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Title:
PHOSPHINO-AMINOPHOSPHINES, CATALYST COMPLEXES AND ENANTIOSELECTIVE HYDROGENATION
Document Type and Number:
WIPO Patent Application WO/2002/026750
Kind Code:
A2
Abstract:
Disclosed are substantially enantiomerically pure bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phosphorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone. The compounds, which have exhibited surprising air stability, are useful as ligands for metal catalysts for asymmetric reactions and have demonstrated excellent results, in particular as rhodium complexes for asymmetric hydrogenation of enamide, itaconate, and $g(a)-ketoester compounds. Also disclosed are novel processes for the preparation of the bis-phosphine compounds and novel intermediate compounds useful in the preparation of the bis-phosphine compounds.

Inventors:
Boaz, Neil Warren (1342 Watauga Street Kingsport, TN, 37660, US)
Debenham, Sheryl Davis (2 Blue Ridge Circle Scotch Plains, NJ 7076, US)
Application Number:
PCT/US2001/030663
Publication Date:
April 04, 2002
Filing Date:
September 28, 2001
Export Citation:
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Assignee:
EASTMAN CHEMICAL COMPANY (100 North Eastman Road Kingsport, TN, 37660, US)
International Classes:
B01J31/24; C07B61/00; C07C51/36; C07C55/02; C07C67/31; C07C69/675; C07C227/16; C07C229/14; C07C231/18; C07C253/30; C07C269/06; C07C271/12; C07D203/04; C07D205/08; C07D207/27; C07D211/76; C07D223/10; C07D225/02; C07F9/24; C07F9/553; C07F9/564; C07F9/568; C07F9/572; C07F9/59; C07F17/00; C07F17/02; C07C233/47; C07C233/83; C07C233/84; C07C255/60; C07C271/22; C07D207/26; (IPC1-7): C07F9/02
Foreign References:
US5760264A1998-06-02
Other References:
FAURE B ET AL: "Reactivity of Chiral Oxazaphospholidines on Activated Halide Compounds: Synthesis and Coordination Studies of Chiral Hybrid Phosphine-Phosphine Oxide Ligands" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 53, no. 34, 25 August 1997 (1997-08-25), pages 11577-11594, XP004106025 ISSN: 0040-4020
MUENZENBERG R ET AL: "CHIRAL PLATINUM (II) COMPLEXES WITH PHOSPHORUS DERIVATIVES OF THE AMINO ACID L-PROLINE. NMR SPECTROSCOPIC AND X-RAY STRUCTURE INVESTIGATIONS OF THE CIS INFLUENCE OF TERTIARY PHOSPHORUS LIGANDS" JOURNAL OF MOLECULAR STRUCTURE, ELSEVIER, AMSTERDAM, NL, vol. 444, no. 1/3, 1998, pages 77-90, XP000865815 ISSN: 0022-2860
SLUGOVC C ET AL: "THERMODYNAMICALLY CONTROLLED FORMATION OF DIASTEREOPURE THREE-LEGGED PIANO-STOOL COMPLEXES. THE SUBSTITUTION CHEMISTRY OF RUCP(AMINOPHOSPHINOFERROCENE)(CH3CN)PF6" ORGANOMETALLICS, ACS, COLUMBUS, OH, US, no. 18, 1999, pages 3865-3872, XP001038235 ISSN: 0276-7333
AUCOTT S M ET AL: "Preparation and organometallic complexes of the new unsymmetrical ligand: Ph2PNHC6H4PPh2" JOURNAL OF ORGANOMETALLIC CHEMISTRY, ELSEVIER-SEQUOIA S.A. LAUSANNE, CH, vol. 582, no. 1, 10 June 1999 (1999-06-10), pages 83-89, XP004169835 ISSN: 0022-328X
RICHARDS C J ET AL: "Recent advances in the generation of non-racemic ferrocene derivatives and their application to asymmetric synthesis" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 9, no. 14, 17 July 1998 (1998-07-17), pages 2377-2407, XP004129001 ISSN: 0957-4166
PRACEJUS G ET AL: "CHIRAL AMINO DIAMINO PHOSPHINES AS LIGANDS FOR ASYMMETRIC HYDROGENATION CATALYSTS" TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, no. 39, 1977, pages 3497-3500, XP001027472 ISSN: 0040-4039
FIORINI M ET AL: "AMINOPHOSPHINE-RHODIUM COMPLEXES AS CATALYSTS IN ASYMMETRIC HYDROGENATION. THE DEPENDENCE OF THE ENANTIOSELECTIVITY ON THE STRUCTURE OF THE CHIRAL LIGANDS" JOURNAL OF MOLECULAR CATALYSIS, LAUSANNE, CH, vol. 5, 1979, pages 303-310, XP001026858 cited in the application
ARGOUARCH G ET AL: "A New Class of Ferrocene-Based 1,2-Bis(phosphanes) Possessing only Planar Chirality" EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2000, pages 2893-9, XP002196647 ISSN: 1434-193X
CARPENTIER J-F ET AL: "Catalytic Asymmetric Hydrogenation of Activated Keto Compounds by some Homogeneous and Silica-Supported di(mu-carboxylato)bis(aminophosphine phosphinite)dirhodium Complexes" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 6, no. 1, 1995, pages 39-42, XP004048483 ISSN: 0957-4166
SIMONS K E ET AL: "A New Class of Chiral Modifiers for the Enantioselective Hydrogenation of alpha-Ketoesters with Pt/Al2O3" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 6, no. 2, 1 February 1995 (1995-02-01), pages 505-518, XP004048458 ISSN: 0957-4166
WHITE J D ET AL: "ASYMETRIC TOTAL SYNTHESIS OF (+)-CODEINE VIA INTRAMOLECULAR CARBENOID INSERTION" JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 64, 1999, pages 7871-7884, XP001022929 ISSN: 0022-3263
FRANCIO ET AL: "Asymmetric catalysis with chiral phosphane/ phosphoramidite ligands derived from quinoline (QUINAPHOS)" ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 39, no. 8, 17 April 2000 (2000-04-17), pages 1428-1430, XP002151554 ISSN: 0570-0833
YONEHARA K ET AL: "Highly Enantioselective Hydrogenation of Enamides and Itaconic Acid in Water in the Presence of Water-Soluble Rhodium(I) Catalyst and Sodium Dodecyl Sulphate" JOURNAL OF ORGANIC CHEMISTRY, vol. 64, no. 26, 1999, pages 9381-5, XP002196648 ISSN: 0022-3263
Attorney, Agent or Firm:
Blake, Michael J. (P.O. Box 511 Kingsport, TX, 37662-5075, US)
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Claims:
CLAIMS We claim :
1. A substantially enantiomerically pure bisphosphine compound comprising a substantially enantiomerically pure chiral backbone linking two phosphines residues wherein one of the phosphine residues has three phosphoruscarbon bonds and the other phosphine residue has two phosphoruscarbon bonds and one phosphorusnitrogen bond wherein the nitrogen is part of the chiral backbone.
2. A substantially enantiomerically pure compound according to Claim 1 having formula 1: 1 wherein R is selected from substituted and unsubstituted, branchedand stralghtchain C1C20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R', R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and Vlil.
3. A compound according to Claim 2 wherein R is methyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium.
4. A compound according to claim 3 where R1 is hydrogen, methyl, ethyl, or npropyl and M is iron.
5. A substantially enantiomerically pure compound according to Claim 1 having formula 2: 2 wherein R is selected from substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C2o heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R', R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3; m is 0 to 5; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and Vill.
6. A compound according to Claim 5 where R is methyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium.
7. A compound according to claim 6 where R1 is hydrogen, methyl, ethyl, or npropyl and M is iron.
8. A compound comprising a substantially enantiomerically pure bis phosphine compound defined in Claim 1 in complex association with a Group VIII metal.
9. A compound comprising a substantially enantiomerically pure compound defined in Claim 2 in complex association with a Group Vlil metal.
10. A compound according to Claim 9 wherein (i) in the substantially enantiomerically pure compound defined in Claim 2 R is methyl, rut is hydrogen, methyl, ethyl, or npropyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium and (ii) the Group VIII metal is rhodium, iridium or ruthenium.
11. A compound comprising a substantially enantiomerically pure compound defined in Claim 5 in complex association with a Group Veil metal.
12. A compound according to Claim 11 wherein (i) in the substantially enantiomerically pure compound defined in Claim 5 R is methyl, R'is hydrogen, methyl, ethyl, or npropyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium and (ii) the Group VIII metal is rhodium, iridium or ruthenium.
13. A process for the preparation of a substantially enantiomerically pure compound having formula 1: which comprises the steps of: (1) contacting a dialkylamine having formula 3: with a carboxylic anhydride having the formula (R'°CO) 20 to obtain an ester compound having formula 4: 4 (2) contacting the ester produced in step (1) with an amine having the formula H2NR1 to obtain an intermediate compound having formula 5: (3) contacting intermediate compound 5 with a halophosphine having the formula XP (R2) 2; wherein R, R8, and R9 are independently selected from substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted or unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R', R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C2o heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; M is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII ; Rlo is a Ci to C4 alkyl radical ; and X is chlorine, bromine, or iodine.
14. A process according to Claim 13 wherein R, R8, and R9 are methyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, X is chlorine or bromine, n and m are 0, and M is iron, ruthenium, or osmium.
15. A process according to Claim 14 where R'is hydrogen, methyl, ethyl, or npropyl, X is chlorine, and M is iron.
16. A process according to Claim 13 wherein the carboxylic anhydride is selected from acetic, propionic, or butyric anhydride and the lower alcohol solvent is selected from methanol, ethanol, npropanol, isopropanol, nbutanol, secbutanol, or tertbutanol.
17. A process according to Claim 16 wherein step (3) is carried out in the presence of a C3C15 trialkylamine and a nonpolar, aprotic solvent selected from aliphatic and aromatic hydrocarbons containing 6 to 10 carbon atoms, halogenated hydrocarbons containing up to 6 carbon atoms, and cyclic and acyclic ethers containing from 4 to 8 carbon atoms.
18. A process according to Claim 17 wherein step (3) is carried out in the presence of triethylamine and toluene.
19. A process for the preparation of a substantially enantiomerically pure compound having formula 2: which comprises the steps of: (1) contacting a dialkylamine having formula 6: 6 with a carboxylic anhydride having the formula (R1°CO) 20 to obtain an ester compound having formula 7: 7 (2) contacting the ester produced in step (1) with an amine having the formula H2NR1 to obtain an intermediate compound having formula 8: (3) contacting intermediate compound 8 with a halophosphine having the formula XP (R2) 2; wherein R, R8, and R9 are independently selected from substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R', R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; M is selected from the metals of Groups IVB, VB, VIB, VIIB and Vlil ; R10 is a Ci to C4 alkyl radical ; and X is chlorine, bromine, or iodine.
20. A process according to Claim 19 wherein R, R8, and R9 are methyl, R2 is phenyl, ethyl, isopropyl, or cyclohexyl, R3 is phenyl, X is chlorine or bromine, n and m are 0, and M is iron, ruthenium, or osmium.
21. A process according to Claim 20 wherein R1 is hydrogen, methyl, ethyl, or npropyl, X is chlorine, and M is iron.
22. A process according to Claim 19 wherein the carboxylic anhydride is selected from acetic, propionic, or butyric anhydride and the lower alcohol solvent is selected from methanol, ethanol, npropanol, isopropanol, nbutanol, secbutanol, or tertbutanol.
23. A process according to Claim 22 wherein step (3) is carried out in the presence of a C3C15 trialkylamine and a nonpolar, aprotic solvent selected from aliphatic and aromatic hydrocarbons containing 6 to 10 carbon atoms, halogenated hydrocarbons containing up to 6 carbon atoms, and cyclic and acyclic ethers containing from 4 to 8 carbon atoms.
24. A process according to Claim 22 wherein step (3) is carried out in the presence of triethylamine and toluene.
25. An aminophosphine compound having the formula 5 wherein R and R1 are independently selected from substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted or unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain C1C20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C2o heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and VlIl ;.
26. A compound according to Claim 25 wherein R is methyl, R1 is methyl, ethyl, or npropyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium.
27. An aminophosphine compound having the formula 8 wherein R and R'are independently selected from substituted and unsubstituted, branchedand straightchain C1C20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain C1C20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and Veil.
28. A compound according to Claim 27 wherein R is methyl, R'is methyl, ethyl, or npropyl, R3 is phenyl, n and m are 0, and M is iron, ruthenium, or osmium.
29. A method for the enantioselective hydrogenation of a hydrogenatable compound which comprises contacting the hydrogenatable compound with hydrogen in the presence of a catalyst complex defined in any of claims 8 through 12.
30. A method according to Claim 29 wherein the hydrogenatable compound contains the residue C=C (NC=O)C=O.
31. A method according to Claim 30 wherein the hydrogenatable compound has formula 10: wherein: R", R12, and R14 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; and R13 is selected from hydrogen, substituted and unsubstituted Ci to C20 alkyl, substituted and unsubstituted Ci to C20 alkoxy, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C3 to C8 cycloalkoxy, substituted and unsubstituted carbocyclic C6 to Cao aryl, substituted and unsubstituted carbocyclic C6 to C20 aryloxy, substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen and substituted and unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; or R13 ands R14 collectively represent a substituted or unsubstituted alkylen group of 14 chain carbon atoms forming a lactam.
32. A method according to Claim 29 wherein the hydrogenatable compound has formula 14: wherein: R15 is selected from hydrogen, substituted and unsubstituted, branchedand straightchain C1C20 alkyl, and substituted and unsubstituted CsCg cycloalkyl, and R16 and R17 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain ClC20 alkyl, substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.
33. A method according to Claim 29 wherein the hydrogenatable compound has formula 16: 16 wherein: R18 and R19 are independently selected from hydrogen, substituted and unsubstituted, branchedand straightchain C1C20 alkyl, and substituted and unsubstituted C3C8 cycloalkyl, substituted and unsubstituted C6C20 carbocyclic aryl, and substituted and unsubstituted C4C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, or oxygen ; or R18 and R'9 collectively represent a substituted or unsubstituted alkylen group of 14 chain carbon atoms forming an aketolactone.
Description:
PHOSPHINO-AMINOPHOSPHINES Cross Reference to Related Application This application claims the benefit of U. S. Provisional Applications Serial No. 60/236,564, filed September 29,2000, and Serial No. 60/264,411, filed January 26,2001.

