John M. Harrison

1,3,2-Oxazaphospholidines from (–)-ephedrine. Intermediates for the stereospecific synthesis of optically active dialkyl alkylphosphonothioates and -selenoates, trialkyl phosphoro-thioates and -selenoates, dialkyl methylphosphonates, and trialkyl phosphates

The configurations of the cis- and trans-isomers of 2-substituted 1,3,2-oxazaphospholidin(e)-2-ones, -2-thiones, and 2-selones derived from (–)-ephedrine have been established by spectroscopic and chemical methods. Displacements of the exocyclic 2-substituents occur with retention of configuration at phosphorus. With sodium alkoxides, the 1,3,2-oxazaphospholidine ring is opened by P–N rather than P–O bond cleavage, and inversion of configuration at phosphorus is observed. Under basic conditions the 2-methylamino-1-phenylpropyl phosphates derived from (–)-ephedrine rearrange to afford aziridines and phosphoric acid derivatives; in the cases of the sulphur- and selenium-containing derivatives optically active phosphorus thioacids and phosphorus selenoacids are formed and can be isolated as SMe and SeMe derivatives. These latter derivatives are converted into O-alkyl derivatives on treatment with alcohols in the presence of alkoxides or bromine or silver nitrate, and the stereoselectivities of these reactions have been determined. The optical purities of the title compounds have been measured by an n.m.r. method using chiral shift reagents.

Biological fate of sulphur mustard (1,1'-thiobis(2-chloroethane)): urinary and faecal excretion of 35S by rat after injection or cutaneous application of 35S-labelled sulphur mustard

1. A technique for the quantitative cutaneous application of sulphur mustard vapour is described. The maximum rate of uptake of the agent vapour by shaved rat skin in vivo was estimated as 7 micrograms/cm2 per min. 2. The major route of excretion was through the kidneys: greater than 70% of the radioactivity of all doses was excreted in 3 days after either i.v. or i.p. injections of 35S-labelled sulphur mustard, but less (50-70% depending on dose) was excreted in the same time following cutaneous application. 3. This urinary excretion of 35S had a half-life of 1.4 days, and the decreased proportion of the applied dose excreted following cutaneous application may be accounted for by retention of radioactivity in the skin. 4. The contribution of faecal excretion was greater following cutaneous application.

THE CHEMISTRY OF 1,1′-THIOBIS-(2-CHLOROETHANE) (SULPHUR MUSTARD) PART I. SOME SIMPLE DERIVATIVES

Abstract Some derivatives of 1,1′-thiobis(2-chloroethane) (sulphur mustard) have been synthesised for use as reference compounds in a wide range of studies embracing analysis, metabolism, environmental degradation and decontamination. Compounds include products formed by hydrolysis, substitution and elimination reactions and their oxidised sulphoxide and sulphone analogues. A comprehensive series of methylthio, methylsulphinyl and methylsulphonyl derivatives has been synthesised in support of metabolic studies.

The fate of 2-chlorobenzylidene malononitrile (CS) in rats.

