Search

The unreported title compound and its 2,6-di-O-benzyl derivative have been prepared from methyl β-D-galactopyranoside through a sequence involving the bisglycoside methyl 2,6-di-O-benzyl-5-O-methoxv-β-D-galactopyranoside 8, the precursor of L-orabino-hexos-5-ulose, that was converted to the L-lyxo series by inversion at C-3. The inversion was achieved in acceptable yields by selective triflation, followed by displacement with benzoate, and by an oxidation/reduction sequence. Whereas 2,5-di-O-benzyl-L-lyxo-hexos-5-ulose exists entirely as a mixture of the two anomeric 1,4-furanosic forms, the unprotected hexos-5-ulose involves at equilibrium in CD3CN/D2O at least eight tautomers, one of which is predominant.

The known oxidation-oximation-reduction sequence leading from d -galactopyranosides to 2-amino-2-deoxy- d -talopyranosides through replacement of the 2-hydroxy by a 2-amino group with inversion has been reinvestigated. The easily obtainable methyl 3,4-O- isopropylidene -6-O-(1- methoxy-1-methylethyl)-β- d -galactopyranoside ( 1 ) was chosen as the suitably protected starting material. The single steps in the synthetic sequence were analyzed in some detail from the point of view of different reagents, stereoselectivities, side products, NMR spectra and conformations of intermediates. Owing to side reactions in the oxidative and reductive steps and to the incomplete diastereoselectivity in the latter, the overall yields in the conversion of 1 into methyl 2- acetamido -6-O- acetyl-2-deoxy -3,4-O- isopropylidene-β- d -talopyranoside did not exceed 50%.

An improved method for the preparation of 4,6-O- benzylidene- d -glucopyranose (BG), and new or corrected data on its 1H and 13C NMR spectra, specific rotations, and tautomeric equilibria, and on those of its anomeric sodium salt (BGNa), are reported. Evidence is presented in favour of the hypothesis that crystalline BGNa exists entirely in its β-anomeric form and that it can be useful in the access to β-glucosides in reactions with strong electrophiles under strictly heterogeneous conditions.

3,4-Epoxytetrahydrofuran is hydrolyzed by rabbit liver microsomal epoxide hydrolase (MEH) with a high preference for the attack by water at the (S) epoxide carbon to give the (R,R)-diol with an e.e. of 96.5±0.3%. In the acid catalyzed hydrolysis of trans-3,3a-epoxyoctahydrobenzofuran the oxirane ring is opened with inversion exclusively on the tertiary carbon atom to give the corresponding trans-diol, whereas hydrolysis of the cis isomer is less regioselective, the ratio of attack at the tertiary and secondary carbons being 81:19. The MEH catalyzed hydrolysis of the same two substrates occurs exclusively at their secondary epoxide carbons and with a very high enantioselectivity: only enantiomers of configuration (3S,3aR) of the cis- and trans-epoxide are substrates for the enzyme and give the corresponding (3R,3aR)-diols with at least 98% e.e., the corresponding (3R,3aS)-epoxides being totally resistant to enzymatic hydrolysis. These results agree well with previously formulated rules on steric requirements of MEH subtrates. Absolute configurations and optical purities of new chiral compounds were obtained by chiroptical, NMR and chiral chromatographic techniques. Conformations of the octahydrobenzofuran derivatives were derived from coupling constants and found to be in fairly good agreement with those deduced from molecular mechanics calculations.

3,4-Epoxytetrahydrofuran is hydrolyzed by rabbit liver microsomal epoxide hydrolase (MEH) with a high preference for the attack by water at the (S) epoxide carbon to give the (R,R)-diol with an e.e. of 96.5±0.3%. In the acid catalyzed hydrolysis of trans-3,3a-epoxyoctahydrobenzofuran the oxirane ring is opened with inversion exclusively on the tertiary carbon atom to give the corresponding trans-diol, whereas hydrolysis of the cis isomer is less regioselective, the ratio of attack at the tertiary and secondary carbons being 81:19. The MEH catalyzed hydrolysis of the same two substrates occurs exclusively at their secondary epoxide carbons and with a very high enantioselectivity: only enantiomers of configuration (3S,3aR) of the cis- and trans-epoxide are substrates for the enzyme and give the corresponding (3R,3aR)-diols with at least 98% e.e., the corresponding (3R,3aS)-epoxides being totally resistant to enzymatic hydrolysis. These results agree well with previously formulated rules on steric requirements of MEH subtrates. Absolute configurations and optical purities of new chiral compounds were obtained by chiroptical, NMR and chiral chromatographic techniques. Conformations of the octahydrobenzofuran derivatives were derived from coupling constants and found to be in fairly good agreement with those deduced from molecular mechanics calculations.

