Synlett 2006(18): 3081-3087  
DOI: 10.1055/s-2006-951492
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Utility of the Classical and Oxidative Heck Reactions in Natural Product Synthesis: Studies Directed toward the Total Synthesis of Dragmacidin F

Neil K. Garg, Daniel D. Caspi, Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 164-30, Pasadena, CA 91125, USA
Fax: +1(626)5649297; e-Mail: stoltz@caltech.edu;
Further Information

Publication History

Received 20 April 2006
Publication Date:
25 October 2006 (online)

Abstract

The syntheses of complex pyrrole-fused [3.3.1] and [3.3.2] bicycles using classical and oxidative Heck cyclizations are described. While both [3.3.1] and [3.2.2] bicyclic products are formed in the classical Heck reaction, the oxidative Heck cyclization reaction furnishes solely the [3.3.1] bicycle. The [3.3.1] bicyclic product has been used as an intermediate to synthesize the complex marine alkaloid dragmacidin F.

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6

In the case of the oxidative Heck route, an alternative Wacker-type mechanism involving nucleophilic attack of a Pd-activated olefin by the pyrrole species cannot be ruled out. It should be noted that in two extensively studied systems for oxidative Heck cyclization, both were shown to involve initial palladation of the aromatic system followed by olefin insertion and β-hydrogen elimination, see ref. 7.

21

Reactions conducted in the presence of CH3COOD led to deuterium incorporation in the pyrrole ring of both the starting material (3) and the product (5), mostly at C(4).

23

The instability of the starting material and product to oxidation was confirmed by a series of control experiments where aliquots of reactions were carefully monitored by 1H NMR analysis with an internal standard. In the presence of oxidants, substantial non-specific decomposition readily took place.