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Synfacts 2014; 10(9): 0897
DOI: 10.1055/s-0034-1378568
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Saxagliptin Fragment

Contributor(s):
Philip Kocienski
Ramirez A, * Truc VC. * et al. Bristol-Myers Squibb Company, New Brunswick, USA
The Effect of Additives on the Zinc Carbenoid-Mediated Cyclopropanation of a Dihydropyrrole.

J. Org. Chem. 2014;
79: 6233-6243
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Publication History

Publication Date:
18 August 2014 (online)

 
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Key words

saxagliptin - dipeptidyl peptidase-4 inhibitor - cyclopropanation - dihydropyrroles - zinc carbenoids

Significance

The target 4,5-methanoproline G is a fragment of the dipeptidyl peptidase-4 inhibitor saxagliptin that is prescribed for the treatment of diabetes. A detailed investigation of the substrate-directed zinc carbenoid mediated cyclopropanation of dihydropyrrole F based on stoichiometry, kinetics, NMR spectroscopy, IR spectroscopy, DFT studies and the role of additives enabled the definition of a scalable, reproducible, highly dia­stereoselective process as summarized in the scheme.


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Comment

The synthesis of C from (S)-(–)-pyroglutamic acid derivative A was described by J. Yu et al. Tetrahedron Lett. 2005, 46, 4011. For the conversion of G into saxagliptin, see: S. A. Savage et al. Org. Process Res. Dev. 2009, 13, 1169. A key finding is that substoichiometric amounts of water and trifluoroacetic acid accelerate the cyclopropanation. The water generates ZnO by reaction with Et2Zn and the trifluoroacetic acid generates the zinc amidate species J.


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