Preparation of 6-deuteriopenicillins

Abstract

When penicillin (S)-S-oxide esters are treated with triethylamine and acetonitrile containing DzO, both epimerization and deuteration at the 6-position occurs. This reaction is found to be a convenient method for the preparation of 6-deuteriopenicillins. 6-Deuteriobenzylpenicillin (S)-S-oxide benzyl ester (containing more than 95% D in the 6-position) was obtained from the (S)-S-oxide of penicillin G benzyl ester. Deoxygenation of the sulfoxide followed by catalytic debenzylation gave penicillin G deuterated in the 6-position. A kinetic study of deuterium incorporation and epimerization at C-6 was carried out for the (S)-S-oxide of penicillin V benzyl ester and for its 6-epimer. Deuteration was found to be faster than epimerization when the sulfoxide with the natural configuration was used as starting material. In the experiment starting with the 6-epimer, epimerization is faster than deuteration. A revised mechanism for the epimerization and deuteration of penicillin S-oxide esters is proposed.