Field of the Invention This invention pertains to novel, substantially enantiomerically pure bis-phosphine compounds possessing the unique feature of having both a carbon-bonded phosphine and a nitrogen-bonded phosphine connected by a divalent chiral group. The compounds are useful as ligands for metal catalysts for asymmetric reactions and have demonstrated surprising stability as well as excellent results, in particular as rhodium complexes for asymmetric hydrogenation. This invention also pertains to novel processes and intermediate compounds useful for the preparation of the bis-phosphine compounds and to compounds comprising one or more of the bis- phosphine compounds in complex association with one or more Group Vlil metals and their use for asymmetric hydrogenation.

Background of the Invention Asymmetric catalysis is the most efficient method for the generation of products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature.

The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types. Synthetic asymmetric

catalysts are usually composed of a metal reaction center surrounded by an organic ligand. The ligand usually is generated in high enantiomeric purity, and is the agent inducing the asymmetry. These ligands are, in general, difficult to make and therefore expensive.

As is described by Richards, C. J.; Locke, A. J. Tetrahedron : Asymmetry 1998,9,2377-2407, asymmetric ferrocene derivatives have found great utility as ligands for asymmetric catalysis in reactions as varied as asymmetric hydrogenations, asymmetric Aldol reactions, asymmetric organometallic additions, and asymmetric hydrosilations. These ferrocene species usually are bidentate in nature, using a variety of ligating species.

In the cases where the ligands-are phosphines they invariably are carbon- linked phosphines. In no cases do these ferrocene-based ligands have heteroatom linkage to the phosphorus atom. Fiorini, M. and Giongo, G. M.

J. Mol. Cat. 1979,5,303-310, and Pracejus, G.; Pracejus, H. Tetrahedron Lett. 1977,3497-3500, report that bis-aminophosphine-based asymmetric ligands afford moderate results for asymmetric hydrogenations (<90% enantiomeric excess-ee), but in no cases have these ligands had either a metallocenyl moiety or a mixture of carbon and nitrogen-bonded phosphines included therein. Indeed, there appear to be no reports of chiral, non-racemic, bis-phosphine ligands where one phosphine is bonded to three carbon atoms and the other is bonded to two carbons and one nitrogen.

Brief Summary of the Invention The novel bis-phosphine compounds provided by our invention are substantially enantiomerically pure bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus- carbon bonds and the other phosphine residue has two phophorus-carbon

bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone. These compounds are the first examples of chiral bis- phosphines combining a tri-hydrocarbylphosphine with a dihydrocarbyl- aminophosphine. These species can be utilized as bidentate ligands for asymmetric catalysis for a variety of reactions. They are of particular interest for asymmetric hydrogenations, and as the rhodium complex they have afforded hydrogenation products with high enantiomeric excess, in particular for the rhodium-catalyzed hydrogenation of prochiral olefins and ketones. The activity of these compounds is readily modified by the choice of the amine substituents.

Detailed Description We have discovered a broad group of novel substantially enantiomerically pure bis-phosphine compounds comprised of one phosphine residue having three phosphorus-carbon bonds and the other having two phosphorus-carbon bonds and one phosphorus-nitrogen bond.

Examples of the substantially enantiomerically pure, i. e., an enantiomeric excess of 90% or greater, compounds include phosphinometallocenyl- aminophosphines having the general formulas 1 and 2 (the enantiomer of 1) : wherein

R is selected from substituted and unsubstituted, branched-and straight-chain Cl-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; R', R2, R3, R4, and R5 are independently selected from hydrogen, substituted and unsubstituted, branched-and straight-chain Cl-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3 ; m is 0 to 5 ; and M is selected from the metals of Groups IVB, VB, VIB, VIIB and Vlil.

The alkyl groups which may be represented by each of R, R', R2, R3, R4, and R5 may be straight-or branched-chain, aliphatic hydrocarbon radicals containing up to 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1-C6-alkoxy, cyano, C2- C6-alkoxycarbonyl, C2-C6-alkanoyloxy, hydroxy, aryl and halogen. The <BR> <BR> <BR> <BR> terms"C1-C6-alkoxy","C2-C6-alkoxycarbonyl", and"C2-C6-alkanoyloxy"are used to denote radicals corresponding to the structures-OR6,-C02 R6, and -OCOR6, respectively, wherein R6 is C1-C6-alkyl or substituted C1-C6-alkyl.

The term"C3-C8-cycloalkyl"is used to denote a saturated, carbocyclic hydrocarbon radical having three to eight carbon atoms. The aryl groups which each of R, R', R2,R3,R4, and R5 may represent may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from C1-C6-alkyl, substituted Ci-Ce- alkyl, C6-C10 aryl, substituted C6-C10 aryl, C1-C6-alkoxy, halogen, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl,

trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino and -0-ruz S-R7, -SO2-R7, -NHSO2R7 and -NHCO2R7, wherein R7 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl, d-Ce-atkoxy and halogen.

The heteroaryl radicals include a 5-or 6-membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl radicals may be substituted, for example, with up to three groups such as Ci-Ce- alkyl, C1-C6-alkoxy, substituted C1-C6-alkyl, halogen, C1-C6-alkylthio, aryl, arylthio, aryloxy, C2-C6-alkoxycarbonyl and C2-C6-alkanoylamino. The heteroaryl radicals also may be substituted with a fused ring system, e. g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence.

The term"halogen"is used to include fluorine, chlorine, bromine, and iodine.

The compounds of the invention which presently are preferred have formulas 1 and 2 wherein R is Ci to C6 alkyl ; R1 is hydrogen or Ci to C6 alkyl ; R2 is aryl (preferably phenyl), ethyl, isopropyl, or cyclohexyl ; R3 is aryl, most preferably phenyl ; R4 and R5 are hydrogen; and M is iron, ruthenium, or osmium, most preferably iron.

The compounds of our invention contain both a carbon-linked and a nitrogen-linked phosphine. This mixture of features is not known in the literature (and is particularly not known for metallocene-based ligands) and affords a different electronic environment when complexed to a catalyst metal center as compared to other ligands. In addition, the metallocene- based ligands are readily modifiable by varying R'according to the choice

of the amine used, and thus allow simple modification of the reactivity and selectivity of the catalyst prepared from these ligands. An unexpected but particularly advantageous characteristic of this metallocene-based phosphino-aminophosphine structural class is their resistance to oxidative degradation. Indeed, these types of compounds retain activity and enantioselectivity (as demonstrated by both physical properties and trial reactions of their metal complexes) over extended periods at ambient temperature in an air atmosphere, conditions under which many phosphines oxidize to the inactive phosphine oxides.

Our invention also provides novel processes for the preparation of compounds of formulas 1 and 2. Thus, one embodiment of the processes of the present invention involves a process for the preparation of a substantially enantiomerically pure compound having formula 1:

which comprises the steps of: (1) contacting a dialkyl amine having formula 3: with a carboxylic anhydride having the formula (R1°CO) 2O to obtain an ester compound having formula 4:

4 (2) contacting the ester produced in step (1) with an amine having the formula H2N-R1 to obtain an intermediate amino-phosphine compound having formula 5 :

(3) contacting intermediate compound 5 with a halophosphine having the formula X-P (R2) 2;

wherein R, R', R2, R3, R4, R5, n, m, and M are defined hereinabove, R8 and R9 are independently selected from substituted and unsubstituted, branched-and straight-chain Cl-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen, R10 is a Ci to C4 alkyl radical, and X is chlorine, bromine, or iodine. The compounds of formula 2 may be prepared when dialkylamine having formula 6:

6 is used as the starting material affording intermediates 7 and 8 analogous to 4 and 5, respectively.

7 8 In the first step of the process, dialkylamine reactant compound 3 is contacted with a carboxylic anhydride. The amount of anhydride used may be 1 to 100 moles, preferably 2 to 10 moles, per mole of dialkylamine

reactant 3. Although the carboxylic anhydride may contain up to 8 carbon atoms, acetic anhydride is particularly preferred. The first step of the process may be carried out at a temperature between 20°C and the boiling point of the anhydride, preferably 80 to 120°C. While an inert solvent may be used in step (1), such a solvent is not essential and the carboxylic anhydride may function as both solvent and reactant. At the completion of the first step, the ester intermediate may be isolated for use in the second step by conventional procedures such as crystallization or removing the carboxylic anhydride and any extraneous solvent present, e. g., by distillation.

Dialkylamine reactant compounds 3 can be prepared in high enantiomeric purity by several known methods. For example, precursor 9 having the formula: 9 can be prepared in high enantiomeric purity using the procedures described by Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, l. J. Am.

Chem. Soc. 1970,92,5389-5393; Armstrong, D. W.; DeMond, W.; Czech, B. P. Anal. Chem. 1985,57,481-484; and Boaz, N. W. Tetrahedron Letters 1989,30,2061-2064. Precursor 9 then can be converted by known procedures to dialkylamine reactant 3, e. g., using the procedures described in Hayashi, T. et al. Bull Chem. Soc. Jpn. 1980,53,1130-1151; and the references mentioned in the preceding sentence. The enantiomeric species 6 can be prepared in a like manner.

In the second step of the process, the ester intermediate obtained from step (1) is contacted and reacted with an amine having the formula H2NR'in the presence of a Ci to C4 alkanol solvent, preferably methanol or 2-propanol. The second step may be carried out at a temperature between 20°C and the boiling point of the solvent, preferably 25 to 50°C. The mole ratio of the amine: ester intermediate 4 (or 7) typically is in the range of 1: 1 to 25 : 1. Intermediate 5 (or 8) may be recovered for use in step (3) by conventional procedures such as extractive purification or crystallization.

In the third step of our novel process, intermediate 5 (or 8) is contacted and reacted with a halophosphine of the formula XPR22 wherein X is chlorine, bromine, or iodine using a halophosphine : intermediate 5 (or 8) mole ratio in the range of 0.8: 1 to 1.3: 1. The reaction of step (3) is carried out in the presence of an acid acceptor such as a tertiary amine, e. g., trialkylamines containing a total of 3 to 15 carbon atoms, pyridine, substituted pyridines and the like. The amount of acid acceptor used normally is at least 1 mole of acid acceptor per mole of halophosphine employed and up to 5 moles of acid acceptor per mole of halophosphine.

Step (3) is carried out in the presence of an inert solvent. Examples of inert solvents include, but are not limited to, non-polar, aprotic solvents such as aliphatic and aromatic hydrocarbons containing 6 to 10 carbon atoms, e. g., hexane, heptane, octane, toluene, the various xylene isomers and mixtures thereof, and the like ; halogenated, e. g., chlorinated, hydrocarbons containing up to 6 carbon atoms such as dichloromethane, chloroform, tetrachloroethylene, chorobenzene and the like ; and cyclic and acyclic ethers containing from 4 to 8 carbon atoms, e. g., ter-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like. The acid acceptor and solvent particularly preferred are triethylamine and toluene, respectively.

Step (3) may be carried out at a temperature between-20°C and the boiling point of the solvent, preferably 0 to 30°C.

Intermediate amino-phosphine compounds 5 and 8 are novel compounds and constitute an additional embodiment of our invention. Also included within the scope of the present invention are catalytically-active compounds comprising one or more substantially enantiomerically pure, bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus- nitrogen bond wherein the nitrogen is part of the chiral backbone in complex association with one or more Group Vlil metals, preferably rhodium, iridium or ruthenium.

Examples The novel compounds and processes provided by the present invention are further illustrated by the following examples.

