Intermolecular Stacking-Instructed Chiral Preference in Covalent 2 + 2 Macrocyclization

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 meso dihydrazide L,D-AA is used, a strong preference for forming L,D,D,L-AAAA over L,D,L,D-AAAA was observed. Despite being hetero- and homochiral of the two amino acid residues in the 1,4-benzenediamidothiourea edges, the two kinds of the preferred macrocycles, L,L,D,D-AAAA and L,D,D,L-AAAA, share the same configurations of four edges: parallel LL/DD and LD/LD. This chiral preference arises from the enhanced intermacrocycle stacking. Structural analyses reveal that both L,L,D,D-AAAA and L,D,D,L-AAAA exhibit more symmetric molecular conformations upon stacking compared to L,L,L,L-AAAA and L,D,L,D-AAAA. These distinct structural features lead to a 30-40 °C increase in decomposition temperature for the favored macrocycles. Being orthogonal to most reported entropy-driven homochiral preferences that rely on intramolecular bonding, this study establishes a new scheme to leverage intermolecular interactions for covalent, catalyst-free stereoselective macrocyclization.