cm−1) 3230, 3055, 1753, 1525, 1204. HRMS (ESI) calcd C20H16F7N2O6+ [M+H]+: 513.0891. Found: 513.0894.
(−)-63 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S63 (126.4 mg, 0.2 mmol) for 12 h using the general procedure (112.3 mg, 93% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=70/30, 0.8 mL/min, 254 nm; tr (minor)=8.43 min, tr (major)=15.19 min) gave the isomeric composition of the product: 82% e.e. (76% Yield, 98% e.e., single recrystallized from acetone/hexane), [α]D20=−6.9 (c=1.00, CHCl3 (98% e.e.)). 1H NMR (400 MHz, CDCl3) δ 7.96-7.87 (m, 2H), 7.54 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.20-5.00 (m, 1H), 4.57 (t, J=11.8 Hz, 2H), 3.81 (s, 3H), 3.47 (dd, J1=14.0, J2=6.0 Hz, 1H), 3.32 (dd, J1=14.2, J2=8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.9, 164.4, 150.1, 142.1, 139.8, 139.0, 138.7, 130.3, 129.2, 128.7, 125.9, 120.5, 114.9, 101.1, 66.2 (t, J=28.5 Hz), 53.5, 52.9, 42.2. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.8 Hz). IR (neat, cm−1) 3222, 3050, 1751, 1539, 1198. HRMS (ESI) calcd C20H17F5N2O6I+ [M+H]+: 603.0046. Found: 603.0047.
(+)-64 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S64 (111.3 mg, 0.2 mmol) for 10 h using the general procedure (95.5 mg, 91% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=16.71 min, tr (major)=22.30 min) gave the isomeric composition of the product: 91% e.e., [α]D23=+69.5 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89-7.67 (m, 4H), 7.58 (s, 1H), 7.53-7.39 (m, 3H), 7.31-7.20 (m, 2H), 6.82 (d, J=7.6 Hz, 1H), 5.21-5.06 (m, 1H), 4.48 (t, J=11.8 Hz, 2H), 3.82 (s, 3H), 3.48 (dd, J1=13.8, J2=5.8 Hz, 1H), 3.37 (dd, J1=14.0, J2=6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.9, 164.3, 150.1, 142.1, 139.0, 133.4, 132.9, 132.5, 128.5, 128.1, 127.7, 127.4, 127.0, 126.5, 126.1, 126.0, 120.3, 114.7, 66.1 (t, J=28.6 Hz), 53.8, 52.7, 37.8. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3232, 2975, 1753, 1538, 1198. HRMS (ESI) calcd C24H20F5N2O6+ [M+H]+: 527.1236. Found: 527.1237.
(+)-65 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S65 (111.1 mg, 0.2 mmol) for 10 h using the general procedure (99.2 mg, 94% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/iPrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=12.04 min, tr (major)=21.71 min) gave the isomeric composition of the product: 81% e.e. (81% Yield, 97% e.e., single recrystallized from DCM/hexane), [α]D23=+6.6 (c=1.02, CHCl3 (97% e.e.)). 1H NMR (400 MHz, CDCl3) δ 8.16-8.02 (m, 1H), 7.93-7.83 (m, 1H), 7.83-7.67 (m, 2H), 7.60-7.45 (m, 2H), 7.40 (t, J=7.4 Hz, 1H), 7.36-7.26 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 5.26-5.13 (m, 1H), 4.47 (t, J=11.6 Hz, 2H), 3.85-3.56 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 172.1, 164.4, 150.0, 142.0, 138.9, 133.9, 132.2, 131.9, 129.1, 128.3, 127.5, 126.5, 125.93, 125.87, 125.3, 123.2, 120.4, 114.6, 66.1 (t, J=28.2 Hz), 53.8, 52.6, 34.6. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3230, 2973, 1750, 1538, 1196. HRMS (ESI) calcd C24H20F5N2O6+ [M+H]+: 527.1236. Found: 527.1234.
