Claims
- 1. A process of stereoselective chemical synthesis which comprises reacting a π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically-enriched addition product, wherein said substrate comprises a carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral, non-racemic catalyst comprises an asymmetric tetradentate ligand complexed with a main-group metal atom, said catalyst having a rectangular planar or rectangular pyramidal geometry.
- 2. The process of claim 1, wherein the metal atom is a main-group metal from Groups 1, 2, 12, 13, or 14.
- 3. The process of claim 2, wherein the metal atom is selected from groups 12, 13, or 14.
- 4. The process of claim 2, wherein the metal atom is selected from the group comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn.
- 5. The process of claim 1, wherein the tetradentate ligand is selected from the group consisting of a chiral, non-racemic ligand represented by the formula 102, a chiral, non-racemic ligand represented by the formula 104, a chiral, non-racemic ligand represented by the formula 106, a chiral, non-racemic ligand represented by the formula 108, a chiral, non-racemic ligand represented by the formula 110, a chiral, non-racemic ligand represented by the formula 112, a chiral, non-racemic ligand represented by the formula 114, a chiral, non-racemic ligand represented by the formula 116, and chiral, non-racemic crown ethers.
- 6. The process of claim 1, wherein the tetradentate ligand has at least one Schiff base which complexes with the main-group metal atom.
- 7. The process of claim 1, wherein the chiral catalyst has a molecular weight of less than 5,000 a.m.u.
- 8. The process of claim 1, wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2:
- 9. The process of claim 8, wherein R and R′ in 1 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure.
- 10. The process of claim 8, wherein R, and R′ are chosen such that 1 does not have an internal plane of symmetry.
- 11. The process of claim 1, wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions.
- 12. The process of claim 1, wherein the catalyst is immobilized on an insoluble matrix.
- 13. The process of claim 1, which process is an enantioselective reaction.
- 14. The process of claim 1, which process is a diastereoselective reaction.
- 15. The process of claim 14, which diastereoselective reaction is a kinetic resolution.
- 16. A process of stereoselective chemical synthesis which comprises reacting a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically-enriched product, wherein said π-bond-containing substrate comprises a carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral, non-racemic catalyst comprises an asymmetric tridentate ligand complexed with a main-group metal atom.
- 17. A stereoselective nucleoplilic addition process which comprises:
combining a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product, wherein said π-bond-containing substrate comprises at least one carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral, non-racemic catalyst comprises a chiral ligand having at least one Schiff base nitrogen complexed with a -main-group metal; and maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleoplilic addition reaction between said chiral or prochiral π-bond-containing substrate and said nucleophile.
- 18. The process of claim 17, wherein the main-group metal is selected from Groups 1, 2, 12, 13, or 14 of the periodic table.
- 19. The process of claim 17, wherein the metal is a Group 12, 13, or 14 main-group metal.
- 20. The process of claim 17, wherein the metal atom is selected from the set comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn.
- 21. The process of claim 17, wherein the catalyst comprises a tetradentate ligand.
- 22. The process of claim 21, wherein the catalyst is represented by the general formula:
- 23. The process of claim 17, wherein the catalyst comprises a tridentate ligand.
- 24. The process of claim 17, wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2:
- 25. The process of claim 24, wherein R and R′ in 1 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure.
- 26. The process of claim 24, wherein R and R′ are chosen such that 1 does not have an internal plane of symmetry.
- 27. The process of claim 17, wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions.
- 28. The process of claim 17, which process is an enantioselective reaction.
- 29. The process of claim 17, which process is a diastereoselective reaction.
- 30. The process of claim 29, which diastereoselective reaction produces a kinetic resolution.
- 31. The process of claim 17, wherein the chiral, non-racemic catalyst has a molecular weight of less than 5,000 a.m.u.
- 32. A method for catalyzing a stereoselective nucleophilic addition reaction which comprises:
combining a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product, wherein said π-bond-containing substrate comprises at least one carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral catalyst comprises a chiral tetradentate ligand complexed with a main-group metal; and maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said π-bond-containing substrate and said nucleophile.
- 33. The method of claim 32, wherein the chiral, non-racemic catalyst is represented by the general formula 100:
- 34. The method of claim 33, wherein
R1, R2, R′1 and R′2, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7; each R40 and R41 occuring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
- 35. The method of claim 33, wherein each Z1, Z2, Z3 and Z4 are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur.
