Elucidation of the Active Conformation of Antiproliferative Sulfonamides, 5N‑Arylsulfonyl-1,5-benzodiazepin-2-ones

The 5N-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (a¹R,a²R)- and (a¹S,a²S)-atropisomers with extraordinary stability (ΔG^⧧ = ∼130 kJ/mol) by freezing the conformation around the sp²–sp² axis in an Ar–N­(SO₂) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (a¹R*,a²R*,3R*). The (a¹S) stereochemistry was crucial for exerting the antiproliferative activity.