Soman chirality

Typical production batches of nerve agents formerly intended for military use are mixtures of enantiomers obtained from nonchiral synthesis (Figure 50.1). Sarin, cyclosarin, tabun, and VX consist of mixtures of two enantiomers each of which differs in the chirality at the central phosphorus atom thus enabling rotation of linearly polarized light clockwise [P(+)-enantiomers] or anticlockwise [P(—)-enantiomers] (Figure 50.1). In contrast, chirality of soman appears more complex based on two chiral centers, which reside at the phosphorus atom, P(-f) and P(—), and additionally in the pinacolyl moiety, C(-f) and C( ). Hence, soman occurs in four stereoisomeric conformations as two pairs of diastereomers P(-E)C(+),... 

Benschop and De Jong, 1988). In the case of toxicokinetic studies, it is important to differentiate between the two isomers because it is essential to know which isomer is stiU present in the circulation. Chiral gas chromatography can fulfill this requirement for G-agents like sarin and soman. Soman has two asymmetric atoms, phosphorus and carbon in the pinacolyl group. Therefore, the compound consists of four different stereoisomers. 

Benschop, H.P. (1975). Absolute configuration of chiral organo-phosphorus anticholinesterases.Biocliem. Physiol. 5 348. Benschop, H.P., De Jong, L.P.A. (1988). Nerve agent stereoisomers analysis, isolation and toxicology. Tcc. Chem. Res. 21 368. Benschop, H.P., De Jong, L.P.A. (1991). Toxicokinetics of soman species variation and stereospecificity in elimination pathways. Neurosci. Biobehavi. Rev. 15 73. 

Of particular interest is the study of the biological mechanisms associated with enzyme stereoselectivity and enantioselectivity. For example, MD simulations have been successful in explaining the different affinities of trypsin and acetylcholinesterase to the diastereomers of soman inhibitors [154] and the ability of subtilisin Carlsberg and a-chymotrypsin to discriminate between R-and S- configurations of chiral aldehyde inhibitors [155, 156]. 

Tabun has a stereogenic (chiral) phosphoms atom and exists as a pair of enantiomers. A gas chromatograph study of the enantiomers of tabun has been reported (Degenhardt et al., 1986). Separation was achieved through the use of bis[(l/f)-3-(heptafluorobutyryl-camphorate)nickel(II). This approach also separated stereoisomers of both sarin and soman. These authors also reported the stereospecific hydrolysis of racemic tabun using phosphorylphosphatases. They noted the species (mouse, rat, horse) dependence of the hydrolysis. Dilute solutions of tabun in inert solvents (e.g., carbon tetrachloride) exhibit optical stability for months at — 25°C. 

Physical Properties. Pure soman is a colorless liquid with a somewhat fruity odor. It has density 1.01 g/mL (20°C), vapor pressure of 0.27 mm/Hg (20°C), mp of —80°C, and bp of 190°C (85°C at 15 mm/Hg). Distillation is accompanied by decomposition that begins near 130°C. Soman s solubility in water is about 20% at 25°C. It is only about 20% as soluble in water as is tabun. With two different chiral centers, it exists as four stereoisomers (Benschop et al., 1985), each with a different toxicity. The lethal concentration (inhalation) in humans is estimated at approximately 25-50 mg min/m (Somani et al., 1992). 

Interpretation and understanding of the toxicokinetics of nerve agents would not be possible without taking into consideration that these agents consist of mixtures of stereoisomers, which are often extremely different in their toxicokinetic and toxico-dynamic properties. A common feature of these agents is the presence of chirality (asymmetry) around the phosphorus atom. Therefore, O-isopropyl methylphos-phonofluoridate (sarin) and 0-ethyl S-(2-diisopropylaminoethyl) methylphospho-nothioate (VX) consist of equal amounts of stereoisomers, denoted as (-1-)- and (-)-sarin and (-1 )- and (-)-VX, respectively. In the case of 0-1,2,2-trimethylpropyl methylphosphonofluoridate (soman), an additional chiral center resides in the 1,2,2-methylpropyl (pinacolyl) moiety, leading to the presence of four stereoisomers. Synthetic soman, i.e., a mixture of the four stereoisomers, is denoted as C( )P( )-soman, whereas the individual four stereoisomers are denoted as C(+)P(-l-), C(-H)P(-), C(-)P(+), and C(-)P( ), in which C stands for chirality in the pinacolyl moiety and P for chirality around phosphorus. The enantiomeric pairs [C(-r)P(+) + C(-)P( )] and [C(+)P(-) -l- C(-)P(+)] are present in synthetic... 

When properly installed, the analytical system involving thermodesorption cold trap injection and two-dimensional chromatography can be used routinely for analysis of the stereoisomers of soman and sarin in blood and tissue samples at minimum detectable concentrations of 1 -5 pg of stereoisomer per ml blood or gram tissue. In recent toxicokinetic experiments in pigs, the analytical system comprised chiral gas chromatography on a Chirasil-L-Val column with splitless injection and detection... 

Stereoselectivity of the enzymatic hydrolysis of the chiral phosphonofluoridates C( )P( )-soman and ( )-sarin has been studied extensively. " In various tissues of several species, (+)-sarin and C( )P(+)-soman are much more rapidly degraded by phosphoryl phosphatases than the more toxic stereoisomers of these nerve agents. The relative order for the rate of hydrolysis of the four stereoisomers of C( )P( )-soman is C(+)P(+)- C( )P(+)- >> C(-)P(-)- > C(+)P(-)-stereoisomer (Table 2.9). 

Near baseline resolution of the two diastereoisomers of soman can be obtained on nonpolar columns under normal analysis conditions and complete resolution can be obtained on more polar columns such as poly (ethylene glycol) Chiral resolution of the four iso-... 

Organophosphoms chemical agents are often mixtures of isomers. It is possible to separate, chromatographicaUy, four stereoisomers of soman and enantiomers of sarin and tabun using short capillary columns packed with chiral... 

Besides chlorinated pesticides, some of the phosphorous pesticides are also chiral (see Table 2.1). The phosphorous pesticides also differ in their enantioselective toxicities. These pesticides were introduced in the 1950s to control insects in fruit, vegetables and other crops. Malathion is biotransformed into a racemic malaxon that has anti-acetylcholinesterate (insecticidal) activity. The /f-enantiomer has a 22 times greater inhibitory potency than the 5-enantiomer for bovine erythrocyte cholinesterase [39, 40]. The nerve agent, soman, has two chiral centres, and the two (—)-diastereoisomers are more potent inhibitors than their corresponding (-1-)-counteiparts for acetylcholinesterase and a-chymotrypsin. 

Li, W.S., Lum, K.T., Chen-Goodspeed, M., et al, 2001. Stereoselective detoxification of chiral sarin and soman analogues by phosphotriesterase. Bioorg. Med. 

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