An Easy Access to Bicyclic Peptides with an Octahydro[2H]pyrazino[1,2-a]pyrazine Skeleton

A new route to octahydrospiro(cyclopropane-1,1′-[2H]-pyrazino[1,2-a]pyrazine)-3′,6′,9′-triones 12–15 has been developed. Michael additions of primary amines onto methyl 2-Me or tert-butyl 2-tBu 2-chloro-2-cyclopropylideneacetates, followed by DCC- or EDC-induced coupling with Boc- or FmocGlyOH, deprotection and cyclization led to α-amino esters 4a–c and chlorohexahydrodiazepinediones 5a–c, or in the case of 2-tBu to the α-amino ester 7 exclusively. This reaction sequence with (S)-BocPheOH and (S)-BocTrpOH diastereoselectively gave (3′R,5′S)-9a,b and (2′S,6′R)-11a,b as the main products. Further peptide coupling, deprotection and cyclization with 4a–c yielded octahydrospiro(cyclopropane-1,1′-[2H]pyrazino[1,2-a]pyrazine)-3′,6′,9′-triones (7′S,9a′S)-12a–d, (6a′S,11a′S)-12e, (7′S,9a′R)-13a–d and (6a′S,11a′R)-13e which were easily separated. The α-amino esters 9a,b yielded (4′S,9a′R)-14a (≡15a) and (4′S,9a′R)-14b (≡15b), (4′S,7′S,9a′R)-14c and (4′R*,7′S*,9a′S*)-15c. The formation of compounds with three stereogenic centers 14c and 15c was accompanied by partial racemization. The versatility of the reported reaction sequence is limited by the steric availability of the secondary amino group in the intermediates 4, 9 and 10, as well as in the Michael adducts formed from primary amines and 2-Me.