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.