- 36. The method of claim 33, wherein the M represents a main-group metal selected from Groups 1, 2, 12, 13, or 14 of the periodic table.
- 37. The method of claim 33, wherein the metal atom is selected from the set comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn.
- 38. The method of claim 33, wherein the M is a Group 12, 13, or 14 main-group metal.
- 39. The method of claim 38, wherein the M is Al(III).
- 40. The method of claim 32, wherein the tetradentate ligand is selected from the group consisting of a chiral, non-racemic ligand represented by the formula 102, a chiral, non-racemic ligand represented by the formula 104, a chiral, non-racemic ligand represented by the formula 106, a chiral, non-racemic ligand represented by the formula 108, a chiral, non-racemic ligand represented by the formula 110, a chiral, non-racemic ligand represented by the formula 112, a chiral, non-racemic ligand represented by the formula 114, a chiral, non-racemic ligand represented by the formula 116, and chiral, non-racemic crown ethers.
- 41. The process of claim 32, wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2:
- 42. The method of claim 41, wherein R and R″ in 1 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure.
- 43. The method of claim 41, wherein R, and R′ are chosen such that 1 does not have an internal plane of symmetry.
- 44. The process of claim 41, wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α, β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions.
- 45. The method of claim 27, which process is an enantioselective reaction.
- 46. The method of claim 27, which process is a diastereoselective reaction.
- 47. The method of claim 46, which diastereoselective reaction produces a kinetic resolution.
- 48. A method for catalyzing a stereoselective nucleophilic addition reaction which comprises:
combining a chiral or prochiral π-bond-containing substrate and a nucleophile in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product, wherein said π-bond-containing substrate comprises at least one carbon-carbon or carbon-heteroatom π-bond, said nucleophile comprises at least one pair of Lewis basic electrons, and said chiral catalyst comprises a chiral tridentate ligand complexed with a main-group metal; and maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said π-bond-containing substrate and said nucleophile.
- 49. The method of claim 48, wherein the chiral tridentate ligand of the chiral catalyst is represented by the general formula:
- 50. A method for synthesis of stereoisomerically enriched chiral compounds, comprising reacting a prochiral or chiral π-bond-containing substrate with a nucleophile in the presence of a chiral, non-racemic catalyst, and under conditions wherein said chiral catalyst catalyzes a stereoselective nucleophilic addition reaction between said π-bond-containing substrate and said nucleophile, to produce a product which is stereoisomerically-enriched relative to a racemic mixture produced—in the case of a prochiral π-bond-containing substrate—or to the 1:1 ratio of diastereoisomers produced—in cases wherein the π-bond-containing substrate is chiral—in the absence of said chiral catalyst;
wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2: 71wherein R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80; X is selected from the group comprising CR2, O, S, Se, and NR″; Y is selected, independently for each occurrence, from the set comprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR3, and SnR3; and Nu is selected from the set comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions; R80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and m is an integer in the range 0 to 8 inclusive; and the chiral catalyst is represented by the general formula: 72the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7,
or any two or more of the substituents taken together form a carbocyle or heterocycle ring having from 4 to 8 atoms in the ring structure, with the proviso that at least one of R1, Y1, X1 and X2 is covalently bonded to at least one of R2, Y2, X3 and X4 to provide the β-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y1 and Y2 is a hydrogen; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle; m is zero or an integer in the range of 1 to 8; M represents the main-group metal; and A represents a counterion or a nucleophile, wherein each of of the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4, are selected such that the catalyst is asymmetric.
- 51. The method of claim 50, wherein the M represents a main-group metal selected from Groups 1, 2, 12, 13, or 14 of the periodic table.
- 52. The method of claim 51, wherein the metal atom is selected from the group comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn.
- 53. The method of claim 50, wherein M is a Group 12, 13, or 14 main-group metal.
- 54. The method of claim 53, wherein M is Al(III).
- 55. The method of claim 50, wherein the chiral, non-racemic catalyst is represented by the general formula 104:
- 56. The method of claim 50, wherein R and R′ in 1 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure.
- 57. The method of claim 50, wherein R, and R′ are chosen such that 1 does not have an internal plane of symmetry.
- 58. The method of claim 50, wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions.
- 59. The method of claim 50, which process is an enantioselective reaction.
