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Modular Total Synthesis of Archazolid A and B

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Dirk Menche*†‡, Jorma Hassfeld‡^§, Jun Li‡, Kerstin Mayer† and Sven Rudolph‡

^† Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg

^‡ Helmholtz-Zentrum für Infektionsforschung, Medizinische Chemie, Inhoffenstrasse 7, D-38124 Braunschweig, Germany

J. Org. Chem., 2009, 74 (19), pp 7220–7229

DOI: 10.1021/jo901565n

Publication Date (Web): September 9, 2009

*To whom correspondence should be addressed. Phone: +49 6221 546207. Fax: + +49 6221 544205., §

Present address: Bayer Schering Pharma AG, Berlin

Present address: Institut für Pharmazeutische Wissenschaften, ETH Zürich

Present address: MOLISA GmbH, Magdeburg.

Section:

Biomolecules and Their Synthetic Analogs

Abstract

A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still−Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko−Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.

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