Patent Grant
9446393
This invention relates to transition metal/substituted organo di-amine ligand complexes and their function as catalysts, particularly for carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond forming reactions.
Enantioselective catalysts are desirable for producing high value added enantiopure chemicals. Examples of applications of enantiopure chemicals are as pharmaceutical chemicals and as agricultural chemicals. Production of pharmaceutical chemicals or that of agricultural chemicals tends to involve carbon-carbon, carbon-heteroatom, and/or carbon-hydrogen bond forming reactions. Enantiopure chemicals may be alternately described as optically active, or as right or left rotation forms, or as chiral. Enantiopure chemicals possess the characteristic that they have a 3 dimensional handedness and are substantially pure. In addition, enantiopure chemicals can be at least one of the other of two forms that are not mirror images of each other.
The use of existing transition metal complexes as catalysts, for mediating carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond forming reaction, is limited for commercial applications. The limited commercial use is attributed to the existing transition metal complexes being substitution labile, having poor solubility in organic solvents, or further having low enantioselectivity. Therefore, there remains a need for substitution inert transition metal complexes with activity as enantioselective catalysts for carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond forming reactions that are suitable for commercial/industrial applications.
In some embodiments, the present disclosure pertains to a compound, comprising a transition metal complex having the formula Φ-[M(x,y)-L1(w,v)-L2(t,u)-L3]p+An−mZ−p-m In an embodiment of the present disclosure Φ may be Λ. In another embodiment Φ may be Δ. In some embodiments of the present disclosure, M is a transition metal. In some embodiments, p is an integer corresponding to the oxidation state of M. In some embodiments of the present disclosure, each of x, y, w, v, t, and u independently comprise R. In other embodiments, each of x, y, w, v, t, and u independently comprise S. In some embodiments of the present disclosure, each of L1, L2, and L3 independently is a ligand comprising a substituted diamine. In some embodiments An− comprises a lipophilic anion, where m is from 1 to 3, and where Z− comprises an optional second anion.
In some embodiments, the present disclosure relates to a compound comprising a transition metal complex having the formula Φ-[M((x,y)-L1)3-b-c((w,v)-L2)b((t,u)-L3)c]p+An−mZ−p-m. In some embodiments of the present disclosure, Φ is Λ. In some embodiments of the present disclosure, Φ is Δ. In some embodiments of the present disclosure, M is a transition metal. In some embodiments, p is an integer corresponding to the oxidation state of M. In some embodiments, each of x, y, w, v, t, and u independently comprises R. In other embodiments, each of x, y, w, v, t, and u independently comprises S. In some embodiments, each of L1, L2 and L3 independently is a ligand comprising ethylene diamine. In some embodiments, L3 is a ligand comprising a pendant Lewis base derivative of ethylene diamine. In some embodiments, c is from 1 to 3. In some embodiments, b is from 0 to 2. In some embodiments of the present disclosure, An− comprises a lipophilic anion, where m is from 1 to 3, and where Z− comprises a second anion.
In some embodiments, the present disclosure relates to a compound comprising a transition metal complex having the formula Φ-[M(x,y)-L1(w,v)-L2XY](p+a)+An−mZ−p-m. In some embodiments, Φ is Λ. In some embodiments, Φ is Δ. In some embodiments of the present disclosure, M is a transition metal. In some embodiments, p is an integer corresponding to the oxidation state of M. In some embodiments of the present disclosure, each of x, y, w, and v is independently R. In other embodiments, each of x, y, w, and v is independently S. In some embodiments of the present disclosure, each of L1 and L2 comprises a chelating ligand comprising at least two nitrogens. In some embodiments, each of L1 and L2 independently comprises a chelating ligand comprising at least two metal coordinating atoms. In some embodiments of the present disclosure, Y comprises a mono-coordinated diamine ligand. In some embodiments of the present disclosure, X comprises one out of a second mono-coordinated diamine ligand and a nucleophilic ligand. In some embodiments, “a” is the total charge of the mono-coordinated ligand(s). In some embodiments of the present disclosure, An− comprises a lipophilic anion, where m is from 1 to p, and where Z− comprises a second optional anion.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention, as claimed. In this application, the use of the singular includes the plural, the word “a” or “an” means “at least one”, and the use of “or” means “and/or”, unless specifically stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements or components comprising one unit and elements or components that comprise more than one unit unless specifically stated otherwise.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated herein by reference in their entirety for any purpose. In the event that one or more of the incorporated literature and similar materials defines a term in a manner that contradicts the definition of that term in this application, this application controls.
Described in U.S. Pat. No. 4,598,091 are (1,2)-diphenyl-ethylenediamine-platinum (II) complex compounds with antitumor activity. The compounds described have one (1,2)-diphenyl-ethylenediamine portion that may be optically active and two of an X ligand that is a physiologically compatible anion. The Pt(II) compounds described tend to be substitution labile. Substitution labile ligands tend to go on and off a metal center easily.
Described in U.S. Pat. No. 6,410,749 is a process for the preparation of optically active amino alcohols from corresponding α-aminocarbonyl compounds in the presence of an optically active transition metal complex. The transition metal complexes described tend to be soluble in organic solvents and to be substitution labile. Substitution lability in a catalyst tends to open up a binding site available for reactions.
Werner complexes were introduced by Werner in 1911. Werner salts of the chiral tris(ethylenediamine)-substituted octahedral cation [Co(en)3]3+ and related species have played important historical roles in the development of inorganic chemistry and stereochemistry. However, the known salts of [Co(en)3]3+, such as [Co(en)3]3+(Cl−)3, have been generally regarded as undesirable for catalysis because a) they are soluble only in water, whereas most industrial processes occur in organic solvents; and b) they are substitution inert, in that the complexes contained ligands that did not go on and off the metal center easily, to open up a binding site for reactions.
Described in Chem. Euro. J. 2008, 14, 5397-5400, by C. Ganzmann and J. Gladysz, is phase transfer of enantiopure Werner cations into organic solvents: an overlooked family of chiral hydrogen bond donors for enantioselective catalysis. This reference described Δ-[Co(en)3]3+(Cl−)2 (BArf−)3.14H2O where BArf− is tetrakis[(3,5-trifluromethyl)phenyl]borate. This complex was reported to be soluble in CH2Cl2, acetone, ethyl acetate, THF, DMSO, and alcohols. The NH bonds of the complex were thought to be catalytic sites. However, the reported enantioselectivity was 33%, which tends to be insufficient for commercial applications. The work is further described in a master's thesis of Carola Ganzmann, reporting similarly low enantioselectivity. A need in the art exists for substitution inert metal complexes that can function as enantioselective catalysts for producing high value added enantiopure chemicals for commercial use.
The present disclosure relates to transition metal/substituted organo di-amine ligand complexes and their function as catalysts, particularly for carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond forming reactions. More particularly, the present disclosure, in some embodiments relates to such complexes incorporating cobalt (Co), iron (Fe), nickel (Ni), chromium (Cr), manganese (Mn), molybdenum (Mo), tungsten (W), rhenium (Re), ruthenium (Ru), technetium (Tc), osmium (Os), rhodium (Rh), iridium (Ir), platinum (Pt), or palladium (Pd). In some embodiments, the present disclosure pertains to such complexes incorporating cobalt, iron, or nickel. Specifically, in some embodiments, the present disclosure relates to such complexes incorporating cobalt.
The transition metal complexes disclosed herein present a new class of complexes soluble in organic solvents and suitable as catalysts for enantioselective organic synthesis. The present inventors have discovered identities and arrangements of ligands that provide sufficient enantioselectivity to the transition metal complexes for commercial application as catalysts for the manufacture of enantiopure chemicals. As used herein, enantioselectivity may be expressed as enantiomeric excess. According to some embodiments, the transition metal complex has activity in enantioselective hydrogen bond mediating catalysis. According to some embodiments, the hydrogen bond mediating catalysis is suitable for carbon-carbon bond forming reactions. In some embodiments, the hydrogen bond mediating catalysis is suitable for carbon-heteroatom bond forming reactions. Alternatively or in combination, according to some embodiments, the hydrogen bond mediating catalysis is suitable for carbon-hydrogen bond forming reactions. The present metal complexes have the advantage of at least 60% entantioselectivity. For example, enatioselectivities of at least 75% have been achieved. More particularly, enantioselectivities of at least 85% have been achieved. Still more particularly, enantioselectivities of at least 94% have been achieved. The transition metal complexes disclosed herein further have the advantage of producing high yields. For example, conversions of at least 95% have been achieved. More particularly, conversions of at least 97% have been achieved. Still more particularly, conversions of at least 99% have been achieved.
According to some embodiments, transition metal complexes of type 1 are represented by the formula Φ-[M(x,y)-L1(w,v)-L2(t,u)-L3]p+An−mZ−p-m, where Φ is Λ or Δ, where M is a transition metal, where p corresponds to the oxidation state of M, where each of x, y, w, v, t, and u is independently R or S, where each of L1, L2, and, L3 independently represents a ligand that is a substituted diamine, where An− represents a lipophilic anion, m is from 1 to 3, and where Z− represents a conventional anion. Suitable substituted diamines include, but are not limited to, diphenylethylenediamine, derivatives of diphenylethylenediamine, and cyclohexanediamine.