Example 1 Preparation of (R)-1- (S)-2- (Diphenylphosphino) ferrocenyllethylamine (R, S-5a) (R = H) (R)-N, N-Dimethyl-1-[(S)-2-(diphenylphosphino) ferrocenyl] ethylamine (R, S-3a, R = R3 = R9 = methyl, R3 = phenyl-Ph, R4 = R5 = H, M = Fe)) (10.0 g; 22.7 mmol) was combined with acetic anhydride (14.25 mL; 150 mmol ; 6.7 equivalents) in a 250-mL flask. The flask was evacuated and filled with nitrogen ten times and then heated to 100°C for 2 hours, at which point thin layer chromatography (tic) analysis indicated no 3a present. The residual acetic anhydride was evaporated at reduced pressure to afford a solid mass containing acetate ester R, S-4a. A portion (1.0 g) of acetate ester R, S-4a was removed and the remainder was dissolved in isopropanol (200 mL) and treated with concentrated ammonium hydroxide (28% NH3 ; 24.3 mL; 360

mmol ; 17.5 equiv). The reaction mixture was heated to 50°C overnight to completely consume 4 according to tic analysis. The mixture was concentrated to small volume at reduced pressure. The residue was dissolved in ethyl acetate and extracted with 10% aqueous citric acid (3 x 75 mL). The acidic extracts were neutralized with 4 N NaOH (115 mL) to pH 12 and extracted with ethyl acetate (3 x 50 mL). The combined organic solution was dried with magnesium sulfate and concentrated in vacuo to afford 7.34 g (87% yield) of R, S-5a (R1 = hydrogen). S, R-8a was prepared in the same manner from S, R-6a.

H NMR (CDC13) 8 7.6-7.2 (m, 10H) ; 4.43 (brs, 1H) ; 4.28 (m, 1H) ; 4.20 (m, 1H) ; 4.016 (s, 5H); 3.76 (m, 1H) ; 1.439 (d, 3H, J = 6 59 Hz).

Preparation of (S)-N-diphenylphosphino-1-fR)-2- (diphenylphosphino)- ferrocenyl1ethylamine (S, R-2a) (R1 = H) Amine S, R-8a (1.9 g; 4.6 mmol) was dissolved in 11 mL of toluene.

Triethylamine (1.3 mL; 9.3 mmol ; 2 equivalents) was added. The mixture was cooled in ice water and degassed with a nitrogen purge for 10 minutes.

Chlorodiphenylphosphine (860 pL ; 4.8 mmol ; 1.04 equivalents) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to almost completely consume 8a and afford a new spot on tic. Heptane (11 mL) was added and the reaction mixture was filtered and the precipitate was washed with toluene. The filtrate was concentrated to afford 2a (R1 = hydrogen) contaminated with some triethylamine hydrochloride. The crude product was triturated with 1: 1 toluene : heptane (20 mL) at 4°C for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 2.6 g of S, R-2a (95% yield) as an oil. R, S-1a was prepared in the same manner from R, S-5a.

H NMR (CDC13) 8 7.8-7.1 (m, 20H); 4.50 (m, 1H) ; 4.46 (br s, 1 H) ; 4.30 (m, 1H) ; 3.915 (s, 5H); 1.515 (d, 3H, J = 6.59 Hz). FDMS: m/z 597.25 (M+).

[a] D25 +233.3° (c 1.12, toluene).

Example 2 Preparation of (S)-N-Methyl-1-flR)-2-Ldiphenylphosphino)- ferrocenvllethylamine (S, R-8b) (R' = Me) (S)-N, N-Dimethyl-1-[(R)-2-(diphenylphosphino) ferrocenyl] ethylamine (S, R-6a) (5.0 g; 11.3 mmol) was combined with acetic anhydride (7.1 mL; 75.2 mmol ; 6.7 equivalents) in a 100-mL flask. The flask was evacuated and filled with nitrogen ten times and then heated to 100°C for 2 hours, at which point tic analysis indicated no 6a present. The residual acetic anhydride was evaporated at reduced pressure to afford a solid mass containing acetate ester S, R-7a. This material was dissolved in isopropanol (110 mL) and treated with 40% aqueous methylamine (14.6 mL; 170 mmol ; 15 equivalents). The reaction mixture was heated to 50°C for 48 hours to completely consume 7a according to tic analysis. The mixture was concentrated to small volume at reduced pressure. The residue was dissolved in 1: 1 ethyl acetate: heptane and extracted with 10% aqueous citric acid (4 x 10 mL). The acidic extracts were neutralized with 2 N NaOH (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic solution was dried with magnesium sulfate and concentrated in vacuo to afford 4.33 g (90% yield) of S, R-8b (R1 = methyl) as an orange solid. R, S-5b was prepared in the same manner from R, S-3a.

'H NMR (CDCI3) 6 7.55 (m, 2H); 7.37 (m, 3 H); 7.26 (m, 5H); 4.463 (br s, 1H) ; 4.286 (m, 1H) ; 4.028 (s, 5H); 3.94 (m, 1H) ; 3.78 (m, 1H) ; 1.943 (s, 3H); 1.445 (d, 3H, J = 6.59 Hz). FDMS: m/z 427 (M+).

Preparation of (S)-N-Methyl-N-diphenYlphosphino-1-z (R)-2- (Diphenylphosphino)ferrocenyl]ethylamine (S,R-2b)(R1 = Me) Amine S, R-8b (427 mg; 1.0 mmol) was dissolved in 2.5 mL of toluene. Triethylamine (0.29 mL; 2.1 mmol ; 2.1 equiv) was added. The mixture was cooled in ice water and degassed with an argon purge for 10 minutes. Chlorodiphenylphosphine (180 uL ; 1.0 mmol ; 1.0 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to afford almost complete consumption of 8b and a new spot on tic. Heptane (2.5 mL) was added and the reaction mixture was filtered and the precipitate was washed with heptane. The filtrate was concentrated in vacuo to afford 0.68 g of S, R-2b (R1 = methyl) as a yellow foam. R, S-1b was prepared in the same manner from R, S-5b.

H NMR (CDC13) 8 7.65 (m, 2H); 7.4-7.0 (m, 14H); 6.82 (m, 4H); 5.006 (m, 1 H) ; 4.502 (brs, 1H) ; 4.40 (m, 1H) ; 4.15 (m, 1H) ; 3.798 (s, 5H); 2.148 (d, 3H, J = 3.30 Hz); 1.471 (d, 3H, J = 6 87 Hz). FDMS: m/z 611 (M+).

[α] 25 +229.8° (c 1.10, toluene) Example 3 Preparation of (R)-1-E (S)-2-(DiphenylphosPhino) ferrocenvl1ethyl acetate (R, S-4a) (R)-N,N-Dimethyl-1-[(S)-2-(diphenylphosphino) ferrocenyl]- ethylamin (R, S-3a) (10. 4 g; 24.0 mmol) was combined with acetic anhydride (15 mL; 136 mmol ; 5.7 equiv) in a 100-mL flask. The flask was evacuated and filled with nitrogen ten times and then heated to 100°C for 2 hours, at which point tic analysis indicated no 3a present. The residual acetic anhydride was evaporated at reduced pressure to afford acetate R, S-4a.

This material could be recrystallized from an ethyl acetate-heptane mixture.

H NMR (CDC13) 8 7.52 (m, 2H); 7.37 (m, 3H); 7.3-7.15 (m, 5H); 6.206 (q, 1 H, J = 2.75 Hz); 4.568 (m, 1 H) ; 4.349 (m, 1 H) ; 4.045 (s, 5H); 3.800 (m, 1 H) ; 1.630 (d, 3H, J = 6.32 Hz); 1.170 (s, 3H). FDMS: m/z 456 (M+).

Preparation of (R)-N-Ethyl-1-[(S)-2-(diphenylphosphino)- ferrocenvl1ethylamine (R, S-5c) (Rl = Et) (R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl] ethyl acetate (R, S- 4a) (1.37 g; 3.0 mmol) was slurried in isopropanol (25 mL) and treated with 70% aqueous ethylamin (3.6 mL; 45 mmol ; 15 equivalents). The reaction mixture was heated to 50°C for two days to completely consume 4a according to tlc analysis. The mixture was concentrated to small volume at reduced pressure. The residue was dissolved in 1: 1 ethyl acetate: heptane and extracted with 10% aqueous citric acid (2 x 25 mL). The acidic extracts were neutralized with 4 N NaOH (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic solution was dried with magnesium sulfate and concentrated in vacuo to afford 1.19 g (90% yield) of R, S-5c (R1 = ethyl) as an orange solid. S, R-8c was prepared in the same manner from S, R-7a.

H NMR (CDCI3) 6 7.6-7.2 (m, 10H) ; 4.5 (br s, 1 H) ; 4.28 (m, 1H) ; 4.05 (s, 5H); 4.0 (m, 1 H) ; 3.78 (m, 1 H) ; 2.4-2.2 (m, 2H); 1.45 (d, 3H); 0.42 (t, 3H).

Preparation of (R)-N-Ethyl-N-diphenvlphosphino-1-1'lS)-2- (Diphenylphosphino)ferrocenyl]ethylamine (R,S-1c)(R1 = Et) Amine R, S-5c (1.1 g; 2.5 mmol) was dissolved in 6 mL of toluene.

Triethylamine (0.69 mL; 5.0 mmol ; 2.0 equiv) was added. The mixture was cooled in ice water and degassed with an argon purge for 10 minutes.

Chlorodiphenylphosphine (470 pL ; 2.6 mmol ; 1.05 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to afford almost complete consumption of 5c and a new spot on tic. Heptane (7 mL) was added and the reaction mixture was filtered and the precipitate was washed with toluene and heptane. The filtrate was concentrated and then re-suspended in heptane.

This mixture was filtered and concentrated in vacuo to afford 1.41 g (90%)

of R, S-1c (R1 = ethyl) as a yellow foam. S, R-2c was prepared in the same manner from S, R-8c. oh NMR (CDC13) 8 7.7-7.05 (m, 18H); 6.987 (m, 2H); 4.766 (br s, 1 H) ; 4.7 (m, 1 H) ; 4.405 (br s, 1 H) ; 4.139 (br s, 1 H) ; 3.822 (s, 5H); 2.65 (m, 2H); 1.768 (d, 3H, J = 6.87 Hz); 0.698 (t, 3H, J = 6.87 Hz). FDMS: m/z 625.25 (M+). [α]D25 -278.3° (c 1.02, toluene).

Example 4 Preparation of (R)-N-Propyl-1-r (S)-2-(diphenYlphosphino)- ferrocenyllethylamine (R, S-5d) (R' = Pr) (R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl] ethyl acetate (R, S- 4a) (2.50 g; 5.5 mmol) was dissolved in methanol (45 mL) and treated with n-propylamine (2.2 mL; 26.8 mmol ; 4.9 equivalents). The reaction mixture was heated to 50°C for 2 hours to completely consume 4a according to tlc analysis. The mixture was concentrated to small volume at reduced pressure. The residue was dissolved in 1: 1 ethyl acetate: heptane and extracted with 10% aqueous citric acid (3 x 25 mL). The acidic extracts were neutralized with 4 N NaOH (38 mL) and extracted with ethyl acetate (3 x 25 mL). Solid was noted in the organic extracts. This was collected by filtration and air-dried to afford 0.58 g of the citric acid salt of R, S-5d (R1 = propyl) as orange crystals. The organic solution was dried with magnesium sulfate and concentrated to afford 1.27 g ( (51%) of R, S-5d (R1 = propyl) as an oil. S, R-8d was prepared in the same manner from S, R-7a.

1H NMR (CDC13) 8 7.6-7.2 (m, 10H) ; 4.497 (brs, 1H) ; 4.290 (brs, 1H) ; 4.025 (s, 5H); 3.764 (brs, 1H) ; 3.205 (q, 1H, J = 7.14 Hz); 2.35-2.1 (m, 2H); 1.462 (d, 3H, J = 6. 59 Hz) ; 0.9-0.6 (m, 2H); 0.506 (t, 3H, J = 7. 14 Hz).

Preparation of (R)-N-Propyl-N-diphenylphosphino-1- (fS)-2- (diphenylphosphino)ferrocenyl]ethylamine (R,S-1d)(R1 = Pr) Amine R, S-5d (400 mg; 0.88 mmol) was dissolved in 2.1 mL of toluene. Triethylamine (250 gel ; 1.8 mmol ; 2.0 equiv) was added. The mixture was cooled in ice water and degassed with an nitrogen purge for 10 min. Chlorodiphenylphosphine (200 uL ; 1.1 mmol ; 1.25 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to afford almost complete consumption of 5d and a new spot on tic. Heptane (5 mL) was added and the reaction mixture was filtered and the precipitate was washed with toluene and heptane. The filtrate was concentrated in vacuo to afford 0.55 g (86%) of R, S-1d (R1 = propyl). S, R-2d was prepared in the same manner from S, R- 8d.

