Thomas D. Inch

Phosphorus stereochemistry : Mechanistic implications of the observed stereochemistry of bond forming and breaking processes at phosphorus in some 5- and 6-membered cyclic phosphorus esters

Abstract The stereochemistry of endocyclic and exocyclic bond forming and breaking processes in 5- and 6-membered cyclic phosphorus esters is summarised and comparisons are made with analogous reactions in acyclic phosphorus esters. The factors that determine which bonds are broken and whether reactions occur with inversion or retention of configuration at phosphorus are complex and usually have more obvious effects for reactions in cyclic than in acyclic phosphorus esters ; in particular conformational effects may be important. The stereochemistry of migration of phosphorus ester groups across 1,3-diols is also described. It is suggested that nucleophilic substitutions at phosphorus are inherently stereospecific in the sense that trigonal bipyramidal reaction intermediates break down either directly or following a single Berry Pseudorotation or Turnstile rotation process. Multiple Turnstile rotations which would lead to racemisation, and which apparently do occur in stable phosphoranes, are insignificant for reactions involving trigonal bipyramidal intermediates.

Asymmetric synthesis: Part I. A stereoselective synthesis of benzylic centres. Derivatives of 5-C-phenyl-d-gluco-pentose and 5-C-phenyl-l-ido-pentose

Abstract Methods for the stereoselective synthesis and configurational assignment of asymmetric, benzylic carbon atoms have been investigated. The reaction between phenylmagnesium bromide and 3- O -benzyl-1,2- O -isopropylidene-α- d - xylo -pentodialdo-1,4-furanose in ether is highly stereoselective, giving a mixture of 3- O -benzyl-1,2- O -isopropylidene-5- C -phenyl-α- d - gluco -pentofuranose and 3- O -benzyl-1,2- O -isopropylidene-5- C -phenyl-β- l - ido -pentofuranose in the ratio 1:14.4. The stereoselectivity of the reaction was appreciably different when ether was replaced by tetrahydrofuran as solvent. The novel, crystalline sugars, 5- C -phenyl- d - gluco -pentose and 4- C -benzyl- d - xylo -tetrose are described.

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.

The central and peripheral activities of anti-acetylcholine drugs. Some concepts of practical relevance.

Five procedures have been used to compare the pharmacological effects and time‐activity profiles of anti‐acetylcholine drugs in the central and peripheral nervous system (ens, pns). In particular, the potencies of optically pure enantiomers of anti‐acetylcholine drugs which contain an asymmetric centre have been determined. The following four observations are made which are of relevance to all studies of anti‐acetylcholine drugs. (1) Times to onset of activity of anti‐acetylcholine drugs in three in vivo tests and the duration of action in one in vivo test are shown to increase as affinity constants, determined in vitro, increase. (2) Below a dose of ca 0.03 μmol kg−1no anti‐acetylcholine drug produces maximum mydriatic effects and all anti‐acetylcholine drugs which have log affinity constant values >9.49 produce maximal effects at approximately this dose. (3) The receptor with which anti‐acetylcholine drugs interact is essentially the same in the eye, salivary gland and ens of the mouse, the guinea‐pig ileum, and in the cat ens. (4) For any anti‐acetylcholine drug the time to onset of effects in the ens is similar to the time of onset of effects in the pns and appears to depend on the affinity constant rather than on the partition properties of the drug. The practical and theoretical significance of these and other observations are discussed.

The synthesis of branched-chain, deoxy sugars by sugar epoxide-grignard reagent reactions

Abstract Alkylmagnesium chlorides react with methyl 2,3-anhydro-4,6- O -benzylidene-α- d -mannopyranoside ( 1 ) and -α- d -allopyranoside ( 2 ) to give, preponderantly, 3-alkyl and 2-alkyl, branched-chain, deoxy sugars. In contrast, alkylmagnesium iodides and bromides do not give branched-chain, deoxy sugars with 1 and 2 but give, initially, halohydrins which undergo elimination and reduction with excess of Grignard reagent. Preliminary investigations of the reaction of 2 with a complex derived from alkyl-magnesium iodides and tetrahydropyran indicate the formation of methyl 4,6- o -benzylidene-3-deoxy-3-iodo-α- d -glucopyranoside ( 13b ) by trans -diequatorial opening of epoxide 2 , whereas normal Grignard reagents (alkylmagnesium iodides) react with 2 in tetrahydropyran to give the usual trans -diaxial product ( 14b ).

Differences between some biological properties of enantiomers of alkyl S-alkyl methylphosphonothioates.

BASELT, R. C. & CASARETT, L. J. (1972). Biochem. Pharmac., 21, 2705-2712. BECKETT, A. H., MITCHARD, M. & SHIHAB, A . A. (1971). J. Pharm. Pharmac., 23, 347-353. BECKETT, A. H. , VAUGHAN, D. P. & ESSIEN, E. E. (1972). Ibid., 24, 244. DAVIS, C. M. & FENIMORE, D. C. (1975). J . Chromat., 104, 193-195. MISRA, A. L., MULE, S. J . , BLOCK, R. & VADLAMANI, . L. (1973). J. Pharmac. exp. Ther., 185, 287-299. MISRA, A. L., BLOCH, R., VADLAMANI, . L. & MULL, S. J. (1974). Ibid., 188, 3 4 4 4 . SULLIVAN, H. R . & DUE, S. L. (1973). J . medl Chem., 16, 909-913. SULLIVAN, H. R., DUE, S. L. & MCMAHON, R. E. (1973). J. Pharm. Pharmac., 25, 1009-1010. Clin. Pharmac. Ther., 17, 258-266.

