Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765.

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Tanoury GJ, Chen M, Dong Y, Forslund RE, Magdziak D

Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765.

Org Lett. 2008 Jan 17;10(2):185-8. Epub 2007 Dec 15.

PubMed ID
18081302 [ View in PubMed
]
Abstract

A novel Pd-catalyzed coupling of Cbz-protected proline amide with 4-bromo-5-ethoxyfuran-2(5H)-one was developed for the synthesis of the P1-P2 unit (5) of VX-765. The process afforded quantitative coupling in the presence of water, providing a 1:1 mixture of 5 and its ethoxy epimer epi-5. Compound 5 was isolated as a single diastereomer via fractional crystallization, which was stereoselectively converted to 17 via hydrogenation, and subsequently transformed to VX-765. Nine examples of the Pd coupling are presented with yields ranging from 76-98%.

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