H NMR (CDC13) 8 7.65 (m, 2H); 7.5-7.1 (m, 16H); 6.95 (m, 2H); 4.75 (br s, 1H) ; 4.65 (m, 1H) ; 4.4 (m, 1H) ; 4.15 (brs, 1H) ; 3.82 (s, 5H); 2.42 (m, 2H); 1.81 (d, 3H); 1.4-1.2 (m, 2H); 0.39 (t, 3H). FDMS: m/z 639.34 (M+).

[a] D25-101. 4° (c 1.05, toluene).

Example 5 Preparation of (S)-N-Methyl-N-diethylphosphino-1-[(R)-2-(diphenyl- Phosphino) ferrocenyl7ethylamine (S, R-2e, R'= Me, R 2 = Et) Amine S, R-8b (500 mg; 1.17 mmol) was slurried in 5 mL of toluene.

Triethylamine (0.33 mL; 2.34 mmol ; 2.0 equiv) was added. The mixture was cooled in ice-water and degassed with an argon purge for 15 minutes.

Chlorodiethylphosphine (0.17 mL; 1.40 mmol ; 1.2 equiv) was added dropwise. The reaction mixture was stirred in ice-water for 30 min to completely consume 8b according to tic analysis. The reaction mixture was allowed to warm to ambient temperature overnight. Heptane (10 mL) was added and the reaction mixture was filtered and the precipitate was washed

with heptane. The filtrate was concentrated in vacuo to afford 0.59 g (98%) of S, R-2e as a yellow foam.

1H NMR (DMSO-d6) 8 7. 53 (m, 2H); 7.40 (m, 3H); 7.18 (m, 3H); 6.969 (m, 2H); 4. 503 (m, 2H); 4.392 (m, 1H) ; 3.873 (m, 1H) ; 3.831 (s, 5H); 1.914 (d, 3H, J = 3. 02 Hz); 1.438 (d, 3H, J = 6.87 Hz); 1.3-1.0 (m, 4H); 0.841 (dd, 2H, J = 7.42,15.11 Hz); 0.55-0.4 (m, 2H). FDMS: m/z 515 (M+).

[a] D25 +328.9° (c 1.01, toluene).

Example 6 Preparation of (R)-N-Methyl-N-diisopropylphosphino-1- (, (S)-2- (diphenylphosphino)ferrocenyl]ethylamine (R,S-1f, R1 = Me, R2 = i-Pr) Amine R, S-5b (1.00 g; 2.34 mmol) was dissolved in 5 mL of toluene.

Triethylamine (0.65 mL; 4.7 mmol ; 2.0 equiv) was added. The mixture was cooled in ice water and degassed with an argon purge for 15 minutes.

Chlorodiisopropylphosphine (0.39 mL; 2.46 mmol ; 1.05 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to afford partial consumption of 5b and a new spot according to tic analysis. The mixture was heated to 50°C for 18 hours to afford marginally more conversion. Heptane (10 mL) was added and the reaction mixture was filtered and the precipitate was washed with heptane. The filtrate was concentrated in vacuo and the crude product was filtered through a pad of alumina, eluting with 85: 15: 5 heptane: ethyl acetate : triethylamine to afford 0.83 g (65%) of R, S-1f as a yellow foam.

S, R-2f was prepared in a similar fashion from S, R-8b.

1H NMR (DMSO-d6) 8 7.57 (m, 2H); 7.40 (m, 3H); 7.20 (m, 3H); 7.09 (m, 2H); 4.538 (br s, 1 H); 4.436 (m, 1 H); 4.31 (m, 1 H); 4.04 (br s, 1 H); 3.784 (s, 5H); 2.103 (d, 3H, J = 2.20 Hz); 1.62 (m, 1H) ; 1.557 (d, 3H, J = 6.87 Hz); 1.34 (m, 1H) ; 0.85-0.60 (m, 12 H). FDMS: m/z 543.40 (M+).

[a] 25-301. 9° (c 1.15, toluene).

Example 7 Preparation of (R)-N-Meth ly-N-dicyclohexylphosphino-1- (S)-2- <BR> <BR> <BR> (diphenylphosphino) ferrocenyl1ethvlamine (R, S-1g R1 = Me, R2 = c-C6HX Amine R, S-5b (2.00 g; 4.7 mmol) was dissolved in 10 mL of toluene.

Triethylamine (1.30 mL; 9.4 mmol ; 2.0 equiv) was added. The mixture was cooled in ice water and degassed with an argon purge for 15 minutes.

Chlorodicyclohexylphosphine (1. 05 mL; 4.94 mmol ; 1.05 equiv) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight to afford partial consumption of 5b and a new spot according to tic analysis. The mixture was heated to 50°C for 18 hours to afford significantly more conversion. Heptane (20 mL) was added and the reaction mixture was filtered, the precipitate was washed with heptane, and the combined filtrate and wash were concentrated in vacuo.

The crude product was filtered through a pad of alumina, eluting with 85: 15: 5 heptane: ethyl acetate: triethylamine to afford 1.50 g (52%) of R, S- 1g as a yellow foam. S, R-2g was prepared in a similar fashion from S, R- 8b.

'H NMR (DMSO-d6) 8 7.60 (m, 2H); 7.415 (m, 3H); 7.19 (m, 3H); 7.04 (m, 2H); 4.532 (brs, 1H) ; 4.442 (m, 1H) ; 3.312 (m, 1 H) ; 4.112 (brs, 1H) ; 3.712 (s, 5H); 2.143 (d, 3H, J = 1.92 Hz); 1.549 (d, 3H, J = 6. 87 Hz) ; 1.7-0.7 (m, 22H). FDMS: m/z 624 (M+). [a] o25-292. 2° (c 1.01, toluene).

The utilization of diphosphine 1 or 2 requires the complexation of the ligand with a catalytically active metal ("metal") which is not the structural metal of the metallocene. The particular metal chosen depends on the desired reaction. There are a large number of possible reactions of a wide variety of substrates using catalysts based on compounds 1 and 2, including but not limited to asymmetric hydrogenations, asymmetric

reductions, asymmetric hydroborations, asymmetric olefin isomerizations, asymmetric hydrosilations, asymmetric allylations, and asymmetric organometallic additions. The utility of ligands 1 and 2 will be demonstrated through asymmetric hydrogenation reactions of their metal complexes, which is also an embodiment of our invention. Thus, the present invention includes a process for the hydrogenation of a hydrogenatable compound which comprises contacting the hydrogenatable compound with hydrogen in the presence of a catalyst complex comprising ligands 1 or 2 in complex association with a metal. Although not wishing to be bound to a particular substrate type, the asymmetric hydrogenation of enamide substrates to afford amino acid derivatives is of particular interest in the pharmaceutical industry, and catalysts based on ligands 1 and 2 show particularly high enantioselectivity for these transformations. Enamide compounds that can be hydrogenated under these circumstances contain the residue C=C (N-C=O)-C=O, such that if this residue is present in the hydrogenatable compound the transformation will proceed with high enantioselectivity.

The preferred enamide reactants have the general formula 10, 10 wherein R", R12, and R14 are independently selected from hydrogen, substituted and unsubstituted, branched-and straight-chain Ci to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6to C2o carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, or oxygen; and

R13 is selected from hydrogen, substituted and unsubstituted Ci to C20 alkyl, substituted and unsubstituted Ci to C20 alkoxy, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C3 to C8 cycloalkoxy, substituted and unsubstituted carbocyclic C6 to C20 aryl, substituted and unsubstituted carbocyclic C6 to C20 aryloxy, substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, or oxygen and substituted and unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; or R13 and R14 collectively represent a substituted or unsubstituted alkylen group of 1-4 chain carbon atoms forming a lactam.

The enamides reactants having formula 10 can be prepared using the methodology described in Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B.. Synthesis 1992,487- 490.

The products of the hydrogenation of enamides having formula 10 with catalysts based on ligands 1 and 2 are comprised of species with formula 11, 11 wherein R", R12, R13, and R14 are as defined above. These compounds are generally produced with very high enantioselectivity (>90% ee), with the particular enantiomer produced depending upon whether ligand 1 or ligand 2 is used.

Catalysts based on ligands 1 and 2 also show high enantioselectivity for the asymmetric hydrogenation of various itaconate and a-ketoester derivatives. The itaconate compounds which may be selectively hydrogenated have general formula 14, 14 wherein R15 is selected from hydrogen, substituted and unsubstituted, branched-and straight-chain C1-C20 alkyl, and substituted and unsubstituted C3-C8 cycloalkyl, and R16 and R17 are independently selected from hydrogen, substituted and unsubstituted, branched-and straight-chain Cl-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen. The preferred itaconate reactants have formula 14 wherein R15 is hydrogen and R16 and R17 are independently selected from hydrogen and Ci-Cio alkyl. The itaconate substrates of formula 14 are generally commercially available or can prepared by methods known to those skilled in the art.

The products of the hydrogenation of itaconates having formula 14 with catalysts based on ligands 1 and 2 are comprised of species with formula 15,

wherein R15,R16, and R17 are as defined above. These compounds are generally produced with high enantioselectivity (>80% ee), with the particular enantiomer produced depending upon whether ligand 1 or ligand 2 is used.

The a-ketoester compounds which may be selectively hydrogenated have general formula 16: 16 wherein R'8 and R19 are independently selected from hydrogen, substituted and unsubstituted, branched-and straight-chain Cl-C20 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C20 carbocyclic aryl, and substituted and unsubstituted C4-C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; or R18 and R19 may collectively represent a substituted or unsubstituted alkylen group of 1-4 chain carbon atoms forming an a-ketolactone.

The a-ketoester substrates of formula 16 are generally commercially available or can prepared by methods known to those skilled in the art.

The preferred a-ketoester reactants have formula 16 wherein R'8 and R19 are independently selected from hydrogen, C1-C10 alkyl, C3-C6

cycloalkyl, phenyl, and benzyl. The preferred a-ketoester reactants also include the compounds of formula 16 wherein R13 and R19 collectively represent a substituted or unsubstituted alkylen group of 2-3 chain carbon atoms forming an a-ketolactone.

The products of the hydrogenation of a-ketoesters having formula 16 with catalysts based on ligands 1 and 2 are comprised of species with formula 17, 17 wherein R18 and R19 are as defined above. These compounds are generally produced with high enantioselectivity (>80% ee), with the particular enantiomer produced depending upon whether ligand 1 or ligand 2 is used.

For an asymmetric hydrogenation reaction, the metal complexed can be chosen from the group consisting of rhodium, iridium, or ruthenium, and is most preferably rhodium. The ligand-metal complex can be prepared and isolated, but it is preferable to prepare the complex in situ from ligand 1 or 2 and a metal pre-catalyst. The ligand to metal molar ratio may be in the range of 0.5: 1 to 5: 1, preferably 1: 1 to 1.5: 1. The amount of complex may vary between 0.00005 and 0.5 equivalents based on the reactant compound, with more complex usually providing faster reaction rates. The atmosphere is hydrogen, but may also contain other materials that are inert to the reaction conditions. The reaction can be run at atmospheric pressure or at elevated pressure, from 0.5-200 bars gauge (barg) (50 to 20,000 kPa).

The reaction is run at a temperature which affords a reasonable rate of conversion, which can be as low as-50°C but is usually between ambient

temperature and the boiling point (or apparent boiling point at elevated pressure) of the lowest boiling component of the reaction mixture. The reaction is usually run in the presence of a solvent chosen from aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, lower alcohols such as methanol, ethanol, n-propanol, isopropanol, n- butanol and the like, halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, tetrachloroethylene, chloroform, chlorobenzene and the like, dialkyl ketones such as acetone, 2-butanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide and the like.

These reactions are exemplified by the asymmetric hydrogenation reactions of various enamides, itaconates, and a-ketoesters as shown below. The amino-acid derivatives generated from the asymmetric hydrogenation of enamide substrates using a rhodium complex formed in situ from ligands 1 or 2 are generally obtained in very high enantiomeric excess (>90% ee), while the succinate and a-hydroxyester derivatives generated from the asymmetric hydrogenation of, respectively, the itaconate and a-ketoester substrates using a rhodium complex formed in situ from ligands 1 or 2 are generally obtained in high enantiomeric excess (>80% ee).

General Procedure A-Low Pressure Asymmetric Hvdroaenation Bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate was placed into a reaction vessel and purged with argon for 15 minutes. A solution of the ligand (1 or 2) in anhydrous tetrahydrofuran (THF, 2.0 mL) was degassed with Ar for 15 minutes, then added via cannula to the bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate. This solution

was stirred at 25°C under argon for 15 minutes. A solution of enamide 10 (0.5 mmol) in anhydrous THF (2.0 mL) was degassed with argon for 20 minutes, then added to the catalyst solution via canula. The solution was then flushed with hydrogen and pressurized to 0.69-1.38 bars gauge (10-20 pounds per square inch gauge-psig ; or 69 to 138 kPa) hydrogen.

Samples were taken and analyzed for enantiomeric excess using standard analytical techniques (see below).

General Procedure B-High Pressure Asymmetric Hydrogenation Bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate and the ligand (1 or 2) were placed in a high pressure reaction vessel which was sealed and purged with argon. The desired solvent was degassed with Ar for 15 minutes, then 2.0 mL was added to the reaction vessel via syringe.

