Patent Application
20240199521
The present invention belongs to the technical field of chemical synthesis, particularly to a method for directly synthesizing highly optically active tetra-substituted allenoic acid compounds.
Chiral allenes compounds are widely found in natural products, drug molecules and material science, and are a very important class of compounds (Ref: (a) Hoffmann-Röder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51, 2818.). The axial chiral cumulative carbon-carbon double bonds in these compounds can be efficiently converted into central chiral compounds by one-step or multi-step reactions, which has important application value in synthetic chemistry. Therefore, how to efficiently construct chiral allenes compounds with high optically active has been widely concerned by synthetic chemists. How to construct tetra-substituted chiral quaternary carbon centers has been extensively studied in the past decade and has achieved fruitful results (Ref: (a) Quasdorf, K. W.; Overman, L. E. Nature 516, 2014, 181. (b) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Chem. Rev. 116, 2016, 7330.). Compared with the construction of compounds containing tetra-substituted chiral quaternary carbon centers, the synthesis of tetra-substituted axial chirality allenes compounds still faces great challenges. At present, the methods reported in the known literature for the synthesis of such compounds are still very limited, and can be generally divided into two categories: the asymmetric addition reaction of nucleophilic reagents to the conjugated alkyne system catalyzed by metal or organic small molecule and the stereoselectivity addition of allenyl group nucleophilic reagents to different electrophilic reagents. The main reason is that the accumulated carbon-carbon double bonds in the structure of chiral allenes are mutually perpendicular in space, and the substituents at 1,3-position of the allenes are located in a relatively far mutually perpendicular space. Compared with the compact spatial arrangement of central chirality, the formation of chiral allenes requires a larger chiral shielding environment in order to induce the formation of their axial chirality with high enantioselectivity, and excessive chiral shielding may lead to the decline of reaction activity. (Ref: (a) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305. (b) Qian, D.; Wu, L.; Lin, Z.; Sun, J. Nat. Commun. 2017, 8, 567. (c) Hashimoto, T.; Sakata, K.; Tamakuni, F.; Dutton, M. J.; Maruoka, K. Nat. Chem. 2013, 5, 240. (d) Mbofana, C. T.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 3285. (e) Zhang, P.; Huang, Q.; Cheng, Y.; Li, R.; Li, P.; Li, W. Org. Lett. 2019, 21, 503. (f) Zhang, L.; Han, Y.; Huang, A.; Zhang, P.; Li, P.; Li, W. Org. Lett. 2019, 21, 7415. (g) Chen, M.; Qian, D.; Sun, J. Org. Lett. 2019, 21, 8127. (h) Yang, J.; Wang, Z.; He, Z.; Li, G.; Hong, L.; Sun, W.; Wang, R. Angew. Chem., Int. Ed. 2020, 59, 642. (i) Li, X.; Sun, J. Angew. Chem., Int. Ed. 2020, 59, 17049. (j) Partridge, B. M.; Chausset-Boissarie, L.; Burns, M.; Pulis, A. P.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2012, 51, 11795. Armstrong, R. J.; (k) Wu, S.; Huang, X.; Wu, W.; Li, P.; Fu, C.; Ma, S. Nat. Commun. 2015, 6, 7946. (1) Wang, G.; Liu, X.; Chen, Y.; Yang, J.; Li, J.; Lin, L.; Feng, X. ACS Catal. 2016, 6, 2482. (m) Tap, A.; Blond, A.; Wakchaure, V. N.; List, B. Angew. Chem., Int. Ed. 2016, 55, 8962. (n) Tang, Y.; Xu, J.; Yang, J.; Lin, L.; Feng, X.; Liu, X. Chem. 2018, 4, 1658. (o) Nandakumar, M.; Dias, R. M. P.; Noble, A.; Myers, E. L.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2018, 57, 8203. (p) Liao, Y.; Yin, X.; Wnag, X.; Yu, W.; Fang, D.; Hu, L.; Wang, M.; Liao, J. Angew. Chem., Int. Ed. 2020, 59, 1176.).
Chiral allenoic acid compounds can be obtained by separated by the splitting method of racemic allenic acid compounds or allenic nitrile compounds (Ref: (a) Ma, S.; Wu, S. Chem. Commun. 2001, 0, 441. (b) Ao, Y.-F.; Wang, D.-X.; Zhao, L.; Wang, M.-X. J. Org. Chem. 2014, 79, 3103.) and the hydrolysis method of chiral allenoic acid esters (Ref: (a) Marshall, J. A.; Bartley, G. S.; Wallace, E. M. J. Org. Chem. 1996, 61, 5729. (b) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2010, 12, 4050), but the examples of the preparation of tetra-substituted allenoic acid compounds using the above methods are very limited. The above methods have the disadvantages of low reaction yield, narrow substrate range, poor functional group tolerance, and low atom economy and so on. Therefore, the development of a highly efficient and enantioselective method for the synthesis of tetra-substituted axial chirality allenoic acid compounds from simple and readily available raw materials will be an important breakthrough in the existing synthesis methods. In 2019, our research group used triphenylphosphine as the supporting ligand in the palladium/DTBM-SEGphos and phosphoric acid co catalytic system, and successfully prepared highly optically active chiral tetra-substituted allenoic acid compounds through the kinetic resolution of tertiary propargyl alcohol. This method has the advantages of a wide range of substrates and good functional group tolerance and mild reaction conditions, etc (Ref: Zheng, W.-F.; Zhang, W.; Huang, C.; Wu, P.; Qian, H.; Wang, L.; Guo, Y-L.; Ma, S. Nat. Catal. 2019, 2, 997.). On this basis, we successfully realized the high stereoselectivity and high yield (theoretical yield as high as 100%) of preparing tetra-substituted chiral allenoic acid compounds by means of dynamic kinetic chiral transfer of tertiary propargyl alcohol.
The object of the present invention is to provide a method for directly synthesizing highly optically active axially chiral tetra-substituted allenoic acid compounds, that is, a one-step process for directly constructing high optically active axially chiral tetra-substituted allenoic acid compounds by using tertiary propargyl alcohol, carbon monoxide and water as reactants in organic additives and an organic solvent in the presence of palladium catalyst, chiral bisphosphine ligand and organophosphoric acid.
The object of the present invention is achieved by using the following solution:
The present invention provides a method for directly constructing highly optically active axially chiral tetra-substituted allenoic acid compounds includes: in the presence of palladium catalyst, chiral diphosphine ligand, and organophosphoric acid, the tertiary propargyl alcohol with different substituents, carbon monoxide and water undergo asymmetric allylation reaction in organic additives and organic solvent through transition metal catalysis, constructing highly optically active axially chiral tetra-substituted allenoic acid compounds in one-step synthesis. The reaction has the following reaction equation (a):
In R1, R2 and R3, the functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, and silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta, and para positions; said heterocyclyl group is furyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents.
Preferably,
In R1, R2 and R3, the functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta and para positions, said heterocyclic group is a furanyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents; said electron-withdrawing substituents in the aryl or heterocyclic groups include halogen, nitro, ester, carboxyl, acyl, amide, and cyano groups, and the electron-donating substituents include alkyl, alkenyl, phenyl, alkoxy group, hydroxyl, amino, silicon group.
Further preferably,
In R2 and R3, the C1-C20 alkyl group is alkyl, alkenyl, phenyl, aryl or heteroaryl group; the C1-C10 alkyl group is alkyl, alkenyl, phenyl, aryl or heteroaryl group; the C1-C5 alkyl group is methyl, ethyl, n-propyl (and its isomers), n-butyl (and its isomers) and n-pentyl (and its isomers) group; in the C1-C20 alkyl group with functional group at the end or the C1-C10 alkyl group with functional group at the end or the C1-C5 alkyl group with functional group at the end, the functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta and para positions, said heterocyclic group is a furanyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents; said electron-withdrawing substituents in the aryl or heterocyclic groups include halogen, nitro, ester, carboxyl, acyl, amide, and cyano groups, and the electron-donating substituents include alkyl, alkenyl, phenyl, alkoxy group, hydroxyl, amino, silicon group.
Further preferably,
In R1, R2 and R3, in the C1-C15 alkyl group with functional group at the end or the C1-C10 alkyl group with functional group at the end or the C1-C5 alkyl group with functional group at the end, the functional group is selected from carbon-carbon triple bond, hydroxyl, acyl, acyloxy, amide, amino, silicon group; said aryl group is phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta and para positions, said heterocyclic group is a furanyl or pyridyl group, or furan or pyridine with electron-donating or electron-withdrawing substituents; said electron-withdrawing substituents in the aryl or heterocyclic groups include halogen, nitro, ester, carboxyl, acyl, amide, and cyano groups, and the electron-donating substituents include alkyl, alkenyl, phenyl, alkoxy group, hydroxyl, amino, silicon group.
Further preferably,
As a further improvement, the present process comprises the following steps:
Wherein, the dosage of the organic solvent is 1.0-10.0 mL/mmol; preferably, is 5.0 mL/mmol. The dosage of functionalized tertiary propargyl alcohol (±1) shown in equation (a) is taken as the basis.
Wherein, the certain volume of the ethyl acetate refers to taking the amount of functionalized tertiary propargyl alcohol (±1) shown in equation (a) as basis, said amount of ethyl acetate is 1.0-100 mL/mmol; preferably, is 5.0 mL/mmol.
As a further improvement, the palladium catalyst used in the present invention is any one or more of dis-(allyl-palladium chloride), tetra-(triphenylphosphine)palladium, tri-(dibenzylidene-acetone)dipalladium, dis-(cinnamyl-palladium chloride), dis-(dibenzylidene-acetone)monopalladium, palladium chloride, palladium acetate, dis-(triphenylphosphine)palladium chloride, bis-(acetonitrile)palladium chloride, and so on; preferably, is dis-(allyl-palladium chloride).
As a further improvement, the chiral diphosphine ligand used in the present invention is selected from one or more of (R)-L1˜(R)-L4 and its enantiomers (S)-L1˜(S)-L4 in the following structure; preferably, the chiral diphosphine ligand is (R)-L4 and/or its enantiomer (S)-L4.
Wherein, Ar is a phenyl, an aryl or heterocyclic group; said aryl group is a phenyl group substituted by alkyl or alkoxy group at the ortho, meta, and para positions; wherein said alkyl group includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl group; said alkoxy group includes methoxy, ethoxyl, propoxyl, isopropoxyl, butoxyl, isobutyloxyl, tert butoxyl group; said heterocyclic group is thienyl, furyl or pyridyl group; preferably, said Ar is phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,5-ditert-butyl-4-methoxyphenyl group.
