Synthesis 2011(12): 1936-1945  
DOI: 10.1055/s-0030-1260036
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Route to β-Silyl-δ-keto Esters by Organocatalyzed Regioselective Michael Addition of Methyl Ketones to a (Silylmethylene)malonate and Their Use in Natural Product Synthesis

Raghunath Chowdhury, Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre Trombay, Mumbai 400085, India
Fax: +91(22)25505151; e-Mail: ghsunil@barc.gov.in;
Further Information

Publication History

Received 28 February 2011
Publication Date:
11 May 2011 (online)

Abstract

The direct Michael addition of alkyl methyl ketones through the acetyl methyl terminal to diethyl {[dimethyl(phenyl)silyl]methylene}malonate was catalyzed by the (S)-N-(pyrrolidin-2-ylmethyl)pyrrolidine/trifluoroacetic acid combination with high yield and excellent regio- and enantioselectivity. The ketone adducts can easily undergo de-ethoxycarbonylation to give β-silyl-δ-keto esters with excellent synthetic potential. This has been demonstrated by the synthesis of a suitably substituted β-silyl-δ-keto ester as an advanced intermediate for a chiral hydroxylated pyrrolidine natural product, (+)-preussin. Silicon-controlled diastereoselective reduction of the ketone functionality of β-silyl-δ-keto esters followed by lactonization of the resulting hydroxy esters gave disubstituted δ-valerolactones. Advanced intermediates for the antipodes of natural products, namely (+)-massoialactone and (+)-mevinolin analogue, and natural products, namely (-)-tetrahydrolipstatin and (+)-5-hexadecanolide, have been achieved.

43

The absolute stereochemistry of addition products 14 and 15 was not determined.

47

The minor diastereomeric lactone was not isolated during chromatographic purification.