Solid-phase synthesis of structurally diverse heterocycles by an amide-ketone condensation/N-acyliminium pictet-spengler sequence

Chemistry : a European Journal
Vitaly V KomnatnyyThomas E Nielsen

Abstract

An efficient approach for the solid-phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone-amide condensation reactions to form cyclic N-acyliminium intermediates. In the presence of a tethered nucleophile, a second cyclization reaction results in the formation of a fused bicyclic ring system. The scope of the methodology was demonstrated by several combinations of substituted ketones and nucleophiles, the latter conveniently originating from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. The cyclization sequence provides diastereomerically pure products in high yields. In one extension of the methodology, the resulting relative stereochemistry of the products enables the formation of bridged ring systems by a unique cyclative release mechanism.

References

Mar 11, 2004·Chemical Reviews·Bruce E MaryanoffCynthia A Maryanoff
May 22, 2004·The Journal of Organic Chemistry·Thomas E Nielsen, Morten Meldal
Sep 20, 2007·Journal of the American Chemical Society·Ting YangDarren J Dixon
Nov 13, 2007·Journal of Combinatorial Chemistry·Sebastian T Le QuementMorten Meldal
Mar 7, 2008·The Journal of Organic Chemistry·Ayman El-Faham, Fernando Albericio
Mar 18, 2008·Organic Letters·Izzat T RaheemEric N Jacobsen
Jul 18, 2009·Journal of the American Chemical Society·Michael E MuratoreDarren J Dixon
Mar 13, 2010·Biopolymers·Sebastian T Le QuementThomas E Nielsen
Sep 4, 2010·Science·Matthias RottmannThierry T Diagana
Nov 26, 2010·The Journal of Organic Chemistry·Matthew J Vanden EyndenJames P Stambuli

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