TY - JOUR
T1 - Solid-phase synthesis of structurally diverse heterocycles by an amide-ketone condensation/N-acyliminium pictet-spengler sequence
AU - Komnatnyy, Vitaly V.
AU - Givskov, Michael
AU - Nielsen, Thomas E
N1 - Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2012/12/21
Y1 - 2012/12/21
N2 - 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. Scaffold builders: An efficient method for the solid-phase synthesis of structurally diverse heterocyclic compounds relies on mutually reactive combinations of ketone-derived N-acyliminium ions with nucleophiles. The latter can be conveniently synthesized from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. In this way, a range of pharmaceutically interesting heterocycles was synthesized in excellent purities and yield.
AB - 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. Scaffold builders: An efficient method for the solid-phase synthesis of structurally diverse heterocyclic compounds relies on mutually reactive combinations of ketone-derived N-acyliminium ions with nucleophiles. The latter can be conveniently synthesized from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. In this way, a range of pharmaceutically interesting heterocycles was synthesized in excellent purities and yield.
U2 - 10.1002/chem.201202745
DO - 10.1002/chem.201202745
M3 - Journal article
C2 - 23132763
SN - 1521-3765
VL - 18
SP - 16793
EP - 16800
JO - Chemistry. A European Journal
JF - Chemistry. A European Journal
IS - 52
ER -