This solution was stirred at 25°C under argon for 15 minutes. A solution of the desired substrate (0.5 mmol) in the desired degassed solvent (2 mL) was then added to the catalyst solution via syringe. The substrate was washed in with 1 mL of the degassed solvent. The solution was then purged five times with argon and pressurized with hydrogen to the desired pressure (6.9-20.7 barg; 100-300 psig; 690 to 2070 kPa) and heated to the desired temperature. The reactions were run for 6 hours at the desired temperature and pressure, and then cooled (if necessary) to ambient temperature, depressurized, and purged with argon. Samples were taken and analyzed for enantiomeric excess using standard analytical techniques (see below).

10 S-11 Example 8 N-Acetyl L-phenylalanine methyl ester (S-11a) Enamide 10a (R11 = phenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11a (R11 = phenyl, R12 = R13 = methyl, R14 = H with 99.2% ee as determined by chiral GC analysis.

H NMR (CD30D, 400 MHz) 8 7.28-7.16 (m, 5H); 4.64-4.61 (m, 1H) ; 3.65 (s, 3H); 3.13-3.08 (dd, 1H, J = 5.5,13.9 Hz); 2.94-2.88 (dd, 1H, J = 8.9,13.9 Hz); 1.87 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0. 12 µm, 160°C for 9 min, 160-185°C at 70°C/min, 185°C for 5 min, 15 psig He]: tR (R-11a) 7.77 min, tR (S-11a) 8.29 min, tR (10a) 13.24 min.

Example 9 N-Acetyl L-phenylalanine methyl ester (S-11a) via High Pressure Hydrogenation in THF Enamide 10a (R11 = phenyl, R12 = R13 =methyl, R14 = H) was hydrogenated according to General Procedure B in THF using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Fmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to

afford 100% conversion to amino acid derivative S-11a (R11 = phenyl, R12 = R13 = methyl, R14 = H) with 96.8% ee as determined by chiral GC analysis.

Example 10 N-Acetyl L-phenylalanine methyl ester (S-11a) via High Pressure Hydrogenation in Acetone Enamide 10a (Rll = phenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in acetone using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limol ; 0.01 equiv) and ligand (R, S)-1 b (3.7 mg; 6 limon ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11a (R" = phenyl, R12 = R13 = methyl, R14 = H) with 97.6% ee as determined by chiral GC analysis.

Example 11 N-Acetyl L-phenylalanine (S-11b) Enamide 10b (Rll = phenyl, R12 = R14 = H, R13 = methyl) was hydrogenated according to General Procedure A using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Fmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 umol ; 0.012 equiv) for 1 hour to afford 100% conversion to amino acid derivative S-11b (Rll = phenyl, R12 = R14 = H, R13 = methyl) with 99.4% ee.

A sample was treated with diazomethane to make the methyl ester before analysis. See Example 8 (N-acetyl phenylalanine methyl ester) for analytical details.

1H NMR (CD30D, 300 MHz) 8 7.20-7.08 (m, 6H); 4.58-4.54 (dd, 1H, J = 5.2, 9.1 Hz); 3.14-3.07 (dd, 1H, J = 4.9,13.9 Hz); 2.88-2.80 (dd, 1H, J = 9.1, 14.0 Hz); 1.8 (s, 3H).

Example 12 N-t-Butyloxycarbonyl L-phenylalanine methyl ester (S-11c) Enamide 10c (Rll = phenyl, R = methyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (3.0 mg; 6.5 µmol ; 0.013 equiv) and ligand (R, S)-1b (4.4 mg; 7.2 pmol ; 0.016 equiv) for 1 hour to afford 100% conversion to amino acid derivative S-11c (R11 = phenyl, R12 = methyl, R13 = t-butoxy, R14 = H) with 99.5% ee as determined by chiral GC analysis.

Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 m, 140°C isothermal, 15 psig He]: tR (R-11c) 19.14 min, tR (S-11 c) 19.66 min, tR (10c) 40.14 min.

Example 13 N-Benzamido L-phenylaalanine methyl ester (S-11d) Enamide 10d (Rll = R13 = phenyl, R = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 pmol ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11d (R11 = R13 = phenyl, R12 = methyl, R14 = H) with 98.4% ee as determined by chiral GC analysis.

H NMR (CD30D, 600MHz) a 7.72-7.70 (d, 2H, J = 7.3 Hz); 7.50-7.47 (m, 1H) ; 7.40-7.23 (m, 2H); 7.20-7.17 (m, 5H); 4.85-4.83 (m, 1H) ; 3.69 (s, 3H); 3.65 (s, 1H) ; 3.29-3.26 (m, 1H) ; 3.13-3.08 (m, 1 H). Chiral GC [Chirasil L- Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 150°C isothermal, 15 psig He]: tR (R-11 d) 11.69 min, tR (S-11 d) 12.68 min, tR (10d) 18.5 min.

Example 14 N-Acetyl D-alanine methyl ester (R-11e) Enamide 10e (R11 = R14 = H, R12 = R13 = methyl) was hydrogenated according to General Procedure A using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (5.8 mg; 12.5 pmol ; 0.025 equiv) and ligand (S, R)-2b (9.3 mg; 15 µmol ; 0.03 equiv) for 1 hour to afford 100% conversion to amino acid derivative R-11e (Rll = R14 = H, R12 = R13 = methyl) with 98.4% ee as determined by chiral GC analysis.

H NMR (CD30D, 600MHz) 5 4.42-4.38 (dd, 1 H, J = 7.3,14.7 Hz); 3.72 (s, 3H); 1.98 (s, 3H); 1.38-1.37 (d, 3H, J = 7.3 Hz). Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, 0.25 um film thickness, 40-100°C at 70°C/min, 100°C for 15 min, 100-170°C at 15°C/min, 170°C for 7 min, 6 psig He for 6 min, 6-20 psig He at 80 psig/min, 20 psig for 22 min]: tR (R- 11e) 19. 36 min, tR (S-11e) 19.12 min, tR (10e) 17.91 min.

Example 15 N-Acetyl L-alanine methyl ester (S-11e) via High Pressure Hydrogenation in Acetone Enamide 10e (Rll = R14 = H, R12 = R13 = methyl) was hydrogenated according to General Procedure B in acetone using bis (1,5-cyclooctadiene)- rhodium trifluoromethanesulfonate (2.3 mg; 5 mol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 1 hour to afford 100% conversion to amino acid derivative R-11e (R11 = R14 = H, R12 = R13 = methyl) with 95.2% ee as determined by chiral GC analysis.

Example 16 N-Acetyl D-alanine (R-110 Enamide 10f (R11 = R12 = R14 = H, R13 = methyl) was hydrogenated according to General Procedure A using bis (1,5-cyclooctadiene) rhodium

trifluoromethanesulfonate (2.3 mg; 5 limon ; 0.01 equiv) and ligand (S, R)-2b (3.7 mg; 6 p. mo) ; 0.012 equiv) for 24 hours to afford 100% conversion to amino acid derivative R-11f (R11 = R12 = R14 = H, R13 = methyl) with 96.1% ee.

A sample was treated with diazomethane to make the methyl ester before analysis. See Example 14 (N-acetyl alanine methyl ester) for analytical details.

Example 17 N-Benzyloxycarbonyl L-alanine methyl ester (S-11g) Enamide 10g (R11 = R14 = H, R = methyl, R13 = benzyloxy) was hydrogenated according to General Procedure A using bis (1,5- cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limon ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 cymol ; 0.012 equiv) for 1 hour to afford 56% conversion to amino acid derivative S-11g (R11 = R14 = H, R12- methyl, R13 = benzyloxy) with 98.8% ee as determined by chiral GC analysis.

H NMR (CDC13, 600MHz) a 7.33-7.26 (m, 5H); 5.07 (s, 2H); 4.23-4.19 (m, 1 H) ; 3.69 (s, 3H); 1.36-1.34 (d, 3H, J = 7.3 Hz). Chiral GC [Chirasil L- Valine (Varian) 25 m x 0.25 mm ID, film thickness 0. 12µm, 150°C isothermal, 15 psig He]: tR (R-11g) 11.37 min, tR (S-11g) 11.70 min, tR (10g) 10.10 min.

Example 18 N-Benzyloxycarbonyl L-homophenylalanine ethyl ester (S-11h) Enamide 10h (Rll = benzyl, R12 = ethyl, R13 = benzyloxy, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) to afford >99%

conversion to amino acid derivative S-11h (R11 = benzyl, R12 = ethyl, R13 = benzyloxy, R14 = H) with 98.1 % ee as determined by chiral HPLC analysis.

H NMR (CDC13, 400 MHz) # 7. 37-7.15 (m, 10H) ; 5.38-5.36 (d, 1H, J=7.9 Hz); 5.12 (s, 2H); 4.44-4.39 (dd, 1H, J = 7.6,13.0 Hz); 4.20-4.15 (dd, 2H, J=7.0,14.3 Hz); 2.73-2.60 (m, 2H); 2.27-2.14 (m, 1H) ; 2.02-1.93 (m, 1H) ; 1.28-1.25 (t, 3H, J = 7.0 Hz). A chiral normal-phase HPLC separation of the two enantiomers was developed using a Cyclobond I 2000 SN column (Advanced Separation Technologies, Inc.). Ultraviolet detection was used at a wavelength of 210 nm. The mobile phase was 97/3 heptane/isopropanol (v/v). tR (R-11h) 28.93 min, tR (S-11h) 30.99 min, tR (10h) 33.39 min.

Example 19 N-Acetyl L-4-chlorophenylalanine methyl ester (S-11i) Enamide 10i (R11 = 4-chlorophenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (4.6 mg; 10 pmol ; 0.02 equiv) and ligand (R, S)-1b (7.4 mg; 12 umol ; 0.024 equiv) for 2 hours to afford 100% conversion to amino acid derivative S-11i (R11 = 4-chlorophenyl, R12 = R13 = methyl, R14 = H) with 98.8% ee as determined by chiral GC analysis.

1H NMR (CD30D, 600 MHz) 87. 27-7.25 (d, 2H, J = 8.7 Hz); 7.18-7.16 (d, 2H, J = 8.7 Hz); 4.64-4.62 (dd, 1H, J = 5.5,9.2 Hz); 3.70 (s, 1H) ; 3.67 (s, 3H), 3.13-3.09 (dd, 1H, J = 5.5,13.7 Hz); 2.93-2.89 (dd, 1H, J = 9.2,13.9 Hz); 1.88 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 175°C isothermal, 20 psig He]: tR (R-11i) 7.29 min, tR (S-11i) 7.76 min, tR (10i) 15.72 min.

Example 20 N-Acetyl L-4-chlorophenylalanine methyl ester (S-11i) via High Pressure Hydrogenation in THF Enamide 10i (R11 = 4-chlorophenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in THF using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11 i (R 1 = 4- chlorophenyl, R12 = R13 = methyl, R14 = H) with 96.2% ee as determined by chiral GC analysis.

Example 21 N-Acetyl L-4-cyanophenylalanine methyl ester (S-11j) Enamide 10j (R11 = 4-cyanophenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Rmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 Rmol ; 0.012 equiv) for 1 hour to afford 100% conversion to amino acid derivative S-11j (R11 = 4-cyanophenyl, R12 = R13 = methyl, R14 = H) with 99.0% ee as determined by chiral GC analysis.

Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm 190°C isothermal, 20 psig He]: tR (R-11j) 8.73 min, tR (S-11j) 9.17 min.

Example 22 N-Acetyl L-4-methoxyphenylalanine methyl ester (S-11k) Enamide 10k (Rll = 4-methoxyphenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (4.6 mg; 10 µmol; 0.02 equiv) and ligand (R, S)-1b (7.4 mg; 12 Mol ; 0.024 equiv) for 30 minutes to afford 90% conversion to amino acid derivative S-11k (R11 = 4-methoxyphenyl,

R12 = R13 = methyl, R14 = H) with 97.9% ee as determined by chiral GC analysis.

1H NMR (CD30D, 400 MHz) a 7.09-7.07 (d, 2H, J = 8.9 Hz); 6.82-6.80 (d, 2H, J = 8.9 Hz); 4.59-4.56 (dd, 1, H J = 5.8,8.9 Hz); 3.73 (s, 3H); 3.70 (s, 1H) ; 3.65 (s, 3H); 3.06-3.01 (dd, 1H, J = 5.8,13.7 Hz); 2.88-2.82 (dd, 1H, J = 8.9,13.9 Hz); 1.88 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 185°C isothermal, 20 psig He]: tR (R- 11k) 6.04 min, tR (S-11k) 6.32 min, tR (10k) 15.13 min.

Example 23 N-Acetyl L-4-methoxyphenylalanine methyl ester (S-11k) via High Pressure Hydrogenation in THF Enamide 10k (Rll = 4-methoxyphenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in THF using bis (1,5- cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limon ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11k (R11 = 4-methoxy- phenyl, R12 = R13 =methyl, R14 = H) with 97.3% ee as determined by chiral GC analysis.