As a further improvement, the chiral diphosphine ligand used in the present invention is selected from one or more of (R)-L4a, (R)-L4b, (R)-L4c, (R)-L4d, (R)-L4e, (R)-L4f and its enantiomer (S)-L4a, (S)-L4b, (S)-L4c, (S)-L4d, (S)-L4e, (S)-L4f; wherein, the structure of said (R)-L4a, (R)-L4b, (R)-L4c, (R)-L4d, (R)-L4e, (R)-L4f is as follows:
As a further improvement, the organophosphoric acid used in the present invention is selected from any one or more of organophosphoric acid 1, organophosphoric acid 2, organophosphoric acid 3, and so on; wherein, R4 is hydrogen, C1˜C6 alkyl, phenyl or aryl group; said aryl group is a phenyl group substituted by C1˜C6 alky at the ortho, meta, and para positions; R5 is hydrogen, R5 is C1˜C6 alkyl, phenyl or aryl group, and said aryl group is a phenyl group substituted by C1-C6 alky, halogenated alkyl, alkoxy group, halogens, nitro group at the ortho, meta, and para positions; preferably, R4 is phenyl group, R5 is 3,5-ditrifluoromethylphenyl group.
As a further improvement, the organic solvent is selected from any one or more of N-methyl pyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, mesitylene, 4-ethyltoluene, 1,4-diethylbenzene, triethylbenzene, trifluorotoluene, dichloromethane, dibromomethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dibromoethane, chloroform, acetic acid, N,N-dimethylformamide and dimethyl sulfoxide, and so on; preferably, is toluene.
As a further improvement, the organic additive is selected from any one or more of 1,1-bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 1,1′-bis (diphenylphosphine)ferrocene, bis(2-diphenylphosphine)ether, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1′-binaphthyl-2,2′-bisdiphenylphosphine, triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-methylphenyl)phosphine, tri(4-fluorophenyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, bromoethane, bromobutane, benzene, fluorobenzene, 1,4-difluorobenzene, hexafluorobenzene, chlorobenzene, 1,4-dichlorobenzene, bromobenzene, 1,4-dibromobenzene, 4-methoxyromobenzene, 4-methylbromobenzene, 4-fluorobromobenzene, 4-trifluoromethylbromobenzene, iodobenzene, trifluorotoluene, aniline, benzenesulfonic acid, phenol, phenylboronic acid, and so on; preferably, is bromobenzene.
As a further improvement, said reaction temperature of the present invention is −20˜100° C.; preferably, is 0˜80° C.; more preferably, is 25˜70° C.
As a further improvement, said reaction time of the present invention is 1-36 hours; preferably, is 12 hours.
As a further improvement, said molar ratio of tertiary propargyl alcohol (±1) with different substituents, water, palladium catalyst, chiral diphosphine ligand, organophosphoric acid and organic additives of the present invention is 1.0:(1.0-30.0):(0.005-0.1):(0.005-0.1):(0.01-0.3):(1.0-30.0); preferably, is 1.0:20.0:0.04:0.06:0.025:10.0.
Under the heating conditions of the synthetic method of the present invention, the following four technical difficulties are mainly overcome, as shown in the following reaction equation (b):
The present invention can effectively overcome the above technical difficulties by using organic additives (such as bromobenzene and bromobenzene derivatives that donate electrons or withdraw electrons on the benzene ring), and successfully realize the preparation of chiral allenoic acid compounds with high enantioselectivity , and avoid the formation of other by-products in the reaction process, and exclusively obtain chiral allenoic acid compounds. Only in the process of condition optimization, (E)-conjugated dienoic acid 1, (E)-conjugated dienoic acid 2 are observed, under optimal conditions, only a small amount of enyne, γ-butyrolactone by-product can be observed in some reactions.
The present invention proposes the following possible mechanisms for the reaction described in the present invention:
The present invention also provides highly optically active axially chiral allenoic acid compounds, the structure of which is shown as(R)-2, (S)-2:
Wherein,
The definitions of R1, R2 and R3 are the same as those of the reaction equation (a).
The list of newly prepared compounds in the synthesis process of the present invention is shown in Table 1 below:
The present invention also provides the application of the highly optically active axially chiral allenoic acid compound shown in formula (R)-2 in the preparation of γ-butyrolactone compounds containing tetrasubstituted chiral quaternary carbon centers, tetrasubstituted allenic alcohol, tetra-substituted allenal, tetra-substituted allenyl ketone, tetra-substituted allenamide and other compounds.
The comparison list of the method of the present invention and the original method:
The innovation of the present invention include:
The present invention has the following advantages: the present invention uses simple and readily available functionalized tertiary propargyl alcohol as starting material, under the action of palladium catalyst, chiral bisphosphine ligand, organophosphoric acid, organic additive and an organic solvent, for the first time, achieves the one-step synthesis of highly optically active axially chiral tetra-substituted allenoic acids compounds by dynamic kinetic chirality transfer. The chiral allenoic acid compounds obtained in the present invention can be used as important synthetic intermediates for constructing γ-butyrolactone compounds containing tetra-substituted chiral quaternary carbon centers, or converted into, tetra-substituted allenic alcohol, tetra-substituted allenal, tetra-substituted allenyl ketone, tetra-substituted allenamide and other compounds. The raw materials and reagents are readily available, preparation is convenient; the reaction conditions are mild, operations are simple; the substrate is widely applicable; the functional group compatibility is good; highly optically axially chirality pure tetrasubstituted allenoic acid compounds can be synthesized in one step; the product has high enantioselectivity (77% ee˜96% ee); the reaction can be applied to the later modification of complex molecules containing natural product backbones or drug molecule fragments; the product is easy to separate and purify; the product can be converted in one or more steps into different functional groups substituted tetra-substituted chiral allenes compounds or γ-butyrolactones compounds containing a chiral quaternary carbon center, etc.
The following examples are given to further illustrating the specific solutions of the present invention. The process, conditions, experimental methods, and so on for implementing the present invention are all general knowledge and common knowledge in the field except for the contents specifically mentioned below, and the present invention has no special limitation. The specific structural formula and the corresponding number (including their enantiomers) of chiral diphosphine ligands involved in all the examples are as follows:
The specific structural formula and the corresponding number (including their enantiomers) of organophosphoric acid involved in all the examples are as follows:
Wherein, “mol” refers to mole, “PhBr” refers to bromobenzene, “PhMe” refers to toluene, “CO balloon” refers to carbon monoxide balloon, “ee” refers to the percentage of enantiomeric excess.
[Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.012 mmol), (S)-CPA-1 (0.0039 g, 0.005 mmol) were added in sequence to a dry Schlenk reaction tube. The reaction tube was plugged with a rubber stopper, and then connected with the vacuum pump, and replaced with the argon three times under an argon atmosphere. And under the protection of the argon, tertiary propargyl alcohol (±)-1a (0.0402 g, 0.2 mmol), toluene (0.8 mL), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol) and water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol) were added. After the argon was closed, the reaction tube was placed in a liquid nitrogen bath to freeze for 3 minutes, inserted by carbon monoxide balloon (about 1 liter), replaced with carbon monoxide three times under a carbon monoxide atmosphere, then the liquid nitrogen bath was removed. After the reaction system returned to the room temperature and melted into liquid, the reaction tube was placed in an oil bath that had been preheated to 50° C. and stirred for 12 hours. The reaction was taken out of the oil bath, and after returning to room temperature, added with H2O2 (8 μL, d=1.13 g/mL, 30 wt. % in H2O, 0.0027 g, 0.08 mmol). After stirred at room temperature for 30 minutes, the reaction solution was diluted by adding ethyl acetate (1 mL), and the resulting mixture was filtered through a short silica gel column (1 cm), washed with ethyl acetate (5 mL), concentrated, and subjected to flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to to afford a product: chiral allenoic acid (S)-2a (0.0385 g, 84%): solid; 93% ee (HPLC conditions: AS-H column, hexane/i-PrOH=98/2, 1.0 mL/min, λ=214 nm, tR (major)=8.7 min, tR(minor)=12.1 min); 1H NMR (400 MHz, CDCl3): δ=7.44-7.27 (m, 4 H, Ar—H), 7.27-7.21 (m, 1 H, Ar—H), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.52-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.8, 135.0, 128.5, 127.6, 126.1, 105.2, 101.8, 30.2, 28.3, 22.2, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0366 g, 0.03 mmol), (S)-CPA-1 (0.0601 g, 0.075 mmol), (±)-1b (0.1104 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 10/1) to afford a product: chiral allenoic acid (S)-2b (0.0841 g, 68%): oil; 88% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.5 min, tR(minor)=13.0 min); [α]D27=+37.5 (c=1.06, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.33 (td, J1=7.8 Hz, J2=1.7 Hz, 1 H, Ar—H), 7.27-7.21 (m, 1 H, Ar—H), 7.12 (td, J1=7.5 Hz, J2=1.1 Hz, 1 H, Ar—H), 7.07-7.00 (m, 1 H, Ar—H), 2.36-2.24 (m, 2 H, CH2), 2.24-2.13 (m, 3 H, CH3), 1.53-1.41 (m, 2 H, CH2), 1.39-1.27 (m, 2 H, CH2), 0.89 (t, J=7.2 Hz, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.9 (d, J=1.6 Hz), 173.1, 160.3 (d, J=248.8 Hz), 129.1 (d, J=8.7 Hz), 128.9 (d, J=3.1 Hz), 124.1 (d, J=3.2 Hz), 123.6 (d, J=11.9 Hz), 116.0 (d, J=22.1 Hz), 100.4, 99.9 (d, J=1.6 Hz), 30.0, 28.2, 22.2, 17.9 (d, J=2.4 Hz), 13.8; 19F NMR (376 MHz, CDCl3): δ=−112.1; IR (neat): ν=2957, 2929, 2859, 1943, 1681, 1493, 1279, 1079 cm−1; MS (70 eV, EI) m/z (%): 248 (M+, 2.21), 161 (100); HRMS calcd for C15H17FO2 [M+]: 248.1207, found: 248.1207.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0367 g, 0.03 mmol), (S)-CPA-1 (0.0402 g, 0.05 mmol), (±)-1c (0.1104 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 10/1) to afford a product: chiral allenoic acid (S)-2c (0.0847 g, 68%): white solid; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.0 min, tR(minor)=11.8 min); [α]D27=+18.0 (c=1.00, CHCl3); melting point: 104.1-105.2° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.34-7.23 (m, 1 H, Ar—H), 7.16 (d, J=8.0 Hz, 1 H, Ar—H), 7.07 (dt, J1=10.4 Hz, J2=2.0 Hz, 1 H, Ar—H), 6.94 (td, J1=7.9 Hz, J2=2.3 Hz, 1 H, Ar—H), 2.33 (t, J=7.4 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.51-1.41 (m, 2 H, CH2), 1.41-1.30 (m, 2 H, CH2), 0.88 (t, J=7.4 Hz, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.7, 163.1 (d, J=244.1 Hz), 137.5 (d, J=7.1 Hz), 129.9 (d, J=8.6 Hz), 121.7 (d, J=2.4 Hz), 114.4 (d, J=21.3 Hz), 112.9 (d, J=22.9 Hz), 104.5 (d, J=3.1 Hz), 102.3, 30.1, 28.2, 22.2, 16.2, 13.8; 19F NMR (376 MHz, CDCl3): δ=−113.6; IR (neat): ν=2961, 2929, 2863, 1937, 1685, 1422, 1264, 1089, 1021 cm−1; MS (70 eV, EI) m/z (%): 248 (M+, 3.61), 161 (100); Anal. Calcd. for C15H17FO2: C 72.56, H 6.90; found C 72.50, H 7.14.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0036 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1d (0.1104 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2d (0.0911 g, 73%): white solid; 94% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.9 min, tR(minor)=11.9 min); [α]D28=+18.7 (c=1.00, CHCl3); melting point: 113.0-114.0° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.41-7.29 (m, 2 H, Ar—H), 7.09-6.96 (m, 2 H, Ar—H), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.51-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.4 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.3 (d, J=2.4 Hz), 172.8, 162.3 (d, J=245.7 Hz), 131.0 (d, J=3.2 Hz), 127.7 (d, J=8.7 Hz), 115.5 (d, J=21.3 Hz), 104.4, 101.9, 30.2, 28.3, 22.2, 16.5, 13.8; 19F NMR (376 MHz, CDCl3): δ=−115.0; IR (neat): ν=2940, 2868, 1939, 1683, 1507, 1284, 1233 cm−1; MS (70 eV, EI) m/z (%): 248 (M+, 2.68), 161 (100); Anal. Calcd. for C15H17FO2: C 72.56, H 6.90; found C 72.72, H 7.14.