(+)-66 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S66 (102.5 mg, 0.2 mmol) for 8 h using the general procedure (90.7 mg, 94% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=14.05 min, tr (major)=25.09 min) gave the isomeric composition of the product: 93% e.e., [α]D20=+71.4 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.30 (dd, J1=5.0, J2=3.0 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.93-6.77 (m, 2H), 5.09-4.95 (m, 1H), 4.59 (t, J=12.0 Hz, 2H), 3.82 (s, 3H), 3.36 (dd, J1=14.4, J2=5.2 Hz, 1H), 3.27 (dd, J1=14.6, J2=5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 171.9, 164.2, 150.2, 142.2, 138.9, 135.6, 128.0, 126.5, 126.0, 123.0, 120.3, 114.9, 66.2 (t, J=28.6 Hz), 53.3, 52.8, 32.0. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3228, 2962, 1750, 1538, 1197. HRMS (ESI) calcd C18H16F5N2O6S+ [M+H]+: 483.0644. Found: 483.0645.
(+)-67 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S67 (99.2 mg, 0.2 mmol) for 10 h using the general procedure (84.4 mg, 91% Yield). Rf=0.4 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=19.53 min, tr (major)=20.81 min) gave the isomeric composition of the product: 92% e.e., [α]D20=+71.6 (c=0.98, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (d, J=1.2 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.31 (t, J=2.6 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 5.07-4.96 (m, 1H), 4.60 (t, J=11.8 Hz, 2H), 3.83 (s, 3H), 3.42-3.26 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 171.3, 164.3, 150.3, 150.0, 142.5, 142.2, 139.1, 126.0, 120.4, 115.1, 110.5, 108.3, 66.3 (t, J=28.0 Hz), 52.9, 52.3, 30.3. 19F NMR (471 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=12.2 Hz). IR (neat, cm−1) 3225, 2962, 1750, 1539, 1197. HRMS (ESI) calcd C18H16F5N2O7+ [M+H]+: 467.0872. Found: 467.0871.
(+)-69 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S69 (86.2 mg, 0.2 mmol) for 10 h using the general procedure (73.3 mg, 91% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.80 min, tr (major)=11.89 min) gave the isomeric composition of the product: 94% e.e., [α]D17=+24.5 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.12 (d, J=6.0 Hz, 1H), 4.78 (dquintet, J1=147.2, J1=7.1 Hz, 1H), 4.60 (t, J=11.6 Hz, 2H), 3.83 (s, 3H), 1.54 (dd, J1=6.6, J2=4.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7 (d, J=61.4 Hz), 164.0, 150.1, 142.1, 138.8, 125.9, 120.4, 114.8, 66.2 (t, J=28.6 Hz), 52.8, 48.8, 18.1 (d, J=34.7 Hz). 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.3 (t, J=11.7 Hz). IR (neat, cm−1) 3366, 2963, 1714, 1530, 1194. HRMS (ESI) calcd C1313CH14F5N2O6+ [M+H]+: 402.0800. Found: 402.0799.
(+)-70 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S70 (86.2 mg, 0.2 mmol) for 12 h using the general procedure (72.6 mg, 90% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.84 min, tr (major)=12.07 min) gave the isomeric composition of the product: 94% e.e., [α]D17=+20.7 (c=1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.48 (dd, J1=8.2, J2=1.4 Hz, 1H), 7.26 (dd, J1=91.7, J2=7.2 Hz, 1H), 4.85-4.72 (m, 1H), 4.59 (t, J=11.8 Hz, 2H), 3.83 (s, 3H), 1.54 (dd, J1=7.2, J2=2.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.9, 164.0 (d, J=16.6 Hz), 150.0, 142.0, 138.6 (d, J=8.7 Hz), 125.8, 120.5, 114.6, 66.1 (t, J=28.6 Hz), 52.8, 48.8 (d, J=12.3 Hz), 18.0. 19F NMR (376 MHz, CDCl3) δ −83.4 (s), −123.2 (t, J=11.8 Hz). 15N NMR (40 MHz, CDCl3) δ 116.9. IR (neat, cm−1) 3356, 1709, 1543, 1228, 1190. HRMS (ESI) calcd C14H14F5N15NO6 [M+H]+: 402.0737. Found: 402.0740.