1. The fate of 3H-ring labelled, 14C-cyanide labelled and (14C = C) side chain labelled 2-chlorobenzylidene malononitrile (CS), 2-chlorobenzyl alcohol and 2-chlorobenzyl malononitrile (dihydro CS) in rats and isolated rat liver cells has been examined. 2. CS was administered both i.v. and i.g. to rats at doses from 0.08 to 159 mumol/kg and in most cases the greatest proportion of the dose was eliminated in the urine (44-100%). The principal urinary metabolites were 2-chlorohippuric acid, 1-O-(2-chlorobenzyl) glucuronic acid, 2-chlorobenzyl cysteine and 2-chlorobenzoic acid. Lesser amounts of 2-chlorophenyl acetyl glycine, 2-chlorobenzyl alcohol and 2-chlorophenyl 2-cyano propionate were identified. 3. The major urinary metabolite from 2-chlorobenzyl alcohol was 2-chlorohippuric acid (43%), 2-chlorobenzyl cysteine, 2-chlorobenzoic acid and 2-chlorobenzyl glucuronic acid were identified. 4. The products of dihydro-CS metabolism were 2-chlorophenyl acetyl glycine, 2-chlorophenyl 2-cyanopropionate and 2-chlorophenyl proprionamide. 5. Urinary thiocyanate levels increased with the dose of CS up to 159 mumol/kg. At 212 mumol/kg there was a large increase in the amount of thiocyanate produced (molar conversion: 21.5-29.9%). Similarly malononitrile, the hydrolysis product of CS, gave a dose related increase in urinary thiocyanate levels. However at a higher dose (212 mumol/kg) the molar conversion was greater than 60%. 6. The metabolism of CS by isolated rat liver cells confirmed the results in vivo but demonstrated a marked limitation of this preparation to form conjugates. 7. It is concluded that CS in vivo is hydrolysed mainly to 2-chlorobenzaldehyde which is then either oxidized to 2-chlorobenzoic acid for subsequent glycine conjugation, or reduced to 2-chlorobenzyl alcohol for ultimate excretion as 2-chlorobenzyl acetyl cysteine or 1-O-(2-chlorobenzyl) glucuronic acid. Malononitrile is converted to thiocyanate via the formation of cyanide.

Synthesis of aryl β-D-glucopyranosides and aryl β-D-glucopyranosiduronic acids

Abstract Tetra-O-benzyl-α-D-glucopyranosyl bromide in dichloromethane reacts stereospecifically with solutions of phenols in aqueous sodium or potassium hydroxide, in the presence of phase transfer catalysts, to give good yields of tetra-O-benzyl aryl-β-D-glucopyranosides which are converted into the corresponding aryl β-D-glucopyranosiduronic acids by sequential catalytic debenzylation and catalytic oxidation.

THE CHEMISTRY OF 1,1′-THIOBIS(2-CHLOROETHANE) (SULPHUR MUSTARD) PART II.1 THE SYNTHESIS OF SOME CONJUGATES WITH CYSTEINE, N-ACETYLCYSTEINE AND N-ACETYLCYSTEINE METHYL ESTER

Abstract The syntheses of a number of conjugates of 1,1′-thiobis(2-chloroethane) (“sulphur mustard”) and its simple derivatives with cysteine, N-acetylcysteine and N-acetylcysteine methyl ester are described. These compounds were synthesised for use as reference compounds to support metabolite identification in metabolic studies and, in some cases, to provide standards for analytical procedures being developed for the retrospective confirmation of exposure to sulphur mustard.

A novel rearrangement of the adduct from CS-epoxide and dioxan-2-hydroperoxide

Abstract Under mild conditions, nucleophiles add across the cyanide moiety of CS epoxide rather than opening the ring. With hydroxide ion in peroxide-free aqueous dioxan isomeric amides are obtained. Hydrolysis in peroxide containing dioxan affords a novel rearrangement involving carbon—carbon bond fission of the dioxan.

Preparation of some dibenz[b,f][1,4]oxazepines and dibenz[b,e]azepines

Some dibenz[b,f][1,4]oxazepines and dibenz[b,e]azepines, variously substituted in the aromatic rings but not substituted at the azomethine group, are described.

The metabolism of dibenz[b,f]-1,4-oxazepine (CR): in vivo hydroxylation of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one and the NIH shift.

Studies of the in vivo metabolism of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one (2) specifically deuteriated at C-7 implicate an arene oxide intermediate during the conversion to 7-hydroxy-2 (4) as evidenced by the observation of the NIH shift.

Addition of chloroketens to spiro[2.4]hepta-4,6-diene

Addition of chloroketens to spiro[2.4]hepta-4,6-diene is regiospecific, giving 7-chlorospiro(bicyclo[3.2.0]hept-2-ene-4,1′-cyclopropan)-6-ones (6)–(10) rather than the 6-chloro-7-ketones. For alkyl-substituted chloroketens there was an increase in the proportion of 7-endo-alkyl adduct as the size of the alkyl group increased supporting a crosswise approach of the keten and spirodiene. Phenyl(chloro)keten yielded a single 6-keto-adduct with dimethylfulvene.