Operations were conducted by referring to Example 1 [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.0081 g, 0.01 mmol), (±)-1e (0.0471 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2e (0.0415 g, 79%): white solid; 93% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.7 min, tR(minor)=13.3 min); 1H NMR (400 MHz, CDCl3): δ=7.30 (s, 4 H, Ar—H), 2.32 (t, J=7.4 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.49-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 172.3, 133.6, 133.4, 128.7, 127.3, 104.4, 102.1, 30.2, 28.3, 22.2, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.008 g, 0.01 mmol), (±)-1f (0.0565 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2f (0.0499 g, 80%): white solid; 94% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=10.5 min, tR(minor)=14.8 min); 1H NMR (400 MHz, CDCl3): δ=7.50-7.41 (m, 2 H, Ar—H), 7.26-7.19 (m, 2 H, Ar—H), 2.32 (d, J=7.4 Hz, 2 H, CH2), 2.16 (s, 3 H, CH3), 1.49-1.39 (m, 2 H, CH2), 1.39-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 172.4, 134.1, 131.7, 127.6, 121.5, 104.5, 102.2, 30.2, 28.2, 22.2, 16.2, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0165 g, 0.0012 mmol), (S)-CPA-1 (0.0159 g, 0.02 mmol), (±)-1g (0.0519 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2g (0.0427 g, 74%): white solid; 94% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=10.5 min, tR(minor)=14.8 min); 1H NMR (400 MHz, CDCl3): δ=7.50-7.41 (m, 2 H, Ar—H), 7.26-7.19 (m, 2 H, Ar—H), 2.32 (d, J=7.4 Hz, 2 H, CH2), 2.16 (s, 3 H, CH3), 1.49-1.39 (m, 2 H, CH2), 1.39-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 172.4, 134.1, 131.7, 127.6, 121.5, 104.5, 102.2, 30.2, 28.2, 22.2, 16.2, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.0403 g, 0.05 mmol), (±)-1h (0.1349 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 65° C. for 24 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=10/1, then 15/1) to afford a product: chiral allenoic acid (S)-2h (0.0911 g, 73%): white solid; 90% ee (HPLC conditions: AD-H column, hexane/iPrOH=99/1, 1.0 mL/min, λ=214 nm, tR(minor)=17.8 min, tR(major)=27.0 min); [α]D26=+19.2 (c=1.00, CHCl3); melting point: 101.4-102.4° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.59 (d, J=8.4 Hz, 2 H, Ar—H), 7.48 (d, J=8.4 Hz, 2 H, Ar—H), 2.34 (t, J=7.6 Hz, 2 H, CH2), 2.21 (s, 3 H, CH3), 1.51-1.41 (m, 2 H, CH2), 1.40-1.30 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.9, 172.5, 139.0, 129.5 (q, J=32.4 Hz), 126.3, 125.5 (q, J=3.7 Hz), 124.1 (q, J=270.2 Hz), 104.5, 102.5, 30.2, 28.2, 22.2, 16.2, 13.8; 19F NMR (376 MHz, CDCl3): δ=−63.1; IR (neat): ν=2957, 2939, 2867, 1943, 1689, 1418, 1327, 1267, 1125, 1075 cm−1; MS (70 eV, EI) m/z (%): 299 (M++1, 1.65), 298 (M+, 9.88), 211 (100); Anal. Calcd. for C16H17F3O2: C 64.42, H 5.74; found C 64.60, H 5.87.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0036 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0369 g, 0.03 mmol), (S)-CPA-1 (0.1202 g, 0.15 mmol), (±)-1i (0.1137 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 65° C. for 24 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ether/dichloromethane=10/1/1, petroleum ether (60˜90° C.)/ethyl acetate=15/1) to afford a product: chiral allenoic acid (S)-21 (0.0772 g, 60%): white solid; 84% ee (HPLC conditions: AS-H column, hexane/iPrOH=90/10, 1.0 mL/min, λ=214 nm, tR(minor)=10.7 min, tR(major)=12.8 min); [α]D25=+17.1 (c=1.00, CHCl3); melting point: (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.63 (d, J=8.4 Hz, 2 H, Ar—H), 7.47 (d, J=8.4 Hz, 2 H, Ar—H), 2.35 (t, J=7.6 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 1.50-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.1, 172.2, 140.1, 132.3, 126.5, 118.7, 110.9, 104.4, 102.8, 30.1, 28.2, 22.2, 16.0, 13.7; IR (neat): ν=2962, 2930, 2862, 2227, 1939, 1693, 1419, 1285, 1059 cm−1; MS (70 eV, EI) m/z (%): 256 (M++1, 1.41), 255 (M+, 4.50), 168 (100); Anal. Calcd. for C16H17NO2: C 75.27, H 6.71; found C 75.16, H 6.65.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.004 g, 0.005 mmol), (±)-1j (0.0465 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 14 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2j (0.0416 g, 80%): white solid; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=11.9 min, tR(minor)=16.1 min); 1H NMR (400 MHz, CDCl3): δ=7.26 (t, J=8.0 Hz, 1 H, Ar—H), 6.98 (d, J=8.0 Hz, 1 H, Ar—H), 6.92 (t, J=2.0 Hz, 1 H, Ar—H), 6.81 (dd, Ji =8.4 Hz, J2=2.4 Hz, 1 H, Ar—H), 3.81 (s, 3 H, OCH3), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.18 (s, 3 H, CH3), 1.52-1.41 (m, 2 H, CH2), 1.41-1.30 (m, 2 H, CH2), 0.88 (t, J=7.4 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.4, 159.8, 136.6, 129.5, 118.6, 112.8, 112.0, 105.1, 101.8, 55.2, 30.2, 28.3, 22.3, 16.4, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.0012 mmol), (S)-CPA-1 (0.0041 g, 0.005 mmol), (±)-1k (0.0432 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 65° C. for 5 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2k (0.0319 g, 65%): white solid; 87% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.3 min, tR(minor)=9.6 min); 1H NMR (400 MHz, CDCl3): δ=7.29-7.12 (m, 3 H, Ar—H), 7.07 (d, J=7.2 Hz, 1 H, Ar—H), 2.41-2.27 (m, 5 H, CH2 and CH3), 2.18 (s, 3 H, CH3), 1.52-1.41 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.4 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.7, 138.1, 134.9, 128.42, 128.38, 126.7, 123.2, 105.2, 101.6, 30.2, 28.3, 22.3, 21.5, 16.4, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0147 g, 0.0012 mmol), (S)-CPA-1 (0.0039 g, 0.005 mmol), (±)-1l (0.043 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 10 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2l (0.0325 g, 67%): white solid; 95% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.4 min, tR(minor)=10.9 min); 1H NMR (400 MHz, CDCl3): δ=7.27 (d, J=8.0 Hz, 2 H, Ar—H), 7.15 (d, J=8.0 Hz, 2 H, Ar—H), 2.38-2.26 (m, 5 H, CH2 and CH3), 2.17 (s, 3 H, CH3), 1.50-1.40 (m, 2 H, CH2), 1.39-1.29 (m, 2 H, CH2), 0.87 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.9, 137.4, 132.0, 129.2, 126.0, 105.1, 101.7, 30.2, 28.3, 22.3, 21.1, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0038 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0369 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1m (0.1223 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 10 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1) to afford a product: chiral allenoic acid (S)-2m (0.0821 g, 60%): white solid; 95% ee (HPLC conditions: AD-H column, hexane/iPrOH=99/1, 1.0 mL/min, λ=214 nm, tR(major)=16.7 min, tR(minor)=18.6 min); [α]D27=+20.7 (c=1.01, CHCl3); melting point: 79.6-80.2° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.31 (d, J=8.4 Hz, 2 H, Ar—H), 7.20 (d, J=8.4 Hz, 2 H, Ar—H), 2.90 (heptet, J=6.8 Hz, 1 H, CH), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.51-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 1.24 (d, J=6.8 Hz, 6 H, 2 x CH3), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.9, 148.4, 132.4, 126.6, 126.0, 105.0, 101.7, 33.8, 30.2, 28.3, 23.90, 23.87, 22.3, 16.3, 13.8; IR (neat): ν=2958, 2927, 1941, 1679, 1419, 1278, 1067 cm−1; MS (70 eV, EI) m/z (%): 272 (M+, 3.98), 143 (100); Anal. Calcd. for C18H24O2: C 79.37, H 8.88; found C 79.32, H 8.82.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0036 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0367 g, 0.03 mmol), (S)-CPA-1 (0.0102 g, 0.0125 mmol), (±)-1n (0.1375 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 10 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1) to afford a product: chiral allenoic acid (S)-2n (0.1372 g, 91%): white solid; 96% ee (HPLC conditions: AD-H column, hexane/iPrOH=99/1, 1.0 mL/min, λ=214 nm, tR(major)=10.6 min, tR(minor)=12.9 min); [α]D29=+20.3 (c=1.00, CHCl3); melting point: 80.8-81.3° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.50 (d, J=8.0 Hz, 2 H, Ar—H), 7.37 (d, J=8.4 Hz, 2 H, Ar—H), 2.32 (t, J=7.4 Hz, 2 H, CH2), 2.18 (s, 3 H, CH3), 1.53-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3), 0.26 (s, 9 H, 3 x CH3); 13C NMR (100 MHz, CDCl3): δ=213.7, 173.9, 140.9, 136.5, 134.6, 126.3, 106.2, 102.9, 31.2, 29.3, 23.3, 17.2, 14.8, −0.2; IR (neat): ν=2956, 2928, 1942, 1682, 1416, 1249, 1058 cm−1; MS (70 eV, EI) m/z (%): 303 (M++1, 1.80), 302 (M+, 7.35), 73 (100); Anal. Calcd. for C18H26O2Si: C 71.47, H 8.66; found C 71.45, H 8.55.