(+)-71 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S71 (86.7 mg, 0.2 mmol) for 12 h using the general procedure (72.1 mg, 89% Yield). Rf=0.3 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (minor)=8.72 min, tr (major)=11.84 min) gave the isomeric composition of the product: 94% e.e., [α]D18=+21.3 (c=1.02, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H), 4.76 (d, J=7.0 Hz, 1H), 4.60 (t, J=12.0 Hz, 2H), 3.82 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 173.8, 164.2, 149.9, 141.9, 138.7, 125.7, 120.5, 118.3 (qt, J1=284.4 Hz, J2=34.1 Hz), 114.5, 111.9 (tq, J1=254.5 Hz, J2=38.0 Hz), 66.0 (t, J=27.9 Hz), 52.7, 48.6, 16.9 (hept, J=19.8 Hz). 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.2 (t, J=11.1 Hz). IR (neat, cm−1) 3361, 2938, 1717, 1530, 1194. HRMS (ESI) calcd C14H11D3F5N2O6+ [M+H]+: 404.0955. Found: 404.0958.
[α]D18=+15.7 (c=0.95, CHCl3). 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.47-5.32 (m, 1H), 5.05-4.75 (m, 5H), 4.35-4.25 (m, 1H), 3.86 (d, J=12.4 Hz, 1H), 3.80-3.66 (m, 4H), 3.43 (dd, J1=15.0, J2=4.6 Hz, 1H), 3.34-3.24 (m, 1H), 2.96-2.80 (m, 1H), 2.77-2.63 (m, 1H), 1.87 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 172.7, 167.5, 166.3, 152.2, 150.9, 144.8, 143.3, 140.2, 138.2, 126.6, 124.2, 122.5, 115.8, 111.7, 86.6, 86.3, 66.9 (t, J=28.3 Hz), 62.1, 61.0, 54.4, 53.1, 38.9, 28.4, 12.5. 19F NMR (376 MHz, CD3OD) δ −84.7 (s), −124.6 (t, J=12.4 Hz). IR (neat, cm−1) 3293, 3050, 1670, 1530, 1267, 1199. HRMS (ESI) calcd C26H27F5N7O10+ [M+H]+: 692.1734. Found: 692.1735.
[α]D18=+28.0 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=7.2 Hz, 2H), 8.02 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.64-7.55 (m, 3H), 7.50 (t, J=7.4 Hz, 1H), 7.45-7.34 (m, 3H), 7.25 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.39-6.28 (m, 2H), 5.63-5.42 (m, 2H), 5.26 (t, J=3.2 Hz, 1H), 5.12-5.00 (m, 1H), 4.58 (t, J=11.8 Hz, 2H), 4.00 (dd, J1=12.4, J2=2.0 Hz, 1H), 3.85 (dd, J1=12.6, J2=3.8 Hz, 1H), 3.80 (s, 3H), 3.45 (dd, J1=12.2, J2=5.4 Hz, 1H), 3.37 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.26 (dd, J1=14.0, J2=6.0 Hz, 1H), 3.11 (dd, J1=12.0, J2=4.8 Hz, 1H), 2.95 (br, 1H), 1.85 (br, 1H). 13C NMR (150 MHz, CDCl3) δ 177.6, 171.6, 164.6, 154.5, 150.0, 149.7, 143.4, 141.9, 138.6, 136.9, 136.6, 135.8, 135.3, 132.7, 130.4, 129.7, 128.2, 125.8, 121.6, 120.5, 114.9, 98.0, 87.1, 86.7, 66.0 (t, J=28.3 Hz), 63.1, 53.9, 52.7, 37.7, 37.5, 36.8. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.8 Hz). IR (neat, cm−1) 3318, 3045, 1648, 1541, 1204. HRMS (ESI) calcd C38H34F5N8O10S+ [M+H]+: 889.2033. Found: 889.2030.
