(608c) Deracemization of Racemic Amines to Create (S)-Amines By Amine Dehydrogenases

Authors: 
Au, S., University of Kentucky
Bommarius, B., Georgia Institute of Technology
Bommarius, A. S., Georgia Institute of Technology

Enantiomerically pure amines are used as precursors for many pharmaceutical drugs, with 40% of the 200 most prescribed brand name drugs in the US containing a chiral amine [1]. Enantiomerically pure amines often require difficult syntheses, as heterogeneous catalysts often feature imperfect selectivity, and less environmentally friendly solvents. This work will focus on the use of biocatalysts, specifically the amine dehydrogenases (AmDHs) [2], as a green alternative to catalyze prochiral ketones to chiral amines. This reaction was one of the top aspirational reactions voted by the ACS Green Chemistry Institute in 2007 [3].

The AmDHs exhibits excellent (R)-enantioselectivity (>99% ee) and can also catalyze the reversible reaction. These characteristics make the amine dehydrogenase an ideal candidate for enzymatic deracemization toward enzymatically pure pharmaceutical intermediates. For proof of concept, we had previously demonstrated the deracemization of racemic methylbenzylamine (MBA) to produce (S)-MBA. Our current pharmaceutically relevant substrates of the AmDH have now been expanded to include the following amines: 1-indanamine, 1-tetrahydronaphthylamine, 2-octylamine and 4-methoxyisopropylamine. This presentation will cover the enantiomeric purity of these products, conversion and reaction parameters. Furthermore, large-scale conversion of these products will be discussed.

[1] Mack DJ, Weinrich ML, Vitaku E, Njarðarson JT. Top 200 Brand Name Drugs by US Retail Sales in 2010

[2] Abrahamson, M. J.; Vazquez-Figueroa, E.; Woodall, N. B.; Moore, J. C.; Bommarius, A. S., Development of an Amine Dehydrogenase for Synthesis of Chiral Amines. Angew Chem Int Edit 2012, 51 (16), 3969-3972; Abrahamson, M. J.; Wong, J. W.; Bommarius, A. S., The Evolution of an Amine Dehydrogenase Biocatalyst for the Asymmetric Production of Chiral Amines. Adv Synth Catal 2013, 355 (9), 1780-1786; Bommarius, B. R.; Schurmann, M.; Bommarius, A. S., A novel chimeric amine dehydrogenase shows altered substrate specificity compared to its parent enzymes. Chem Commun 2014, 50 (95), 14953-14955.

[3] Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y., Key green chemistry research areas - a perspective from pharmaceutical manufacturers. Green Chemistry 2007, 9 (5), 411-420.