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.0041 g, 0.005 mmol), (±)-1o (0.0503 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2o (0.0414 g, 74%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=11.3 min, tR(minor)=15.0 min); 1H NMR (400 MHz, CDCl3): δ=7.87-7.71 (m, 4 H, Ar—H), 7.56-7.40 (m, 3 H, Ar—H), 2.37 (t, J=7.4 Hz, 2 H, CH2), 2.31 (s, 3 H, CH3), 1.54-1.43 (m, 2 H, CH2), 1.42-1.31 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.1, 172.4, 133.5, 132.8, 132.4, 128.09, 128.06, 127.6, 126.3, 126.1, 124.8, 124.2, 105.5, 102.1, 30.2, 28.4, 22.3, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.0012 mmol), (S)-CPA-1 (0.0015 g, 0.002 mmol), (±)-1p (0.0503 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 3 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2p (0.0321 g, 68%): white solid; 93% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=11.5 min, tR(minor)=15.9 min); 1H NMR (400 MHz, CDCl3): δ=7.28 (dd, J1=5.2 Hz, J2=2.8 Hz, 1 H, one proton from thienyl), 7.15 (d, J1=2.8 Hz, J2=1.2 Hz, 1 H, one proton from thienyl), 7.04 (d, J1=5.0 Hz, J2=1.0 Hz, 1 H, one proton from thienyl), 2.31 (t, J=7.4 Hz, 2 H, CH2), 2.17 (s, 3H, CH3), 1.50-1.40 (m, 2H, CH2), 1.40-1.30 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.8, 172.2, 136.5, 126.3, 125.9, 120.6, 101.4, 101.3, 30.3, 28.4, 22.2, 16.7, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.004 g, 0.002 mmol), (±)-1q (0.042 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. No target chiral allenoic acid product (S)-2q was formed.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0369 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1r (0.0943 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2r (0.0948 g, 88%): white solid; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.4 min, tR(minor)=12.7 min); [α]D26=+49.4 (c=1.01, CHCl3); melting point: 88.5-89.6° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.38 (d, J=7.6 Hz, 2 H, Ar—H), 7.33 (t, J=7.4 Hz, 2 H, Ar—H), 7.24 (t, J=7.2 Hz, 1 H, Ar—H), 2.30 (t, J=7.6 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.51 (sextet, J=7.4 Hz, 2 H, CH2), 0.92 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.7, 173.0, 135.0, 128.5, 127.5, 126.1, 105.2, 101.6, 30.6, 21.4, 16.3, 13.7; IR (neat): ν=2961, 2929, 1942, 1682, 1415, 1263, 1066 cm−1; MS (70 eV, EI) m/z (%): 217 (M++1, 3.86), 216 (M+, 24.20), 143 (100); Anal. Calcd. for Ci4H1602: C 77.75, H 7.46; found C 77.89, H 7.63.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.0012 mmol), (S)-CPA-1 (0.0118 g, 0.015 mmol), (±)-1s (0.0531 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2s (0.0449 g, 77%): white solid; 96% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 0.5 mL/min, λ=214 nm, tR(major)=23.1 min, tR(minor)=26.0 min); 1H NMR (400 MHz, CDCl3): δ=7.46 (d, J=8.4 Hz, 2 H, Ar—H), 7.25 (d, J=8.4 Hz, 2 H, Ar—H), 2.79 (heptet, J=6.8 Hz, 1 H, CH), 2.17 (s, 3 H, CH3), 1.09 (d, J=6.8 Hz, 6 H, 2 x CH3); 13C NMR (100 MHz, CDCl3): δ=211.2, 171.9, 134.0, 131.7, 127.5, 121.5, 109.0, 105.9, 28.2, 22.1, 22.0, 16.3.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.004 g, 0.015 mmol), (±)-1t (0.0346 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 65° C. for 4 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2t (0.0346 g, 70%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.5 min, tR(minor)=9.9 min); 1H NMR (400 MHz, CDCl3): δ=7.44-7.28 (m, 4 H, Ar—H), 7.28-7.22 (m, 1 H, Ar—H), 2.33 (t, J=8.0 Hz, 2 H, CH3), 2.19 (s, 3 H, CH3), 1.65-1.50 (m, 1 H, CH), 1.42-1.30 (m, 2 H, CH2), 0.87 (t, J=6.0 Hz, 6 H, 2 x CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 172.6, 135.0, 128.5, 127.6, 126.1, 105.3, 102.0, 37.1, 27.7, 26.6, 22.44, 22.40, 16.3.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0147 g, 0.0012 mmol), (S)-CPA-1 (0.0041 g, 0.015 mmol), (±)-1u (0.0431 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2u (0.0434 g, 89%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.8 min, tR(minor)=12.9 min); 1H NMR (400 MHz, CDCl3): δ=7.44-7.30 (m, 4 H, Ar—H), 7.28-7.22 (m, 1 H, Ar—H), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.54-1.41 (m, 2 H, CH2), 1.33-1.23 (m, 4 H, 2 x CH2), 0.84 (t, J=7.0 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.7, 135.0, 128.5, 127.6, 126.1, 105.2, 101.8, 31.3, 28.5, 27.7, 22.4, 16.3, 14.0.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.0012 mmol), (S)-CPA-1 (0.0041 g, 0.015 mmol), (±)-1v (0.0485 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2v (0.0405 g, 79%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.3 min, tR(minor)=12.2 min); 1H NMR (400 MHz, CDCl3): δ=7.41-7.29 (m, 4 H, Ar—H), 7.28-7.22 (m, 1 H, Ar—H), 2.32 (t, J=7.4 Hz, 2 H, CH2), 2.19 (s, 3H, CH3), 1.53-1.41 (m, 2 H, CH2), 1.36-1.15 (m, 6 H, 3 x CH2), 0.84 (t, J=6.8 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.7, 135.0, 128.5, 127.6, 126.1, 105.2, 101.8, 31.6, 28.8, 28.6, 28.0, 22.6, 16.3, 14.0.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0038 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0367 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1w (0.1292 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 10 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1) to afford a product: chiral allenoic acid (S)-2w (0.0812 g, 57%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.2 min, tR(minor)=9.6 min); [α]D31=+3.0 (c=1.00, CHCl3); melting point: 81.4-82.4° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.26 (d, J=8.4 Hz, 2 H, Ar—H), 7.14 (d, J=8.0 Hz, 2 H, Ar—H), 2.38-2.26 (m, 5 H, CH2 and CH3), 2.17 (s, 3 H, CH3), 1.52-1.41 (m, 2 H, CH2), 1.35-1.16 (m, 8 H, 4 x CH2), 0.85 (t, J=6.8 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.9, 137.4, 132.0, 129.2, 126.0, 105.1, 101.6, 31.8, 29.14, 29.07, 28.6, 28.1, 22.6, 21.1, 16.3, 14.0; IR (neat): ν=2955, 2926, 2856, 1941, 1681, 1417, 1278, 1063 cm−1; MS (70 eV, EI) m/z (%): 287 (M++1, 2.80), 286 (M+, 6.61), 157 (100); Anal. Calcd. for C19H26O2: C 79.68, H 9.15; found C 79.78, H 9.18.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0147 g, 0.0012 mmol), (S)-CPA-1 (0.0081 g, 0.01 mmol), (±)-1x (0.0585 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2x (0.0495 g, 77%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=6.4 min, tR(minor)=9.7 min); 1H NMR (400 MHz, CDCl3): δ=7.30 (s, 4 H, Ar—H), 2.31 (t, J=7.4 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.51-1.39 (m, 2 H, CH2), 1.34-1.17 (m, 10 H, 5 x CH2), 0.86 (t, J=6.8 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.5, 133.6, 133.4, 128.7, 127.3, 104.4, 102.2, 31.8, 29.3, 29.2, 29.1, 28.5, 28.0, 22.6, 16.3, 14.0.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0036 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.037 g, 0.03 mmol), (S)-CPA-1 (0.02 g, 0.025 mmol), (±)-1y (0.211 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1) to afford a product: chiral allenoic acid (S)-2y (0.1459 g, 65%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 0.5 mL/min, λ=214 nm, tR(major)=10.2 min, tR(minor)=14.5 min); [α]D25=−3.4 (c=1.04, CHCl3); melting point: 81.1-81.6° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.45 (d, J=8.4 Hz, 2 H, Ar—H), 7.23 (d, J=8.4 Hz, 2 H, Ar—H), 2.31 (t, J=7.4 Hz, 2 H, CH2), 2.16 (s, 3 H, CH3), 1.51-1.39 (m, 2 H, CH2), 1.36-1.12 (m, 22 H, 11 x CH2), 0.88 (t, J=6.6 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.7, 134.1, 131.6, 127.6, 121.5, 104.5, 102.2, 31.9, 29.68, 29.66, 29.64, 29.59, 29.4, 29.3, 29.2, 28.5, 28.0, 22.7, 16.2, 14.1; IR (neat): ν=2921, 2854, 1940, 1685, 1475, 1417, 1271, 1079, 1017 cm−1; MS (70 eV, EI) m/z (%): 450 (M+ (81Br), 4.83), 448 (M+ (79Br), 4.76), 143 (100); Anal. Calcd. for C25H37BrO2: C 66.81, H 8.30; found C 66.84, H 8.21.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.004 g, 0.005 mmol), (±)-1z (0.0503 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), Toluene (0.8 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2z (0.0455 g, 81%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=14.3 min, tR(minor)=25.7 min); 1H NMR (400 MHz, CDCl3): δ=7.34-7.21 (m, 7 H, Ar—H), 7.19-7.13 (m, 3 H, Ar—H), 2.84 (t, J=7.6 Hz, 2 H, CH3), 2.75-2.59 (m, 2 H, CH2), 2.02 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.9, 172.6, 141.1, 134.7, 128.5, 128.3, 127.6, 126.1, 125.9, 105.5, 100.7, 34.0, 30.3, 16.1.