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

Abstract

AbstractUnder a newly developed set of mild conditions [EtN(iPr)2, LiI, DMF, 20 °C, 3 d], methyl 2‐chloro‐2‐cyclopropylideneacetate (1) smoothly undergoes Michael addition ofvarious benzylamines (4 examples) with ensuing ring enlargement and elimination to give in very good yields (81–99 %) 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 β‐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‐aminocyclobutanecarboxylate 19 as a mixture of cis and trans isomers.