Unnatural amino acids (UAAs) are growing in importance as pharmaceutical intermediates, with applications in a number of current and future drugs. Since UAAs are most always required as pure stereoisomers, a chiral synthesis is preferred over the resolution methods that are most commonly employed. In this proposal a one-pot deracemization process will be developed to prepare pure stereoisomers of UAAs from the readily available and inexpensive racemic mixtures. Deracemization will be accomplished by selectively oxidizing the D-amino acid in a D,L-mixture to the corresponding 2-ketoacid, using D-amino acid oxidase, and converting the 2-ketoacid to the L-amino acid using a stereoselective enzyme-catalyzed reaction. Yields are expected to approach 100 percent, affording almost complete conversion of the racemic starting materials to the optically-pure L-UAA. Importantly, the method coverts the racemic amino acid directly to L-form in a single reaction step without the need for protecting groups or derivitization. Further, this method has broad scope, and will be applicable to a wide range of UAA products. Two alternative coupled enzymatic systems will be studied, and the results compared to select the biocatalytic method. The method will be demonstrated by producing gram quantities of four current commercial targets.
Intermediates for the production of pharmaceuticals spanning a wide mage of therapeutic indications.
| Lepesheva, Galina I; Hargrove, Tatiana Y; Rachakonda, Girish et al. (2015) VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis. J Infect Dis 212:1439-48 |
