Resolution and Improved Synthesis of (±)-Arsenicin A: A Natural Adamantane-Type Tetraarsenical Possessing Strong Anti-Acute Promelocytic Leukemia Cell Line Activity

Abstract

The resolution and improved synthesis of the naturally occurring, adamantane-type, tetraarsenical (±)-Arsenicin A is reported. The five-step synthesis of (±)-Arsenicin A from methylenebis(phenylarsinic acid) affords (±)-Arsenicin A as air-stable, colorless crystals having an mp of 182–184 °C after column chromatography and recrystallization from benzene (overall yield: 36%). The resolution of (±)-Arsenicin A was achieved by preparative HPLC on a Chiralpak IA column with the use of dichloromethane as eluent to give both enantiomers in >99% enantiomeric purity (HPLC); the isolated enantiomers had [α]58920 = −60.2 and +62.3 (0.01% NEt3/CH2Cl2). (S)-(−)-Arsenicin A, having an mp of 241–242 °C from dichloromethane, crystallizes in the space group P212121 with one molecule having the (SAs,SAs,SAs,SAs) or overall S configuration in the asymmetric unit. The adamantane-type structure of (±)-Arsenicin A is reminiscent of arsenic(III) oxide (As4O6), but where three of the oxygen atoms in the inorganic oxide have bee...