According to some embodiments, transition metal complexes of type 2 are represented by the formula Φ-[M((x,y)-L1)3-b-c((w,v)-L2)b((t,u)-L3)c]p+An−mZ−p-m, where Φ is Λ or Δ, M is a transition metal, p corresponds to the oxidation state of M, where each of x, y, w, v, t, and u is independently R or S, where each of L1 and L2 independently represents a ligand that is ethylene diamine (also herein termed “EN” or alternately diaminoethane), where L3 represents a ligand that comprises a pendant Lewis base derivative of EN, where c is from 1 to 3, where b is from 0 to 2, where An− represents a lipophilic anion, where m is from 1 to 3, and where Z− represents a conventional anion. Suitable ligands comprising a pendant Lewis base derivative of EN include, but are not limited to, EN(CH2)—NR1R2, where n is from 2 to 4. According to some embodiments, the pendant Lewis base derivative imparts bifunctionality to the transition metal complex, when the transition metal complex is used as a catalyst.
According to some embodiments, transition metal complexes of type 3 are represented by the formula Φ-[M(x,y)-L1(w,v)-L2XY](p+a)+An−mZ−p-m, where Φ is Λ or Δ, wherein M is a transition metal, where p is an integer corresponding to the oxidation state of M, where each of x, y, w, and v is independently R or S, wherein each of L1, and L2 comprises a chelating ligand comprising at least two nitrogens, where p is an integer corresponding to the oxidation state of M, wherein each of L1 and L2 independently comprises a chelating ligand comprising at least two metal coordinating atoms, where Y comprises a mono-coordinated diamine ligand, where X comprises one out of a second mono-coordinated diamine ligand and a nucleophilic ligand, where a is the total charge of the mono-coordinated ligand(s), where An− represents a lipophilic anion, where m is from 1 to p, and where Z− represents a second optional anion. Suitable chelating ligands include, but are not limited to, chelating ligands comprising at least two nitrogen atoms. According to some embodiments, the mono-coordinated ligand is chiral. The chirality may be (S)- or (R)-.
Suitable transition metals include, but are not limited to, cobalt (Co), iron (Fe), nickel (Ni), chromium (Cr), manganese (Mn), molybdenum (Mo), tungsten (W), rhenium (Re), ruthenium (Ru), technetium (Tc), osmium (Os), rhodium (Rh), iridium (Ir), platinum (Pt), and palladium (Pd). For example, according to some embodiments the transition metal is cobalt, iron, or nickel. Cobalt, iron, and nickel have the advantage of low cost. In some embodiments, the transition metal is cobalt. Suitable oxidation states of the transition metal include, but are not limited to, M(III) and M(IV).
Suitable lipophilic anions include, but are not limited to, tetrakis[(3,5-trifluromethyl)phenyl]borate); tetrakis[pentafluorophenyl]borate; carboranes of the general formula CB11H12—, and its derivatives; TRISPHAT of the general formula P(O2C6C14)3−; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
Suitable conventional anions include, but are not limited to, Cl−, perchlorate, and nitrate. The variable numbers p, m, n, a, b, and c are each integers. According to some embodiments, the transition metal complex is in hydrated form.
Transition Metal Complexes of Type 1
The Stereochemistry of the Chiral Ligand and the Chiral Metal Center
Referring to
Referring to
Referring to
It will be understood that it is possible to use combinations of these 3 ligands within one compound, so the following list of compounds would also be available (not shown): 1) Λ-[Co((S,S)-dpen)2((R,R)-dpen)]3+; 2) Λ-[Co((S,S)-dpen)2((S,R)-dpen)]3+; 3) Λ-[Co((R,R)-dpen)2((S,S)-dpen)]3+; 4) Λ[Co((R,R)-dpen)2((S,R)-dpen)]3+; 5) Λ-[Co((S,R)-dpen)2((S,S)-dpen)]3+; 6) Λ-[Co((S,R)-dpen)2((R,R)-dpen)]3+; and 7) Λ-[Co((S,S)-dpen)((R,R)-dpen)((S,R)-dpen)]3+.
Further, it will be understood that for all of these Λ complexes mentioned above, the corresponding Δ complex would also be available. Thus, the following list of compounds would also be available (not shown): 1) Δ-[Co((S,S)-dpen)2((R,R)-dpen)]3+; 2) Δ-[Co((S,S)-dpen)2((S,R)-dpen)]3+; 3) Δ-[Co((R,R)-dpen)2((S,S)-dpen)]3+; 4) Δ[Co((R,R)-dpen)2((S,R)-dpen)]3+; 5) Δ-[Co((S,R)-dpen)2((S,S)-dpen)]3+; 6) Δ-[Co((S,R)-dpen)2((R,R)-dpen)]3+; and 7) Δ-[Co((S,S)-dpen)((R,R)-dpen)((S,R)-dpen)]3+.
Other Transition Metals
Besides cobalt, the other transition metals that could be used in a similar way in this catalysis include, but are not limited to, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, and palladium. Thus, according to some embodiments the transition metal is cobalt, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, or palladium. For example, according to some embodiments the transition metal is cobalt, iron, or nickel. Further, for example, according to some embodiments the transition metal is cobalt.
Counteranions
It is desirable for these catalysts to be soluble in aprotic organic solvents. This is accomplished by using counteranion pairings with the cationic cobalt complex that render the complex soluble in aprotic organic solvents. The counteranion pairings are an assembly of counter anion groups that render the cobalt cation soluble in organic solvents.
An Counteranions
Suitable assemblies use between 1 and 3 anions that are deemed, “lipophilic” or “organic soluble”. In some embodiments, BArf-(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion. Other suitable lipophilic anions include, but are not limited to; tetrakis[pentafluorophenyl]borate; carboranes of the general formula CB11H12−, and its derivatives; TRISPHAT of the general formula P(O2C6C14)3−; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
Z Counteranions
Often only one or two “organic soluble” anions are required in the package of 3 anions to render the whole complex soluble in aprotic organic solvents. In this case, the other one to two anion spaces can be filled by any possible anion even if it is not considered “lipophilic”. Such anions include, but are not limited to; Hydride H—, Oxide O2−, Fluoride F, Sulfide S2−, Chloride Cl−, Nitride N3−, Bromide Br−, Iodide I−, Arsenate AsO43−, Phosphate PO43−, Arsenite AsO33−, Hydrogen phosphate HPO42−, Dihydrogen phosphate H2PO4−, Sulfate SO4, Nitrate NO3−, Hydrogen sulfate HSO4−, Nitrite NO2−, Thiosulfate S2O32−, Sulfite SO32−, Perchlorate CiO4−, Iodate IO3−, Chlorate ClO3−, Bromate BrO3−, Chlorite ClO2−, Hypochlorite OCl−, Hypobromite OBr−, Carbonate CO32−, Chromate CrO42−, Hydrogen carbonate or Bicarbonate HCO3−, Dichromate Cr2O72−, Acetate CH3COO−, formate HCOO−, Cyanide CN−, Amide NH2−, Cyanate OCN−, Peroxide O22, Thiocyanate SCN−, Oxalate C2O42, Hydroxide OH−, Permanganate MnO4−, Azide N3−, and tartrate C4H4O62−. Further suitable conventional anions include, but are not limited to, triflate OSO3CF3− and tetraflouroborate BF4− and hexafluorophosphate PF6−.
Derivatives of the DPEN Ligand
It will be understood that derivatives of the above mentioned DPEN ligands may be used to make cobalt complexes. The stereochemistry rules that apply to the original DPEN ligands apply to the derivatives below. Further, the stereochemistry rules that apply to the metal centers of these complexes formed by the addition of these DPEN derivatives are the same as described above. For example, suitable DPEN derivatives include, but are not limited to, (S,S,)-, (R,R)-, and (S,R)- versions of 2-bis-(4-methoxyphenyl)-1,2-diaminoethane; 2-bis-(4-chlorophenyl)-1,2-diaminoethane; 2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane; 2-bis-(4-nitrophenyl)-1,2-diaminoethane; 2-bis-(1-napthyl)-1,2-diaminoethane; 2-bis-(2-napthyl)-1,2-diaminoethane; 1,2-bis(2-methoxyphenyl)ethane-1,2-diamine; 1,2-bis(3-methoxyphenyl)ethane-1,2-diamine; 1,2-bis(2-methylphenyl)ethane-1,2-diamine; 1,2-bis(3-methylphenyl)ethane-1,2-diamine; 1,2-bis(4-methylphenyl)ethane-1,2-diamine; 1,2-di(pyridin-2-yl)ethane-1,2-diamine; 1,2-di(pyridin-3-yl)ethane-1,2-diamine; 1,2-di(pyridin-4-yl)ethane-1,2-diamine; 1,2-bis-(4-methoxyphenyl)-1,2-diaminoethane; 1,2-bis-(4-chlorophenyl)-1,2-diaminoethane; 1,2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane; 1,2-bis-(4-nitrophenyl)-1,2-diaminoethane; 1,2-bis-(1-napthyl)-1,2-diaminoethane; and 1,2-bis-(2-napthyl)-1,2-diaminoethane.
