Non-naturally occurring amino acids, along with other chiral amine-containing compounds, are a rapidly growing class of pharmaceutical intermediates. Combinatorial synthesis strategies routinely employ libraries prepared from non-naturally occurring amino acids and amines, creating an immediate need for methods to prepare these compounds in research quantities. As drug candidates move through testing and clinical development, the amounts needed increase. This proposal focuses on the development of a transamination process for the production of non-naturally occurring amino acids. The process is a chiral synthesis, not a resolution, leading to efficient use of carbon and reduced waste. High chemical yields can be achieved from simple, inexpensive precursors. A method for driving the reaction to completion will be demonstrated on four target non-naturally occurring amino acids having immediate commercial applications. The attractive features of the method are its applicability to a broad range amino acids and amines and the high degree of stereochemical purity that can be obtained. In addition to non-naturally occurring amino acids, the technology will be applied and evaluated for the production of beta-amino acids, gamma amino acids, and chiral amines, both in aqueous and non-aqueous media. Finally, the stereoselective production of optically pure N-15 labeled amino acids will be demonstrated.
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