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.0012 mmol), (S)-CPA-1 (0.0081 g, 0.01 mmol), (±)-1aa (0.0475 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 65° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2aa (0.0328 g, 62%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=16.8 min, tR(minor)=25.0 min); 1H NMR (400 MHz, CDCl3): δ=7.42-7.31 (m, 4 H, Ar—H), 7.29-7.24 (m, 1 H, Ar—H), 3.50 (t, J=6.6 Hz, 2 H, CH2), 2.36 (t, J=7.6 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 1.84-1.76 (m, 2 H, CH2), 1.69-1.57 (m, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.6, 134.7, 128.6, 127.7, 126.1, 105.7, 101.1, 44.6, 32.0, 27.8, 25.3, 16.4.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0073 g, 0.02 mmol), chiral bisphosphine ligand (S)-L4d (0.0733 g, 0.06 mmol), (S)-CPA-1 (0.01 g, 0.0125 mmol), (±)-1ab (0.1069 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.786 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate/dichloromethane=10/1/1, then petroleum ether (60˜90° C.)/ethyl acetate=3/1) to afford a product: chiral allenoic acid (S)-2ab (0.0328 g, 62%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=16.8 min, tR(minor)=25.0 min); 1H NMR (400 MHz, CDCl3): δ=7.42-7.31 (m, 4 H, Ar—H), 7.29-7.24 (m, 1 H, Ar—H), 3.50 (t, J=6.6 Hz, 2 H, CH2), 2.36 (t, J=7.6 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 1.84-1.76 (m, 2 H, CH2), 1.69-1.57 (m, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.6, 134.7, 128.6, 127.7, 126.1, 105.7, 101.1, 44.6, 32.0, 27.8, 25.3, 16.4.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0038 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.01 g, 0.0125 mmol), (±)-1ac (0.1775 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 65° C. for 10 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ether/dichloromethane=10/1/1, then petroleum ether (60˜90° C.)/ethyl acetate=8/1) to afford a product: chiral allenoic acid (S)-2ac (0.1166 g, 61%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=90/10, 1.0 mL/min, λ=214 nm, tR(major)=6.8 min, tR(minor)=8.2 min); [α]D25=−31.4 (c=1.00, CHCl3); melting point: 171.1-172.2° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=8.07 (d, J=7.6 Hz, 2 H, Ar—H), 7.43-7.23 (m, 9 H, Ar—H), 7.19 (t, J=7.4 Hz, 2 H, Ar—H), 4.30 (t, J=7.4 Hz, 2 H, CH2), 2.46 (t, J=7.4 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.12-1.98 (m, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.2, 172.1, 140.3, 134.6, 128.7, 127.9, 126.1, 125.6, 122.8, 120.3, 118.8, 108.5, 106.3, 100.9, 42.6, 27.2, 26.3, 16.5; IR (neat): ν=3054, 2936, 1940, 1682, 1454, 1335, 1262, 1021 cm−1; MS (70 eV, EI) m/z (%): 382 (M++1, 7.06), 381 (M+, 20.11), 193 (100); Anal. Calcd. for C26H23NO2: C 81.86, H 6.08; found C 81.97, H 6.07.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0035 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1ad (0.1234 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate/dichloromethane=10/1/1, then petroleum ether (60˜90° C.)/ethyl acetate=8/1) to afford a product: chiral allenoic acid (S)-2ad (0.1134 g, 83%): oil substance; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=90/10, 1.0 mL/min, λ=214 nm, tR(major)=7.8 min, tR(minor)=10.8 min); [α]D27=+7.5 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.45-7.29 (m, 4 H, Ar—H), 7.29-7.24 (m, 1 H, Ar—H), 4.09 (t, J=6.4 Hz, 2 H, CH2), 2.42 (t, J=7.6 Hz, 2 H, CH2), 2.21 (s, 3 H, CH3), 2.02 (s, 3 H, CH3), 1.88-1.76 (m, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.3, 172.3, 171.2, 134.6, 128.6, 127.7, 126.0, 105.8, 100.8, 63.7, 27.0, 25.2, 20.8, 16.3; IR (neat): ν=2956, 2929, 1942, 1737, 1717, 1681, 1367, 1238, 1041 cm−1; MS (70 eV, ESI) m/z: 297 (M+Na+), 275 (M+H+); HRMS calcd for C16H19O4 [M+H+]: 275.1278, found: 275.1271.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0149 g, 0.0012 mmol), (S)-CPA-1 (0.0041 g, 0.005 mmol), (±)-1ae (0.0347 g, 0.2 mmol), bromobenzene (211 μL, d=1.49 g/mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 65° C. for 15 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2ae (0.0237 g, 55%): white solid; 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=16.8 min, tR(minor)=25.0 min); 1H NMR (400 MHz, CDCl3): δ=7.42-7.31 (m, 4 H, Ar—H), 7.29-7.24 (m, 1 H, Ar—H), 3.50 (t, J=6.6 Hz, 2 H, CH2), 2.36 (t, J=7.6 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 1.84-1.76 (m, 2 H, CH2), 1.69-1.57 (m, 2 H, CH2); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.6, 134.7, 128.6, 127.7, 126.1, 105.7, 101.1, 44.6, 32.0, 27.8, 25.3, 16.4.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol), (±)-1af (0.142 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2af (0.0904 g, 59%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 0.5 mL/min, λ=214 nm, tR(major)=13.1 min, tR(minor)=16.7 min); [α]D25=−5.4 (c=1.00, CHCl3); melting point: (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.44-7.34 (m, 4 H, Ar—H), 7.32-7.27 (m, 1 H, Ar—H), 2.47 (td, J1=7.5 Hz, J2=2.0 Hz, 2 H, CH2), 2.29 (t, J=7.2 Hz, 2 H, CH2), 2.24 (s, 3 H, CH3), 1.80-1.70 (m, 2 H, CH2), 0.15 (s, 9 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.6, 134.8, 128.6, 127.7, 126.1, 106.6, 105.6, 100.9, 84.9, 27.8, 26.9, 19.3, 16.4, 0.1; IR (neat): ν=2958, 2173, 1941, 1682, 1417, 1281, 1250, 1026 cm−1; MS (70 eV, ESI) m/z: 313 (M+H+); Anal. Calcd. for C19H24O2Si: C 73.03, H 7.74; found C 73.19, H 7.75.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0038 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0369 g, 0.03 mmol), (S)-CPA-1 (0.0102 g, 0.0125 mmol), (±)-1af (0.1421 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (R)-2af (0.0965 g, 62%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 0.5 mL/min, λ=214 nm, tR(minor)=13.3 min, tR(major)=16.0 min); [α]D25=+5.5 (c=1.00, CHCl3); melting point: 97.2-98.5° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.45-7.33 (m, 4 H, Ar—H), 7.33-7.26 (m, 1 H, Ar—H), 2.47 (td, J1=7.5 Hz, J2=2.3 Hz, 2 H, CH2), 2.29 (t, J=7.0 Hz, 2 H, CH2), 2.24 (s, 3 H, CH3), 1.81-1.70 (m, 2 H, CH2), 0.15 (s, 9 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.6, 134.8, 128.6, 127.7, 126.1, 106.6, 105.6, 100.9, 84.9, 27.8, 26.9, 19.3, 16.4, 0.1; IR (neat): ν=2957, 2173, 1941, 1681, 1416, 1281, 1249, 1026 cm−1; MS (70 eV, ESI) m/z: 335 (M+Nat), 313 (M+H+); Anal. Calcd. for C19H24O2Si: C 73.03, H 7.74; found C 73.26, H 8.01.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0074 g, 0.02 mmol), chiral bisphosphine ligand (S)-L4d (0.0763 g, 0.06 mmol), (S)-CPA-1 (0.02 g, 0.025 mmol)), (±)-1ag (0.1085 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2ag (0.0975 g, 80%): white solid; 89% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.4 min, tR(minor)=9.1 min); [α]D25=+12.3 (c=1.00, CHCl3); melting point: 64.4-65.4° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.38 (d, J=7.2 Hz, 2 H, Ar—H), 7.33 (t, J=7.8 Hz, 2 H, Ar—H), 7.27-7.21 (m, 1 H, Ar—H), 2.55 (quartet, J=7.3 Hz, 2 H, CH2), 2.33 (t, J=7.6 Hz, 2 H, CH2), 1.52-1.41 (m, 2 H, CH2), 1.41-1.29 (m, 2 H, CH2), 1.17 (t, J=7.4 Hz, 3 H, CH3), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.2, 173.3, 134.9, 128.6, 127.5, 126.3, 112.1, 103.8, 30.4, 28.4, 23.2, 22.4, 13.8, 12.3; IR (neat): ν=2960, 2931, 2873, 1939, 1678, 1415, 1277 cm−1; MS (70 eV, EI) m/z (%): 245 (M++1, 1.08), 244 (M+, 5.31), 129 (100); Anal. Calcd. for C16H20O2: C 78.65, H 8.25; found C 78.73, H 8.40.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0075 g, 0.02 mmol), chiral bisphosphine ligand (S)-L4d (0.0735 g, 0.06 mmol), (S)-CPA-1 (0.0302 g, 0.0375 mmol), (±)-1ag (0.1152 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2ag (0.1025 g, 79%): white solid; 77% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.2 min, tR(minor)=9.1 min); [α]D26=+12.7 (c=1.02, CHCl3); melting point: 62.9-64.0° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=7.38 (d, J=6.8 Hz, 2 H, Ar—H), 7.33 (t, J=8.0 Hz, 2 H, Ar—H), 7.28-7.21 (m, 1 H, Ar—H), 2.51 (t, J=7.4 Hz, 2 H, CH2), 2.32 (t, J=7.6 Hz, 2 H, CH2), 1.64-1.51 (m, 2H, CH2), 1.51-1.40 (m, 2 H, CH2), 1.40-1.29 (m, 2 H, CH2), 1.01 (t, J=7.4 Hz, 3 H, CH3), 0.87 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 173.2, 134.9, 128.6, 127.5, 126.4, 110.3, 102.9, 32.2, 30.4, 28.4, 22.4, 21.0, 13.9, 13.8; IR (neat): ν=2957, 2929, 2872, 1938, 1676, 1494, 1453, 1276 cm−1; MS (70 eV, EI) m/z (%): 258 (M+, 6.49), 129 (100); Anal. Calcd. for C17H22O2: C 79.03, H 8.58; found C 79.26, H 9.12.