Other Ligands
It will be understand that other substituted diamines may be used to make the complex. Referring to
Transition Metal Complexes of Type 2
Stereochemistry of the Chiral Ligand and the Chiral Metal Center
Referring to
Referring to
Referring to
When X=1
Referring to
Referring to
When X=2
Referring to
The cobalt complex (X=2) may also have six stereoisomers (or diastereomers) when the same ligand with (R) configuration at the chiral center has been used.
When X=3
Referring to
Four other stereoisomers (or diastereomers) of the cobalt complex may also be possible when the same ligand with (R) configuration at the chiral center has been used.
Other Transition Metals
Besides cobalt, the other transition metals that could be used in a similar way in this catalysis include, but are not limited to, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, and palladium. Thus, according to some embodiments, the transition metal is cobalt, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, or palladium. For example, according to some embodiments, the transition metal is cobalt, iron, or nickel. Further, for example, according to some embodiments, the transition metal is cobalt.
The Counteranions
It is desirable for these catalysts to be soluble in aprotic organic solvents. This is accomplished by using counteranion pairings with the cationic cobalt complex that render the complex soluble in aprotic organic solvents. The counteranion pairings are an assembly of counter anion groups that render the cobalt cation soluble in organic solvents.
An Counteranions
Suitable assemblies use between 1 and 3 anions that are deemed “lipophilic” or “organic soluble”. BArf-(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion. Further, other suitable lipophilic anions include, but are not limited to; tetrakis[pentafluorophenyl]borate; carboranes of the general formula CB11H12−, and its derivatives; TRISPHAT of the general formula P(O2C6Cl4)3−; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
Z Counteranions
Often only one or two “organic soluble” anions are required in the package of 3 anions to render the whole complex soluble in aprotic organic solvents. In this case, the other one to two anion spaces can be filled by any possible anion even if it is not considered “lipophilic”. Such anions include, but are not limited to; Hydride H−, Oxide O2−, Fluoride F−, Sulfide S2−, Chloride Cl−, Nitride N3−, Bromide Br−, Iodide I−, Arsenate AsO43−, Phosphate PO43−, Arsenite AsO33−, Hydrogen phosphate HPO42−, Dihydrogen phosphate H2PO4−, Sulfate SO42−, Nitrate NO3−, Hydrogen sulfate HSO4−, Nitrite NO2−, Thiosulfate S2O32−, Sulfite SO32−, Perchlorate ClO4−, Iodate IO3−, Chlorate ClO3−, Bromate BrO3−, Chlorite ClO2−, Hypochlorite OCl−, Hypobromite OBr−, Carbonate CO32−, Chromate CrO42−, Hydrogen carbonate or Bicarbonate HCO3−, Dichromate Cr2O72−, Acetate CH3COO−, formate HCOO−, Cyanide CN−, Amide NH2−, Cyanate OCN−, Peroxide O22, Thiocyanate SCN−, Oxalate C2O42−, Hydroxide OH−, Permanganate MnO4−, Azide N3−, and tartrate C4H4O62−. Further suitable conventional anions include, but are not limited to, triflate OSO3CF3−, tetraflouroborate BF4− and hexafluorophosphate PF6−.
Transition Metal Complexes of Type 3
Stereochemistry of the Chiral Metal Center
Referring to
Referring to
Hierarchy of Chiral Metal Complexes
Referring to
Chelating Ligand
Referring to
Ligands X and Y
The X and Y ligands may be the same or they may be different. At least one of X and Y is a diamine. In some embodiments, one amine of the diamine coordinates to the metal while the other amine remains uncoordinated.
Referring to
Metal Complexes
Other Transition Metals
Besides cobalt, the other transition metals that could be used in a similar way in this catalysis include, but are not limited to, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, and palladium. Thus, according to some embodiments the transition metal is cobalt, iron, nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium, technetium, osmium, rhodium, iridium, platinum, or palladium. For example, according to some embodiments, the transition metal is cobalt, iron, or nickel. Further, for example, according to some embodiments, the transition metal is cobalt.
The Counteranions
It is desirable for these catalysts to be soluble in aprotic organic solvents. This is accomplished by using counteranion pairings with the cationic cobalt complex that render the complex soluble in aprotic organic solvents. The counteranion pairings are an assembly of counter anion groups that render the cobalt cation soluble in organic solvents.
An Counteranions
Suitable assemblies use between 1 and 3 anions that are deemed “lipophilic” or “organic soluble”. BArf-(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion. Further, other suitable lipophilic anions include, but are not limited to; tetrakis[pentafluorophenyl]borate; carboranes of the general formula CB11H12, and its derivatives; TRISPHAT of the general formula P(O2C6C14)3−; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
Z Counteranions
In some embodiments, one or two “organic soluble” anions are required in the package of 3 anions to render the whole complex soluble in aprotic organic solvents. In such embodiments, the other one to two anion spaces can be filled by any possible anion even if it is not considered “lipophilic”. Such anions include, but are not limited to; Hydride H−, Oxide O2−, Fluoride F−, Sulfide S2−, Chloride Cl−, Nitride N3−, Bromide Br−, Iodide I−, Arsenate AsO43−, Phosphate PO43−, Arsenite AsO33−. Hydrogen phosphate HPO42−, Dihydrogen phosphate H2PO4−, Sulfate SO42−, Nitrate NO3−, Hydrogen sulfate HSO4−, Nitrite NO2−, Thiosulfate S2O32−, Sulfite SO32−, Perchlorate ClO4−, Iodate IO3−, Chlorate ClO3−, Bromate BrO3−, Chlorite ClO2−, Hypochlorite OCl−, Hypobromite OBr−, Carbonate CO32−, Chromate CrO42−, Hydrogen carbonate or Bicarbonate HCO3−, Dichromate Cr2O72−, Acetate CH3COO−, formate HCOO−, Cyanide CN−, Amide NH2−, Cyanate OCN−, Peroxide O22−, Thiocyanate SCN−, Oxalate C2O42−, Hydroxide OH−, Permanganate MnO4−, Azide N3−, and tartrate C4H4O62−. Further suitable conventional anions include, but are not limited to, triflate OSO3CF3−, tetraflouroborate BF4− and hexafluorophosphate PF6−.
Applications and Advantages
The transition metal complexes of the present disclosure provide an attractive low cost catalyst system for the commercial manufacture of enantiopure chemicals. In various embodiments, the transition metal complexes of the present disclosure are highly enantioselective and stable. Further, the transition metal complexes of the present disclosure can be synthesized and separated as pure diastereomers on a gram scale. These have the added advantage of being easily tunable electronic and steric factors with modified DPEN ligands. Further, the transition metal complexes of the present disclosure demonstrate unique features compared to other hydrogen bond mediated catalysts, for example improved function in polar solvents or aqueous media.
Reference will now be made to various embodiments of the present disclosure and experimental results that provide support for such embodiments. Applicants note that the disclosure herein is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way.
Preparation of DPEN Ligand Derivatives
Referring to
Referring to
Preparation of DPEN Ligand Derivatives
Procedure A.
To a cloudy solution of 0.9 g (4.10 mmol) of 1,2-bis(hydroxylphenyl)-1,2-diamonoethane in ethanol (30 mL) was added (9.84 mmol, 2.4 eq.) of the corresponding aldehyde. The resulting clear solution was stirred at room temperature overnight during which time a yellow precipitate develops. The solid is collected by filtration, washed with ethanol, and dried in vacuum.
Or
Procedure B.
To a clear solution of 0.9 g (4.10 mmol) of 1,2-bis(hydroxylphenyl)-1,2-diamonoethane in DMSO (30 mL) as added (9.84 mmol, 2.4 eq.) of the corresponding aldehyde. The resulting mixture was stirred at room temperature overnight and then the mixture was poured into distilled water (150 mL). The aqueous layer was extracted with diethyl ether (3×100 mL) and the organic layers were dried over Na2SO4, filtered, and concentrated by rotovap. The resulting diimine was further dried by oil pump vacuum.
The diimine products from either procedure A or B were dissolved in THF (30 mL) and aqueous HCl (3 mL, 12 M) was added. The mixture stirred at room temperature for 3 hours then was partitioned between H2O (100 mL) and CH2Cl2 (100 mL). The organic phase was removed and the aqueous phase washed with CH2Cl2 (100 mL). The aqueous phase was made basic by slow addition of 3 M NaOH. The resulting cloudy solution was extracted with CH2Cl2 (3×150 mL). The organic phases were dried over Na2SO4, filtered, and concentrated by rotovap. The resulting diamines are further dried by oil pump vacuum.
The following list of DPEN derivatives have been prepared by this method: (S,S)-2-bis-(4-methoxyphenyl)-1,2-diaminoethane (procedure A); (S,S)-2-bis-(4-chlorophenyl)-1,2-diaminoethane (procedure B) (S,S)-2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane (procedure B); (S,S)-2-bis-(4-nitrophenyl)-1,2-diaminoethane (procedure A); (S,S)-2-bis-(1-napthyl)-1,2-diaminoethane (procedure B); and (S,S)-2-bis-(2-napthyl)-1,2-diaminoethane (procedure B).
