ABSTRACT: We report the discovery of unexpected chiral preferences in 2 + 2 macrocyclization, where a racemic pair of 2,6-pyridine-(dicarbonylamino-acid)-hydrazides or two equiv of the meso analogue are reacted with two molecules of achiral, structurally symmetric bidentate, 1,4-pheylenediisothiocyanate. Using racemic alanine (A)-based dihydrazides L,L-AA and D,D-AA as reactants, heterochiral macrocycle L,L,D,D-AAAA forms exclusively in ca. 80% yield in acetonitrile/DMF at 110 °C, with no detectable formation of homochiral L,L,L,L- or D,D,D,D-counterparts. This heterochiral preference extends to other amino acid residues, as demonstrated by the selective formation of L,L,D,D-FFFF and L,L,D,D-/D,D,L,L-AAFF when employing phenylalanine (F)-based or mixed F- and A-based dihydrazides. Surprisingly, when