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0036 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0367 g, 0.03 mmol), (S)-CPA-1 (0.0502 g, 0.0625 mmol)), 5 (0.192 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid 10 (0.1492 g, 72%): oil substance; >20:1 dr; [α]D24=−37.7 (c=1.54, CHCl3); 1H NMR (400 MHz, CDCl3): δ=8.02 (d, J=8.4 Hz, 2 H, Ar—H), 7.44 (d, J =8.4 Hz, 2 H, Ar—H), 4.92 (td, J1=11.0 Hz, J2=4.4 Hz, 1 H, CH), 2.34 (t, J=7.4 Hz, 2 H, CH2), 2.21 (s, 3 H, CH3), 2.17-2.09 (m, 1 H, CH), 2.02-1.86 (m, 1 H, CH), 1.73 (d, J=11.2 Hz, 2 H, CH2), 1.64-1.50 (m, 2 H, CH2), 1.50-1.40 (m, 2 H, CH2), 1.40-1.30 (m, 2 H, CH2), 1.20-1.02 (m, 2 H, CH2), 1.00-0.84 (m, 10 H, CH and 3 x CH3), 0.79 (d, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.1, 172.3, 165.8, 139.7, 129.81, 129.76, 125.9, 104.8, 102.3, 74.9, 47.3, 40.9, 34.3, 31.4, 30.2, 28.2, 26.6, 23.7, 22.2, 22.0, 20.7, 16.6, 16.2, 13.8; IR (neat): ν=2956, 2928, 2868, 1941, 1709, 1683, 1271, 1112 cm−1; MS (70 eV, ESI) m/z: 435 (M+Na+); HRMS calcd for C26H36O4Na [M+Na+]: 435.2506, found: 435.2501.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.0504 g, 0.0625 mmol)), 6 (0.1902 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid 11 (0.1445 g, 71%): oil substance; >20:1 dr; [α]D25=−22.3 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=8.03 (d, J=8.4 Hz, 2 H, Ar—H), 7.44 (d, J=8.4 Hz, 2 H, Ar—H), 5.84 (s, 1 H, ═CH), 4.95-4.43 (m, 4 H, ═CH2 and CH2), 2.34 (t, J=7.4 Hz, 2 H, CH2), 2.28-2.07 (m, 7 H, 2 x CH2 and CH3), 2.05-1.96 (m, 1 H, one proton of CH2), 1.91-1.82 (m, 1 H, one proton of CH2), 1.75 (s, 3 H, CH3), 1.58-1.40 (m, 3 H, CH and CH2), 1.39-1.29 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.1, 172.2, 166.2, 149.5, 139.9, 132.6, 129.9, 129.3, 125.9, 125.6, 108.8, 104.8, 102.3, 68.8, 40.8, 30.4, 30.1, 28.2, 27.3, 26.4, 22.2, 20.7, 16.2, 13.8; IR (neat): ν=2957, 2925, 2863, 1941, 1716, 1683, 1415, 1268, 1104 cm−1; MS (70 eV, EI) m/z (%): 409 (M++1, 1.37), 408 (M+, 4.44), 257 (100); HRMS calcd for C26H32O4 [M+]: 408.2301, found: 408.2299.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0367 g, 0.03 mmol), (S)-CPA-1 (0.0506 g, 0.0625 mmol), 7 (0.1922 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid 12 (0.1488 g, 72%): oil substance; >20:1 dr; [α]D25=+11.2 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=8.01 (d, J=8.0 Hz, 2 H, Ar—H), 7.44 (d, J=8.4 Hz, 2 H, Ar—H), 5.10 (t, J=6.8 Hz, 1 H, ═CH), 4.45-4.23 (m, 2 H, CH2), 2.34 (t, J=7.6 Hz, 2 H, CH2), 2.21 (s, 3 H, CH3), 2.09-1.92 (m, 2 H, CH2), 1.86-1.77 (m, 1 H, CH), 1.72-1.52 (m, 8 H, CH2 and 2 x CH3), 1.50-1.21 (m, 6 H, 3 x CH2), 0.97 (d, J=6.8 Hz, 3 H, CH3), 0.88 (t, J=7.4 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.1, 172.3, 166.4, 139.8, 131.3, 129.8, 129.4, 125.9, 124.5, 104.8, 102.3, 63.5, 36.9, 35.4, 30.1, 29.6, 28.2, 25.7, 25.4, 22.2, 19.5, 17.6, 16.2, 13.8; IR (neat): ν=2959, 2923, 2864, 1941, 1717, 1683, 1457, 1271, 1108 cm−1; MS (70 eV, EI) m/z (%): 412 (M+, 2.99), 81 (100); HRMS calcd for C26H36O4 [M+]: 412.2614, found: 412.2609.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0038 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0368 g, 0.03 mmol), (S)-CPA-1 (0.06 g, 0.0625 mmol)), 8 (0.3078 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a crude product: chiral allenoic acid S1-13 (0.2963 g), all of which was put to the next reaction.
S1-13 (0.2963 g, ˜0.5 mmol), NBS (N-bromosuccinimide) (0.1064 g, 0.6 mmol) and CHCl3 (5 mL) were added in sequence to a dry Schlenk reaction tube. The reaction tube was plugged with a rubber stopper, then reacted at room temperature for 2 hours, concentrated, and subjected to flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: bromo chiral γ-butyrolactone 13 (0.2603 g, 72%): oil substance; >20:1 dr; [α]D23=+63.5 (c=1.00, CHCl3); melting point: 183.3-184.2° C. (petroleum ether/DCM); 1H NMR (400 MHz, CDCl3): δ=8.05 (d, J=8.4 Hz, 2 H, Ar—H), 7.45 (d, J=8.4 Hz, 2 H, Ar—H), 5.48-5.32 (m, 1 H, ═CH), 4.95-4.74 (m, 1 H, CH), 2.45 (d, J=7.6 Hz, 2 H, CH2), 2.36 (t, J=7.6 Hz, 2 H, CH2), 2.06-1.67 (m, 9 H), 1.64-1.42 (m, 8 H), 1.40-1.29 (m, 5 H), 1.29-0.96 (m, 14 H), 0.95-0.89 (m, 6 H), 0.87 (dd, J1=6.8 Hz, J2=1.6 Hz, 6 H, 2 x CH3), 0.69 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=170.1, 165.2, 149.8, 141.9, 139.4, 131.6, 131.3, 129.8, 125.5, 122.8, 87.7, 74.8, 56.6, 56.1, 50.0, 42.2, 39.7, 39.4, 38.1, 36.9, 36.6, 36.1, 35.7, 31.9, 31.8, 28.9, 28.2, 27.9, 27.8, 24.8, 24.2, 23.9, 23.8, 22.8, 22.5, 22.3, 21.0, 19.3, 18.7, 13.7, 11.8; IR (neat): ν=2939, 2861, 1749, 1717, 1461, 1274, 1111, 1025 cm−1; MS (DART) m/z: 740 (M(81Br)+NH4+); 738 (M(79Br)+NH4+; Anal. Calcd. for C43H61BrO4: C 71.55, H 8.52; found C 71.42, H 8.71.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0037 g, 0.01 mmol), chiral bisphosphine ligand (S)-L4d (0.0364 g, 0.03 mmol), (S)-CPA-1 (0.0101 g, 0.0125 mmol)), 9 (0.2087 g, 0.5 mmol), bromobenzene (527 μL, d=1.49 g/mL, 0.7860 g, 5 mmol), water (180 μL, d=1.0 g/mL, 0.18 g, 10 mmol), toluene (2 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=10/1, then petroleum ether (60˜90° C.)/ether/dichloromethane=4/1/1) to afford a product: chiral allenoic acid 14 (0.1379 g, 62%): oil substance; >20:1 dr; [α]D21=+15.7 (c=1.10, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.70-7.54 (m, 3 H, Ar—H), 7.36 (dd, J1=8.6 Hz, J2=1.4 Hz, 1 H, Ar—H), 7.33-7.21 (m, 5 H, Ar—H), 7.09 (dd, J1=9.0 Hz, J2=2.6 Hz, 1 H, Ar—H), 7.07-7.03 (m, 1 H, Ar—H), 4.15-4.02 (m, 2 H, CH2), 3.90-3.75 (m, 4 H, CH and OCH3), 2.39-2.21 (m, 2 H, CH2), 2.11 (s, 3 H, CH3), 1.82-1.70 (m, 2 H, CH2), 1.54 (d, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.4, 174.6, 172.2, 157.5, 135.6, 134.6, 133.6, 129.2, 128.8, 128.5, 127.7, 127.0, 126.1, 126.0, 125.8, 118.8, 105.7, 105.5, 100.6, 63.8, 55.2, 45.3, 26.9, 25.1, 18.3, 16.2; IR (neat): ν=2938, 2850, 1941, 1725, 1682, 1454, 1265, 1182, 1029 cm−1; MS (70 eV, ESI) m/z: 467 (M+Na+); HRMS calcd for C28H28O5Na [M+Na+]: 467.1829, found: 467.1826.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0368 g, 0.1 mmol), chiral bisphosphine ligand (S)-L4d (0.3638 g, 0.3 mmol), (S)-CPA-1 (0.1009 g, 0.0125 mmol), (±)-1a (1.0109 g, 5.0 mmol), bromobenzene (5.27 mL, d=1.49 g/mL, 7.8523 g, 50 mmol), water (1.8019 g, 100 mmol), toluene (20 mL) were reacted at 50° C. for 12 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=15/1, then 10/1) to afford a product: chiral allenoic acid (S)-2a (1.0227 g, 89%): white solid; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.5 min, tR(minor)=11.9 min); 1H NMR (400 MHz, CDCl3): δ=7.44-7.29 (m, 4 H, Ar—H), 7.28-7.21 (m, 1 H, Ar—H), 2.32 (t, J=7.4 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.52-1.41 (m, 2 H, CH2), 1.40-1.28 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.8, 135.0, 128.5, 127.6, 126.1, 105.2, 101.8, 30.2, 28.3, 22.2, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0184 g, 0.1 mmol), chiral bisphosphine ligand (S)-L4d (0.1818 g, 0.3 mmol), (S)-CPA-1 (0.1007 g, 0.0125 mmol), (±)-1a (1.0115 g, 5.0 mmol), bromobenzene (5.27 mL, d=1.49 g/mL, 7.8523 g, 50 mmol), water (1.8008 g, 100 mmol), toluene (20 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (S)-2a (0.8994 g, 78%): white solid; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.7 min, tR(minor)=12.3 min); 1H NMR (400 MHz, CDCl3): δ=7.43-7.28 (m, 4 H, Ar—H), 7.27-7.22 (m, 1 H, Ar—H), 2.32 (t, J=7.6 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.52-1.41 (m, 2 H, CH2), 1.40-1.28 (m, 2 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.5, 172.5, 135.0, 128.5, 127.6, 126.1, 105.2, 101.8, 30.2, 28.3, 22.3, 16.3, 13.8.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0367 g, 0.1 mmol), chiral bisphosphine ligand (S)-L4d (0.3634 g, 0.3 mmol), (S)-CPA-1 (0.1008 g, 0.0125 mmol), (±)-1af (1.4219 g, 5.0 mmol), bromobenzene (5.27 mL, d=1.49 g/mL, 7.8523 g, 50 mmol), water (1.8012 g, 100 mmol), toluene (20 mL) were reacted at 50° C. for 18 hours. Flash column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1, then 15/1) to afford a product: chiral allenoic acid (R)-2af (1.1935 g, 76%): white solid; 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(minor)=6.7 min, tR(major)=8.1 min); 1H NMR (400 MHz, CDCl3): δ=7.42-7.32 (m, 4 H, Ar—H), 7.28-7.23 (m, 1 H, Ar—H), 2.43 (td, J1=7.5 Hz, J2=2.3 Hz, 2 H, CH2), 2.26 (t, J=7.0 Hz, 2 H, CH2), 2.21 (s, 3 H, CH3), 1.76-1.65 (m, 2 H, CH2), 0.12 (s, 9 H, CH3); 13C NMR (100 MHz, CDCl3): δ=212.6, 172.6, 134.8, 128.6, 127.7, 126.1, 106.6, 105.5, 100.9, 84.9, 27.8, 26.9, 19.3, 16.4, 0.1.
