An Improved Synthesis of S-3,4-Dehydroproline

Abstract

S-3,4-dehydroproline (5, S-Δ^3,4-Pro) has been shown¹ to be a potent inhibitor of collagen synthesis in mammalian cells due, at least in part, to its action as a prolyl hydroxylase inhibitor. The replacement in peptides of proline with S-Δ^3,4-Pro has given analogues with modified biological activities.^2,3 In addition, reductive deuteration or tritiation of these S-Δ^3,4-Pro containing peptides gives 3,4-²H₂-Pro or 3,4-³H₂-Pro analogues of high specific enrichment.⁴ S-Δ^3,4-Pro was initially obtained⁵ by chemical resolution or selective enzymatic hydrolysis of R,S-3,4-dehydroprolinamide. A better process⁴ involves resolution of R,S-N-t-butyloxycarbonyl-3,4-dehydroproline with R-α-methyl-p-nitrobenzylamine. In this paper, we report improvements in the synthesis of R,S-Δ^3,4-Pro (3) and the direct resolution of this material with natural (+)-tartaric acid. An important feature