Cyclopropyl building blocks in organic synthesis, 50 - 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 a mines onto methyl 2-Me or tert-butyl 2-tBu 2-chloro-2-cyclopropylidene-acet ates, followed by DCC- or EDC-induced coupling with Boc- or FmocGlyOH, depr otection and cyclization led to alpha-amino esters 4a-c and chlorohexahydro diazepinediones 5a-c, or in the case of 2-tBu to the alpha-amino ester 7 ex clusively. This reaction sequence with (S)-BocPheOH and (S)-BocTrpOH diaste reoselectively 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 o ctahydrospiro(cyclopropane-1,1'-[2H]pyrazino[1,2-a]pyrazine)-3 ',6',9'-trio nes (7'S,9a'S)-12a-d, (6a'S,11a'S)-12e, (7'S,9a'R)-13a-d and (6a'S,11a'R)-1 3e which were easily separated. The alpha-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 rep orted reaction sequence is limited by the steric availability of the second ary amino group in the intermediates 4, 9 and 10, as well as in the Michael adducts formed from primary amines and 2-Me.