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Highly Enantioselective Synthesis of Glycidic Amides Using Camphor-Derived Sulfonium Salts. Mechanism and Applications in Synthesis

Supporting Info

Varinder K. Aggarwal,*^† Jonathan P. H. Charmant,^‡ Daniel Fuentes,^† Jeremy N. Harvey,^† George Hynd,^† Diasuke Ohara,^† Willy Picoul,^† Raphaël Robiette,^† Catherine Smith,^† Jean-Luc Vasse,^† and Caroline L. Winn^†

Contribution from the School of Chemistry and Structural Chemistry Laboratory, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K.

J. Am. Chem. Soc., 2006, 128 (6), pp 2105–2114

DOI: 10.1021/ja0568345

Publication Date (Web): January 25, 2006

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

†

School of Chemistry.

‡

Structural Chemistry Laboratory, School of Chemistry.

, v.aggarwal@bristol.ac.uk

Abstract

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.

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