Dual mechanism of the antidotal action of atropine‐like drugs in poisoning by organophosphorus anticholinesterases

ABSTRACT Although more potent anti-acetylcholine drugs than atropine have been described, attempts to find atropine-like drugs that are significantly superior to atropine for the treatment of poisoning by anticholinesterases have been unsuccessful. Possible reasons for this have been investigated by comparing enantiomeric pairs of atropine-like drugs in a variety of tests for anti-acetylcholine activity (e.g. affinity constants on ileum, mydriasis, blockade of oxotremorine-induced tremors and salivation) and for their anticholinesterase antidotal properties. Large and consistent anti-acetylcholine enantiomeric potency ratios were observed, thereby providing an indication of a similar receptor structure in the PNS, CNS and in different species. However, the enantiomers of any compound studied showed equal antidotal properties. The conclusion reached was that atropine-like drugs have anti-convulsant as well as anti-acetylcholine properties.

Glycol-cleavage products from 1,2-O-isopropylidene-α-d-glucofuranose

Abstract Oxidation of 1,2- O -isopropylidene-α- d -glucofuranose with sodium periodate has been shown to yield primarily bis(5-aldo-1,2- O -isopropylidene-α- d - xylo -pentofuranose) 5,5′:3′5-cyclic acetal ( 4 ) with 1,2- O -isopropylidene-3,5- O -methylene-(5-hydroxy-α- d -xylofuranose) ( 7 ) as the minor product. When 1,2- O -isopropylidene-α- d -glucofuranose was oxidised with lead tetraacetate the proportions of 4 and 7 produced were reversed, and 7 became the major product of the reaction. Neither method of oxidation gave any 1,2- O -isopropylidene-α- d - xylo -pentodialdo-1,4-furanose. A first-order analysis of the n.m.r. spectra of 7 and its derivatives and of the diacetate from 4 permits tentative assignments for their configurations and conformations.

The synthesis and degradation of benzyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside and -mannopyranoside

Abstract The use of carbohydrates for establishing, by synthesis, the absolute configuration of branched aliphatic alcohols is demonstrated by the synthesis and degradation of carbohydrate derivatives that contain two branch points. Benzyl 4,6- O -benzylidene-2,3-dideoxy-3- C -ethyl-2- C -hydroxymethyl-α- d -glucopyranoside ( 23 ) and -mannopyranoside ( 24 ) were formed from benzyl 2,3-anhydro-4,6- O -benzylidene-α- d -mannopyranoside ( 17 ) by a reaction sequence that involved ring-opening with ethylmagnesium chloride, oxidation, epimerisation, methylenation, and hydroboronation. The gluco isomer 23 was converted into (+)-( R )-2,3-bisacetoxymethylpentyl acetate ( 1 ) by sequential hydrogenolysis, borohydride reduction, periodate oxidation, borohydride reduction, and acetylation. The synthesis of 1 provides confirmatory evidence for the absolute configuration of the alkaloid pilocarpine ( 2 ). Unidentified products, and not the expected free-sugars, were obtained by acidic hydrolysis of methyl 4,6- O -benzylidene-2,3-dideoxy-3- C -ethyl-2- C -hydroxymethyl-α- d -glucopyranoside ( 8 ) and -mannopyranoside ( 9 ). Convenient syntheses of benzyl α- d -glucopyranoside derivatives are described.

A stereochemical comparison of some addition reactions to methyl 4,6-O-benzylidene-3-deoxy-3-C-ethyl-α-D-hexopyranosid-2-uloses

Abstract Methyl 4,6-O-benzylidene-3-deoxy-3-C-ethyl-α- D -ribo-hexopyranosid-2-ulose (2) reacts with lithium aluminium hydride, methylmagnesium iodide, and phenylmagnesium bromide to give products having only the allo configuration. The C-3 epimer of 2, methyl 4,6-O-benzylidene-3-deoxy-3-C-ethyl-α- D -arabino-hexopyranosid-2-ulose (7), reacts with lithium aluminium hydride to give only a product having a gluco configuration. With methylmagnesium iodide and phenylmagnesium bromide, 7 gives products having gluco and manno configurations. The 2-C-methyl-glucopyranoside preponderates in the former reaction, and the 2-C-phenyl-mannopyranoside is the major product in the latter reaction. The reaction between 2 and diazomethane gives a spiro-epoxide having the allo configuration as the major product (i.e., the same configuration as the 2-MeMgI reaction product), whereas the 7-diazomethane reaction gives a spiro-epoxide having the manno configuration (i.e., the same configuration as the minor product from the 7-MeMgI reaction) as the major product. With the thionyl chloride-pyridine reagent, 3-deoxy-3-C-ethyl-2-C-methyl-α- D -hexopyranosides are dehydrated endocyclically when H-3 and HO-2 are antiparallel and exocyclically when H-3 and HO-2 have a gauche relationship.