An improved method for the preparation of 4,6-O- benzylidene- d -glucopyranose (BG), and new or corrected data on its 1H and 13C NMR spectra, specific rotations, and tautomeric equilibria, and on those of its anomeric sodium salt (BGNa), are reported. Evidence is presented in favour of the hypothesis that crystalline BGNa exists entirely in its β-anomeric form and that it can be useful in the access to β-glucosides in reactions with strong electrophiles under strictly heterogeneous conditions.

3,4-O-Isopropylidene derivatives of the title compounds have been prepared by new methods and found to exhibit a high preference for tautomeric forms deriving from hemiacetalization between 6-CH2OH, or 6-CH(OH)2, and 2-CO functions.

1,5-Anhydro- d -galactitol, easily available from d -galactose, was selectively protected in positions 2, 3 and 4 and converted into 5-O-acetyl-2,6-anhydro-3-deoxy l -threo-hex-2-enonic acid methyl ester, which, on reaction with MCPBA in acetic acid gave 2,5-di-O-acetyl-α- l -lyxo-hex-2-ulopyranosonic acid methyl ester. Reaction of the latter with sodium methoxide produced sodium l -ascorbate in high yield. Several side-reactions and the conformations of some of the intermediates are also discussed.

Meta-chloroperbenzoic acid can be used as a mild and selective reagent for the removal of the O-propenyl group in the deprotection sequence of allyl protected hydroxyl functions. Its use is illustrated in four synthetic pathways, leading, respectively, to methyl 3-0-acetyl-4- deoxy-6-0-( 1-methoxy-1-methylethyl)-α-L-threo-4-hexenopyranoside, to methyl 2-O-acetyl-3,4,6-tri-O-methyl-α- and β-D-galactopyranoside and to benzyl 6-O-allyl-3,4-0-isopropylidene-β-D-galactopyranoside.

The title compound, previously unreported in either enantioform, and its 2,6-di-O-benzyl derivative have been synthesized through a stereocontrolled epimerization at C-2 of 6-O-protected methyl 3,4-O-isopropylidene-5-C-methoxy-β-D-galactopyranosides. The epimerization, performed through a high yielding sequence of oxidation-reduction owing to the cooperative role of the equatorial C-1 aglycon and the steric hindrance of the isopropylidene group, turned out to be completely diastereoselective. Whereas the unprotected L-ribo-hexos-5-ulose exists, as proved by NMR in D2O, in five main tautomeric forms in a ratio of about 4:2:2:1:1, only two anomeric 1,4-furanosic forms are present at equilibrium in its 2,6-di-O-benzyl derivative, in ratios ranging from 10:1 to 7:3, depending on the prevalence of D2O or CD3CN in the solvent mixture.

The double reductive amination of l - arabino -hexos-5-ulose with benzhydrylamine and NaBH 3 CN takes place in a diastereospecific manner giving in moderate chemical yield (36 %) the galactosidase inhibitor 1-deoxy- d -galactostatin. The aminocyclization of 2,6- di -O- benzyl- l -arabino- hexos-5-ulose is more complicated giving results dependent from the type of amine: with ammonia or methylamine a mixture of C-5 epimeric 1-deoxyazapyranoses ( d -galacto l -altro ratio ≈ 4:1 ) is obtained in 45–65% combined yield, while with benzhydrylamine substantial amounts of an acyclic 1-deoxy-1-benzydrylamino-hexitol (10 % yield) is isolated together with the expected 1-deoxy-azasugars of the d - galacto and l - altro series.

A new approach to d - xylo -hexos-5-ulose, a useful synthetic intermediate, is described, starting from methyl β- d -galactopyranoside and involving as the key step an epoxidation/methanolysis of 3- O -protected methyl 2,6- di -O- benzyl-4-deoxy-α- l -threo- hex-4-enopyranosides , to produce bis-glycosides of the parent dicarbonylic sugar, which can be obtained free or selectively protected through hydrogenolytic and/or hydrolytic procedures. The diastereo- and regioselectivity of the epoxidation and solvolysis steps are investigated and tentatively interpreted, and new products characterized by NMR techniques.

