Crystal structures of chiral 2-[bis(2-chloroethyl)amino]-1,3,2-oxazaphospholidin-2-one derivatives for the absolute configuration at phosphorus

Abstract

`Nitrogen mustard' bis(2-chloroethyl)amine derivatives (2R,4S,5R)- and (2S,4S,5R)-2-[bis(2-chloroethyl)amino]-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidin-2-one (2a and 2b, respectively), C14H21Cl2N2O2P, and (2R,4R)- and (2S,4R)-2-[bis(2-chloroethyl)amino]-4-isobutyl-1,3,2-oxazaphospholidin-2-one (3a and 3b, respectively), C10H21Cl2N2O2P, were synthesized as a mixture of diastereomers through a 1:1 reaction of enantiomerically pure chiral amino alcohols with bis(2-chloroethyl)phosphoramidic dichloride. Flash column chromatography yielded diastereomerically pure products, as supported by 31P NMR. The crystal structures of 2b and 3b were obtained to determine their absolute configuration at phosphorus, and 31P NMR chemical shift trends are proposed based on the spatial relationship of the bis(2-chloroethyl)amine moiety and the chiral substituent of the amino alcohol. Oxazaphospholidinones were observed to have a more downfield 31P NMR chemical shift when the aforementioned substituents are in a syn configuration and vice versa for when they are anti.