Synlett 2004(4): 684-687  
DOI: 10.1055/s-2004-815439
LETTER
© Georg Thieme Verlag Stuttgart · New York

HIV Protease Inhibitors Part 2: [3+2] Cycloaddition, Isomerization; and Ring Expansion en route to 4,5-Substituted Cyclohexenones

Emmanuel Demont*, Andrew Eatherton, Christopher S. Frampton, Irfan Kahn, Sally Redshaw
Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK
Fax: 44(1438)782088; e-Mail: emmanuel.h.demont@gsk.com;
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Publikationsverlauf

Received 12 January 2004
Publikationsdatum:
29. Januar 2004 (online)

Abstract

4,5-Substituted cyclohexanone 10 and its derivatives are carbocyclic analogues of Indinavir 3 and are expected to have antiviral activity. Early attempts to obtain these compounds via a dia­stereoselective [3+2] cycloaddition between 19 and 14 failed due to the sensitivity of the cycloadduct 24. It proved possible to obtain 30 from the α,β-unsaturated ester 27: [3+2] cycloaddition, isomerization, and ring expansion provided α,β-unsaturated ketone 31 from ester 26 in good yields. Further transformations of 31 gave the ­hydroxyethylamino inhibitor analogues of Indinavir 3.

1

Present address: GlaxoSmithKline. The Frythe, Welwyn, AL6 9AR Hertfordshire, UK.

16

CCDC No. 217035 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC 12 Union Road Cambridge CB2 1EZ UK; fax:+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk)

21

The reaction of 14 with oxazolidinone 4 was non-selective. Adduct 28 was obtained as a 1:1 mixture of trans-isomers.

22

The direct reduction of allylic sulfone 28 gave a mixture of alkenes.