- 60. The method of claim 50, which process is a diastereoselective reaction.
- 61. The method of claim 60, which diastereoselective reaction produces a kinetic resolution.
- 62. A method of realizing a stereoselective addition of a nucleophile to a prochiral or chiral π-bond-containing substrate, wherein the π-bond-containing substrate is represented by the general formula 1, and the nucleophile is represented by NuY, to give a product represented by 2:
- 63. The method of claim 62, wherein the metallosalenate catalyst is represented by the general formula 106:
- 64. The method of claim 62, wherein the substituents R1, R2, R3, and R4 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7;
or any two of the substituents R1, R2, and R50, or R3, and R4 taken together form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
- 65. The method of claim 62, wherein R, and R′ are chosen such that 1 does not have an internal plane of symmetry.
- 66. The method of claim 62, wherein the π-bond-containing substrate is selected from the group comprising aldehydes, conjugated enals, thioaldehydes, conjugated thioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugated enones, thioketones, conjugated thioenones, selenoketones, conjugated selenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates, conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides, lactones, thionolactones, thiolactones, dithiolactones, lactams, and thiolactams; and the nucleophile is selected from the group comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions.
- 67. The method of claim 63, wherein M represents a main-group metal from Group 1, 2, 12, 13, or 14 of the periodic table.
Nu is selected from the set comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions; R80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and m is an integer in the range 0 to 8 inclusive; the method comprising contacting said racemic mixture of the π-bond-containing substrate (1) or racemic mixture of the nucleophile with an achiral nucleophile or π-bond-containing substrate, respectively, able to react with the racemic substrate in the presence of a chiral catalyst having the form: 76in which Z1, Z2, Z3 and Z4 each represent a Lewis base; the C1 moiety, taken with Z1, Z3 and M, and the C2 moiety, taken with Z2, Z4 and M, each, independently, form a heterocycle; R1, R2, R′1 and R′2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached, R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached, or any two or more of the R1, R2, R′1, R′2 R40 and R41 taken together form a bridging substituent; with the proviso that C1 is substituted at at least one site by R1, R′1 or R41, and C2 is substituted at at least one site by R2, R′2 or R40, and at least one of R1, R′1 and R41 is taken together with at least one of R2, R′2 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as a tetradentate; M represents the main-group metal; and A represents a counterion or a nucleophile, wherein each R1, R2, R′1, R′2 R40 and R41 are selected to provide at least one stereogenic center in said tetradentate ligand, under conditions wherein one enantiomer of the racemic π-bond-containing substrate or racemic nucleophile reacts with an achiral nucleophile or π-bond-containing substrate, respectively, in a nucleophilic addition leaving the other enantiomer of the racemic substrate substantially unchanged.
- 75. The method of claim 74, wherein
R1, R2, R′1 and R′2, occuring in 100 independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7; each R40 and R41 occuring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R7; R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
- 76. The method of claim 74, wherein each Z1, Z2, Z3 and Z4 are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur.
- 77. A method of providing a chiral, non-racemic α-amino nitrile, comprising reacting a prochiral or chiral imine with hydrogen cyanide, or a surrogate thereof, in the presence of a chiral, non-racemic catalyst such that a chiral, non-racemic cc-amino nitrile is formed, wherein the chiral, non-racemic catalyst comprises an asymmetric tetradentate ligand complexed with a main-group metal atom, said complex having rectangular planar or rectangular pyramidal geometry.
- 78. A method of providing a chiral, non-racemic α-amino nitrile, comprising reacting a prochiral or chiral imine with hydrogen cyanide, or a surrogate thereof, in the presence of a chiral, non-racemic catalyst such that a chiral, non-racemic α-amino nitrile is formed, wherein the chiral, non-racemic catalyst comprises an asymmetric tridentate ligand complexed with a main-group metal atom, said complex having a planar or trigonal pyramidal geometry.
- 79. The method of claim 49, wherein the chiral, non-racemic tridentate ligand of the chiral catalyst is represented by the general formula:
GOVERNMENT FUNDING
[0001] Work described herein was supported in part with funding from the National Institutes of Health. The United States Government has certain rights in this invention.
Divisions (1)
|
Number |
Date |
Country |
Parent |
09071842 |
May 1998 |
US |
Child |
10325592 |
Dec 2002 |
US |