Convergent Diastereoselective Synthesis of Isopilocarpine by One-Pot Michael-Addition-Alkylation Reaction

Abstract

The metalated dithiane 7b available from imidazole aldehyde 6 is reacted with furanone 4 and ethyl iodide to give the lactone 8, which forms diastereoselectively. Its configuration is determined to be trans by means of a crystal structure analysis. The desulfurization of 8 leads to the alkaloid isopilocarpine 2 in three steps and 25% overall yield. The relative energies of the diastereomeric alkaloids 1 and 2 have been calculated.

Key words

alkaloids - diastereoselectivity - drugs - lactones - metalations

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Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 249730. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: [phone] or e-mail: [e-mail]).