Amino acid–azetidine chimeras: synthesis of enantiopure 3‐substituted azetidine‐2‐carboxylic acids

Abstract

Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.

Direct Access to L‐Azetidine‐2‐carboxylic Acid

“…Cyclization occurred under smooth basic conditions with excellent yield (97 %) within 12 h at room temperature (Scheme 3). Similar intramolecular displacement was described from a differently protected aspartate derivative to occur in only 58 % under optimized conditions (Cs 2 CO 3 in refluxing acetonitrile), [13] thus demonstrating the efficiency of the double role of the SES group in our strategy. In addition, we improved the cyclization yield up to 99 % in 20 min by using nonconventional microwave heating (Scheme 3), thus bringing the overall yield to 65 %.…”

“…[7][8][9][10] Various -amino acids were used as starting materials for the preparation of -Aze, including -homoserine by using hydrogen bromide under drastic conditions, [11] -methionine in 11 % yield, [12] or -aspartate derivatives in 38 % overall yield. [13] Access to 1 and its analogues has been recently reviewed. [14] The work in this paper describes a direct method to synthesize 1 in high yield from the chiral pool.…”

Using the ONIOM hybrid method to apply equation of motion CCSD to larger systems: Benchmarking and comparison with time-dependent density functional theory, configuration interaction singles, and time-dependent Hartree–Fock

“…S-azetidine-2-carboxylic acid is a non-natural amino acid that has chemical and biochemical applications [41][42][43][44][45][46] ͓see Fig. 2͑a͔͒.…”

Diversity-Oriented Synthesis of Azapeptides with Basic Amino Acid Residues: Aza-Lysine, Aza-Ornithine, and Aza-Arginine

“…The protease trypsin cleaves peptides specifically at the C -terminal of lysine and arginine residues . Peptide mimics with constrained conformations and chemical modifications at lysine and arginine residues are thus desirable tools for studying and regulating such phenomena. − …”