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Synthesis of Substituted γ‐ and δ‐Lactams through Mannich‐Type Reactions of Solid‐Supported N ‐Acyliminium Ions
Author(s) -
Komnatnyy Vitaly V.,
Taveras Kennedy M.,
Nandurkar Nitin S.,
Le Quement Sebastian T.,
Givskov Michael,
Nielsen Thomas E.
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500054
Subject(s) - chemistry , hydroxymethyl , aldehyde , iminium , amide , nucleophile , reactivity (psychology) , benzoic acid , combinatorial chemistry , intermolecular force , organic chemistry , polymer chemistry , medicinal chemistry , ion , molecule , catalysis , medicine , alternative medicine , pathology
We report the results of our recent investigations into the reactivity of cyclic solid‐supported N ‐acyliminium ions. An intermolecular Mannich‐type transformation of these intermediates was used to generate libraries of substituted lactams. Masked aldehyde building blocks were readily prepared and coupled to peptides immobilized on PEGA 800 (polyethylene glycol dimethyl acrylamide) resin through an HMBA [4‐(hydroxymethyl)benzoic acid] linker. When treated with acid, the aldehyde was cleanly released and condensed with the amide backbone to form a hydroxylactam/ N ‐acyliminium ion, which underwent intermolecular reactions with a series of nucleophilic heterocycles, such as substituted indoles, thiophenes, furans, and electron‐rich benzenes. The resulting lactams were formed within a few minutes and in high purities (typically >85 %).