Procedures for the synthesis of cobalt complexes are illustrated in the example below. These 2 procedures are generally representative for any DPEN ligand set (i.e. a DPEN ligand or DPEN derivative of any stereochemistry could be substituted in this procedure). The only difference between the two procedures is whether the end product is a Λ or Δ metal complex.
Procedure 1. Λ-[Co(dpen)3](BArf)Cl2 (Λ-1)
Cobalt acetate tetrahydrate (0.601 g, 2.49 mmol) and (S,S)-dpen (1.61 g, 7.60 mmol, 3.32 eq.) were dissolved in methanol (75 mL) and charcoal (0.1 g) was added. Air was passed through the vigorously stirred suspension at room temperature for 16 hours. The suspension was filtered through a pad of celite and the bright orange filtrate was acidified with aqueous HCl (2M, 2 mL). The solvents were gently evaporated in an oil bath at 45° C. under a stream of nitrogen until the volume reached ca. 10 mL. The remaining solid was suspended in methanol (30 mL) and water (100 mL) and filtered. The residue was suspended and filtered three times from hot acetone (30 mL) The bright orange solid was dried under oil pump vacuum to yield the trichloride salt (0.708 g).
A portion of the orange solid (0.452 g) was suspended in dichloromethane (10 mL) and NaBArf (0.501 g, 0.5655 mmol) was added. The suspension was mixed by sonication and the colorless dichloromethane rapidly turned bright orange as a faint white precipitate of NaCl developed. The new suspension was filtered and the filtrate loaded onto a silica gel column. The sorbed orange band was washed with CH2Cl2 (100 mL) and then was eluted with 98.5/1.5 CH2Cl2:MeOH. A very faint green band elutes first followed by a singular intense orange band. The orange band is collected and concentrated by rotary evaporation and further dried under oil pump vacuum for 15 hours to yield a bright orange solid (0.659 g).
1H NMR (CD2Cl2, 500 MHz) δ 8.30 (br s, NH, 6H), 7.74 (s, o-CH BArf-, 8H), 7.56 (s, p-CH BArf-, 4H), 7.41 (t, 6.5 Hz, p-CH dpen, 6H), 7.35 (t, 7.5 Hz, m-CH dpen, 12H), 7.30 (d, 8.0 Hz, o-CH dpen, 12H) 4.48 (s, CH, dpen, 6H), 3.82 (br s, NH, 6H), 2.18 (br s, H2O, 3H), 1.80 (s, HOD, 3H). 13C NMR (CD2Cl2, 125 MHz) for BArf- δ 161.7 (q, 1JBC=49.4 Hz, i), 134.8 (s, o), 128.8 (q, 2JCF=31.0 Hz, m), 124.5 (q, 1JCF=270.9 Hz, CF3), 117.4 (s, p), for dpen 133.9 (s), 130.7 (s), 130.1 (s), 127.4 (s), 63.0 (s, PhCHNH2).
Procedure 2. Δ-[Co(dpen)3](BArf)Cl2
Cobalt perchlorate hexahydrate (0.233 g, 0.775 mmol) and S,S-dpen (0.496 g, 2.33 mmol, 3.01 eq.) were dissolved in MeOH (50 mL) and charcoal (0.1 g) was added. Air was passed through the vigorously stirred suspension at room temperature for 16 hours. The mixture was filtered through celite and the filtrate acidified with HClO4 (2 mL, 35% in H2O). The methanol was gently evaporated by heating in an oil bath to 45° C. under a stream of nitrogen. A brownish yellow precipitate developed when most of the MeOH had been removed. A suspension was made by adding H2O (100 mL) which was filtered and washed with more H2O (100 mL). The residue was then dissolved in MeOH (50 mL) and sorbed on a Dowex cation exchange column. The orange band was washed with 1:1 H2O/MeOH (100 mL). The orange band was eluted with increasing gradients of aqueous HCl in methanol; 1M aq. HCl in MeOH (100 mL), 2M aq. HCl in MeOH (100 mL), 3M aq. HCl in MeOH (100 mL), 4M aq. HCl in MeOH (200 mL). At 4M HCl, the orange band elutes from the column. The collected fraction is concentrated by a rotary evaporator equipped with a base trap to yield a bright orange solid as the crude trichloride (0.155 g). A portion of this solid (0.103 g) was suspended in CH2Cl2 and NaBArf (0.109 g, 0.123 mmol) was added. The mixture was sonicated for a few seconds and the solution became bright orange as a faint white precipitate of NaCl developed. The mixture was filtered and the orange filtrate was loaded onto a silica gel column. The adsorbed orange band was washed with CH2Cl2 (100 mL) then eluted with CH2Cl2:MeOH 98.5/1.5. Two orange bands separated. The fast moving minor band was Λ-1. The slower moving major band was collected and concentrated by rotary evaporation to a bright orange solid which was further dried under oil pump vacuum at room temperature for 15 hours to yield Δ-1 (0.108 g).
1H NMR (CD2Cl2, 500 MHz) δ 7.72 (s, o-CH BArf-, 8H), 7.55 (s, p-CH BArf-, 4H), 7.34-7.28 (m, o-, m-, p-dpen, 30H), 6.14 (br s, NH), 5.75 (br s, NH), 4.30 (s, CH, dpen, 6H), 2.48 (br s H2O and HDO, 11H) 13C NMR (CD2Cl2, 125 MHz) 13C NMR (CD2Cl2, 125 MHz) for BArf- δ 161.7 (q, 1JBC=49.5 Hz, i), 134.7 (s, o), 128.8 (q, 2JCF=28.4 Hz, m), 124.5 (q, 1JCF=270.9 Hz, CF3), 117.4 (s, p), for dpen 134.0 (s), 129.9 (s), 129.3 (s), 127.3 (s), 65.8 (t, 2JCD=14.5 Hz, PhCHND2).
1H NMR spectra of cobalt complexes in CD2Cl2 after BArf- metathesis was obtained. Strong hydrogen bonding between one diastereotopic set of N—H bonds and Cl− may be shown by a large downfield shift in 1H NMR spectra. In comparison with Cl− weak hydrogen bond accepting anions such as triflate or tetraflouroborate leads to an upfield shift for these N—H bonds.
Referring to
The following three procedures are representative of how the catalysts are used in a reaction. The main difference in the procedures 1a and 1b is the solvent and base used in the reaction; however the reactants are the same. For procedure 2, the reactant has changed from dimethylmalonate to diphenylphosphite. In any of these procedures, the exact catalyst can be interchanged without any change in the reaction procedure. (For instance, in procedure 1, the Λ catalyst is used, but could just as easily have used the Δ catalyst. Procedure 1 was used to generate the results shown in
General Procedure 1
An NMR tube was charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol), Λ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025 mL) in CD2Cl2 (0.4 mL). A 1H NMR of the bright orange solution was observed for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036 mmol) was added to the NMR tube and the reaction proceeded at room temperature. Reaction conversion was monitored by 1H NMR until >99% conversion was achieved (2 h). The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (2 hours, >99% conversion, 80% ee R).
An NMR tube was charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol), Δ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025 mL) in CD2Cl2 (0.4 mL). A 1H NMR of the bright orange solution was observed for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036 mmol) was added to the NMR tube and the reaction proceeded at room temperature. Reaction conversion was monitored by 1H NMR until >99% conversion was achieved (2 h). The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from elute by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (2 hours, >99% conversion, 76% ee S).
General Procedure 1b
A vial is charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol), Λ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and hexadecane (0.0025 mL) in CH2Cl2 (0.4 mL). An aliquot is removed from the mixture for a time=0 GC measurement. The bright orange solution is cooled to 0° C. and a solution of Na2CO3 (0.00038 g, 0.0036 mmol) in H2O (0.15 mL) is added. The biphasic mixture is stirred at 0° C. for 12 hours and the conversion is measured by analyzing a removed aliquot by GC. The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (12 hours, >95% conversion, 90% ee R).
A vial is charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol), Δ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and hexadecane (0.0025 mL) in CH2Cl2 (0.4 mL). An aliquot is removed from the mixture for a time=0 GC measurement. The bright orange solution is cooled to 0° C. and a solution of Na2CO3 (0.00038 g, 0.0036 mmol) in H2O (0.15 mL) is added. The biphasic mixture is stirred at 0° C. for 12 hours and the conversion is measured by analyzing a removed aliquot by GC. The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (12 hours, >99% conversion, 76% ee S).
General Procedure 2
An NMR tube is charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), diphenylphosphite (0.0086 mL, 0.045 mmol), Δ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025 mL) in CD2Cl2 (0.4 mL). A 1H NMR of the bright orange solution was observed for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036 mmol) was added to the NMR tube and the reaction proceeded at room temperature. Reaction conversion was monitored by 1H NMR until full conversion was achieved (2 h). The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (1 hour, >99% conversion, 73% ee S).
An NMR tube is charged with a solution of trans-β-nitrostyrene (0.0054 g, 0.036 mmol), diphenylphosphite (0.0086 mL, 0.045 mmol), Λ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025 mL) in CD2Cl2 (0.4 mL). A 1H NMR of the bright orange solution was observed for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036 mmol) was added to the NMR tube and the reaction proceeded at room temperature. Reaction conversion was monitored by 1H NMR until full conversion was achieved (2 h). The reaction solution was diluted with CH2Cl2 (1 mL) and passed through a short plug of silica with 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotary evaporation and the resulting residue was analyzed by chiral HPLC to determine the enantiopurity of the desired product. (1 hour, >99% conversion, 68% ee R).