[α]D18=+17.9 (c=1.02, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.61 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.10-6.98 (m, 1H), 5.89 (d, J=2.8 Hz, 1H), 5.17-5.04 (m, 1H), 4.88 (q, J=12.8 Hz, 2H), 4.70-4.52 (m, 3H), 4.43-4.30 (m, 1H), 4.18-4.06 (m, 3H), 4.06-3.98 (m, 1H), 3.83 (s, 3H), 3.41 (dd, J1=14.0, J2=5.6 Hz, 1H), 3.28 (dd, J1=13.8, J2=6.2 Hz, 1H), 1.49 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 171.5, 164.2, 150.2, 145.8, 142.2, 138.7, 136.7, 136.1, 130.5, 126.0, 120.6, 120.2, 115.1, 111.9, 109.1, 105.2, 82.5, 81.6, 81.0, 72.2, 67.4, 66.2 (t, J=28.7 Hz), 63.8, 53.8, 52.8, 37.2, 26.8, 26.7, 26.1, 25.4. 19F NMR (376 MHz, CDCl3) δ −83.3 (s), −123.1 (t, J=11.7 Hz). IR (neat, cm−1) 3254, 2982, 1748, 1539, 1204. HRMS (ESI) calcd C35H39F5N5O12+ [M+H]+: 816.2510. Found: 816.2509.
(−)-77 was obtained as white solid from the asymmetric decarboxylation reaction of malonic acid S77 (340.5 mg, 1 mmol) for 12 h using the general procedure with (S)-CPA-8 as catalyst (294.5 mg, 95% Yield). Rf=0.5 (Hexane/EtOAc 2:1). HPLC analysis (Chiralpak IA-3, hexane/PrOH=80/20, 0.8 mL/min, 254 nm; tr (major)=8.06 min, tr(minor)=10.33 min) gave the isomeric composition of the product: 88% e.e., (81% Yield, 94% e.e., single recrystallized from DCM/hexane), [α]D19=−24.5 (c=1.00, CHCl3 (94% e.e.)). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.86 (d, J=6.0 Hz, 1H), 4.87-4.68 (m, 2H), 3.82 (s, 3H), 1.55 (d, J=7.2 Hz, 3H), 1.40 (d, J=5.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 173.4, 164.9, 151.1, 142.6, 138.3, 125.2, 117.6, 115.3, 72.9, 52.6, 48.6, 21.7, 21.6, 18.0. IR (neat, cm−1) 3313, 2987, 1743, 1530, 1262. HRMS (ESI) calcd C14H19N2O6+ [M+H]+: 311.1238. Found: 311.1240.
[α]D19=−10.1 (c=0.90, MeOH). 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.57-7.45 (m, 2H), 6.84 (s, 1H), 4.83-4.78 (m, 1H), 4.49-4.39 (m, 1H), 2.33 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.44 (d, J=6.0 Hz, 3H), 1.32 (d, J=6.0 Hz, 3H). 13C NMR (150 MHz, CD3OD) δ 179.8, 168.1, 159.1, 154.8, 137.0, 129.2, 128.6, 125.8, 120.4, 120.1, 115.0, 114.4, 109.4, 72.6, 52.5, 22.4, 22.2, 19.2, 10.1. IR (neat, cm−1) 3351, 2982, 1700, 1500, 1107. HRMS (ESI) calcd C14H22N3O5C12+ [M+H]+: 442.0931. Found: 442.0930.
The crystal structure of (+)-17 is shown in
Compared with enzymatic catalysis, asymmetric decarboxylation using chemical catalysis is underexplored. Chiral organic bases (e.g., 6) have been examined as the catalyst, but amino acids were only obtained in low enantioselectivity. The method accomplishes asymmetric decarboxylation, especially with chiral phosphoric acids (
The chiral pocket of phosphoric acids is shown in Scheme 19 below. Chiral phosphoric acids can induce the enantioselectivity of the decarboxylation. However, both the backbone and side chains of the acids are needed for their performance. Optimal enantiocontrol can be achieved with the combination of a spirocyclic skeleton and a pair of mesityl substituents.
