Gilbert J. Lewis

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 ).

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.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry : Part VI. A stereochemical comparison of S-alkyl alkylphosphonothioate-sodium methoxide and S-alkyl phosphorothioate-sodium methoxide reactions☆

Abstract Cyclic phosphonamidothioate and cyclic phosphoramidothioate derivatives of carbohydrates are converted stereospecifically into acyclic S -methyl phosphonothioate and phosphorothioate carbohydrate derivatives. These derivatives are convenient substrates for studies of nucleophilic displacement reactions of phosphorus in acyclic phosphorus thioates. The S -methyl group is displaced by methoxide with inversion of configuration at phosphorus in the phosphonothioates and with retention of configuration in the phosphorothioates.

The influence of steric factors in diazoalkane-pyranosid-2-ulose reactions

Abstract The reactions of diazomethane with methyl 4,6-O-benzylidene-3-deoxy-3-C-ethyl-α- D -arabino- and -ribo-hexopyranosid-2-uloses (1 and 2) afford spiro-epoxides preponderantly, whereas the corresponding reactions of 1 and 2 with diazoethane give, exclusively, ring-expansion products. Compound 1 gives, preponderantly, heptoseptanosid-3-uloses with diazoethane and not the expected heptoseptanosid-2-uloses, thereby indicating that the nature of the ring-expansion products is controlled by steric rather than by electronic effects. It is shown that comparisons of pyranosid-ulose-diazoalkane reactions can provide new information about the stereochemical course of diazoalkane ring-expansion reactions. The reactions of 1 and 2 with diazoethane provide a route to higher sugars containing two R-C-H branch points.

Stereospecific synthesis from carbohydrate precurors of (R)- and (S)-ethyl isopropyl methyl phosphate and other optically active neutral phosphorus esters

Stereospecific syntheses starting from carbo-hydrate precursors of (+)-(R) and (–)-(S)-ethyl iso-propyl methyl phosphates, (+)-(R)-O-ethyl O,S-dimethyl phosphorothioate, and (+)-(R)-ethyl methyl methyl-phosphonate are described; the enantiomeric purity of these compounds was determined by an n.m.r. method involving the use of tris-[3-(heptafluoro-n-propylhydroxy-methylene)-(+)-camphorato]europium(III).

Differences in mechanisms of nucleophilic substitution at phosphorus in S-alkyl alkylphosphonothioates and S-alkyl phosphorothioates

Whereas most phosphono-derivatives are hydrolysed more rapidly by hydroxide than the corresponding phosphoro-derivatives, the reverse situation holds for S-alkyl phosphonothioates and S-alkyl phosphorothioates; this reversal of the more usual pattern may be related to a stereochemical difference in that nucleophilic substitution in S-alkyl alkylphosphonothioates proceeds with inversion of configuration, whereas retention of configuration is observed for similar reactions with S-alkyl phosphorothioates.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part III. Stereochemical course of nucleophilic displacements of 2-substituents in 1,3,2-dioxaphosphorinan-2-ones and related compounds

The stereochemistry of displacement of 2-substituents from 1,3,2-dioxaphosphorinan-2-ones, 1,3,2-oxathiaphosphorinan-2-ones, and 1,3,2-dioxaphosphorinan-2-thiones has been shown to depend on the nature of both the entering and the leaving group. Inversion of configuration has been observed for reactions involving good leaving groups and weak nucleophiles whereas with less good leaving groups and stronger nucleophiles the displacement reactions proceed with retention of configuration.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part I. Stereochemistry of 1,3,2-dioxaphosphorinan-2-ones and synthesis of optically active phosphine oxides

Pairs of 1,3,2-dioxaphosphorinan-2-ones, epimeric at phosphorus, have been prepared by treatment of methyl 2,3-di-O-methyl-α-D-glucopyranoside and -galactopyranoside with phosphonic or phosphoric dihalides. The configuration at phosphorus in these derivatives has been assigned on the basis of n.m.r. and i.r. data and of comparison of the rates of formation and relative stabilities of the epimers. For the formation of the 1,3,2-dioxaphosphorinan-2-ones it is suggested that the kinetic preference for the thermodynamically less stable isomers depends on steric interactions in twist-ring transition intermediates, and that the subsequent equilibration depends on the relative stabilities of the chair conformers. The conversions of methyl 2,3-di-O-methyl-α-D-glucopyranoside (R)- and (S)-4,6-methyl phosphonate into (S)- and (R)-ethylmethylphenylphosphine oxide, respectively, by sequential addition of phenylmagnesium bromide and ethylmagnesium bromide provide examples of the utility of carbohydrate 1,3,2-dioxaphosphorinan-2-ones for the stereospecific synthesis of optically active phosphine oxides.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part II. Synthesis and configurational assignments of 1,-3,2-oxathiaphosphorinan-2-ones and 1,3,2-dioxaphosphorinan-2-thiones

Methyl 2,3-di-O-methyl-4(or 6)-thio-α-D-glucopyranoside (R)- and (S)-4,6-methylphosphonothioates and methyl 2,3-di-O-methyl-α-D-glucopyranoside (R)- and (S)-4,6-methyl-(and phenyl)-phosphonothioates have been prepared by conventional procedures. The corresponding ethyl phosphorothioates are also described. The configuration at phosphorus in the thiolates has been assigned on the basis of n.m.r. and i.r. data. The thioxo-compounds have been correlated chemically with the corresponding phosphates of previously determined configuration. The preparation of methyl 2,3-di-O-methyl-4(and 6)-thio-α-D-glucopyranosides is described.