Synthesis of Ligands
Different chiral ethylenediamine derivatives having different numbers of carbon atoms (n=2, 3) in the basic arms have been synthesized. Also, the ligand (n=3) with cycloalkylamine as Lewis base was also synthesized. The synthetic schemes are shown in the following.
Referring to
Referring to
Referring to
The procedures for the synthesis of ligands were adapted from Ghosh, A. K.; Leshchenko-Yashchuk, S.; Anderson, D. D.; Baldridge, A.; Noetzel, M.; Miller, H. B.; Tie, Y. F.; Wang, Y.-F.; Koh, Y.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2009, 52, 3902; Altman, J.; Ben-Ishai, D. Tetrahedron: Asymmetry 1993, 4, 91; and Ganzmann, C. Doctorate Thesis, Universität Erlangen-Nürnberg, 2010.
A round bottom flask was charged with (S)-5-(hydroxymethyl)-2-pyrrolidinone (9.5 g, 82.6 mmol), p-toluenesulfonyl chloride (19.0 g, 100 mmol), and CH2Cl2 (200 mL), and cooled to 0° C. DMAP (2.12 g, 17.34 mmol) and Et3N (14 mL, 100.6 mmol) were added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and stirred for overnight. The reaction was then quenched with 150 mL of water, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with 1 N HCl and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure followed by flash chromatography purification (100% EtOAc as the eluent) yielded (S)-(5-oxopyrrolidin-2-yl) methyl-4-methylbenzenesulfonate (18.43 g, 68.5 mmol, 79%) as a white solid.
1H NMR (500 MHz, CDCl3, δ in ppm): 1.72-1.79 (m, 1H), 2.19-2.31 (m, 3H), 2.44 (s, 3H), 3.85-3.92 (m, 2H), 4.02-3.99 (m, 1H), 6.53 (s, 1H), 7.35 (d, 2H, J=5.0 Hz), 7.77 (d, 2H, J=10 Hz); 13C NMR (125 MHz, CDCl3, δ in ppm): 21.6, 22.7, 29.2, 52.6, 71.9, 121.9, 127.8, 127.6, 130.0, 132.3, 145.3, 117.9.
A round bottom flask was charged with (S)-(5-oxopyrrolidin-2-yl)methyl-4-methylbenzenesulfonate (18.4 g, 68.5 mmol), DMF (400 mL), and NaN3 (17.8 g, 274 mmol). The resulting mixture was stirred at 55° C. for overnight. Removal of solvent under reduced pressure followed by flash chromatography purification (7% MeOH in CHCl3 as the eluent) provided the (S)-5-(azidomethyl) pyrrolidin-2-one (8.45 g, 60.36 mmol, 88%) as a yellow oil.
1H NMR (500 MHz, CDCl3, δ in ppm): 1.78-1.83 (m, 1H), 2.21-2.39 (m, 3H), 3.27-3.31 (dd, 1H, J=5 Hz, 15 Hz), 3.43-3.47 (dd, 1H, J=5 Hz, 15 Hz), 3.78-3.83 (m, 1H), 7.00 (s, 1H); 13C NMR (125.6 MHz, CDCl3, δ in ppm): 24.0, 29.7, 53.5, 55.9, 178.4.
A round bottom flask was charged with the (S)-5-(azidomethyl) pyrrolidin-2-one (8 g, 57.14 mmol), EtOAc (400 mL). Pd/C (750 mg) was added to the reaction mixture. The mixture was stirred at room temperature under a hydrogen filled balloon for overnight, then filtered over Celite, and washed with EtOAc and MeOH. Removal of solvent under reduced pressure followed by flash chromatography purification (15% MeOH in CHCl3 as the eluent) afforded the corresponding (S)-5-(aminomethyl) pyrrolidin-2-one (4.9 g, 42.98 mmol, 75%) as a yellow oil.
1H NMR (500 MHz, CDCl3, δ in ppm): 1.87 (br s, 2H), 1.62-1.68 (m, 1H), 2.07-2.13 (m, 1H), 2.21-2.27 (m, 2H), 2.60-2.56 (dd, 1H, J=5 Hz, 15 Hz), 2.74-2.78 (dd, 1H, J=5 Hz, 15 Hz), 3.57-3.62 (m, 1H), 7.79 (br s, 1H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 24.4, 30.1, 47.8, 56.7, 179.0.
A round bottom flask was charged with (S)-5-(aminomethyl)pyrrolidin-2-one (9.0 g, 79 mmol) and 400 mL of 6M HCl. The reaction mixture was heated to reflux for 20 h. The solvent was evaporated to dryness and the resulting solid was washed with MeOH-diethyl ether. Then the white solid was dried in vacuum to yield (S)-4-carboxybutane-1,2-diaminium chloride (15.75 g, 76.8 mmol, 97%).
1H NMR (500 MHz, D2O, δ in ppm): 1.83-1.99 (m, 2H); 2.48-2.45 (t, 2H); 3.20-3.19 (d, 2H); 3.59-3.53 (m, 1H); 13C NMR (125.6 MHz, D2O, δ in ppm): 27.7, 31.9, 43.3, 51.5, 178.9
A round bottom flask was charged with (S)-4-carboxybutane-1,2-diaminium chloride (9.5 g, 46 mmol) and water (45 mL). The solution was neutralized with 1M KOH (145 mL) and cooled in an ice-bath. Simultaneously, from two separate additional funnels, isobutyryl chloroformate (13.3 mL) in THF (190 mL) and 1M KOH (145 mL) were slowly added. The mixture was stirred for 1 h at 0° C. and overnight at room temperature. THF was removed in vacuum and the water layer was extracted with EtOAc. The water layer was acidified with 2M HCl and extracted with EtOAc. The combined extract was dried over anhydrous Na2SO4. Removal of solvent under reduced pressure, gave 15.03 g (45.3 mmol, 98%) of (S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid as white solid.
1H NMR (500 MHz, CDCl3, δ in ppm): 0.88-0.89 (d, 12H); 1.74-1.89 (m, 4H); 2.42-2.57 (m, 2H), 3.28 (m, 2H), 3.74-3.81 (m, 5H), 5.22-5.30 (br, 2H).
A round bottom flask was charged with crude S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid (14.22 g, 42.84 mmol) and 1,2-dimethoxyethane (70 mL). N-methyl morpholine (5.24 mL, 47.1 mmol) was added with stirring and the resulting solution was cooled to −25° C. Then isobutyl chloroformate (6.8 mL, 51.4 mmol) was added slowly and a white precipitate formed. The cold bath was removed, and the mixture was allowed to warm to room temperature. The precipitate was collected by filtration and washed with 1,2-dimethoxyethane (2×30 mL). The combined filtrate and washings were deoxygenated with a stream of nitrogen, and a solution of NaBH4 (2.43 g, 64.3 mmol) in EtOH (150 mL) was added dropwise at 0° C. After 2 h, water (10 mL) was cautiously added. The mixture was stirred overnight and the 0° C. bath was allowed to warm to room temperature. The solvent was removed by rotary evaporation. The resulting solid was dissolved in EtOAc (300 mL) and water (200 mL) was added. The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organic phases were dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and the crude product was purified on a silica gel column (1:1 v/v EtOAc/Hexane). The solvent was removed and dried in vacuum to give (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate as a white solid (11.13 g, 35 mmol, 82%).
1H NMR (500 MHz, CDCl3, δ in ppm): 5.17 (br s, 1H), 5.06 (br s, 1H), 3.90-3.76 (m, 4H), 3.75-3.59 (t, 3H), 3.36-3.18 (m, 2H), 1.97-1.81 (m, 2H), 1.69-1.56 (m, 3H), 1.55-1.43 (m, 1H), 0.97-0.86 (m, 12H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.6, 157.3, 71.1, 62.4, 51.7, 45.1, 29.2, 28.6, 28.0, 19.0.
A round bottom flask was charged with (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate (5.0 g, 15.7 mmol), CH2Cl2 (80 mL), and triethylamine (5.3 mL, 38 mmol), and cooled to −78° C. Methanesulfonyl chloride (2.3 mL, 30 mmol) was added dropwise with stirring and the cold bath was allowed to warm to 0° C. over the course of 5 h. Aqueous citric acid (20%, 140 mL) and CH2Cl2 (150 mL) were added and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, and then dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and dried in oil pump vacuum. The product (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate was obtained as a yellowish white solid. The crude product was used without further purification in the next procedure.
An airfree round bottom flask was charged with the crude (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate from the previous synthesis and a solution of HNMe2 in THF (80 mL, 2.0 M). Then the stopper of the flask was tightened to stop the evaporation of HNMe2 during the reaction. The mixture was placed in an 80° C. oil bath. After 15 h, the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2 (200 mL), washed with saturated NaHCO3 (150 mL) and brine (100 mL), and dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and the oily yellow residue was purified by a silica gel column (with CH2Cl2/MeOH). The solvent was removed from the product-containing fractions to give (S)-diisobutyl-(5-(dimethylamino) pentane-1,2-diyl) dicarbamate as an oily yellow residue (4.66 g, 13.55 mmol, 88% for two steps).
