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

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.

Key words:

[3+2] cycloaddition - cyclopentene - ring expansion - cyclohexenone - HIV protease inhibitor

References

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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:[phone]; e-mail: [e-mail])

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.