Example 24 N-Acetyl L-3-methoxyphenylalanine methyl ester (S-11m) Enamide 10m (R11 = 3-methoxyphenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (4.6 mg; 10 µmol ; 0.02 equiv) and ligand (R, S)-1b (7.4 mg; 12 limon ; 0.024 equiv) for 30 minutes to afford 100% conversion to amino acid derivative S-11m (R11 = 3-methoxyphenyl, R12 = R13 = methyl, R14 = H) with 98.0% ee as determined by chiral GC analysis.

'H NMR (CD30D, 400 MHz) s 7.19-7.15 (t, 1H, J = 7.9 Hz,); 6.78-6.74 (m, 3H); 4.66-4.62 (dd, 1H, J = 5.5,9.0 Hz); 3.75 (s, 3H); 3.72-3.69 (m, 1H) ; 3.67 (s, 3H); 3.12-3.07 (dd, 1H, J = 5.8,13.9 Hz); 2.92-2.88 (dd, 1H, J = 8.9,13.7 Hz); 1.89 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 185°C isothermal, 20 psig He]: tR (R- 11m) 7.73 min, tR (S-11m) 8.18 min.

Example 25 N-Acetyl L-2-methoxyphenylalanine methyl ester (S-11n) Enamide 10n (R11 = 2-methoxyphenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclo- octadiene) rhodium trifluoromethanesulfonate (4.6 mg; 10 pmol ; 0.02 equiv) and ligand (R, S)-1b (7.4 mg; 12 limol ; 0.024 equiv) for 2 hours to afford 99.5% conversion to amino acid derivative S-11n (R11 = 2-methoxyphenyl, pi2 = R13 = methyl, R14 = H) with 97.7% ee as determined by chiral GC analysis.

H NMR (CD30D, 600 MHz) # 7. 21-7.19 (t, 1H, J = 7.3 Hz); 7.06-7.05 (d, 1 H, J = 7.3 Hz); 6.92-6.90 (d, 1 H, J = 7.8 Hz); 6.84-6.82 (t, 1 H, J = 7.8 Hz); 4.67-4.66 (m, 1H) ; 3.82 (s, 3H); 3.70 (s, 1H) ; 3.63 (s, 3H); 3.16-3.13 (dd, 1H, J = 6.0,13.5 Hz); 2.90-2.86 (dd, 1H, J = 8.7,13.3 Hz); 1.86 (s, 3H).

Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 185°C isothermal, 20 psig He]: tR (R-11n) 4.87 min, tR (S-11n) 5.07 min, tR (10n) 8.96 min.

Example 26 N-Acetyl L-2-methoxyphenylalanine methyl ester (S-11n) via High Pressure Hydrogenation in THF Enamide 10n (R11 = 2-methoxyphenyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in THF using bis (1,5- cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 umol ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative S-11n (R11 = 2- methoxyphenyl, R12 = R13 = methyl, R14 = H) with 96.7% ee as determined by chiral GC analysis.

Example 27 N-Acetyl L-4-nitrophenylalanine methyl ester (S-11o) Enamide 10o (R"= 4-nitrophenyl, R 12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 pmol ; 0.012 equiv) for 30 minutes to afford 100% conversion to amino acid derivative S-11o (R11 = 4-nitrophenyl, R12 = R13 = methyl, R14 = H) with 97.7% ee as determined by chiral GC analysis.

1 H NMR (CD30D, 400 MHz) # 8. 15-8.13 (d, 2H, J = 8.9 Hz,); 7.45-7.43 (d, 2, H J = 8.6 Hz); 4.75-4.71 (dd, 1H, J = 5.5,9.2 Hz,); 3.69 (s, 3H); 3.67 (s, 1 H) ; 3.30-3.25 (m, 1 H) ; 3.08-3.02 (m, 1 H) ; 1.88 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm D, film thickness 0.12 sium, 185°C isothermal, 20 psig He]: tR (R-l I o) 15.73 min, tR (S-110) 16.79 min.

Example 28 N-t-Butyloxycarbonyl L-3-furanylalanine methyl ester (S-11p) Enamide 10p (R11 = 3-furanyl, R12 = methyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-

cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limon ; 0.012 equiv) for 6 hours to afford 98% conversion to amino acid derivative S-11p (R11 = 3-furanyl, R12 = methyl, R13 = t-butoxy, R14 = H) with 97.2% ee as determined by chiral GC analysis. oh NMR (CDC13, 300 MHz) 8 7.36 (s, 1H) ; 7.25 (s, 1H) ; 6.21 (s, 1H) ; 5.12- 5.09 (m, 1 H) ; 4.53-4.51 (m, 1 H) ; 3.73 (s, 3H); 2.93-2.92 (m, 2H); 1.44 (s, 9H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0. 12 µm, 140°C isothermal, 20 psig He]: tR (R-11p) 7.61 min, tR (S- 11p) 7.89 min, tR (10p) 17.97 min.

Example 29 N-Benzamido D-3-furanylalanine methyl ester (R-11q) Enamide 10q (R1'= 3-furanyl, R12 = methyl, R13 = phenyl, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limol ; 0.01 equiv) and ligand (S, R)-2b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 100% conversion to amino acid derivative R-11q (R11 = 3-furanyl, R12 = methyl, R = phenyl, R14 = H) with 96.6% ee as determined by chiral GC analysis.

'H NMR (CD30D, 400 MHz) # 7.77-7.75 (m, 2H); 7.53-7.36 (m, 6H); 4.79- 4.75 (dd, 1H, J = 5.2,9.3 Hz); 3.72 (s, 3H); 3.69 (s, 1H) ; 3.11-3.06 (dd, 1H, J = 5.2,14.6 Hz); 2.99-2.93 (dd, 1H, J = 9.5,14.6 Hz). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 pm, 175°C isothermal, 20 psig He]: tR (R-11 q) 12.57 min, tR (S-11 q) 13.29 min, tR (10q) 9.39 min.

Example 30 N-t-Butyloxycarbonyl L-cyclopropylalanine methyl ester (S-11rJ Enamide 10r (R11 = cyclopropyl, R12 = methyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 Rmol ; 0.012 equiv) for 6 hours to afford 90% conversion to amino acid derivative S-11r (R11 = cyclopropyl, R12 = methyl, R13 = t-butoxy, R14 = H) with 98.6% ee as determined by chiral GC analysis.

'H NMR (CDC13, 300 MHz) 8 5.22-5. 20 (m, 1H) ; 4.41-4.34 (m, 1H) ; 3.74 (s, 3H); 1.69-1.64 (t, 2H, J = 6.6 Hz); 0.73-0.67 (m, 1 H) ; 0.51-0.44 (m, 2H); 0.10-0.05 (m, 2H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 µm, 175°C isothermal, 15 psig He]: tR (R-11r) 14.59 min, tR (S-11r) 15.21 min, tR (10r) 26.34 min.

Example 31 N-Benzamido D-cyclopropylalanine methyl ester (R-11s) Enamide 10s (R11 = cyclopropyl, R12 = methyl, R13 = phenyl, R H) was hydrogenated according to General Procedure A using bis (1,5- cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Zmol ; 0.01 equiv) and ligand (S, R)-2b (3.7 mg; 6 µmol ; 0.012 equiv) for 24 hours to afford 100% conversion to amino acid derivative R-11s (R11 = cyclopropyl, R12 = methyl, R13 = phenyl, R14 = H) with 91.6% ee as determined by chiral GC analysis.

1 H NMR (CDC13, 300 MHz) 8 7.80-7.76 (m, 2H); 7.50-7.36 (m, 3H) ; 4.62- 4.57 (m, 1H) ; 3.66 (s, 3H); 1.81-1.75 (m, 1H) ; 1.69-1.63 (m, 1H) ; 0.80-0.75 (m, 1H) ; 0.45-0.39 (m, 2H); 0.09-0.04 (m, 2H). 13C NMR (CDCl3, 75 MHz) 8 133.0,129.7,128.7,55.3,52.9,37.5,23.6,9.1,5.4,4.8. Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm D, film thickness 0.12 sim, 175°C

isothermal, 20 psig He]: tR (R-11s) 10.76 min, tR (S-11s) 11.18 min, tR (10s) 17.73 min.

Example 32 N-t-Butyloxycarbonyl L-cyclopropylalanine benzyl ester (S-11t) Enamide 10t (R11 = cyclopropyl, R12 = benzyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A in acetone as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limol ; 0.012 equiv) for 1 hour to afford 94% conversion to amino acid derivative S-11t (R11 = cyclopropyl, R12 = benzyl, R13 = t-butoxy, R14 = H) with >99% ee as determined by chiral GC analysis.

1H NMR (CDC13, 300MHz) 8 7.41-4.30 (m, 5H); 5.13-5.12 (m, 1H) ; 5.02 (s, 2H); 1.70-1.60 (m, 2H); 1.45 (s, 9H); 0.69-0.61 (m, 1 H) ; 0.42-0.39 (m, 2H); 0.02-0.01 (m, 2H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 1m, 175°C isothermal, 15 psig He]: tR (R-11t) 15.03 min, tR (S-11t) 15.48 min, tR (10t) 25.98 min.

Example 33 N-t-Butyloxycarbonyl L-cyclopropylalanine benzyl ester (S-11t) via High Pressure Hydrogenation in Acetone Enamide 10t (Rll = cyclopropyl, R12 = benzyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure B in acetone as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 1 hour to afford 100% conversion to amino acid derivative S-11t (R11 = cyclopropyl, R12 = benzyl, R13 = t-butoxy, R14 = H) with 95.5% ee as determined by chiral GC analysis.

Example 34 N-Acetyl 1-Naphthylalanine methyl ester (S-11u) Enamide 10u (R11 = 1-naphthyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure A in THF as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 (J. moi ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford >95% conversion to amino acid derivative S-11u (R11 = 1-naphthyl, R12 = R43 = methyl, R14 = H) with 99.3% ee as determined by chiral GC analysis.

1H NMR (CDCl3, 300MHz) 8 8.083 (d, 1H, J = 8.24 Hz); 7.855 (d, 1H, J = 7.69 Hz); 7.769 (d, 1H, J = 7.97 Hz) ; 7.510 (m (5), 2H, J = 7. 97 Hz) ; 7.385 (t, 1H, J = 7.14 Hz); 7.230 (d, 1H, J = 6.87 Hz); 5.98 (br s, 1 H) ; 5.017 (q, 1H, J = 6.59 Hz); 3.626 (s, 3H); 3.57 (m, 2H); 1.926 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm ID, film thickness 0.12 jum, 185°C for 22 min, 185-195°C at 10°C/min, 195°C for 17 min, 15 psig He]: tR (R-11u) 18. 83 min, tR (S-11 u) 19.76 min.

Example 35 N-Acetyl 1-Naphthylalanine methyl ester (S-11u) via High Pressure Hydrogenation Enamide 10u (R11 = 1-naphthyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in acetone as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limol ; 0.012 equiv) for 6 hours to afford >95% conversion to amino acid derivative S-11u (R11 = 1- naphthyl, R12 = R13 = methyl, R14 = H) with 97.4% ee as determined by chiral GC analysis.

Example 36 N-t-Butyloxycarbonyl 1-Naphthylalanine methyl ester (S-11v) Enamide 10v (Rll = 1-naphthyl, R12 = methyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A in THF as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 mol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 Rmol ; 0.012 equiv) for 6 hours to afford >95% conversion to amino acid derivative S-11v lv = 1-naphthyl, R12 =methyl, R13 = t-butoxy, R14 = H) with 98.2% ee as determined by chiral HPLC analysis.

'H NMR (CDC13, 300MHz) 8 8.075 (d, 1H, J = 7.96 Hz); 7.858 (d, 1H, J = 7.69 Hz); 7.767 (d, 1H, J = 8.24 Hz) ; 7.512 (m (5), 2H, J = 7. 97 Hz) ; 7.391 (t, 1H, J = 7.14 Hz); 7.27 (m, 1H) ; 5.057 (brd, 1H, J = 7.69 Hz); 4.719 (q, 1H, J = 7.69 Hz); 3.744 (s, 3H); 3.7-3.4 (m, 2H); 1.395 (s, 9H). Chiral HPLC [Chiralcel OD-H (Diacel Chemical), 250 x 4.6 mm, 95: 5 hexane: isopropanol, 1 mL/min, X = 254 nm]: tR (R-11v) 14.05 min, tR (S-11v) 17.64 min.

Example 37 N-Acetyl 2-Naphthylalanine methyl ester (S-11w) Enamide 10w (R11 = 2-naphthyl, R12 = R13 =methyl, R14 = H) was hydrogenated according to General Procedure A in THF as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 1 hour to afford >95% conversion to amino acid derivative S-11w (R11 = 2-naphthyl, R12 = R13 = methyl, R14 = H) with 98.1% ee as determined by chiral GC analysis.

