A Simple and Modular Strategy for Small Molecule Synthesis: Iterative Suzuki−Miyaura Coupling of B-Protected Haloboronic Acid Building Blocks

Eric P. Gillis and Martin D. Burke*
Department of Chemistry, University of Illinois at UrbanaChampaign, Urbana, Illinois 61801
J. Am. Chem. Soc., 2007, 129 (21), pp 6716–6717
DOI: 10.1021/ja0716204
Publication Date (Web): May 9, 2007
Copyright © 2007 American Chemical Society

Abstract

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We herein describe a simple and highly modular strategy for small molecule synthesis involving the iterative cross-coupling of B-protected bifunctional haloboronic acids. Enabling this approach, we have newly discovered that the pyramidalization of boronic acids via complexation with the trivalent ligand N-methyliminodiacetic acid inhibits their reactivity towards cross-coupling. This ligand is remarkably stable to anhydrous Suzuki−Miyaura conditions yet readily cleaved using mild aqueous base (1 M aqueous NaOH/THF, 10 min, 23 °C or saturated aqueous NaHCO3/MeOH, 23 °C, 6 h). Although the reactivity of aryl, heteroaryl, alkenyl, and alkyl boronic acids can vary dramatically, this methodology is effective for protecting and deprotecting all four classes of nucleophiles. Harnessing this potential, we achieved the first total synthesis of the natural product ratanhine using the Suzuki−Miyaura reaction iteratively to bring together a collection of easily synthesized, readily purified, and highly robust building blocks.

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History

  • Published In Issue May 30, 2007
  • Received March 7, 2007

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