Studies on Amino Acids and Peptides, 13 Improved Synthesis of 5‐Thioxo‐L‐proline and of Some N‐Acyl and S‐Alkyl Derivatives as Building Blocks in Peptide Synthesis

Abstract

We herein report an improved synthetic pathway to 5‐thioxo‐L‐proline (2) (using R,S nomenclature, the L form here possesses the S configuration). Compound 2 is synthesized from naturally occurring 5‐oxo‐L‐proline (1) at room temperature with 2,4‐bis(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphosphetane 2,4‐disulfide (3) (Lawesson′s reagent, LR). The synthesis is an improved version of our previously published method. The optical purity of 2 has been proven by thin‐layer chromatography based on chiral ligand exchange. The synthesis of N‐acyl and S‐alkyl derivatives of 5‐thioxo‐L‐proline (Top‐OH), 5‐thioxo‐L‐proline methyl ester (Top‐OCH3), and the pseudodipeptide Boc‐L‐Phe‐Top‐OCH3 is also described.

Sulfur, An Important Element in my Life

“…A number of graduate students with synthetic thiopeptide projects centered on 5-thioxo-L-proline (for which an improved synthetic procedure was developed) [147] were 'inherited' on my Å rhus colleague Sven-Olov Lawesson's untimely death in 1985. These projects were by and large completed along the lines laid down upon their conception in the Lawesson group [147][148][149][150][151].…”

“…These projects were by and large completed along the lines laid down upon their conception in the Lawesson group [147][148][149][150][151]. For instance, in one of the projects 5-thioxo-L-proline was used as the N-terminal of a series of melanocyte stimulating hormone-inhibiting factor analogs [151].…”

Applications of Lawesson′s Reagent in Organic and Organometallic Syntheses

“…Thioamino acids can also readily be prepared by reaction of the corresponding amino acids with LR. Larsen et al 78 transformed 5-oxo-L-proline 47 into 5-thioxo-L-proline 48 by thionation of the lactam function with LR in 1,2-dimethoxyethane (DME) at room temperature (Scheme 15). Protection of the carboxy group of 5-oxo-Lprolin is not necessary, as nucleophilic attack by the carboxy group on LR does not occur at room temperature.…”