Preparative deracemization of unnatural amino acids.

Unnatural amino acids are a growing class of intermediates required for pharmaceuticals, agrochemicals and other industrial products. However, no single method has proven sufficiently versatile to prepare these compounds broadly at scale. To address this need, we have developed a general chemoenzymatic process to prepare enantiomerically pure L- and D-amino acids in high yield by deracemization of racemic starting materials. This method involves the concerted action of an enantioselective oxidase biocatalyst and a non-selective chemical reducing agent to effect the stereoinversion of one enantiomer and can result in an enantiomeric excess of >99% from the starting racemate, and product yields of over 90%. This approach compares very favourably with resolution processes, which have a maximum single-pass yield of 50%. We have developed efficient methods to adapt the process towards new target compounds and to optimize key factors that influence process efficiency and offer competitive economics at scale.

[1]  Sven Panke,et al.  Trends and innovations in industrial biocatalysis for the production of fine chemicals. , 2004, Current opinion in biotechnology.

[2]  N. Turner,et al.  Deracemisation and stereoinversion of alpha-amino acids using D-amino acid oxidase and hydride reducing agents. , 2002, Chemical communications.

[3]  N. Turner,et al.  Amine–boranes: effective reducing agents for the deracemisation of dl-amino acids using l-amino acid oxidase from Proteus myxofaciens , 2002 .

[4]  Ramesh N. Patel,et al.  Biocatalytic synthesis of intermediates for the synthesis of chiral drug substances. , 2001, Current opinion in biotechnology.

[5]  Stephen Stinson,et al.  CHIRAL PHARMACEUTICALS: Drug firms continue to develop chiral drugs as single enantiomers, to carry out racemic switches, and to use chirality to manage drug life cycles , 2001 .

[6]  Mauro F. A. Adamo,et al.  Epoxidation of Alkenes by Amine Catalyst Precursors: Implication of Aminium Ion and Radical Cation Intermediates , 2000 .

[7]  W. Kerr,et al.  Enantioselective deprotonation reactions using a novel homochiral magnesium amide base , 2000 .

[8]  K. Soda,et al.  Synthesis of l-proline from the racemate by coupling of enzymatic enantiospecific oxidation and chemical non-enantiospecific reducation , 1992 .

[9]  E. W. Hafner,et al.  Demonstration of imino acids as products of the reactions catalyzed by D- and L-amino acid oxidases. , 1971, Proceedings of the National Academy of Sciences of the United States of America.