Conformationally restricted peptides can be used for asymmetric catalysis. We previously reported helical octapeptide-catalyzed asymmetric Michael addition reactions of nitroalkanes to α,β-unsaturated ketones. We applied the peptide catalyst for an asymmetric Michael addition reactions of malonates to α,β-unsaturated ketones and Michael adducts were converted to 2,4,5-trisubstituted tetrahydropyrans in three steps. First, asymmetric Michael addition reactions of dimethyl malonate to various α,β-unsaturated ketones catalyzed by 20 mol % of H-(L-Trp)2-[(L-Leu)2-Ac5c]2-OMe were performed and the desired products were obtained in 67–99% yields with 83–98% ee. The carbonyl group of Michael adducts was protected with neopentyl glycol and diester moiety was reduced by LiAlH4 to give 1,3-diol. The obtained cyclization precursors were submitted to Kishi’s reductive cyclization conditions using TMSOTf and triethylsilane to produce 2S,4R,5R-trisubstituted tetrahydropyrans with high diastereoselectivities.

Helical peptide-catalyzed asymmetric Michael addition reactions of malonates to α,β-unsaturated ketones and their synthetic applications

2019 Fall National Meeting

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