Chiral vicinal aminoalcohols are important intermediates in the synthesis of many important pharmaceutical compounds. However, their synthesis remains a significant synthetic challenge. Gaining control over the stereochemistry of chiral centers at carbons bearing both the alcohol and amino groups at reasonable cost is the key to the successful production of these important chemical intermediates. Currently, no broadly-applicable route exists for the production of chiral vicinal aminoalcohols in high yield and with high stereochemical purity. The proposed research will develop a general method for the production of chiral vicinal aminoalcohols that relies on a stereoselective alcohol dehydrogenase-catalyzed conversion to introduce two chiral centers in a single step, with high yield and stereoselectivity. In preliminary work with whole cells, it has been shown that multiple enzyme systems present give rise to competing reactions that lower stereochemical purity. The use of an isolated dehydrogenase offers the potential to produce any single diastereomer in high stereochemical purity. The economics of this method depend upon efficient cofactor recycling. In Phase 1 we plan to establish the feasibility of a reaction using a stereoselective alcohol dehydrogenase coupled with formate dehydrogenase for cofactor recycling, laying the foundation for the production a variety of chiral vicinal aminoalcohols.
Production of key intermediates for existing and new pharmaceutical products