As shown in Scheme 19, while the decarboxylation of diacid 13 using the pocketless BINOL-derived CPA-1 provided benzoylated alanine (14) as a nearly racemic mixture, moderate enantiocontrol can be obtained with a pair of bulky side arms in place (CPA-2 to CPA-5). Meanwhile, the backbone of the acid is equally important in tuning the microenvironment. Particularly, the combination of a spirocyclic scaffold (CPA-6 to CPA-10) and mesityl substituents (CPA-8) induced a much-enhanced enantioselectivity for the decarboxylation. Several other skeletons of phosphoric acids, including H8-BINOL (CPA-11) and TADDOL (CPA-12), were also examined (Table 1).
The decarboxylation is influenced by solvents (
Reaction conditions unless noted otherwise: 1 (0.1 mmol). (R)-CPA (10 mol %), in THF (0.5 mL) at 80° C. for 3 h. The yield was determined by crude 1H NMR analysis using dibromomethane as the internal standard and e.e. was determined by HPLC analysis of isolated product.
nPrNO2
tBuOMe
The amine protecting group provides another handle for improving the enantiocontrol. A further boost in enantioselectivity was obtained via screening of varied amine protecting groups, indicating its engagement with the chiral phosphoric acid during the enantioinduction (
Reaction conditions unless noted otherwise: 1 (0.1 mmol), (R)-CPA-8 (10 mol %), in CPME (2.0 mL) at 80° C. for 2 h. The yield was determined by crude 1H NMR analysis using dibromomethane as the internal standard and e.e. was determined by HPLC analysis of isolated product. aThe reaction was run for 5 h.
Aminomalonic acids bearing the customized protecting group (Bz7) can be prepared in a divergent and modular fashion (
Structurally distinct amino acids have unique functions, and the method can prepare a diversity of them. The chiral phosphoric acid is tolerant of alkyl groups of distinct shapes (19-24). The chiral phosphoric acid can accommodate extended alkyl chains (19-22) and cycloalkyl (23) groups to generate unnatural amino acids, including those isomeric to proteinogenic ones, such as norvaline (20) and norleucine (21). The method also tolerates more crowded secondary alkyl substituents (24), with slightly lower enantioselectivity. The diversity of functional groups that can be introduced to amino acids (25-40) is immense, which can serve as a handle to further modify the amino acids or bring varied functions to peptides or proteins. When unsaturated motifs are present in the side chain, they diversify not only the shape but also further modification of the amino acids. As such, various types of olefins, including monosubstituted (25), 1,1/1,2-disubstituted (26 and 27), and trisubstituted (28) ones, as well as terminal (29) and internal (30) alkynes, can be integrated. Chains with multiple such motifs, including a diene derived from geraniol (31) and an enyne (32), are also compatible. Further transformations of these olefins and alkynes, such as coupling and oxidation reactions, can generate amino acids of higher complexity. These functional groups can also facilitate chemical modification of peptides and proteins via metathesis or click reactions. The functional groups are beyond unsaturated moieties. When a phenyl, indole, or phthalimide was attached to the alkyl chain, unnatural analogs to phenylalanine (33), tryptophan (34), and ornithine (35) were forged, respectively. The reduced enantioselectivity of 35 may result from the imide carbonyls that may interfere with the hydrogen bonding between the phosphoric acid and the enol intermediate. Malonic acids with a nitrile (36), acetal (37), or azide (38) group can also participate to give amino acids that inherit their versatile reactivity. Additionally, the acid catalyst operated smoothly on substrates with polyfunctionalized skeletons derived from cholic acid (39) and estrone (40), and the stereocontrol remained excellent despite their large sizes.
