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Issue 21, 2003
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Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (±)-3-methylcyclopentene-1-carboxylate

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Abstract

Conjugate addition of lithium dibenzylamide to tert-butyl (±)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic α,β-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (±)-3-methylcyclopentene-1-carboxylate and an excess of lithium (±)-N-benzyl-N-α-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (±)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-α-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3RS)-3-methyl-2-N-benzyl-N-α-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 ± 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in >98% de and 98 ± 1% ee. Selective epimerisation of tert-butyl (1R,2S,3RS)-3-methyl-2-N-benzyl-N-α-methylbenzylaminocyclopentane-1-carboxylate by treatment with KOtBu in tBuOH gives tert-butyl (1S,2S,3RS)-3-methyl-2-N-benzyl-N-α-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in >98% de and 97 ± 1% ee.

Graphical abstract: Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (±)-3-methylcyclopentene-1-carboxylate

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Publication details

The article was received on 17 Jun 2003, accepted on 18 Jul 2003 and first published on 11 Aug 2003


Article type: Paper
DOI: 10.1039/B306935B
Citation: Org. Biomol. Chem., 2003,1, 3698-3707
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    Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (±)-3-methylcyclopentene-1-carboxylate

    M. E. Bunnage, A. M. Chippindale, S. G. Davies, R. M. Parkin, A. D. Smith and J. M. Withey, Org. Biomol. Chem., 2003, 1, 3698
    DOI: 10.1039/B306935B

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