Isolation, anticholinesterase properties, and acute toxicity in mice of the four stereoisomers of the nerve agent soman

Abstract The four stereoisomers of the nerve agent pinacolyl methylphosphonofluoridate (soman), designated as C(+)P(+), C(+)P(−), C(−)P(+), and C(−)P(−), have different toxicologic properties due to stereospecific interactions in living organisms. We report the isolation of these stereoisomers with more than 99% optical purity. This result was realized by means of (i) complete optical resolution of pinacolyl alcohol, (ii) synthesis of C(+)- and C(−)-soman from the (+)- and (−)-enantiomers of the alcohol, (iii) optimalization of conditions for stereospecific inhibition of α-chymotrypsin with the P(−)-isomers of C(+)- and C(−)-soman, followed by isolation of the C(+)P(+)- and C(−)P(+)-isomers, (iv) isolation of the C(+)P(−)- and C(−)P(−)-isomers after incubation of C(+)- and C(−)-soman, respectively, in rabbit plasma, which hydrolyzes stereospecifically the P(+)-isomers. The bimolecular rate constants for inhibition of electric eel acetylcholinesterase (AChE) at pH 7.7, 25°C, are at least 3.6 × 10 4 larger for the P(−)- than for the P(+)-isomers. The enzyme inhibited with C(+)P(−)-soman is much more effectively reactivated with the oximes HI-6, HGG-42, and obidoxime than AChE inhibited with C(−)P(−)-soman. The LD50 values (sc, mice) are in accordance with the P(−) P(+) ratio of inhibition rates of AChE, i.e. 99, 38, >5000, >2000, 214, 133, and 156 μg/kg for C(+)P(−)-, C(−)P(−)-, C(+)P(+)-, C(−)P(+)-, C(+)-, C(−)-soman, and “soman,” respectively. The relative LD50 values of the C(−)P(−)- and C(+)P(−)-isomers do not correspond with the small differences in their rates of inhibition of AChE, indicating that such small rate ratios may be overruled by other stereospecific effects, e.g., in vivo rates of detoxification.