Chiral Phosphine Ligands for Asymmetric Hydrogenation

In homogeneous catalysis, phosphines are particularly important ligands in late-transition metal-catalyzed processes such as hydrosilylation, hydroformylation, carbonylation, olefin dimerization, and, last but not least, hydrogenation reactions [88]. For example, industrially important hydrogenations are involved in the synthesis of L-dopa (Monsanto) and Merck's novel HIV protease inhibitor, indinavir, marketed currently as Crixivan® [89].

Phosphine-containing amino acids were originally synthesized to effect con-formational states of peptides and to stabilize and control peptide structures upon metal binding [90]. Their application in catalytic asymmetric hydrogenation was reported in 1996 by Gilbertson and Wang [91]. Geysen's polyethylene pin technique was used to synthesize a 63-member library of peptidomimetic ligands for the Rh(I)-catalyzed hydrogenation of methyl 2-acetamidoacrylate to the corresponding amino acid derivative N-acetyl alanine. The general primary structure of the ligands, best described as Ac-Ala-Aib-Ala-[P-containing, internal peptide]-Ala-Aib-Ala-NH2, shared terminal Ala-Aib-Ala sequences to force an overall a-helical secondary structure and to bring the phosphine groups of the internal peptide sequence into close proximity with each other (Scheme 32.13). For the internal sequence, three classes of structurally unique chiral tetra- or pentapeptides were synthesized by combining the novel amino acids dicyclohexyl- and diphenylphosphane serine (Cps and Pps respectively) with two or three hydrophobic amino acids. Each ligand was screened directly on-bead in a parallel 24-vial reactor that was coupled to a gas chromatograph (GC) equipped with a chiral stationary phase to determine enantiose-lectivity and overall conversion. Unfortunately, only modest enantiomeric excesses up to 18% were observed, but some trends and correlation between peptide sequence and selectivity were established. In a more recent publication, the same group synthesized larger libraries, giving access to ligands that were used for the catalytic asymmetric hydrogenation of methyl-2-acetamidoacrylate in the presence of rhodium. Enantiomeric excesses up to 38% were obtained [92].

Phosphane Containing Amino Acids

Phosphane Containing Amino Acids

i and /'+4 position of peptide helix NHAc

Scheme 32.13. Screening of a library of support-bound a-helical peptide/phosphine-Rh(I) catalysts in enantio-selective hydrogenation reactions of prochiral methyl-2-acetamidoacrylate to N-acetyl alanine methyl ester.

i and /'+4 position of peptide helix NHAc

Scheme 32.13. Screening of a library of support-bound a-helical peptide/phosphine-Rh(I) catalysts in enantio-selective hydrogenation reactions of prochiral methyl-2-acetamidoacrylate to N-acetyl alanine methyl ester.

Was this article helpful?

0 0

Post a comment