Synthesis of specifically deuterated S-benzylcysteines and of oxytocin and related diastereomers deuterated in the half-cystine positions.

Abstract

S-Benzylcysteine derivatives specifically deuterated at the ..cap alpha.. carbon only, the ..beta.. carbon only, and at both the ..cap alpha.. and ..beta.. carbons have been synthesized. These labeled compounds have been enzymatically resolved and the enantiomers and reacemates have been converted to the N-tert-butyloxycarbonyl derivatives. The deuterium labels were not exchanged under the conditions of the syntheses. Condensation of the sodium salt of diethyl ..cap alpha..-acetami-domalonate with benzyl chloromethyl sulfide followed by hydrolysis with DCl afforded S-benzyl-DL-(..cap alpha..-/sup 2/H/sub 1/) cysteine. Acetylation followed by treatment with hog renal acylase separated the stereoisomers. A Mannich reaction with (/sup 2/H/sub 2/) methylene diacetate, diethyl ..cap alpha..-acetamido-..cap alpha..-dimethylamino(/sup 2/H/sub 2/)methylmalonate methiodide (15). Treatment of 15 with sodium benzylmercaptide gave diethyl ..cap alpha..-acetamido-..cap alpha..-benzylthio(/sup 2/H/sub 2/)methylmalonate, which was hydrolyzed with HCl to yield S-benzyl-DL-(..beta..,..beta..-/sup 2/H/sub 2/)cysteine or with DCl to afford S-benzyl-DL-(..cap alpha..,..beta..,..beta..,-/sup 2/H/sub 3/)cysteine. These compounds were resolved as before. The preparation of S-benzyl-DL-(..cap alpha..,..beta..,..beta..-/sup 2/H/sub 3/)cysteine required an efficient source of ethanol-d. This deuterated solvent was prepared in quantitative yield in 2 h from tetraethoxysilane, D/sub 2/O, 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 more » deuteration appears in either the 1-hemicystine or the 6-hemicystine residues. « less