Synthesis of 4-(Arylmethyl)proline Derivatives

Abstract

A synthesis of 4-(arylmethyl)proline by using Suzuki cross-couplings was developed. The route permits access to a variety of 4-substituted proline derivatives bearing various aryl moieties that expand the toolbox of proline analogues for studies in chemistry and ­biology.

A convenient synthetic route to (2S,4S)-methylproline and its exploration for protein engineering of thioredoxin

“…[11a] Wittig olefination of the resulting oxopyrrolidine was undertaken according to literature procedures to deliver 3 with a 35 % overall yield after purification. [17] Hydrogenation of compound 3 with 10% Pd/C gave isomers 4 and 5 (ratio 4S:4R 65:35), consistent with literature data. The ratio between the two diastereoisomers was determined using a chiral HPLC column packed with cellulose tris (4-methylbenzoate) coated on silica-gel.…”

Incorporation of Aliphatic Proline Residues into Recombinantly Produced Insulin

“…For instance, 4 R -Me and 4 S -Me have opposing conformational preferences relative to their more commonly used 4-fluoroproline counterparts ,, and together have been used to validate the stereoelectronic origin of collagen stability. , The amplitude of the pyrrolidine ring pucker of 4ene is expected to be attenuated compared to proline (Figure S7) and may approach that of the planar 3,4-dehydroproline . Furthermore, the olefin present in 4ene might be used as a chemical handle for protein modification at proline residues. , …”

An Enantioselective Approach to 4-Substituted Proline Scaffolds: Synthesis of (S)-5-(tert-Butoxy carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic Acid

“…Non-natural amino acids are often used as building blocks of active pharmaceutical compounds [1][2][3][4]. In particular, proline analogues are especially attractive since their presence in peptide chains causes conformational restrictions which are critical for biological activity [3].…”