3,4- O -Isopropylidene- d - lyxo -hexopyranosid-2-ulose derivatives, obtained by oxidation of 3,4,6-protected d -galactopyranosides, can be alkylated in their anionic 2,6-pyranose forms to produce bis-glycosides containing the 2,5-dioxabicyclo[2.2.2]octane ring system. The 1-benzyl-2-methyl bis-glycoside 4b , when subjected to catalytic hydrogenolysis, produces the methyl d - lyxo -hexopyranos-2-uloside 10 , existing as an 8:2 mixture of 1,5-pyranose anomers 9 . Computational and NMR evidence is presented in favour of the hypothesis that the major anomer has the α configuration. Reduction of 9/10 with NaBH 4 gives methyl 3,4- O -isopropylidene-β- d -tagatopyranoside, that can be hydrolyzed to d -tagatose. A simple synthesis of 1,5-anhydro- d -tagatose, starting from 1,5-anhydro- d -galactitol, is also presented. All new compounds were fully characterized by elemental analysis and by 1 H and 13 C NMR spectroscopy.

5-C-alkoxy-β-D-galactopyranosides, which are easily convertible into L-arabino-hexos-5-uloses, can be prepared from β-D-galactopyranosides via peroxyacid oxidation in an alcoholic solvent of intermediate 4-deoxy-α-L-threo-hex-4-enopyranosides.

Meta-chloroperbenzoic acid can be used as a mild and selective reagent for the removal of the O-propenyl group in the deprotection sequence of allyl protected hydroxyl functions. Its use is illustrated in four synthetic pathways, leading, respectively, to methyl 3-0-acetyl-4- deoxy-6-0-( 1-methoxy-1-methylethyl)-α-L-threo-4-hexenopyranoside, to methyl 2-O-acetyl-3,4,6-tri-O-methyl-α- and β-D-galactopyranoside and to benzyl 6-O-allyl-3,4-0-isopropylidene-β-D-galactopyranoside.

Racemic isobutyl 3,4-anhydro-2,6-dideoxy-α- lyxo -hexopyranoside, 3, was prepared starting from the cycloadduct between 3-buten-2-one and isobutyl vinyl ether, through a sequence involving hydroboration-oxidation, mesylation, anomeric equilibration, elimination and epoxidation. The intermediate isobutyl 2,3,4,6-tetradeoxy-α-3-DL-hexenopyranoside, 10 was not stable under the conditions used for its preparation ( t -BuOK in DMSO), being converted in part into the corresponding 2-hexenopyranoside. Under the same conditions the -anomer of 10 was stable. Complete hydrolysis of DL-3 with aqueous NaOH, or with microsomial epoxide hydrolase (MEH) gave exclusively the xylo -diol (isobutyl DL-α-boivinopyranoside 5). When the hydrolysis with MEH was stopped near 50% conversion and the product diol was separated from the unchanged epoxide, both were optically active, the former having the L and the latter the D configuration. An ee of at least 96% was found for both the diol and the epoxide by the use of a chiral shift reagent.

The reaction of 1,2-epoxy-1-(p-nitrophenyl)cyclohexane with boron trifluoride–diethyl ether exhibits a pronounced solvent dependence: in benzene it gives a 9 : 1 ratio of cis-2-fluoro-2-(p-nitrophenyl)cyclohexanol to 1-(p-nitrophenyl)cyclopentanecarbaldehyde, which does not change with reaction time; in dichloromethane the cis-fluorohydrin is again the main primary product, but is rapidly converted into the aldehyde in the reaction medium; and in ether about equimolar amounts of cis- and trans-2-fluoro-2-(p-nitrophenyl)cyclohexanol are formed. The presence of small amounts of water in the dichloromethane solvent causes the formation of a ca. 6 : 4 mixture of cis-fluorohydrin and aldehyde, the composition of which changes little with reaction time. This solvent dependence of the reaction can be useful for preparative purposes. A reaction mechanism is suggested.

The steric course of some reactions of 2,3-dihalotetrahydropyrans with sodium methoxide and with methyl- and phenyl-magnesium bromides has been reinvestigated. Whereas the methanolysis of the cis - and trans -dichlorides occurs with practically complete inversion, it has been confirmed that their reactions, as well as those of the dibromides, with methyl-magnesium bromide are non-stereospecific, yielding mixtures of trans - and cis -3-halo-2-methyl-tetrahydropyrans in ratios that are independent of the configurations of the starting dihalides. It has been further established that Grignard reagents cause equilibration of cis - and trans -dihalide mixtures in a reaction that is much faster than the Grignard coupling step.

Triethylamine and bromine in 1,2-dichloroethane give a non isolable 1:1 charge transfer complex with Kf>107 M−1, which undergoes a fast intramolecular oxidation to N,N-diethylethyldeneiminium bromide and hydrogen bromide.

Reaction of several α- and β-galactopyranosides with 2,2-dimethoxypropane produced up to five types of mono-, bis-, and tris(isopropylidene)acetals, among which the 3,4-0-iso-propylidene-6-0-(2-methoxyisopropyl) derivatives can be obtained in high yield and be useful intermediates for selective syntheses of 2-, 6-, and 2,6-0-substituted galactose derivatives.