1H NMR (500 MHz, CDCl3, δ in ppm): 5.71 (br s, 1H), 5.27 (br s, 1H), 3.90-3.75 (d, J=10 Hz, 4H), 3.70-3.58 (m, 1H), 3.33-3.08 (m, 2H), 2.30-2.23 (m, 2H), 2.20 (s, 6H), 1.96-1.79 (m, 2H), 1.62-1.38 (m, 4H), 0.97-0.82 (m, 12H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.4, 157.3, 71.0, 59.1, 51.5, 45.4, 45.2, 30.4, 28.0, 23.6, 19.0.
A round bottom flask was charged with (S)-diisobutyl-(5-(dimethylamino)pentane-1,2-diyl)dicarbamate (4.2 g, 12.2 mmol) and 6.0 M HCl (250 mL), and the solution was refluxed for 36 h. The acidic solvent was evaporated in vacuum and the hydrochloride salt of (S)—N5,N5-dimethylpentane-1,2,5-triamine was obtained as sticky solid with 71% yield (2.994 g, 8.7 mmol). The compound was highly hygroscopic.
1H NMR (500 MHz, D2O, δ in ppm): 1.84-1.58 (m, 4H); 2.76 (s, 6H); 3.12-3.03 (m, 2H), 3.24-3.21 (m, 2H); 3.60-3.55 (m, 1H). 13C NMR (125.6 MHz, D2O, δ in ppm): 22.6, 29.6, 41.07, 43.1, 45.4, 51.6, 59.2.
A round bottom flask was charged with (S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid (4.0 g, 12 mmol) and anhydrous THF (130 mL). N-methyl morpholine (1.7 mL, 15.4 mmol) was added with stirring and the resulting solution was cooled to −20° C. Then isobutyl chloroformate (2.0 mL, 15.4 mmol) was added slowly and the mixture was stirred for 0.5 h. Conc. ammonium hydroxide (30%) (8.8 mL) was added and the mixture was stirred at −20° C. to 0° C. for 6 hours and then evaporated to dryness. The residue was purified by silica gel column chromatography using 7% (15% concentrated ammonium hydroxide in methanol)-CH2Cl2 as eluent. The solvent was removed and dried in vacuum to give (S)-diisobutyl-(5-amino-5-oxopentane-1,2-diyl) dicarbamate as a white solid (3.42 g, 10.2 mmol, 85%).
1H NMR (500 MHz, DMSO-d6, δ in ppm): 0.76-0.97 (m, 12H); 1.31-2.11 (m, 5H); 2.84-3.04 (m, 2H), 3.33 (s, 1H), 3.37-3.6 (m, 1H), 3.62-3.74 (m, 4H), 6.24-7.64 (br m, 4H).
13C{1H} NMR (125.6 MHz, DMSO-d6, δ in ppm): 174.0, 156.6, 156.2, 69.7, 69.4, 50.6, 44.2, 31.7, 27.7, 27.5, 19.0, 18.9.
A round bottom flask was charged with (S)-diisobutyl-(5-amino-5-oxopentane-1,2-diyl)dicarbamate (3.0 g, 9 mmol), CH3CN (25 mL), EtOAc (25 mL), water (12 mL), and iodosobenzene diacetate (4.2 g, 13 mmol). The reaction mixture was stirred at room temperature. After 15 hours the solvents were evaporated and the crude mixture was purified by silica gel column chromatography (5% to 20% MeOH in CH2Cl2) to afford (S)-diisobutyl (4-aminobutane-1,2-diyl)dicarbamate as a colorless sticky liquid (1.55 g, 5.1 mmol, 57%).
1H NMR (500 MHz, CDCl3, δ in ppm): 0.80-0.98 (d, 12H, J=5 Hz); 1.42-1.77 (m, 2H), 1.79-1.99 (m, 2H); 2.70-2.91 (m, 2H), 3.36-3.08 (br s, 2H), 3.82 (m, 5H), 5.2-5.60 (br, 2H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.5, 157.3, 71.1, 50.0, 45.2, 38.4, 35.6, 28.0, 28.0, 19.0.
A fisher porter bottle was charged with (S)-diisobutyl (4-aminobutane-1,2-diyl)dicarbamate (1.8 g, 6 mmol), methanol (50 mL) and distilled water (15 mL) and 37% aqueous formaldehyde (1.6 mL). The mixture was stirred for 1 h and 10% wet Pd-C (1.2 g) was added in portions and the mixture was hydrogenated at 50 psi for 24 h at RT. The mixture was filtered through a plug of Celite and washed with methanol-distilled water (1:1). The solvent was removed and the residue was chromatographed on a silica gel column (5% to 20% methanol in CH2Cl2 to give (S)-diisobutyl (4-(dimethylamino)butane-1,2-diyl)dicarbamate (1.016 g, 51%) as colorless oil.
1H NMR (500 MHz, CDCl3, δ in ppm): 0.80-1.02 (m, 12H); 1.52-1.99 (m, 4H), 2.14-2.41 (m, 6H); 2.41-2.66 (m, 2H), 3.13-3.38 (m, 2H), 3.66-3.94 (m, 5H), 5.36-6.12 (br, 2H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.7, 157.4, 72.1, 71.2, 71.1, 50.9, 50.7, 45.0, 29.2, 28.0, 28.0, 19.9.
A round bottom flask was charged with (S)-diisobutyl (4-(dimethylamino)butane-1,2-diyl)dicarbamate (0.9 g, 2.7 mmol) and 6 M HCl (50 mL). The reaction mixture was refluxed for 50 h. The acidic solvent was evaporated in vacuum and the hydrochloride salt (S)—N4,N4-dimethylbutane-1,2,4-triamine was obtained as sticky solid (0.607 g). The compound was highly hygroscopic.
1H NMR (500 MHz, D2O, δ in ppm): 2.39-2.18 (m, 4H); 2.96 (s, 6H), 3.51-3.33 (m, 2H), 3.86-3.75 (m, 1H). 13C NMR (125.6 MHz, D2O, δ in ppm): 26.3, 41.2, 43.6, 47.8, 53.8.
Hydrochloride salt of (S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine (n=3)
(S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate.
An air free round bottom flask was charged with the previously synthesized crude (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate (1.79 g, 4.52 mmol) and THF (15 mL). Pyrrolidine (3.7 mL, 45.2 mmol) was added to the reaction mixture. Then the stopper of the flask was tightly closed. The mixture was placed in an 80° C. oil bath. After 15 h, the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2 (40 mL), washed with saturated NaHCO3 (30 mL) and brine (20 mL), and dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and the oily yellow residue was purified by a silica gel column (with CH2Cl2/MeOH). The solvent was removed from the product-containing fractions to give (S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate (1.45 g, 4.08 mmol, 90%).
1H NMR (500 MHz, CDCl3, δ in ppm): 5.99 (br s, 1H), 5.27 (br s, 1H), 3.95-3.73 (d, J=10 Hz, 4H), 3.72-3.54 (m, 1H), 3.36-3.06 (m, 2H), 2.58-2.29 (m, 6H), 1.94-1.80 (m, 2H), 1.79-1.75 (m, 4H), 1.66-1.38 (m, 4H), 0.99-0.78 (d, J=15 Hz, 12H); 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.6, 157.5, 71.2, 71.1, 56.1, 54.1, 51.4, 45.6, 30.9, 28.1, 24.9, 23.5, 19.2.
A round bottom flask was charged with (S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate (1.44 g, 4.05 mmol) and 6.0 M HCl (70 mL), and the solution was refluxed for 30 h. The acidic solvent was evaporated in vacuum and the hydrochloride salt of (S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine was obtained as yellowish sticky solid (1.30 g). The compound was highly hygroscopic. See
1H NMR (500 MHz, D2O, δ in ppm): 3.77-3.62 (m, 3H); 3.44-3.32 (m, 2H); 3.31-3.21 (m, 2H), 2.24-2.08 (m, 2H); 2.06-1.73 (m, 6H); 13C NMR (125.6 MHz, D2O, δ in ppm): 54.8, 54.4, 49.6, 41.1, 27.8, 23.2, 22.0.
Synthesis and purification of cobalt complexes were adapted from Ganzmann, C. Doctorate Thesis, Universität Erlangen-Nürnberg, 2010.
