Nancy E. Williams

Structure-activity relations for anticholinergic 2(1-aryl(or cyclohexyl)-1-hydroxy-1-phenyl)methyl-1,3-dioxolans.

The syntheses and configurational assignments of some 4‐dimethyl aminomethyl‐2[1‐aryl (or cyclohexyl)‐1 ‐hydroxy‐1‐phenyl]methyl‐1,3‐dioxolans are described. The anticholinergic potency of the 4‐dimethylaminomethyl‐2[l‐cyclohexyl‐l‐hydroxy‐l‐phenyl]methyl‐1,3‐dioxolans, both in tertiary and quaternary form, depends principally on the configuration of the benzylic carbon atom, secondly on the C‐2 configuration and thirdly, and to a much lesser extent, if at all, on the C‐4 configuration. The dioxolans, which are derived formally from 4‐dimethylaminomethyl‐2‐methyl‐1,3‐dioxolan methiodide (or its tertiary analogue) by replacement of the 2‐methyl substituent by a 2[l‐aryl (or cyclohexyl)‐l‐hydroxy‐l‐phenyl]methyl group and the glycollates which are derived formally from acetylcholine (or its tertiary analogue) by corresponding substitution of the acetoxymethyl group have closely similar anticholinergic potencies.

The preparation and some reactions of 1,3,2-thiazaphospholidine-2-ones

Abstract 1,3,2-Thiazaphospholidine-2-ones have been prepared by rearrangement of the corresponding 1,3,2-oxazaphospholidine-2-thiones. The stereochemical course of ring opening reactions has been investigated.

Stereochemistry of some reactions between alkyl S-methyl methylphosphonothioates and chiral alkoxides

Abstract With R-(+) ethyl (or methyl) S-methyl methylphosphonothioate and (+)-pinacolyl alkoxide competitive and highly stereoselective displacements of O-alkyl and S-methyl occur, both reactions being with inversion of configuration. With the enantiomeric S-(-) ethyl (and methyl) S-methyl methylphosphonothioates and (+)-pinacolyl alkoxide the reactions, although still competitive, are no longer stereoselective. In contrast similar reactions with the sodium salt of (-)-menthol, (which might be considered to be the mirror image of (+)-pinacolyl alkoxide) occur highly stereoselectively with the S-(-) but not with R-(+) enantiomers. The displacement of O-alkyl from alkyl S-methyl methyl-phosphonothioates by ethoxide, pinacolyl alkoxide and menthyl alkoxide is not observed when methoxide is the nucleophile; in this case only displacement of S-alkyl group occurs.

Elevation of Endogenous Nucleophiles in Rat Lung by Cysteine and Glutathione Esters In Vitro

In this study, we have compared the uptake of L-cysteine (L-CySH), D-cysteine (D-CySH), L-cysteine isopropyl ester (L-CIPE) and D-cysteine isopropyl ester (D-CIPE) in rat lung slices and tracheal sections and determined the effectiveness of glutathione (GSH), GSH isopropyl monoester, GSH isopropyl diester, gamma-glutamylcysteine (gamma-glu-cys) isopropyl monoester and gamma-glu-cys isopropyl diester to elevate and prolong intracellular GSH concentrations in rat lung slices. Lung slices were incubated with 1.0 mM of thiol and the concentrations determined intracellularly and extracellularly with time. Slices incubated with GSH, GSH isopropyl diester and gamma-glu-cys isopropyl diester had cellular GSH concentrations increased by up to 60%, 95% and 58%, respectively, whereas GSH isopropyl monoester and gamma-glu-cys isopropyl monoester did not increase the intracellular GSH concentration. Extracellularly, the GSH concentration had decreased by 15%, GSH isopropyl diester by 27%, gamma-glu-cys isopropyl diester by 66% and both isopropyl monoesters by over 90% at 120 min. Lung slices and tracheal sections incubated with L- or D-CySH at 37 degrees had increased cellular concentrations of L- and D-CySH which ranged between 0.88-1.25 nmol mg(-1) and 1.35-2.25 nmol mg(-1) , respectively. Reducing the incubation temperature to 4 degrees had little effect on the accumulation of D-CySH; however, L-CySH concentrations increased progressively in the trachea and lung to reach 2.73 and 2.63 nmol mg(-1) at 90 min, respectively. Lung slices incubated with L- or D-CIPE had increased L- or D-CySH concentrations up to a max of 13.7 and 11.1 nmol mg(-1) and tracheal sections up to a max of 5.56 and 11.09 nmol mg(-1). In the lung slice medium, L- and D-CIPE levels had decreased by 75.2% and 74.0% at 90 min, respectively, and from the tracheal section medium, L- and D-CIPE concentrations had decreased by 66.7% and 32.7%, respectively. Preincubation of lung slices and tracheal sections with the carboxylesterase inhibitor, bis (p-nitrophenyl) phosphate (BNPP), almost completely prevented the disappearance of L- and D-CIPE extracellularly and greatly reduced the appearance of cellular L- and D-CySH. GSH, GSH isopropyl diester and gamma-glu-cys isopropyl diester elevated and prolonged GSH concentrations in rat lung slices, but GSH isopropyl monoester and gamma-glu-cys isopropyl monoester did not increase GSH levels. The uptake of L-CySH, but not D-CySH, is temperature sensitive in rat lung slices and tracheal sections and carboxylesterases appear to have a major influence on the uptake and metabolism of L- and D-CIPE by rat lung slices and tracheal sections.

