Hallena Strotman

Development of an Immobilized Transaminase Capable of Operating in Organic Solvent

Considerable effort has been spent to develop efficient, catalytic methods for the preparation of enantiomerically pure chiral amines as pharmaceutical building blocks. Biocatalytic approaches have largely relied on kinetic resolution of racemic amines using lipases. In some instances, in situ racemization of the unreactive enantiomer has permitted dynamic kinetic resolutions to be performed. Racemic amines can also be deracemized using an amine oxidase combined with a nonselective reducing agent. The emergence of transaminases, which catalyze the direct amination of prochiral ketones, has provided an attractive alternative option for the synthesis chiral amines. Tufvesson et al. have published an excellent review of the process challenges encountered when using transaminases for the synthesis of chiral amines. We previously reported on the creation of an active and stable R-selective amine transaminase for the synthesis of sitagliptin by using a combination of modeling and directed evolution (Scheme 1). A limitation of the protocol in its current

A Highly Efficient Asymmetric Synthesis of Vernakalant

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

CCDC 1417569: Experimental Crystal Structure Determination

Related Article: John Y. L. Chung, Benjamin Marcune, Hallena R. Strotman, Rositza I. Petrova, Jeffrey C. Moore, Peter G. Dormer|2015|Org.Process Res.Dev.|19|1418|doi:10.1021/acs.oprd.5b00259