Chiral amines are an important class of pharmaceutical intermediates. In Phase 1 we propose to use directed evolution methods to create the first group of amine dehydrogenase enzymes evolved to catalyze the stereoselective reductive amination of ketones to the corresponding chiral amines. A patent-pending assay for use in high throughput screening has already been developed and validated for the detection of new amino acid dehydrogenase activities, and we will adapt this method to establish a high throughput screen for detecting new """"""""amine dehydrogenases."""""""" These new enzymes will then be characterized and evaluated for the production of chiral amines by the reductive amination of ketones. In contrast to resolution methods, the reductive amination process is a chiral synthesis, and up to 100 percent of the starting material can be converted into the enantiomerically pure product in a single step using readily available, inexpensive ketone starting materials. Success in Phase 1 will lay the foundation for an expanded development of amine dehydrogenases capable of catalyzing the production of a wide range of chiral amines in Phase 2.
Chiral amines produced using the technology developed have applications as key intermediates for the synthesis of a wide range of pharmaceutically active compounds.