1H NMR (CDC13, 300MHz) # 7. 85-7.75 (m, 3H); 7.553 (s, 1H) ; 7.47 (m, 2H); 7.218 (d, 1 H, J = 8.52 Hz); 6.01 (br s, 1 H) ; 4.966 (q, 1 H, J = 6.04 Hz); 3.727 (s, 3H); 3.314 (dd, 1H, J = 5.77,13,74 Hz); 3.244 (dd, 1H, J = 6.04,14.01 Hz); 1.973 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m x 0.25 mm

ID, film thickness 0.12 µm, 185°C isothermal, 15 psig He]: tR (R-11w) 22.02 min, tR (S-11w) 23.26 min.

Example 38 N-Acetyl 2-Naphthylalanine methyl ester (S-llw) via High Pressure Hydrogenation Enamide 10w (R11 = 2-naphthyl, R12 = R13 = methyl, R14 = H) was hydrogenated according to General Procedure B in acetone as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limon ; 0.012 equiv) for 6 hours to afford >95% conversion to amino acid derivative S-11w (R11 = 2- naphthyl, R12 = R13 = methyl, R14 = H) with 97.6% ee as determined by chiral GC analysis.

Example 39 N-t-Butyloxycarbonyl 2-Naphthylalanine methyl ester (S-11x) Enamide 10x (R11 = 2-naphthyl, R12 =methyl, R13 = t-butoxy, R14 = H) was hydrogenated according to General Procedure A in THF as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 mol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limol ; 0.012 equiv) for6 hours to afford 97% conversion to amino acid derivative S-11x (R11 = 2-naphthyl, R12 =methyl, R13 = t-butoxy, R14 = H) with 97.4% ee as determined by chiral HPLC analysis.

1H NMR (CDC13, 300MHz) s 7.80 (m, 3H); 7.586 (s, 1H,) ; 7.45 (m, 2H); 7.26 (m, 1H) ; 5.000 (brd, 1H, J = 7.14 Hz); 4.677 (q, 1H, J = 6.87 Hz); 3.713 (s, 3H); 3.35-3.15 (m, 2H); 1.399 (s, 9H). Chiral HPLC [Chiralcel OD-H (Diacel Chemical), 250 x 4.6 mm, 95: 5 hexane: isopropanol, 1 mL/min, X = 254 nm]: tR(R-11x) 12.86 min, tR (S-11x) 14.41 min.

Example 40 Ligand substituent effects on the hydrogenation to produce N-acetyl phenylalanine methyl ester (11a) C02Me Rh (COD) 2OTf C02Me NHAc Ligand AcHN H 10a S-11a Enamide 10a was hydrogenated according to General Procedure A for 1 hour using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 ßmol ; 0.01 equiv) and the ligands indicated below (6 pmol ; 0.012 equiv) to afford in all cases 100% conversion to amino acid derivative 11a with the indicated enantiomeric purity as determined by chiral GC analysis (see Example 8 for analytical details). Ligand 11a Configuration 11a ee (%) (R,S)-1a S 97.2 (R,S)-1 b 99. 1 (R,S)-1c S 94.3 (S,R)-2d R 93.3 Example 41 Solvent effects on the hydrogenation to produce N-acetyl L-phenylalanine methyl ester (S-11a) CO Me Rh (COD) 20Tf CO2Me Ph 1- H2, solvent-Ph NHAc (R, S)-1b AcHN H

10a S-11a Enamide 10a was hydrogenated according to General Procedure A for 1 hour using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate and ligand (R, S)-1b in the indicated solvent to afford amino acid derivative S-11a with the conversion and enantiomeric excess indicated (see Example 8 for analytical details). Solvent % ee % conv. Solvent % ee % conv. THF 99. 1 100 EtOAc 98. 5 100 MeOH 98. 5 100 TBME >99 2% iPrOH 97. 7 100 DMF 96. 5 25 Acetone 98. 3 97 DMSO 94. 4 15 PhMe 97.4 100 CH2Cl2 97.9 99

Tetrahydrofuran (THF), toluene (PhMe), t-butyl methyl ether (TBME), and methanol (MeOH) were anhydrous and used as received. Dichloromethane (CH2CI2), acetone, 2-propanol (iPrOH), ethyl acetate (EtOAc), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) were not strictly anhydrous nor dried prior to use.

Example 42 Demonstration of ligand stability

10a S-11a (R, S)-1b was placed in an uncapped vial and left exposed to ambient conditions (25°C) for seven months prior to use. Bis (1,5-cyclooctadiene)- rhodium trifluoromethanesulfonate (2.3 mg; 5 simol, 0.01 equiv) was placed into a reaction vessel and purged with argon for 15 minutes. A solution of (R, S)-1b (3.7 mg; 6 simol, 0.012 equiv) in anhydrous THF (2.0 mL) was degassed with argon for 15 minutes, then added via cannula to the bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate. This solution was stirred at 25°C under argon for 15 minutes. A solution of enamide 10a (0.5 mmol) in anhydrous THF (2.0 mL) was degassed with argon for 20 minutes, then added to the catalyst solution via canula. The solution was then flushed with hydrogen and pressurized to 0.69-1.38 barg (10-20 psig; 69 to 138 kPa) hydrogen. The reaction was depressurized after 1 hour. N- acetyl L-phenylalanine methyl ester (S-11a) was isolated in 100% yield and 98.8% ee (see Example 8 for analytical details).

Example 43 Demonstration of High Substrate to Catalyst Ratios

10a S-11a Enamide 10a (5.48 g; 25.0 mmol) was added to a dry nitrogen- purged Fisher-Porter bottle. Argon-degassed methanol (32 mL) was added to afford a homogeneous solution which was purged with argon for 10 minutes. The bottle was fitted with a pressure head and evacuated and filled with argon ten times. To a dry 25-mL flask was added bis (1,5- cyclooctadiene) rhodium trifluoromethanesulfonate (1.2 mg; 0.0025 mmol ; 0.0001 equiv) and ligand (R, S)-1b (1.7 mg, 0.0028 mmol ; 0.00011 equiv) which had been open to the air at ambient temperature for more than seven months. The flask was purged with argon and 2 mL of argon-degassed THF was added to afford a homogeneous solution. This was allowed to stand for 15 min and then added via a gas-tight syringe to the Fisher-Porter bottle containing the methanolic solution of 10a. The bottle was evacuated and filled with argon ten times, and then evacuated and filled with hydrogen 5 times. The bottle was pressurized with 45 psig hydrogen, sealed, and stirred vigorously at ambient temperature. Hydrogen uptake was immediate and rapid, and was essentially complete after 70 minutes. The reaction mixture was evacuated and filled with argon five times and then depressurized. The reaction mixture was sampled and analyzed by chiral GC to indicate 96.3% conversion to S-11a with 96. 8% ee. The reaction mixture was evaporated to afford 5.27 g (95%) of product. See Example 8 for analytical details.

Example 44 Hydrogenation of enamide 12 to produce ester 13 using ligand (R, S)-1b A Fischer-Porter tube was charged with ligand (R, S)-1 b (22 mg, 0.036 mmol ; 0.064 equivalents) and anhydrous THF (4.0 mL) under an argon atmosphere. Argon was bubbled through the solution for 20 minutes before the addition of bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfo- nate (12 mg; 0.026 mmol ; 0.047 equivalents). The solution was stirred at 25°C for 5 minutes or until all of the bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate had dissolved. Enamide 12 (100 mg, 0.55 mmol) was added via syringe. The vessel was capped and pressurized to 2.75 barg (40 psig; 275 kPa) hydrogen. After 18 hours, the mixture was diluted with hexane (4.0 mL) and filtered through silica gel to remove the catalyst.

The product 13 was isolated as an oil (99% yield, 96.2% ee as determined by chiral GC).

1H NMR (CDC13) 6 4.71-4.65 (m, 1H) ; 3.71 (s, 3H); 3.55-3.47 (m, 1H) ; 3.38- 3.30 (m, 1H) ; 2.45-2.40 (t, 2H, J = 8.4 Hz); 2.12-1.97 (m, 3H); 1.74-1.64 (m, 1 H) ; 0.94-0.89 (t, 3H, J = 7.5 Hz). Chiral GC [Cyclosil-B (J&W Scientific), 40°C for 4 min, 40°C to 175°C at 70°C/min, hold at 175°C for 12 minutes]: tR = 23. 19 (major enantiomer), tR = 23.24 (minor enantiomer).

Example 45 Hydrogenation of enamide 12 to produce ester 13 using ligand (S, R)-2a This hydrogenation was carried out as in the previous example except that ligand (S, R)-2a was used instead of (R, S)-1b. This afforded the product 13 in 90.8% ee.

Example 46 Hydrogenation of enamide 12 to produce ester 13 using ligand (R, S)-1b via High Pressure Hydrogenation in THF Enamide 12 was hydrogenated according to General Procedure B in THF as solvent using bis (1,5-cyclooctadiene) rhodium trifluoromethane- sulfonate (2.3 mg; 511mol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limol ; 0.012 equiv) for 6 hours to afford 94.9% conversion to amino acid derivative 13 with 92.8% ee as determined by chiral GC analysis.

14 15 Example 47 Dimethyl Methylsuccinate (15a, R15=H, R16 = R'7 = Me) using Ligand (R, S)-1a in THF at Low Pressure : Dimethyl itaconate (14a, R"'= H, R16 = R17 = Me) was hydrogenated according to General Procedure A in THF at 0.69-1.38 bars gauge (10-20 psig; 69 to 138 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1a (3.6 mg; 6, mol ; 0.012 equiv) for 6 hours to

afford 95% conversion to dimethyl methylsuccinate (15a, R15 = H, R16 = R17 = Me) with 80.2% ee as determined by chiral GC analysis. The analytical properties of 15a were identical to an authentic sample.

Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 cm, 90°C isothermal, 15 psig He]: tR (enantiomer 1,15a) 17.36 min, tR (enantiomer 2,15a) 17.82 min, tR (14a) 23.16 min.

Example 48 Dimethyl Methylsuccinate (15a, R15 = H, R16 = R17 = Me) using Ligand (R, S)-1a in Acetone at High Pressure : Dimethyl itaconate (14a, R15 = H, R16 = R17 = Me) was hydrogenated according to General Procedure B in acetone at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 gmol ; 0.01 equiv) and ligand (R, S)-1a (3.6 mg; 6 mol ; 0.012 equiv) for 6 hours to afford 100% conversion to dimethyl methylsuccinate (15a, R15 = H, R16 = R17 = Me) with 89.1% ee as determined by chiral GC analysis.

16 17 Example 49 Methyl Lactate (17a, R18 = H, R'9 = Me) using Ligand (R, S)-1b in THF at Low Pressure : Methyl pyruvate (16a, R18 = H, R19 = methyl) was hydrogenated according to General Procedure A in THF at 0.69-1.38 bars gauge (10-20 psig; 69 to 138 kPa) hydrogen at ambient temperature using

bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1 b (3.7 mg; 6 limon ; 0.012 equiv) for 8 hours to afford 90.2% conversion to methyl R-lactate (R-17a, R'8 = H, R19 = methyl) with 88.2% ee as determined by chiral GC analysis. The analytical properties of 17a were identical to an authentic sample.

Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 pm, 75°C isothermal, 15 psig He]: tR (R-17a) 7.75 min, tR (S-17a) 9.16 min, tR (16a) 5.16 min.

Example 50 Methyl Lactate (17a, R18 = H, R19 = Me) using Ligand (R, S)-1b in THF at High Pressure : Methyl pyruvate (16a, R'8 = H, R19 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 j. moi ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 limol ; 0.012 equiv) for 8 hours to afford 98.3% conversion to methyl R-lactate (R-17a, R18 = H, R19 = methyl) with 86.8% ee as determined by chiral GC analysis.

Example 51 Methyl Lactate (17a, R18 = H, R'9 = Me) using Ligand (R, S)-1b in Toluene at High Pressure : Methyl pyruvate (16a, R'8 = H, R19 = methyl) was hydrogenated according to General Procedure B in toluene at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 umol ; 0.012 equiv) for 6 hours to

afford >95% conversion to methyl R-lactate (R-17a, R18 = H, R19 = methyl) with 83. 2% ee as determined by chiral GC analysis.

Example 52 Methyl Lactate (17a, R'8 = H, R'9 = Me) using Ligand (RS)-ld in THF at Low Pressure : Methyl pyruvate (16a, R 17 = H, R18 = methyl) was hydrogenated at ambient temperature according to General Procedure A in THF at 0.69-1.38 bars gauge (10-20 psig; 69 to 138 kPa) hydrogen using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Fmol ; 0.01 equiv) and ligand (R, S)-1d (3.8 mg; 6 limon ; 0.012 equiv) for 1 hour to afford 21. 1% conversion to methyl R-lactate (R-17a, R18 = H, R'9 = methyl) with 87.4% ee as determined by chiral GC analysis.