[Co(en)7(S)-en CH2CH2CH2NMe2]3+3 BArf-
A round bottom flask was charged with [Co(en)2CO3]3+Cl− (0.606 g, 2.21 mmol), activated charcoal (0.440 g), and water (20 mL), and fitted with a condenser. The reaction mixture was heated to 40° C. Then the hydrochloric acid salt of (S)—N5,N5-dimethylpentane-1,2,5-triamine (0.519 g, 2.04 mmol) was added in one portion. The temperature was increased to 100° C. After 0.8 h, the activated charcoal was removed by filtration and the red filtrate was evaporated to dryness by rotary evaporation. The red solid was dissolved in 0.5 M HCl (100 mL), and sorbed on a Dowex (50WX2 hydrogen form, 200-400 mesh) column (4.2×15 cm), which was eluted with 1.0 M (250 mL) followed by 2.0 M HCl solution. Three distinguishable orange bands were obtained. When the second orange band reached the column outlet, the eluent was changed to 3.0 M HCl. The second orange band was collected, and evaporated to dryness to give an orange solid (0.380 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.4-4.85 (br m, 10H), 4.64-4.37 (br m, 2H) 3.27-3.13 (m, 2H), 3.12-2.69 (m, 16H), 2.66-2.59 (br s, 1H), 2.01-1.72 (br m, 4H); 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 58.4, 57.6, 57.0, 49.6, 48.7, 45.6, 45.6, 45.5, 45.3, 45.3, 45.2, 45.0, 44.9, 43.2, 29.2, 29.0, 22.0 (Dioxane as ref. at 67.14 ppm).
The orange solid obtained from second band of the Dowex column was redissolved in 40 mL of water and sorbed in a SP Sephadex (C-25) column (4.4×44 cm). Two bands separated upon elution with 0.10 M (250 mL), 0.15 M (250 mL), 0.20 M (500 mL) and 0.25 M 2Na+ d-tart2-.2H2O.
The first band from the Sephadex column was collected and concentrated to 100 mL. This solution was sorbed on a Dowex column. Then, the compound was eluted by using 1 (M) to 3 (M) HCl solutions to give an orange solid (0.230 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.5-4.84 (br m, 10H), 4.69-4.43 (br m, 2H) 3.26-3.13 (m, 2H), 3.11-2.69 (m, 18H), 2.66-2.49 (br s, 1H), 2.04-1.67 (br m, 4H). 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 58.4, 57.6, 49.6, 45.5, 45.3, 45.3, 45.2, 43.2, 29.2, 29.0, 22.0. (Dioxane as ref. at 67.14 ppm).
Similarly, the second band from the Sephadex column was collected and concentrated to 100 mL. Then the solution was sorbed on a Dowex column. Then, the compound was eluted by using 1.0 (M) to 3.0 (M) HCl solutions to give an orange solid (0.134 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.4-5.26 (br s, 1H), 5.22-4.95 (br m, 5H), 4.64-4.35 (br 2H), 3.27-3.08 (m, 3H), 3.07-2.48 (m, 16H), 2.66-2.59 (br s, 1H), 1.98-1.68 (br m, 4H); 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 58.4, 57.0, 48.7, 45.6, 45.0, 44.9, 43.3, 29.1, 22.0 (Dioxane as ref. at 67.14 ppm).
A round bottom flask was charged with Fraction 1-[Co(en)2(S)-en CH2CH2CH2NHMe2]4+4Cl-.3.5H2O (0.070 g, 0.134 mmol), aq. NaOH (1.5 mL, 0.10 mmol), and water (10 mL). Then a solution of Na+ BArf- (0.335 g, 0.361 mmol) in CH2Cl2 (20 mL) was added and the heterogeneous mixture was vigorously stirred for 0.5 h. The orange organic phase was separated from the aqueous phase and washed with water and allowed to evaporate in the air to give Fraction-1 [Co(en)2(S)-en CH2CH2CH2NMe2]3+3BArf-.6.5H2O as an orange powder (0.318 g).
Referring to
1H NMR (500 MHz, DMF-d7, δ in ppm): 7.91-7.69 (m, 35H), 5.56-4.98 (m, 10H), 4.73 (br s, 1H), 3.5 (s, 13H), 3.27 (br s, 1H), 3.15-2.93 (br s, 7H), 2.29-2.07 (m, 14H), 1.84-1.41 (m, 4H). 13C{1H} NMR (125.6 MHz, CD3CN, δ in ppm): 162.6 (q, 1JBC=49.6 Hz), 135.7 (s), 129.9 (q, 2JCF=31.4 Hz), 125.5 (q, 1JCF=271.3 Hz), 118.7, 59.2, 50.1, 45.8, 45.6, 45.3, 45.3, 30.3, 24.6.
A round bottom flask was charged with Fraction-2 [Co(en)2(S)-en CH2CH2CH2NMe2]4+4Cl-.8H2O (0.085 g, 0.143 mmol), aq. NaOH (1.5 mL, 0.1 M), and water (15 mL). Then a solution of Na+ BArf- (0.371 g) in CH2Cl2 (20 mL) was added and the heterogeneous mixture was vigorously stirred for 0.5 h. The orange organic phase was separated from the aqueous phase and the organic phase was washed with water and allowed to evaporate in the air to give Fraction-2 [Co(en)2(S)-en CH2CH2CH2NMe2]3+3BArf-.15H2O as an orange powder.
Referring to
1H NMR (500 MHz, DMF-d7, δ in ppm): 7.86-7.70 (m, 48H), 5.78-5.02 (m, 10H), 4.91-67 (br m, 2H), 3.51 (s, 30H), 3.36 (br s, 1H), 3.18-2.93 (br s, 9H), 2.4-1.95 (br s, 10H), 1.88-1.37 (m, 4H).
Co(en)2(S)-en CH2CH7NMe2]3+3 BArf-
A round bottom flask was charged with [Co(en)2CO3]3+Cl— (0.606 g, 2.21 mmol), activated charcoal (0.440 g), and water (20 mL), and fitted with a condenser. The reaction mixture was heated to 40° C. Then the hydrochloric acid salt of (S)—N4,N4-dimethylbutane-1,2,4-triamine (n=2) (0.494 g, 2.04 mmol) was added in one portion. The temperature was increased to 100° C. After 0.8 h, the activated charcoal was removed by filtration and the red filtrate was evaporated to dryness by rotary evaporation. The red solid was dissolved in 0.5 M HCl (100 mL), and sorbed on a Dowex (50WX2, 200-400 mesh) column (4.2×15 cm), which was eluted with 1.0 M (250 mL) followed by 2.0 M HCl. Three distinguishable orange bands were obtained. When the second orange band reached the column outlet, the eluent was changed to 3.0 M HCl. The second orange band was collected, and evaporated to dryness to give an orange solid (0.372 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.6-4.82 (br m, 9H), 4.75-4.38 (m, 1H), 3.45-3.24 (m, 2H), 3.23-2.56 (m, 17H), 2.30-2.15 (m, 2H). 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 56.0, 55.9, 55.0, 54.8, 54.7, 49.5, 48.6, 45.4, 45.3, 45.2, 45.1, 45.0, 43.5, 43.4, 43.3, 27.3.
The orange solid (0.300 g) obtained from second band of the Dowex column was redissolved in 40 ml of water and sorbed in a SP Sephadex (C-25) column (4.4×44 cm). Two bands separated upon elution with 0.10 M (1000 mL), 0.15 M (1000 mL), 0.20 M (1000 mL) and of 0.25 M 2Na+d-tart2-.2H2O. Each band was collected and concentrated.
The first band from the Sephadex column was collected and concentrated to 100 mL. This solution was sorbed on a Dowex column. Then, the compound was eluted by using 1.0 (M) to 3.0 (M) HCl solutions to give an orange solid (0.181 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.46 (br s, 1H), 5.27-4.84 (br m, 11H), 3.46-3.23 (br m, 2H) 3.19-2.61 (m, 18H), 2.32-2.14 (m, 2H), 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 55.76, 54.9, 49.2, 45.2, 45.1, 45.0, 44.9, 43.5, 43.3 (Dioxane as ref. at 67.14 ppm).
The second band from the Sephadex column was collected and concentrated to 100 mL. This solution was sorbed on a Dowex column. Then, the compound was eluted by using 1(M) to 3 (M) HCl solutions to give an orange solid (0.091 g).
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.38 (br s, 1H), 5.27-5.05 (br m, 5H), 4.74-4.66 (br m, 1H), 4.58-4.48 (br m, 1H), 3.49-3.33 (br m, 2H), 3.32-3.20 (br m, 1H) 3.09-2.68 (m, 16H), 2.34-2.21 (m, 2H), 13C{1H} NMR (125.6 MHz, D2O, δ in ppm): 55.0, 54.8, 48.6, 45.7, 45.6, 45.1, 45.0, 43.4, 43.3 (Dioxane as ref. at 67.14 ppm).
A round bottom flask was charged with Fr 1-[Co(en)2(S)-en CH2CH2NHMe2]4+4 Cl-.4H2O (0.051 g, 0.133 mmol), aq NaOH (1.5 mL, 0.1 M), and water (12 mL). Then a solution of Na+ BArf- (0.250 g) in CH2Cl2 (20 mL) was added and the heterogeneous mixture was vigorously stirred for 0.5 h. The orange organic phase was separated from the aqueous phase and the organic phase was washed with water and allowed to evaporate in the hood to give Fr-1 [Co(en)2(S)-en CH2CH2NMe2]3+3 BArf-.12H2O as an orange powder (0.302 g).