(S)-2a (0.4608 g, 2 mmol, 92% ee), K2CO3 (0.4152 g, 3 mmol), DMF (N,N-dimethylformamide) (10 mL) was added in sequence to a dry Schlenk reaction tube, the reaction tube was placed in a −5° C. cold bath, and then CH3I (iodomethane) (188 μL, d=2.28 g/mL, 0.4286 g, 3 mmol) was added, the reaction was completed after stirred in a −5° C. cold bath for 1.5 hours as monitored by thin layer chromatography (TLC). The reaction was quenched by water (10 mL), the aqueous phase was extracted with ether (10 mL×3), the organic phases were combined, washed once with saturated ammonium chloride solution (10 mL), once with saturated brine (10 mL), separated and dried over anhydrous sodium sulfate, filtered and concentrated to afford an oily chiral allenoate which was used directly in the next reaction. All the S1 and toluene (10 mL) obtained in the previous step were added to a dry Schlenk reaction tube, the reaction tube was placed in a −78° C. cold bath and added with DIBAL-H (diisobutylaluminum hydride) (4.2 mL, 1.0 M in Hexane, 4.2 mmol) dropwise, the reaction was completed after stirred in a −5° C. cold bath for 4 hours as monitored by thin layer chromatography (TLC). The reaction was quenched by methanol (10 mL) at −78° C., the reaction tube was taken out of the cold bath, and after returning to room temperature, added with water (20 mL) and 1 mol/L aqueous hydrochloric acid solution (20 mL), the aqueous phase was extracted with ether (10 mL×3), the organic phases were combined, washed once with saturated brine (10 mL), separated, and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1) to afford chiral allenol S1-15, which is directly used in the next reaction.
All the S1-15 obtained in the previous step, Fe(NO3)3·9H2O (0.121 g, 0.3 mmol), 4-OH-TEMPO (0.0687 g, 0.4 mmol), NaCl (0.0236 g, 0.4 mmol), and DCE (1,2-dichloroethane) (8 mL) were added to a dry Schlenk reaction tube, the reaction was completed after stirred at room temperature for 15 hours as monitored by thin layer chromatography (TLC), and the reaction solution was filtered through a short silica gel column (3 cm), then subjected to flash column chromatography (eluent: petroleum ether (60˜90° C.)/ether/dichloromethane=100/1/1) to afford a product: chiral biuronic acid 15 (0.2478 g, 58%): oil substance; 91% ee (HPLC conditions: AS-H column, hexanePPrOH=99/1, 1.0 mL/min, λ=214 nm, tR(minor)=6.5 min, tR(major)=7.6 min); [α]D23=−5.1 (c=1.02, CHCl3); oil; 1H NMR (400 MHz, CDCl3): δ=9.60 (s, 1 H, CHO), 7.44-7.33 (m, 4 H, Ar—H), 7.32-7.26 (m, 1 H, Ar—H), 2.31 (t, J=7.6 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3), 1.52-1.42 (m, 2 H, CH2), 1.42-1.32 (m, 2 H, CH2), 0.90 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=219.5, 192.1, 134.5, 128.7, 127.9, 125.9, 113.5, 106.6, 29.9, 24.8, 22.4, 16.6, 13.8; IR (neat): ν=2960, 2866, 1931, 1680, 1452, 1171 cm−1; MS (70 eV, EI) m/z (%): 215 (M++1, 3.12), 214 (M+, 5.61), 128 (100); HRMS calcd for C15H18O [M+]: 214.1352, found: 214.1355.
(S)-2a (0.1151 g, 0.5 mmol, 92% ee), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.1245 g, 0.65 mmol), dimethylhydroxylamine hydrochloride (0.0637 g, 0.65 mmol), 4-dimethylaminopyridine (DMAP) (0.0063 g, 0.05 mmol), triethylamine (NEt3) (90 μL, d=0.728 g/mL, 0.0655 g, 0.65 mmol) were added to a dry Schlenk reaction tube, which was replaced with argon three times, then dichloromethane (DCM) (2 mL) was added, and the reaction was completed after stirred in a cold bath at 0° C. for 3 hours as monitored by thin layer chromatography (TLC). After diluted by Dichloromethane (5 mL), the reaction was quenched by water (5 mL), the aqueous phase was extracted with dichloromethane (5 mL×3), the organic phases were combined, washed once with saturated brine (5 mL), separated and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=10/1) to afford a product: allenamide (S)-16 (0.1296 g, 95%): oil substance; 92% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=6.5 min, tR(minor)=7.8 min); [α]D20=+125.0 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.41 (d, J=8.8 Hz, 2 H, Ar—H), 7.34 (t, J=7.6 Hz, 2 H, Ar—H), 7.25-7.19 (m, 1 H, Ar—H), 3.51 (s, 3 H, CH3), 3.22 (s, 3 H, CH3), 2.41 (t, J=7.4 Hz, 2 H, CH2), 2.17 (s, 3 H, CH3), 1.51-1.42 (m, 2 H, CH2), 1.42-1.31 (m, 2 H, CH2), 0.89 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=206.3, 168.1, 136.0, 128.4, 127.0, 125.8, 102.1, 101.0, 61.1, 33.9, 30.2, 30.1, 22.4, 16.5, 13.9; IR (neat): ν=2956, 2928, 2864, 1942, 1637, 1453, 1365, 1186 cm−1; MS (70 eV, ESI) m/z: 296 (M+Na+), 274 (M+H+); HRMS calcd for C17H23O2N [M+H+]: 274.1802, found: 274.1800.
(S)-16 (0.0545 g, 0.2 mmol, 92% ee), and tetrahydrofuran (THF) (1 mL) were added to a dry Schlenk reaction tube, which was replaced with argon three times, then the reaction tube was put in −78° C. cold bath, and methylmagnesium bromide (0.27 mL, 3.0 M in hexane, 0.81 mmol) was added. Then the reaction was completed after stirred in a cold bath at 0° C. for 1 hour as monitored by thin layer chromatography (TLC). The reaction was quenched by saturated ammonium chloride (1 mL)at 0° C., the aqueous phase was extracted with ethyl acetate (2 mL×3), the organic phases were combined, washed once with saturated brine (3 mL), separated and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: petroleum ether (60˜90° C.)/ethyl acetate=20/1) to afford a product: allenone (S)-17 (0.044 g, 97%): oil substance; 92% ee (HPLC conditions: AD-H column, hexane/iPrOH=99.5/0.5, 0.5 mL/min, λ=214 nm, tR(minor)=11.8 min, tR(major)=12.3 min); [α]D21=+58.6 (c=1.01, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.45-7.31 (m, 4 H, Ar—H), 7.30-7.24 (m, 1 H, Ar—H), 2.31 (t, J=7.4 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3), 2.23 (s, 3 H, CH3), 1.46-1.30 (m, 4 H, CH2), 0.88 (t, J=7.2 Hz, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=213.8, 198.9, 134.9, 128.7, 127.5, 125.7, 111.4, 104.8, 30.1, 27.2, 26.7, 22.4, 16.4, 13.8; IR (neat): ν=2955, 2925, 2860, 1931, 1676, 1454, 1358, 1234 cm−1; MS (70 eV, EI) m/z (%): 229 (M++1, 1.53), 228 (M+, 8.77), 185 (100); HRMS calcd for C16H20O [M+]: 228.1509, found: 228.1509.
(S)-2a (0.0462 g, 0.2 mmol, 92% ee), 18 (0.1119 g, 0.28 mmol), and PdCl2 (0.0019 g, 0.01 mmol) were added to a dry Schlenk reaction tube, which was replaced with argon three times, then TFA (trifluoroacetic acid) (12 uL, d=1.535 g/mL, 0.0184 g, 0.16 mmol) and DMA (N,N-dimethylacetamide) (2.5 mL) were added, and the reaction tube was placed in an oil bath that had been preheated to 30° C., the reaction was completed after stirred for 12 hours as monitored by thin layer chromatography (TLC). The reaction was quenched by water (2.5 mL), the aqueous phase was extracted with ether (3 mL×3), the organic phases were combined, washed once with saturated brine (5 mL), separated and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: petroleum ether (60˜90° C.)/ether/dichloromethane=10/1/1) to afford a chiral cyclic product 19 (0.1009 g, 82%): Oil substance; >20:1 dr; [α]D24=+81.2 (c=1.12, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.33-7.20 (m, 5 H, Ar—H), 5.93 (d, J=15.6 Hz, 1 H, ═CH), 5.20-4.98 (m, 2 H, 2 x ═CH), 4.36 (s, 1 H, ═CH), 3.70-3.55 (m, 1 H, CH), 2.15 (td, J1=7.8 Hz, J2=2.1 Hz, 2 H, CH2), 2.00-1.89 (m, 3 H), 1.87-1.73 (m, 7 H), 1.69-1.62 (m, 1 H), 1.61-1.45 (m, 4 H), 1.41-0.94 (m, 20 H), 0.94-0.81 (m, 10 H), 0.61 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=173.4, 164.6, 138.63, 138.58, 135.4, 128.8, 128.2, 128.1, 128.0, 125.3, 116.9, 88.0, 71.7, 56.4, 56.0, 42.6, 42.0, 40.3, 40.1, 36.3, 35.7, 35.3, 35.1, 34.5, 30.4, 29.8, 29.2, 28.2, 27.1, 26.3, 24.2, 24.14, 24.09, 23.3, 22.5, 20.7, 18.3, 13.7, 11.9; IR (neat): ν=3351, 2932, 2862, 2173, 1754, 1449, 1221, 1040 cm−1; MS (70 eV, ESI) m/z: 635 (M+Na+), 613 (M+H+); HRMS calcd for C42H61O3 [M+H+]: 613.4615, found: 613.4612.
