Scope and Mechanism of Direct Indole and Pyrrole Couplings Adjacent to Carbonyl Compounds: Total Synthesis of Acremoauxin A and Oxazinin 3

J. Am. Chem. Soc., 129 (42), 12857 -12869, 2007. 10.1021/ja074392m S0002-7863(07)04392-2
Web Release Date: September 27, 2007

Scope and Mechanism of Direct Indole and Pyrrole Couplings Adjacent to Carbonyl Compounds: Total Synthesis of Acremoauxin A and Oxazinin 3

Jeremy M. Richter, Brandon W. Whitefield, Thomas J. Maimone, David W. Lin, M. Pilar Castroviejo, and Phil S. Baran*

Contribution from the Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037

pbaran@scripps.edu

Received June 16, 2007

Abstract:

Full details are provided for a recently invented method to couple indoles and pyrroles to carbonyl compounds. The reaction is ideally suited for structurally complex substrates and exhibits high levels of chemoselectivity (functional group tolerability), regioselectivity (coupling occurs exclusively at C-3 of indole or C-2 of pyrrole), stereoselectivity (substrate control), and practicality (amenable to scaleup). In addition, quaternary stereocenters are easily and predictably generated. The reaction has been applied to a number of synthetic problems including total syntheses of members of the hapalindole family of natural products, ketorolac, acremoauxin A, and oxazinin 3. Mechanistically, this coupling protocol appears to operate by a single electron-transfer process requiring generation of an electron-deficient radical adjacent to a carbonyl which is then intercepted by an indole or pyrrole anion.

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