Statine and its analogs represent a key class of intermediates for drug spanning a wide range of indications. Presently, only two of these compounds, statine and phenylstatine, are commercially available, and of the four possible diastereomers, only the (3S,4S) and (3R,4S) forms are offered. Furthermore, current prices of more than $1000 per gram are so high that incorporation of these important intermediates into developmental drug candidates is inhibited. In this Phase 1 proposal we seek to establish a simple two-step chemo-enzymatic method for the synthesis of a library of statine analogues in all possible diastereomeric forms. In the first step, homologation of alpha-amino acids into the corresponding beta-keto statine analogues will be achieved using chemical methodology that has been well-established in our laboratory. Stereoselective reduction of the ketone using ketoreductase enzymes is the second step. Ten or more broad range ketoreductases that have been cloned, over-expressed, and produced in our laboratories will be screened for activity against at least ten different beta-keto statine analogues, and the feasibility of the method will be proven by producing at least three different statine analogs at the gram scale. This method, if successful, will make a wide range of statine analogues readily available at significantly lower cost.