Stereospecific halogenation of ethyl methyl phosphorothioic acid

Abstract Tetramethyl-α-halogenoenamines are useful reagents for the stereospecific conversion of phosphorothioic acids to the corresponding phosphoryl halides.

1,3,2-Oxazaphospholidine-2-thiones from (+)-norephedrine: stereospecific ring opening, possibly by an elimination–addition mechanism

1,3,2-Oxazaphospholidine-2-thiones derived from (+)-norephedrine react with alkoxide to give a product of kinetic control, formed by endocyclic P–O cleavage with inversion of configuration, and one of thermodynamic control, formed by endocyclic P–N cleavage also with inversion of configuration. It is suggested that the product of kinetic control is formed by an elimination–addition process involving a metaphosphorimidate intermediate, and that of thermodynamic control by a mechanism involving nucleophilic attack opposite endocyclic nitrogen.

The facile conversion of T-2 toxin and neosolaniol into anguidine

Abstract T-2 Toxin ( 5 ) and neosolaniol ( 6 ) are readily converted into anguidine ( 1 ) by a procedure where deoxygenation at the C-8 position is achieved, after conversion of the 3-TBDMS ether 7 of neosolaniol ( 6 ) to the β-bromide 11 for reduction to the anguidine precursor 12 .

Model studies of histrionicotoxin. The synthesis of the 1-azaspiro[5.5]undecane rings system from carbohydrate starting materials

The base-catalysed condensation of nitroethane with dimethyl-t-butylsilyl 2,3-O-isopropylidene-α-D-lyxopentodialdo-1,4-furanoside (2) gives a diastereoisomeric mixture of nitro alcohols, which on desilylation with fluoride ion in tetrahydrofuran rearranges stereospecifically to 1L-[1,2,5/3,4,6(NO2)]-3,4-O-isopropylidene-6-methyl-6-nitrocyclohexane-1,2,3,4,5-pentaol. The analogous condensation of the tetrahydropyranyl ether of 5-nitropentan-1-ol with aldehyde (2) and the subsequent desilylation and rearrangement occur similarly although the degree of stereoselectivity is lower. The major product, 1L-[1,2,5/3,4,6(NO2)]-3,4-O-isopropylidene-6-nitro 6-[4′-(tetra hydropyranyloxy)butyl] cyclohexane -1,2,3,4,5-pentaol (9), is converted into (6S,7R,8R,9R,10R,11S)-7,8,11-tri-o-acetyl-9,10-o-isopropylidene-1-azaspiro[5.5]undecane-7,8,9,10,11-pentaol (13), which has the ring skeleton of histrionicotoxin (1).

The Stereochemical Course of Substitution Reactions at Halomethylphosphonates

Abstract The stereochemistry of substitution at dihalomethylphosphonothioates is the same as for phosphorothioates whereas that for monohalomethylphosphono-thioates is similar to the unsubstituted phosphonothioates.

Some rearrangements of 2-deoxy-3,4,6-tri-O-methyl-2-methylamino-D-glucose and related compounds in basic solution; a novel base-promoted N→O migration of a phosphonate ester

Treatment of 2-deoxy-2-methylamino-3,4,6-tri-O-methyl-D-glucose (1) with sodium alkoxides affords 1-methyl-5-methoxymethylpyrrole-2-carbaldehyde (2) presumably by a series of elimination reactions and keto–enol equilibrations which precede ring closure and elimination of water. Substitution of nitrogen in (1) to give e.g. 2-N-[(R)-O-ethyl (phenyl)phosphoryl]-2-deoxy-2-methylamino-3,4,6-tri-O-methyl-D-glucose (8) interferes with the elimination sequence at an early stage so that when (8) is treated with sodium ethoxide a novel N→O migration of the phosphonate ester group occurs in a rapid reaction sequence which results in the conversion of (8) into 3-deoxy-2N-methyl-4,6-di-O-methyl-α,β-D-erythro-hexofuran-2-ulosylamine 1,1-diethyl acetal in high yield. The N→O migrations in this type of reaction involve P–N bond cleavage with retention of configuration at phosphorus, an unusual if not unique occurrence for reactions under basic conditions.