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Synfacts 2010(11): 1211-1211  
DOI: 10.1055/s-0030-1258708
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of GSK966587

Contributor(s):Philip Kocienski
E. A. Voight*, H. Yin, S. V. Downing, S. A. Calad, H. Matsuhashi, I. Giordano, A. J. Hennessy, R. M. Goodman, J. L. Wood
GlaxoSmithKline, King of Prussia, USA; GlaxoSmithKline, Stevenage, UK
Target-Directed Synthesis of Antibacterial Drug Candidate GSK966587
Org. Lett.  2010,  12:  3422-3425  
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Publication History

Publication Date:
21 October 2010 (online)

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Key words

GSK966587 - Heck reaction - Negishi cross-coupling - directed ortho-metalation - zincate

Significance

The eight-step synthesis of antibacterial agent GSK966587 (25% overall yield) ­required no protecting groups and involved only three isolated intermediates (C, G and J). Key steps were a Mizoroki-Heck reaction, a Negishi coupling, a directed ortho-metalation, and a Sharpless-Katsuki asymmetric epoxidation.

Comment

The directed ortho-metalation of naphthyridine D was strongly base-dependent. Problems included dianion formation, competing metalation at C6 as well as nucleophilic sub­stitution of the fluorine atom. However, when (i-Pr)2NZnEt2Li was used as base, there was no dianion formation and only 4% metalation at C6 was observed.

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