(R)-2af (0.6242 g, 2.0 mmol, 91% ee), CuCl (0.008 g, 0.08 mmol, weighed in a glove box) were added to a dry Schlenk reaction tube, which was replaced with argon three times, then MeOH (10 mL) was added, and the reaction tube was placed in an oil bath that had been preheated to 50° C., the reaction was completed after stirred for 30 minutes as monitored by thin layer chromatography (TLC). The resulting mixture was quickly filtered through a short silica gel column (3 cm) to remove the copper salt, eluted by 30 mL of ethyl acetate, and spin-dried to afford an oily substance, which was directly used in the next reaction. The above oil substance, K2CO3 (0.8291 g, 6 mmol) were added to a dry Schlenk reaction tube, which was replaced with argon three times, then MeOH (10 mL) was added, the reaction was completed after stirred at room temperature for 2 hours as monitored by thin layer chromatography (TLC), filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: petroleum ether (60˜90° C.)/ether/dichloromethane=20/1/1) to afford a chiral cyclic product (S)-20 (0.4042 g, 84%): oil substance; 91% ee (HPLC conditions: AD-H column, hexane/iPrOH=99/1, 0.9 mL/min, λ=214 nm, tR(minor)=32.5 min, tR(major)=36.4 min); [α]D23=−103.3 (c=1.07, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.44-7.22 (m, 6 H, Ar—H), 2.43 (t, J=7.6 Hz, 2 H, CH2), 2.23 (td, J1=6.9 Hz, J2=2.5 Hz, 2 H, CH2), 1.97 (t, J=2.6 Hz, 1 H, CH), 1.87-1.70 (m, 5 H, CH2 and CH3); 13C NMR (100 MHz, CDCl3): δ=172.9, 152.9, 140.0, 131.3, 128.7, 128.1, 124.7, 86.7, 83.3, 69.2, 26.8, 25.9, 24. 1, 17.9; IR (neat): ν=3294, 2933, 2116, 1750, 1444, 1261, 1036 cm−1; MS (70 eV, ESI) m/z: 263 (M+Na+), 241 (M+El+); HRMS calcd for C16H17O2 a [M+H+]: 241.1223, found: 241.1222.
Zidovudine (0.0681 g, 0.24 mmol), chiral cyclic product (S)-20 (0.0483 g, 0.2 mmol, 91% ee) were added to a dry Schlenk reaction tube, which replaced with argon three times, then DCM (1 mL), aqueous sodium ascorbate (0.012 g, 0.06 mmol, dissolved in 0.5 mL water), aqueous CuSO4·5H2O (0.005 g, 0.02 mmol, dissolved in 0.5 mL water) were added, and the reaction was completed after stirred at room temperature for 24 hours as monitored by thin layer chromatography (TLC). After diluted by DCM (5 mL), the reaction solution was washed with saturated brine (5 mL), separated and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash silica gel column chromatography (eluent: ethyl acetate elution, then dichloromethane/methanol=10/1) to afford product 21 (0.0793 g, 78%): oil substance; >20:1 dr; [α]D22=−62.3 (c=1.19, CHCl3); 1H NMR (400 MHz, CDCl3): δ=10.0-9.71 (m, 1 H, NH), 7.68-7.46 (m, 2 H, 2 x ═CH), 7.41-7.18 (m, 6 H, ═CH and Ar—H), 6.30 (t, J=6.4 Hz, 1 H, CH), 5.55-5.32 (m, 1 H, CH), 4.46-4.32 (m, 1 H, CH), 4.22 (br, 1 H, OH), 4.00 (d, J=11.6 Hz, 1 H, one proton of CH2), 3.81 (d, J=11.2 Hz, 1 H, one proton of CH2), 3.03-2.89 (m, 2 H, CH2), 2.75 (t, J=7.2 Hz, 2 H, CH2), 2.39-2.26 (m, 2 H, CH2), 2.01-1.89 (m, 2 H, CH2), 1.87 (s, 3 H, CH3), 1.77 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3): δ=173.2, 164.3, 153.2, 150.6, 147.4, 139.8, 137.5, 131.4, 128.7, 128.1, 124.6, 121.2, 110.9, 87.1, 86.9, 85.1, 61.3, 59.1, 37.7, 26.9, 26.7, 24.8, 24.4, 12.3; IR (neat): ν=3454, 2932, 2249, 1748, 1684, 1463, 1267, 1101, 1051 cm−1; MS (70 eV, ESI) m/z: 508 (M+El+); HRMS calcd for C26H30O6N5 [M+Na+]: 508.2191, found: 508.2190.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), organophosphoric acid 2b (0.0054 g, 0.01 mmol), (±)-1a (0.0402 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to affored a product: chiral allenoic acid (R)-2a (NMR yield 47%): 79% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.7 min, tR(minor)=11.2 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), organophosphoric acid 2b (0.0053 g, 0.01 mmol), (±)-1a (0.0399 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), fluorobenzene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 38%): 62% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.2 min, tR(minor)=10.4 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0014 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0148 g, 0.0012 mmol), organophosphoric acid 2b (0.0052 g, 0.01 mmol), (±)-1a (0.0402 g, 0.2 mmol), water (72 d=1.0 g/mL, 0.072 g, 4 mmol), chlorobenzene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 42%): 68% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.3 min, tR(minor)=10.5 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), organophosphoric acid 2b (0.0052 g, 0.01 mmol), (±)-1a (0.0403 g, 0.2 mmol), water (72 d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 30%): 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.2 min, tR(minor)=10.4 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), organophosphoric acid 2b (0.0051 g, 0.01 mmol), (±)-1a (0.0402 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), chloroform (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 27%): 88% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.5 min, tR(minor)=11.0 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), organophosphoric acid 2a (0.0025 g, 0.01 mmol), (±)-1a (0.0402 g, 0.2 mmol), water (72 d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 20%): 95% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=7.2 min, tR(minor)=10.9 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), (R)-CPA-2 (0.0079 g, 0.01 mmol)), (±)-1a (0.0408 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (S)-2a (NMR yield 0%).
Operations were conducted by referring to Example 1. PdCl2 (0.0008 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0148 g, 0.0012 mmol), (R)-CPA-1 (0.0077 g, 0.01 mmol), (±)-1a (0.0403 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL), were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 23%): 93% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.8 min, tR(minor)=11.6 min).
Operations were conducted by referring to Example 1. [Pd(n-cinnamyl)C1]2 (0.0022 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), (R)-CPA-1 (0.0077 g, 0.01 mmol), (±)-1a (0.0406 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL) were reacted at 50° C. for 6 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 69%): 83% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.6 min, tR(minor)=11.5 min).
Operations were conducted by referring to Example 1. Pd(PPh3)4 (0.0046 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), (R)-CPA-1 (0.0078 g, 0.01 mmol), (±)-1a (0.0407 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), bromobenzene (1.0 mL) were reacted at 50° C. for 6 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 16%): 82% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.3 min, tR(minor)=11.0 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4a (0.0078 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (±)-1a (0.0402 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL), were reacted at 50° C. for 12 hours. NMR monitored that the reaction hardly occurs.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4b (0.0087 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (±)-1a (0.0405 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4f (0.0151 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (±)-1a (0.0404 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL), were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), dppe (0.0049 g, 0.012 mmol), (±)-1a (0.0403 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0145 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), PPh3 (0.0053 g, 0.01 mmol), (±)-1a (0.0401 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0014 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0041 g, 0.005 mmol)), P(4-MeOC6H4)3 (0.0069 g, 0.01 mmol), (±)-1a (0.0401 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (1.0 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0144 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), P(4-CH3OC6H4)3 (0.0094 g, 0.01 mmol), (±)-1a (0.0398 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol)), toluene (1.0 mL) reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 50%): 75% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.9 min, tR(minor)=12.4 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0145 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), CH2Cl2 (128 μL, d=1.32 g/mL, 0.1698 g, 2 mmol), (±)-1a (0.0400 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.88 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 57%): 72% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=8.9 min, tR(minor)=12.1 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0041 g, 0.005 mmol), CHCl3 (161 μL, d=1.48 g/mL, 0.2388 g, 2 mmol), (±)-1a (0.0399 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.84 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 66%): 87% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.0 min, tR(minor)=12.3 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol)), CCl4 (193 μL, d=1.02 g/mL, 0.3076 g, 2 mmol), (±)-1a (0.0401 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.81 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0014 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), CHBr3 (174 μL, d=2.89 g/mL, 0.502 g, 2 mmol), (±)-1a (0.0401 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.83 mL) were reacted at 50° C. for 12 hours. NMR monitored that the reaction did not occur.
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0145 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), nBuBr (214 μL, d=1.28 g/mL, 0.274 g, 2 mmol), (±)-1a (0.0400 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.8 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 66%): 77% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.0 min, tR(minor)=12.6 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0145 g, 0.0012 mmol), (R)-CPA-1 (0.0041 g, 0.005 mmol), PhF (188 μL, d=1.02 g/mL, 0.1922 g, 2 mmol), (±)-1a (0.0403 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.81 mL) were reacted at 50° C. for 12 hours, purifiec by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 68%): 68% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.3 min, tR(minor)=13.2 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0147 g, 0.0012 mmol), (R)-CPA-1 (0.0041 g, 0.005 mmol), PhCl (220 μL, d=1.02 g/mL, 0.2252 g, 2 mmol), (±)-1a (0.0400 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.78 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 72%): 82% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.3 min, tR(minor)=12.8 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0145 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (4-MeOC6H4)Br (250 μL, d=1.49 g/mL, 0.374 g, 2 mmol), (±)-1a (0.0405 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.75 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 83%): 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.3 min, tR(minor)=13.4 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0016 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (4-MeC6H4)Br (220 μL, d=1.55 g/mL, 0.342 g, 2 mmol), (±)-1a (0.0405 g, 0.2 mmol), water (72 μL, d=1.0 g/mL), 0.072 g, 4 mmol), toluene (0.78 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid (R)-2a (NMR yield 85%): 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.4 min, tR(minor)=13.5 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0148 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol), (4-FC6H4)Br (220 μL, d=1.59 g/mL, 0.350 g, 2 mmol), (±)-1a (0.0405 g, 0.2 mmol), water (72 μL, d=1.0 g/mL), 0.072 g, 4 mmol), toluene (0.78 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid product (R)-2a (NMR yield 85%): 90% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, t R tR(major)=9.3 min, tR(minor)=13.4 min).
Operations were conducted by referring to Example 1. [Pd(π-allyl)Cl]2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (R)-L4d (0.0146 g, 0.0012 mmol), (R)-CPA-1 (0.0040 g, 0.005 mmol)), (4-CF3C6H4)Br (280 μL, d=1.61 g/mL, 0.450 g, 2 mmol), (±)-1a (0.0401 g, 0.2 mmol), water (72 μL, d=1.0 g/mL, 0.072 g, 4 mmol), toluene (0.78 mL) were reacted at 50° C. for 12 hours, purified by preparative plate chromatography (developing solvent: petroleum ether (60˜90° C.)/ethyl acetate=5/1) to afford a product: chiral allenoic acid product (R)-2a (NMR yield: 78%): 91% ee (HPLC conditions: AS-H column, hexane/iPrOH=98/2, 1.0 mL/min, λ=214 nm, tR(major)=9.3 min, tR(minor)=13.5 min).
Ordinary technicians in this field will understand that within the protection scope of the invention, it is feasible to modify, add and replace the above implementation cases, and none of them is beyond the protection scope of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110142014.7 | Feb 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/074914 | 1/19/2022 | WO |