(±)-Chlorofluoroacetic acid ( 1 ) has been resolved into its enantiomers through the dehydroabietylamine salts; LAH reduction of methyl (−)-chlorofluoroacetate has given (−)-chlorofluoroethanol. An approximate estimation of the optical purity of (−) -1 has been carried out by a GLPC method. Partial kinetic resolutions of (±) -1 have been achieved through reactions with half-molar amounts of 5,6α-epoxy-5α-cholestan-3β-ol and 5,6β-epoxy-5β-cholestan-3β-ol.

The stereochemistry of the reaction of cis - and trans -stilbene-2-carboxylic acids with chlorine and bromine, yielding the two diastereoisomeric 3-phenyl-4-halo-3:4-dihydro iso coumarins (III) and (IV) has been investigated. The reactions are entirely stereospecific and involve intramolecular attack by the carboxyl group on an intermediate carbonium or halonium ion. The lactones (III) and (IV) yield the two 3-(α-hydroxybenzyl) phthalides (V) and (VI), with retention of configuration. Thionyl chloride transforms (V) and (VI) into the 3-(α-chlorobenzyl) phthalides (IX) and (X), with inversion. Steric effects are mainly responsible for the alternative formation of halolactones or normal dihalogenated derivatives in the reactions between unsaturated acids and halogens.

The reactions of some methyl derivatives of indole-3-aldehyde with nitric acid in acetic acid medium have been investigated. 2-Methylindole-3-aldehyde gives the 6-nitro derivative, together with some 2-methyl-3-nitro- and 2-methyl-3,6-dinitroindole. 1-Methylindole-3-aldehyde gives 4- and 6-nitro derivatives, 1-methyl-3-nitroindole, 1-methyl-5-nitroisatin, N-formyl-N-methyl-5-nitro-anthranilic acid and N-methyl-5-nitroanthranilic acid. 1,2-Dimethylindole-3-aldehyde gives 1,2-dimethyl-3-nitroindole, 1,2-dimethyl-3,6-dinitroindole, N-methyl-4-nitroanthranilic acid and 4- and 6-nitro-2-methylaminobenzonitrile.

The trans and cis forms of 3- and 4-stillbazole oxide and trans -2-( p -methoxystyryl)pyridine oxide have been prepared from the corresponding stilbazoles, by addition of HClO and HBrO, followed by dehydrohalogenation of the halohydrins with base. The configurations of the epoxides have been confirmed by their NMR spectra. The stereochemistry of the ring opening of the above mentioned compounds with HCl, HBr and CCl 3 COOH has been investigated and compared with that of the similar reactions of the stilbene oxides, very pronounced differences in steric course being observed. The reactions of the stilbazole oxides with the hydrogen halides take place with complete inversion, those with CCl 3 COOH with decreasing degrees of inversion in going from the 2- to the 3- and to the 4-pyridyl derivatives.

In the reaction of mesitoic acid with trans-α-methylstilbene oxide the anion adds exclusively to the tertiary carbon atom, to give the hydroxy ester of type III, which also can be prepared from α-methylbenzoin mesitoate with KBH4 and is transformed into the isomeric ester of type V by the action of alkali; the latter ester also being formed by reaction of threo-1,2-diphenyl-1,2-propanediol with mesitoyl chloride. Other acids yields only esters of type V, probably formed from primary products of type III by a rapid acyl group shift. All esters thus prepared belong to the threo series; corresponding erythro esters were prepared for comparison. The reductions of α-methylbenzoin acetate and mesitoate with LiA1H4 produce exclusively threo-1,2-diphenyl-1,2-propanediol, in contrast with the low stereoselectivity of the similar reduction of α-methylbenzoin itself.

The asymmetric bromination of 4-methylcyclohexene (1) in the presence of dihydrocinchonine gave a levorotatory mixture of trans-3-cis-4- (2) and cis-3-trans-4-dibromo-1-methylcyclohexane (3), containing an excess of (−)-2 and (−)-3. The steric course and optical yields of the reaction were completely analyzed, on the basis of polarimetric, chromatographic and NMR methods, and the absolute configurations of 2 and 3 were deduced from the results of the bromination of (+)-1. The hypothesis that the bromination of alkenes with bromine-dihydrocinchonine gives an excess of the (R:R)-enantiomer was thus confirmed. Partial asymmetric bromination of (±-1 gave (−)-2 of higher optical purity, and the recovered olefin was dextrorotatory. The thermal isomerization of 2 to 3 was also investigated.