3-(Acylamido)-4-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranones. Synthesis of Novel Amino Acid Analogues

Michael J. Sofia, John A. Katzenellenbogen

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We have synthesized the 3R*, 4R* and 3R*, 4S* diastereomers of two 3-(acylamino)-4-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranones (13A,B and 14A,B) by iodolactonization of substituted 5-hexynoic acid precursors (11A,B and 12A,B). Halolactonization of the 2R*, 3R* diastereomers (11A and 12A) is considerably more rapid and efficient than that of the 2R*, 3S* diastereomers (11B and 12B), presumably because of higher torsional strain in the transition states for cyclization of the latter diastereomers. The same 3R*, 4R* precursor acids (11A and 12A) can also be cyclized under mercuric ion catalysis to the protiolactones 15 or 16, but the other diastereomers 11B and 12B fail to cyclize. These precursor acids are synthesized from a substituted malonic acid (3), either by an amination-decarboxylation sequence or by a modified Curtius rearrangement. The lack of stereoselectivity in the Curtius rearrangements of the malonate half ester is accounted for by equilibration of the readily enolizable species under the conditions of the reaction. With each sequence, a mixture of 2R*, 3R* and 2R*, 3S* diastereomers were obtained. The assignment of relative configuration of all the intermediates is made by correlation with the corresponding lactones and is based on the magnitude of the1H NMR coupling constants. These synthetic methods have permitted the preparation of several α-acylamido-β-phenyl-substituted enol and halo enol lactone systems that are close analogues of the amino acid phenylalanine. These compounds are of interest as potential mechanism-based irreversible inactivators of the serine protease α-chymotrypsin.

Original languageEnglish (US)
Pages (from-to)2331-2336
Number of pages6
JournalJournal of Organic Chemistry
Issue number13
StatePublished - Jun 1985

ASJC Scopus subject areas

  • Organic Chemistry


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