Example 53 Methyl Lactate (17a, R'8 = H, R'9 = Me) using Ligand (R, S)-1d in THF at High Pressure : Methyl pyruvate (16a, R18 = H, R19 = methyl) was hydrogenated at ambient temperature according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5, mol ; 0.01 equiv) and ligand (R, S)-1d (3.8 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 98.8% conversion to methyl R-lactate (R-17a, R'8 = H, R19 = methyl) with 83.8% ee as determined by chiral GC analysis.

Example 54 Methyl Lactate (17a, R18 = H, R19 = Me) using Ligand (S, R)-2e in THF at Low Pressure : Methyl pyruvate (16a, R18 = H, R19 = methyl) was hydrogenated at ambient temperature according to General Procedure A in THF at 0.69-1.38 bars gauge (10-20 psig; 69 to 138 kPa) hydrogen using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limon ; 0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6 µmol ; 0.012 equiv) for 1 hour to afford 67% conversion to methyl S-lactate (S-17a, R18 = H, R19 = methyl) with 91.7% ee as determined by chiral GC analysis.

Example 55 Methyl Lactafe (17a, R18 = H, R19 = Me) using Ligand (S, R)-2e in THF at HighPressure : Methyl pyruvate (16a, R'8 = H, R19 = methyl) was hydrogenated at ambient temperature according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6 jj. moi ; 0.012 equiv) for 6 hours to afford 98.7% conversion to methyl S-lactate (S-17a, R18 = H, R19 = methyl) with 88.6% ee as determined by chiral GC analysis.

Example 56 Methyl Lactate (17a, R18 = H, R19 = Me) using Ligand (R, S)-1f in THF at High Pressure : Methyl pyruvate (16a, R18 = H, R'9 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium

trifluoromethanesulfonate (2.3 mg; 5 limol ; 0.01 equiv) and ligand (R, S)-1f (3.3 mg; 6 pmol ; 0.012 equiv) for 6 hours to afford 99.6% conversion to methyl R-lactate (R-17a, R18 = H, R19 = methyl) with 88.6% ee as determined by chiral GC analysis.

Example 57 Methyl Lactate (17a, R18 = H, R'9 = Me) using Ligand (R, S)-1g in THF at Low Pressure : Methyl pyruvate (16a, R18 = H, R19 = methyl) was hydrogenated according to General Procedure A in THF at 0.69-1.38 bars gauge (10-20 psig; 69 to 138 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 511mol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 Fmol ; 0.012 equiv) for 17 hours to afford 99% conversion to methyl R-lactate (R-17a, R'8 = H, R19 = methyl) with 90.8% ee as determined by chiral GC analysis.

Example 58 Methyl Lactate (17a, R18 = H, R19 = Me) using Ligand (R, S)-1g in THF at High Pressure : Methyl pyruvate (16a, R18 = H, R19 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 100% conversion to methyl R-lactate (R-17a, R18 = H, R19 = methyl) with 88.1% ee as determined by chiral GC analysis.

Example 59 Ethyl Lactate (17b, R18 = H, R'9 = ethyl) using Ligand (R, S)-1b in THF at High Pressure : Ethyl pyruvate (16b, R18 = H, R"= ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 98.6% conversion to ethyl R-lactate (R-17b, R18 = H, R'9 = ethyl) with 83.4% ee as determined by chiral GC analysis. The analytical properties of 17b were identical to an authentic sample.

Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 wm, 75°C isothermal, 14 psig He]: tR (R-17b) 11.40 min, tR (S-17b) 13.24 min, tR (16b) 7.73 min.

Example 60 Ethyl Lactate (17b, R18 = H, R19 = ethyl) using Ligand (R, S)-ld in'THF at High Pressure : Ethyl pyruvate (16b, R18 = H, R"= ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limol ; 0.01 equiv) and ligand (R, S)-1d (3.8 mg; 6 pmol ; 0.012 equiv) for 6 hours to afford 99.8% conversion to ethyl R-lactate (R-17b, R18 = H, R"= ethyl) with 87.8% ee as determined by chiral GC analysis.

Example 61 Ethyl Lactate (17b, R18 = H, R'9 = ethyl) using Ligand (S, R)-2e in THF at High Pressure : Ethyl pyruvate (16b, R18 = H, R'9 = ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6 limol ; 0.012 equiv) for 6 hours to afford 99.9% conversion to ethyl S-lactate (S-17b, R18 = H, R19 = ethyl) with 89.8% ee as determined by chiral GC analysis.

Example 62 Ethyl Lactate (17b, R18 = H, R'9 = ethyl) using Ligand (R, S)-1f in THF at High Pressure : Ethyl Pyruvate (16b, R17 = H, R"'= ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 umol ; 0.01 equiv) and ligand (R, S)-1f (3.3 mg; 6 limon ; 0.012 equiv) for 6 hours to afford 99.9% conversion to ethyl R-lactate (R-17b, R18 = H, R'9 = ethyl) with 89.8% ee as determined by chiral GC analysis.

Example 63 Ethyl Lactate (17b, R'8 = H, R'9 = ethyl) using Ligand (R, S)-1g in THF at HighPressure : Ethyl pyruvate (16b, R18 = H, R19 = ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium

trifluoromethanesulfonate (2.3 mg; 5 umol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 99.9% conversion to ethyl R-lactate (R-17b, R18 = H, R19 = ethyl) with 90.8% ee as determined by chiral GC analysis.

Example 64 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R18 = PhCH2, R19 = ethyl) using Ligand (R, S)-1b in THF at High Pressure : Ethyl 2-oxo-4-phenylbutyrate (16c, R18 = PhCH2, R19 = Et) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 umol ; 0.01 equiv) and ligand (R, S)-1b (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 97.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate (R-17c, R18 = PhCH2, R'9 = ethyl) with 85.2% ee as determined by chiral GC analysis.

1H NMR (CDC13) 8 7.4-7.1 (m, 5H); 4.213 (q, 1H, J = 7.14 Hz); 4.15 (m, 1H) ; 2.77 (m, 2H); 2.12 (m, 1H) ; 1.96 (m, 1H) ; 1.286 (t, 3H, J = 7.14 Hz). Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 cm, 150°C isothermal, 18 psig He]: tR (R-17c) 26.49 min, tR (S-17c) 27.09 min, tR (16c) 23.98 min.

Example 65 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R18 = PhCH2, R19 = ethyl) using Ligand (R,S)-1c in THF at High Pressure: Ethyl 2-oxo-4-phenylbutyrate (16c, R18 = PhCH2, R19 = ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 jumbo) ; 0.01 equiv) and ligand (R, S)-1c (3.8 mg; 6 umol ; 0.012 equiv) for 6 hours to

afford 50.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate (R-17c, R18 = PhCH2, R19 = ethyl) with 85.8% ee as determined by chiral GC analysis.

Example 66 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R18 = PhCH2, R19 = ethyl) using Ligand (R, S)-1d in THF at High Pressure : Ethyl 2-oxo-4-phenylbutyrate (16c, R'8 = PhCH2, R19 = Et) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1d (3.8 mg; 6 pmol ; 0.012 equiv) for 6 hours to afford 98.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate (R-17c, R18 = PhCH2, R19 = ethyl) with 88.6% ee as determined by chiral GC analysis.

Example 67 Efhyl 2-Hydroxy-4-phenylbutyrate (17c, R18 = PhCH2, R19 = ethyl) using Ligand (S, R)-2e in THF at High Pressure : Ethyl 2-oxo-4-phenylbutyrate (16c, R18 = PhCH2, R"= ethyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6 Rmol ; 0.012 equiv) for 6 hours to afford 97.2% conversion to ethyl S-2-hydroxy-4-phenylbutyrate (S-17c, R18 = PhCH2, R19 = ethyl) with 89.0% ee as determined by chiral GC analysis.

Example 68 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R'8 = PhCH2, R'9 = ethyl) using Ligand (R, S)-1g in THF at Low Pressure : Ethyl 2-oxo-4-phenylbutyrate (16c, R = PhCH2, R19 = ethyl) was hydrogenated according to General Procedure A in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5, mol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 gmol ; 0.012 equiv) for 24 hours to afford 65% conversion to ethyl R-2-hydroxy-4-phenylbutyrate (R-17c, R18 = PhCH2, R19 = ethyl) with 80.2% ee as determined by chiral GC analysis.

Example 69 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R18 = PhCH2, R19 = ethyl) using Ligand (R, S)-1g in THF at High Pressure : Ethyl 2-oxo-4-phenylbutyrate (16c, R18 = PhCH2, R19 = Et) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 gmol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 limon ; 0.012 equiv) for 6 hours to afford 96.6% conversion to ethyl R-2-hydroxy-4-phenylbutyrate (R-17c, R18 = PhCH2, R19 = ethyl) with 92.4% ee as determined by chiral GC analysis.

Example 70 Methyl 2-Hydroxy-3-phenylpropionate (17d, R'8 = Ph, R19 = methyl) using Ligand (S, R)-2e in THF at High Pressure : Methyl 2-oxo-3-phenylpropionate (16d, R18 = Ph, R19 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5, umol ;

0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6, mol ; 0.012 equiv) for 6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R'8 = Ph, R19 = methyl) with 83.2% ee as determined by chiral GC analysis.

H NMR (DMSO-d6) 6 7.3-7.1 (m, 5H); 5.547 (d, 1H, J = 6.04 Hz); 4.22 (m, 1H) ; 3.584 (s, 3H); 2.923 (dd, 1H, J = 5.22,13.74 Hz); 2.289 (dd, 1H, J = 8.24,13.74 Hz). Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 sam, 140°C isothermal, 18 psig He]: tR (enantiomer 1, 17d) 19.62 min, tR (enantiomer 2, 17d) 21.54 min, tR (16d) 18.54 min.

Example 71 Methyl 2-Hydroxy-3-phenylpropionate (17d, R18 = Ph, R19 = methyl) using Ligand (R,S)-1f in THF at High Pressure: Methyl 2-oxo-3-phenylpropionate (16d, R1° = Ph, R'9 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 µmol ; 0.01 equiv) and ligand (R, S)-1f (3.3 mg; 6, mol ; 0.012 equiv) for 6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R = Ph, R19 = methyl) with 86.0% ee as determined by chiral GC analysis.

Example 72 Methyl 2-Hydroxy-3-phenylpropionate (17d, R18 = Ph, R19 = methyl) using Ligand (R, S)-1g in THF at High Pressure : Methyl 2-oxo-3-phenylpropionate (16d, R = Ph, R19 = methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cycloocta- diene) rhodium trifluoromethanesulfonate (2.3 mg; 5 Fmol ; 0.01 equiv) and ligand (R, S)-1g (3.7 mg; 6 µmol ; 0.012 equiv) for 6 hours to afford 30% conversion to methyl 2-hydroxy-3-phenylpropionate (17d, R = Ph, R19 = methyl) with 85.4% ee as determined by chiral GC analysis.

Example 73 2-Hydroxy-3,3-dimethyl-butyrolactone (19) using Ligand (S, R)-2e in THF at High Pressure : 2-Oxo-3, 3-dimethyl-y-butyrolactone (18) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 limon ; 0.01 equiv) and ligand (S, R)-2e (3.1 mg; 6, mol ; 0.012 equiv) for 6 hours to afford 99.0% conversion to 2- hydroxy-3,3-dimethyl-y-butyrolactone (19) with 95.0% ee as determined by chiral GC analysis.

1H NMR (CDCl3) # 4. 114 (s, 1H) ; 4.023 (d, 1 H, J = 8.52 Hz); 3.936 (d, 1H, J = 8.52 Hz); 1.223 (s, 3H); 1.071 (s, 3H). Chiral GC [Cyclosil-B (J&W Scientific) 30 m x 0.25 mm ID, film thickness 0.25 s1m, 140°C isothermal, 14 psig He]: tR (enantiomer 1,19) 11.18 min, tR (enantiomer2, 19) 11.66 min, tR (18) 7.99 min.

Example 74 <BR> <BR> <BR> <BR> 2-Hydroxy-3, 3-dimethyl-butyrolactone (19) usingLigand (S, R)-2fin THF at High Pressure : 2-Oxo-3, 3-dimethyl-y-butyrolactone (18) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 zmol ; 0.01 equiv) and ligand (S, R)-2f (3.3 mg; 6 zmol ; 0.012 equiv) for 6 hours to afford 99.6% conversion to 2- hydroxy-3,3-dimethyl-y-butyrolactone (19) with 96.6% ee as determined by chiral GC analysis.

Example 75 <BR> <BR> <BR> <BR> 2-Hydroxy-3, 3-dimethyl-butyrolactone (19) using Ligand (S, R)-2g in THF : 2-Oxo-3, 3-dimethyl-y-butyrolactone (18) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig; 2070 kPa) hydrogen at ambient temperature using bis (1,5-cyclooctadiene) rhodium trifluoromethanesulfonate (2.3 mg; 5 pmol ; 0.01 equiv) and ligand (S, R)-2g (3.7 mg; 6 pmol ; 0.012 equiv) for 6 hours to afford 99.6% conversion to 2- hydroxy-3,3-dimethyl-y-butyrolactone (19) with 97.2% ee as determined by chiral GC analysis.