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Versatile Access to 2‐Aminocyclobutene‐1‐carboxylic Acid Derivatives and Their Incorporation into Small Peptides
Author(s) -
de Meijere Armin,
Limbach Michael,
Janssen André,
Lygin Alexander,
Korotkov Vadim S.
Publication year - 2010
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201000283
Subject(s) - chemistry , yield (engineering) , hydrolysis , glycine , sodium cyanide , amino acid , proline , ring (chemistry) , dipeptide , medicinal chemistry , cyanide , stereochemistry , organic chemistry , biochemistry , materials science , metallurgy
Under a newly developed set of mild conditions [EtN( i Pr) 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.