Wednesday, August 13, 2008

Intermolecular Enolate Heterocoupling

ASAP J. Am. Chem. Soc., ASAP Article, 10.1021/ja804159y
Web Release Date: August 5, 2008
Michael P. DeMartino, Ke Chen, and Phil S. Baran

The direct, convergent synthesis of unsymmetrical 2,3-disubstituted-1,4-dicarbonyl compounds from two carbonyl subunits has proven extremely difficult, several methods for the synthesis of hypothetical succinate 1 are depicted in Figure 2.9,
Efficient, enantioselective syntheses of such entities have escaped synthetic grasp, in spite of their presence in countless natural products and innumerable medicinal remedies. All of the methods depicted suffer from one or more of the following limitations: multistep sequences, installation of requisite disposable functionality on one or both of the monomers, and stereoselectivity problems with prefunctionalization methods and/or during the union of the two monomers. No stereoselectivity was observed or necessary for the most efficient of these methods, the Stetter reaction, as the product was subjected to a pyrrole synthesis. This report is a full account of a research program initiated originally to eliminate the first two of these issues and having since evolved to address the third. By taking advantage of an underutilized and underappreciated reactivity of carbonyl enolates, the oxidative heterocoupling of two enolates joins two different sp3-hybridized carbon centers in a single step without requiring prefunctionalization of the corresponding monomers.

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