Synthesis of Specifically Deuterated S-Benzylcysteines and of Oxytocin and Related Diastereomers Deuterated in the Half-Cystine Positions

Donald A. Upson, Victor J. Hruby

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Abstract

S-Benzylcysteine derivatives specifically deuterated at the α carbon only, the β carbon only, and at both the α and β carbons have been synthesized. These labeled compounds have been enzymatically resolved and the enantiomers and reacemates have been converted to the N-tert-hutyloxycarbonyl derivatives. The deuterium labels were not exchanged under the conditions of the syntheses. Condensation of the sodium salt of diethyl α-acetamidomalonate with benzyl chloromethyl sulfide followed by hydrolysis with DCl afforded S-benzyl-dl-[α-2H1]cysteine. Acetylation followed by treatment with hog renal acylase separated the stereoisomers. A Mannich reaction with [2H2]methylene diacetate, diethyl α-acetamidomalonate, and dimethylamine followed by quaternization of the amino nitrogen with methyl iodide gave diethyl α-acetamido-α-dimethylamino[2H2]methylmalonate methiodicle (15). Treatment of 15 with sodium benzylmercaptide gave diethyl α-acetamido-α-benzylthio[2H2]methylmalonate, which was hydrolyzed with HCl to yield S-benzyl-dl-[β,β-2H2]cysteine or with DCl to afford S-benzyl-dl-[α,β,β-2H3]cysteine. These compounds were resolved as before. The preparation of S-benzyl-dl-[α,β,β-2H3]cysteine required an efficient source of ethanol-d. This deuterated solvent was prepared in quantitative yield in 2 h from tetraethoxysilane, D2O, and a catalytic amount of thionyl chloride. The protected deuterated amino acids were used in the preparation of several oxytocin analogues in which the specific deuteration appears in either the 1-hemicystine or the 6-hemicystine residues.

Original languageEnglish (US)
Pages (from-to)1353-1358
Number of pages6
JournalJournal of Organic Chemistry
Volume41
Issue number8
DOIs
StatePublished - Apr 1 1976

ASJC Scopus subject areas

  • Organic Chemistry

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