Versatile Access to 2-Aminocyclobutene-1-carboxylic Acid Derivatives and Their Incorporation into Small Peptides

Under a newly developed set of mild conditions [EtN(iPr)(2), LiI, DMF, 20 degrees C, 3 d], methyl 2-chloro-2-cyclopropylideneacetate (1) smoothly undergoes Michael addition of various benzylamines (4 examples) with ensuing ring enlargement and elimination to give in very good yields (8199 %) the correspondingly substituted methyl 2-(benzylamino)cyclobutenecarboxylates 3a-d, which were subsequently converted into the N-Boc-protected derivatives 4a-d. After hydrolysis of the esters, the free beta-amino acids 5a,b were cleanly condensed with the methyl esters of glycine, (S)-proline, (S)-phenylglycine and (S)-tryptophan to give the dipeptides 6a-8a, 9b in 58-89% yield. The cyclic dipeptides 15e,f, consisting of a 2-aminocyclobutenecarboxylic acid and a glycine fragment, were obtained in 38 and 45 % yield, respectively, upon treatment of the spirocyclopropanated chlorohexahydrodiazepinediones 10e,f with sodium cyanide in DMSO at elevated temperatures. Palladium-catalyzed hydrogenation of 4a afforded methyl N-Boc-2-amino-cyclobutanecarboxylate 19 as a mixture of cis and trans isomers.