Referring the
1H NMR (500 MHz, CD3CN, δ in ppm): 7.76-7.58 (m, 35H), 4.56-3.53 (br m, 12H), 3.03-2.58 (br m, 10H), 2.56-2.44 (m, 2H), 2.40-2.29 (m, 1H), 2.27-2.21 (br s, 24H), 2.19 (s, 1H), 1.91-1.86 (m, 1H), 1.75-1.65 (m, 1H). 13C{1H} NMR (125.6 MHz, CD3CN, δ in ppm): 162.6 (q, 1JBC=50.2 Hz), 135.7 (s), 129.9 (q, 2JCF=31.4 Hz), 125.5 (q, 1JCF=271.3 Hz), 118.7, 58.8, 56.7, 49.4, 45.7, 45.6, 45.3, 45.2, 28.2.
[Co((S)-enCH2CH2CH2NMe2H)3]6+6 Cl—.
A round bottom flask was charged with a solution of CoCl2.6H2O (0.257 g, 1.08 mmol, 1 eq) in 2.5 mL water. Then the hydrochloric acid salt of (S)—N5,N5-dimethylpentane-1,2,5-triamine (1.45 g, 4.3 mmol, 4 eq) was added with stirring. The mixture was stirred for 15 min. NaOH (0.550 g, 12 eq) was added and the mixture was stirred until the NaOH dissolved completely. The solution becomes dark red. 3% H2O2 solution (1.6 mL) was added with stirring. The solution became dark upon addition of peroxide. The mixture was diluted to 6.0 mL and boiled for 0.5 h. Then, 3.0 M HCl (1 mL) was added with stirring. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was dissolved in 1.0 (M) HCl (50 mL) and the mixture was sorbed on a Dowex column (4.2×15 cm), which was eluted with 1.0 M HCl (250 mL) followed by 2.0 M HCl (250 mL), 3.0 M HCl (250 mL) and 4.0 M HCl. The compound was collected by eluting with 4.0 M HCl and the orange to red colored solution was evaporated to dryness to give a deep red solid (0.994 g) which was the mixture of the diastereomers.
Referring to
1H NMR (500 MHz, D2O, δ in ppm): 5.47-4.86 (br m, 8H); 3.24-2.96 (br m, 12H), 2.87 (s, 18H), 2.68-2.53 (br m, 3H), 2.68-2.53 (br m, 12H); 13C{1H} NMR (125.6 MHz, D2O, δ in ppm) 58.55/58.51/58.49/58.44, 57.57/57.54, 49.62/49.61, 43.33/43.28, 28.97/28.87/28.86/28.84, 21.99/21.97.
The complexes Fraction-1 [Co(en)2(S)-en CH2CH2CH2NMe2]3+3 BArf-.6.5 H2O, Fr-2 [Co(en)2(S)-en CH2CH2CH2NMe2]3+3BArf-.15H2O, Fraction-1 [Co(en)2(S)-en CH2CH2NMe2]3+3 BArf-.12H2O were tested as catalysts in the Michael addition of trans-β-nitrostyrene and diethyl malonate.
Referring to
The complex Fraction-1 [Co(en)2(S)-en CH2CH2CH2NMe2]3+3 BArf-.6.5H2O was found to be the best catalyst, with higher yield and enantioselectivity, for the Michael addition of trans-β-nitrostyrene and diethyl malonate.
General Procedure for Michael Addition
A NMR tube was charged with β-nitrostyrene (0.0149 g, 0.10 mmol), diethyl malonate (0.0182 mL, 0.012 mmol), catalyst (7 mol %), 1,2-dichloroethane (0.0080 mL, 0.10 mmol) as internal standard, and CD2Cl2 (0.4 mL). The NMR tube was sealed with a plastic cap and parafilm. The reaction was monitored by 1H NMR. The reaction solution was passed through a short pad of silica with hexanes and ethyl acetate mixture. The solvent was evaporated by rotary evaporation. Then the enantioselectivity for the reactions were measured by chiral HPLC.
Synthesis of Metal Complexes
Referring to
Examples of Synthesis of Metal Complexes
The following experimental illustrates synthesis of cobalt complexes having 1°/3° ligand (L).
Referring to
Referring to
Referring to
Despite being inexpensive and readily available in enantiopure form, Werner complexes of the type [Co(en)3]3+(en=ethylenediamine) ((+)-Λ-1/(−)-Δ-1), and related species, have had no applications in enantioselective organic synthesis since their first preparation nearly a century ago.1 This derives from their poor solubility in organic solvents and the fact that the chelating amine ligands are non-labile, preventing metal based substrate activation. In light of recent advancements in asymmetric hydrogen bond mediated catalysis by chiral alcohols, amines, and thioureas,2 it was conceived that the abundant nitrogen-hydrogen bonds incorporated in the ethylenediamine units could activate Lewis basic substrates towards nucleophilic addition. The enantiopure Δ-(−)-[Co(en)3]3+ cation became soluble in CH2Cl2 solvent by pairing with the large, non-coordinating anion tetrakis[(3,5-trifluoromethyl)phenyl]borate (BArf−) and was used to catalyze the Michael addition of dimethyl malonate to trans-β-nitrostyrene in the presence of triethylamine base in 99% yield and 30% ee.
In efforts to improve enantioselectivity, related Werner-type complexes with bulky, enantiopure (1S,2S)-diphenylethylenediamine (S,S-dpen) ligands were synthesized. Thus, a diastereomeric mixture of (+)-Λ-[Co(S,S-dpen)3]Cl3 and (−)-(Δ)-[Co(S,S-dpen)3]Cl3 was prepared according to an earlier synthesis.3 It was discovered that the anion exchange of these products with one molar equivalent of NaBArf led to the CH2Cl2-soluble (+)-Λ-[Co(S,S-dpen)3](BArf)Cl2 ((+)-Λ-2) and (−)-(Δ)-[Co(S,S-dpen)3](BArf)Cl2 ((−)-Δ-2), which are easily separated by flash chromatography on silica gel.
The Werner complex (+)-Λ-2 demonstrated marked improvement in the enantioselectivity of the Michael addition by catalyzing the reaction in 99% yield and 76% ee. Interestingly, the opposite catalyst diastereomer (−)-Δ-2, which bears the same absolute stereochemistry in the dpen ligand but the opposite sense of chirality at the metal center, promoted the same reaction with 99% yield and 56% ee of the opposite product enantiomer. This demonstrates that the enantioselectivity of the Michael addition is primarily under the control of the chirality at the metal center.
Some optimizations of the reaction conditions led to improved enantioselectivities. It is generally observed that weaker bases promote better selectivity. For instance, the use of pyridine gave the Michael addition product in 80% ee. Surprisingly, the catalyst system performed well even in polar solvents such as acetone, which promoted the Michael addition in 85% ee. This stands out as a unique feature, since most hydrogen bond mediating catalysts are strongly inhibited by polar solvents that are capable of competing with the substrate for hydrogen bonding sites. Additional examination reveals that enantioselectivity is even further improved in the presence of water and an inorganic base, giving up to 90% ee.
The Michael addition of diphenylphosphite to trans-β-nitrostyrene was catalyzed by (+)-Λ-2 in 99% yield and 68% ee. The opposite catalyst diastereomer, (−)-Δ-2 promoted the same reaction in 99% yield to give the opposite product enantiomer in 72% ee, again emphasizing that the absolute product stereochemistry is determined by the chirality at the metal center.
Several derivative Werner complexes have been synthesized with modified, enantiopure S,S-dpen ligands including complexes with electron donating (3), electron withdrawing (4), and sterically bulky functional groups (5).
Werner-type complexes have here for the first time been successfully employed in enantioselective organic synthesis. The mode of activation by hydrogen bond mediation can be applied to a variety of substrates bearing hydrogen bond accepting functional groups. The structure of the S,S-dpen can be modified to allow for rapid fine tuning of the electronic and steric properties of the catalyst to suit a particular reaction. These Werner-type complexes are inexpensive to prepare owing largely to the low cost of cobalt and have been synthesized and resolved into pure diastereomers on a multi-gram scale. The catalysts are stable in the presence of air and moisture and are stored long term on the bench top. Lastly, recovery of the catalyst is possible by routine column chromatography during the purification of the reaction mixture.
The examples herein are included to demonstrate particular embodiments of the present invention. It should be appreciated by those of skill in the art that the methods disclosed in the examples that follow merely represent exemplary embodiments of the present invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments described and still obtain a like or similar result without departing from the spirit and scope of the present invention.
Although the invention has been described with reference to specific embodiments, these descriptions are not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the invention will become apparent to persons skilled in the art upon reference to the description of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims.
It is therefore, contemplated that the claims will cover any such modifications or embodiments that fall within the true scope of the invention.
This application claims priority to U.S. Provisional Application No. 61/676,683, filed Jul. 27, 2012. The entirety of the aforementioned application is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2013/052569 | 7/29/2013 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2014/018978 | 1/30/2014 | WO | A |
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| 4182814 | Bernemann et al. | Jan 1980 | A |
| 4472559 | Maehara et al. | Sep 1984 | A |
| 4598091 | Schonenberger et al. | Jul 1986 | A |
| 5663393 | Jacobsen et al. | Sep 1997 | A |
| 6410749 | Katayama et al. | Jun 2002 | B1 |
| 6686505 | Watanabe et al. | Feb 2004 | B2 |
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| Number | Date | Country | |
|---|---|---|---|
| 20150165429 A1 | Jun 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61676683 | Jul 2012 | US |
