Abstract
'Nitro-gen mustard' bis-(2-chloro-eth-yl)amine derivatives (2R,4S,5R)- and (2S,4S,5R)-2-[bis-(2-chloro-eth-yl)amino]-3,4-dimethyl-5-phenyl-1,3,2-oxaza-phos-pho-lidin-2-one (2a and 2b, respectively), C14H21Cl2N2O2P, and (2R,4R)- and (2S,4R)-2-[bis-(2-chloro-eth-yl)amino]-4-isobutyl-1,3,2-oxaza-phospho-lidin-2-one (3a and 3b, respectively), C10H21Cl2N2O2P, were synthesized as a mixture of diastereomers through a 1:1 reaction of enanti-omerically pure chiral amino alcohols with bis-(2-chloro-eth-yl)phospho-ramidic 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 phospho-rus, and 31P NMR chemical shift trends are proposed based on the spatial relationship of the bis-(2-chloro-eth-yl)amine moiety and the chiral substituent of the amino alcohol. Oxaza-phospho-lidinones 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.
Highlights
Bis(2-chloroethyl)amine moieties, known as a ‘nitrogen mustard’, are of interest due their ability to alkylate DNA, which hinders the cellular growth and replication of cancer cells (Einhorn, 1985). 2-[Bis(2-chloroethyl)amino]-1,32,2oxazaphosphinane 2-oxide, commercially sold as cyclophosphamide, features such a nitrogen mustard moiety and is registered as an FDA-approved chemotherapeutic due to its cytotoxic ability
It is of pharmaceutical interest to be able to readily identify the absolute configuration at phosphorus of cyclophosphamide and other related nitrogen mustard derivatives
Diastereomeric 2-[bis(2-chloroethyl)]-1,3,2-oxazaphospholidin-2-ones, a five-membered ring derivative of cyclophosphamide, have been previously synthesized from l- and d-serine, but lacked X-ray diffraction data to determine the absolute configuration at the P atom (Foster, 1978; Jackson et al, 1992)
Summary
Bis(2-chloroethyl)amine moieties, known as a ‘nitrogen mustard’, are of interest due their ability to alkylate DNA, which hinders the cellular growth and replication of cancer cells (Einhorn, 1985). 2-[Bis(2-chloroethyl)amino]-1,32,2oxazaphosphinane 2-oxide, commercially sold as cyclophosphamide, features such a nitrogen mustard moiety and is registered as an FDA-approved chemotherapeutic due to its cytotoxic ability. Diastereomeric 2-[bis(2-chloroethyl)]-1,3,2-oxazaphospholidin-2-ones, a five-membered ring derivative of cyclophosphamide, have been previously synthesized from l- and d-serine, but lacked X-ray diffraction data to determine the absolute configuration at the P atom (Foster, 1978; Jackson et al, 1992). We report the synthesis and absolute configuration at phosphorus of chiral 2-[bis(2-chloroethyl)amino]-1,3,2oxazaphospholidin-2-ones in attempts to support these spectroscopic trends for the analysis of future potentially chemotherapeutic analogues. Position of the phenyl and isobuytl groups (Fig. 3), indicates that the positions of the aza and oxo groups are swapped between 2b and 3b Another slight difference between the conformations between the two rings is evident, caused by the close to planar configuration of the methylamine N atom of 2b (the sum of angles around N1 is 359.97), giving 3b a slightly more ‘buckled’ appearance than 2b. For a more reliable estimate, data from a larger library of compounds are needed
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