Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation

1. A process for preparing a compound of structural formula I:

having the (R)- or (S)-configuration at the stereogenic center marked with an *; in an enantiomeric excess of at least 70% over the opposite enantiomer, wherein

Z is OR 2 , SR 2 , or NR 2 R 3 ;

R 1 is C 1-8 alkyl, aryl, heteroaryl, aryl-C 1-2 alkyl, or heteroaryl-C 1-2 alkyl;

R 2 and R 3 are each independently hydrogen, C 1-8 alkyl, aryl, or aryl-C 1-2 alkyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring system optionally containing an additional heteroatom selected from O, S, NH, and NC 1-4 alkyl, said heterocyclic ring being unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C 1-4 alkoxy, and C 1-4 alkyl wherein alkyl and alkoxy are unsubstituted or substituted with one to five fluorines; and said heterocyclic ring system being optionally fused with a 5- to 6-membered saturated or aromatic carbocyclic ring system or a 5- to 6-membered saturated or aromatic heterocyclic ring system containing one to two heteroatoms selected from O, S, and NC 0-4 alkyl, said fused ring system being unsubstituted or substituted with one to two substituents selected from hydroxy, amino, fluorine, C 1-4 alkyl, C 1-4 alkoxy, and trifluoromethyl;

comprising the step of hydrogenating a prochiral enamine of structural formula II:

in a suitable organic solvent in the presence of a transition metal precursor complexed to a chiral ferrocenyl diphosphine ligand of structural formula III:

wherein R 4 is C 1-4 alkyl or aryl;

R 5 and R 6 are each independently C 1-6 alkyl, C 5-12 cycloalkyl, or aryl; and

R 7 is C 1-4 alkyl or unsubstituted phenyl.

2. The process of claim 1 wherein said ferrocenyl diphosphine ligand is of structural formula IV:

wherein the stereogenic center marked with an ** has the (R)-configuration.

3. The process of claim 2 wherein R 4 is C 1-2 alkyl, R 5 and R 6 are C 1-4 alkyl, and R 7 is unsubstituted phenyl.

4. The process of claim 3 wherein R 4 is methyl, R 5 and R 6 are t-butyl, and R 7 is unsubstituted phenyl.

5. The process of claim 1 wherein R 1 is benzyl wherein the phenyl group of benzyl is unsubstituted or substituted one to three substituents selected from the group consisting of fluorine, trifluoromethyl, and trifluoromethoxy.

6. The process of claim 1 wherein Z is OR 2 or NR 2 R 3 .

7. The process of claim 6 wherein NR 2 R 3 is a heterocycle of the structural formula VI:

wherein R 8 is hydrogen or C 1-4 alkyl which is unsubstituted or substituted with one to five fluorines.

8. The process of claim 1 wherein said transition metal precursor is [M(cod)Cl] 2 , [M(norbornadiene)Cl] 2 , [M(cod) 2 ]X, or [M(norbornadiene) 2 ]X wherein X is methanesulfonate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, or hexafluoroantimonate and M is rhodium or iridium.

9. The process of claim 8 wherein said transition metal precursor is [Rh(cod)Cl] 2 .

10. A process for preparing a compound of structural formula 1:

having the (R)-configuration at the stereogenic center marked with an ***;

in an enantiomeric excess of at least 70% over the enantiomer having the opposite (S)-configuration; wherein

Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of fluorine, trifluoromethyl, and trifluoromethoxy; and

R 8 is hydrogen or C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

comprising the step of:

hydrogenating a compound of structural formula 2:

in a suitable organic solvent in the presence of a rhodium metal precursor and a chiral ferrocenyl disphosphine of structural formula IV:

wherein R 4 is C 1-4 alkyl or aryl;

R 5 and R 6 are each independently C 1-6 alkyl, C 5-12 cycloalkyl, or aryl; and

R 7 is C 1-4 alkyl or unsubstituted phenyl.

11. The process of claim 10 additionally comprising the step of producing a compound of structural formula 2:

by treating a compound of structural formula 3:

with a source of ammonia in a suitable organic solvent.

12. The process of claim 10 wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl and R 8 is trifluoromethyl.

13. The process of claim 10 wherein said rhodium metal precursor is [Rh(cod)Cl] 2 .

14. The process of claim 10 wherein R 4 is methyl, R 5 and R 6 are both t-butyl, and R 7 is unsubstituted phenyl.

15. The process of claim 14 wherein said rhodium metal precursor is [Rh(cod)Cl] 2 .

16. The process of claim 10 wherein R 4 is methyl, R 5 and R 6 are both t-butyl, R 7 is unsubstituted phenyl, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl, R 8 is trifluoromethyl, and the rhodium metal precursor is chloro(1,5-cyclooctadiene)rhodium(I) dimer.

17. The process of claim 11 wherein said source of ammonia is ammonium acetate.

18. A process for preparing a compound of structural formula 1:

having the (R)-configuration at the stereogenic center marked with an ***;

in an enantiomeric excess of at least 70% over the enantiomer having the opposite (S)-configuration; wherein

Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of fluorine, trifluoromethyl, and trifluoromethoxy; and

R 8 is hydrogen or C 1-4 alkyl unsubstituted or substituted with one to five fluorines;

comprising the steps of:

(a) producing a compound of structural formula 2:

by treating a compound of structural formula 3:

with a source of ammonia in a suitable organic solvent; and

(b) hydrogenating a compound of structural formula 2:

in a suitable organic solvent in the presence of a rhodium metal precursor and a chiral ferrocenyl disphosphine of structural formula IV:

wherein R 4 is C 1-4 alkyl or aryl;

R 5 and R 6 are each independently C 1-6 alkyl, C 5-12 cycloalkyl, or aryl; and

R 7 is C 1-4 alkyl or unsubstituted phenyl.

19. The process of claim 2 wherein Z is OR 2 .

20. The process of claim 19 wherein R 1 is 6-methoxy-pyridin-3-yl and Z is C 1-4 alkoxy.

21. The process of claim 20 wherein Z is methoxy or ethoxy.

22. The process of claim 21 wherein R 4 is methyl, R 5 and R 6 are t-butyl, R 7 is phenyl, and said transition metal precursor is [Rh(cod)Cl] 2 .