Cyclic amino acids (e.g., 44) are also accessible from the decarboxylation products (e.g., 41) through a sequence involving a pair of versatile intermediates (42 and 43). A route from p-methoxybenzyl ether 41 to proline 44 is demonstrated in
Non-proteinogenic derivatives of phenylalanines are particularly prevalent in bioactive peptide drugs and have been heavily used in multiple areas to introduce diverse functions to proteins with their aryl substituents. The asymmetric synthesis can prepare a library of them, which takes advantage of the vast availability of benzyl bromides and their facile substitution for the preparation of aminomalonic acids, as well as the catalyst's tolerance of substituents with different shapes and electronic properties. As such, phenylalanines with abundant functionalities, including fluorophores (59-61), NMR-active nuclei (46 and 54), and photosensitizers (58), can be accessed. The synthesis of functionalized phenylalanines was further investigated due to their prevalence in drugs and role as a vessel to convey varied functions to peptides and proteins. The availability of assorted benzyl bromides and their facile substitution reactions can provide a reliable supply of functionalized phenylalanines using facilitate asymmetric malonic ester synthesis. Indeed, as shown in
Isotope-labeled amino acids are also accessible (Scheme 20). These structures are of high demand given their diverse application across several fields, including proteomics, pharmacokinetics, and diagnostic radiology, and the asymmetric malonic ester synthesis can provide a modular approach that is highly flexible regarding the identity of isotopes and the targeted positions in amino acids. The bottom-up synthesis can be easily adopted to produce isotope-labeled amino acids. By using a unified synthetic sequence, 13C and 15N isotopes can be introduced via an early-stage oxime formation, while the labeled side chains via a later substitution. For example, the α-13C and 15N isotopes can be introduced via a condensation reaction to oxime using labeled diethyl malonate or sodium nitrite, followed by reduction and benzoylation to α-13C- or 15N-16. On the other hand, the labeled side chains can be readily connected via substitution, as demonstrated by the preparation of d3-68 (which has the structure of 68 but with CD3 instead of CH3, i.e., all the H in the CH3 of 68 is replaced with deuterium). Subsequently, all three labeled malonic acids were decarboxylated under acid catalysis to give enantio- and isotope-enriched alanines (69-71).
Non-proteinogenic amino acids with an alkyne or azide motif can conjugate with other biomolecules using click chemistry. Both amino acid-antiretroviral drug and -saccharide conjugates were easily prepared. For example, alkyne- or azide-substituted amino acids generated herein (29, 38, 57, and 60) can rapidly conjugate with biologically active cores, demonstrating their application in discovering amino acid- or peptide-based therapeutic agents (Scheme 21). With a generic copper catalyst, the cycloaddition between the propargyl group in 29 and Zidovudine's azide motif proceeded smoothly (72). Another amino acid-antiretroviral drug conjugate was prepared from the azido-containing product 57 and propargyl-tethered Lamivudine (73). Besides, saccharides and amino acids can also connect using the same strategy (74).
Besides serving as a protecting group, 3-alkoxy-4-nitrobenzamides, once reduced to corresponding anilines, can serve as α-helix mimetics that frequently found in bioactive small molecules and peptides (75,
The excellent enantiocontrol of the acid-catalyzed decarboxylation was achieved using chiral phosphoric acids and the tailored protecting group (such as fluorinated benzoyl) of aminomalonic acids. The diverse interactions between the two components, especially the large number of dispersion forces, help anchor the enol intermediate and allow the phosphoric acid to achieve stereoselective protonation. Using the enantioselective decarboxylation reaction, the long-elusive malonate-based synthesis of chiral α-amino acids is now available. The synthetic protocol disclosed herein introduces the side chains of amino acids via the facile alkylation of aminomalonic esters. With subsequent hydrolysis and decarboxylation, the resulting amino acids have diverse shapes and substituents of the side chains and thus can provide distinct properties and functions.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Further, unless otherwise indicated, use of the expression “wt %” refers to “wt/wt %.”
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
This application claims the benefit of and priority to U.S. Provisional Application No. 63/503,061 filed May 18, 2023, the entire content of which is incorporated herein by reference for all purpose in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63503061 | May 2023 | US |
