Unexpected formation of glycals upon attempted C-alkylation of protected glycosylacetylenes

Treatment of 3,7-anhydro-4,5,6,8-tetra-O-benzyl-1,2-dideoxy-D-glycero-D-galacto-oct-1 -ynitol (beta-D-mannosyl acetylene, 1) with 5 equivalents of n-butyllithium at either 0 or -78 degrees C resulted in the elimination of benzyl alcohol to yield 3,7-anhydro-5,6,8-tri-O-benzyl-1,2,4-trideoxy-D-arabino-oct-3-en-1-yn itol (glycal acetylene, 3) as the major product. Additional studies showed that 3 is also produced from two isomers of 1 with alpha-D-mannosyl and beta-D-glucosyl stereochemistry, but in lower yields. Furthermore, substrates in which the acetylene moiety is replaced by either a methyl or phenyl group do not produce a glycal product under these conditions. Finally, treatment of 1 with phenyllithium provides 3 in low yield. Deuterium labeling studies suggest that the reaction proceeds through an E2, rather than an E1cB, mechanism.     

Steric course of the hydration of D-gluco-octenitol catalyzed by alpha-glucosidases and by trehalase

Crystalline Aspergillus niger alpha-glucosidase and highly purified preparations of rice alpha-glucosidase II and Trichoderma reesei trehalase were found to catalyze the hydration of [2-(2)H]-D-gluco-octenitol, i.e., (Z)-3,7-anhydro-1,2-dideoxy-[2-2H]-D-gluco-oct-2-enitol, to yield 1,2-dideoxy-[2-2H]-D-gluco-octulose. In each case, the stereochemistry of the reaction was elucidated by examining the newly formed centers of asymmetry at C-2 and C-3 of the hydration product. The C-1 to C-3 fragment of each isolated [2-2H]-D-gluco-octulose product was recovered as [2-2H]propionic acid and identified by its positive optical rotatory dispersion as the S isomer, showing that each enzyme had protonated the octenitol (at C-2) from above its re face. 1H NMR spectra of enzyme/D-gluco-octenitol digests in D2O showed that the alpha-anomer of [2-2H]-D-gluco-octulose was exclusively produced by each alpha-glucosidase, whereas the beta-anomer was formed by action of the trehalase. The trans hydration catalyzed by the alpha-glucosidases was found to be very strongly inhibited by the substrate; the cis hydration reaction catalyzed by the trehalase showed no such inhibition. Special importance is attached to the finding that in hydrating octenitol each enzyme creates a product of the same anomeric form as in hydrolyzing an alpha-D-glucosidic substrate. This result adds substantially to the growing evidence that individual glycosylases create the configuration of their reaction products by a means that is independent of donor substrate configuration, that is, by a means other than "retaining" or "inverting" substrate configuration.     

An approach to stereoselective preparation of 3-C-glycosylated d- and l-glucals

An approach to stereoselective synthesis of α- or β-3-C-glycosylated l- or d-1,2-glucals starting from the corresponding α- or β-glycopyranosylethanals is described. The key step of the approach is the stereoselective cycloaddition of chiral vinyl ethers derived from both enantiomers of mandelic acid. The preparation of 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-l-arabino-hex-1-enitol, 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-d-arabino-hex-1-enitol, and 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)methyl]-d-arabino-hex-1-enitol serves as an example of this approach.     

Synthesis of 2,3- or 1,2-unsaturated derivatives of 2-deoxy-2-trifluoromethylhexopyranoses

The attempted conversion, by treatment with CsF/TBFA in MeCN, of acetylated derivatives of 2-chlorodifluoromethyl-2-deoxyhexopyranoses into their corresponding 2-trifluoromethyl derivatives was always accompanied by an elimination reaction. Thus, representative educts with the D-gluco- and D-manno-configuration gave derivatives of 2,3-dideoxy-2-trifluoromethyl-D-erythro-hex-2-enopyranose and 1,5-anhydro-2-deoxy-2-trifluoromethyl-d-arabino-hex-1-enitol, respectively. X-ray analyses are given for 1,3,4,6-tetra-O-acetyl-2-chlorodifluoromethyl-2-deoxy-alpha-D-mannopyranose and 4,6-di-O-acetyl-2,3-dideoxy-2-trifluoromethyl-alpha-D-erythro-hex-2-enopyranose.     

Synthèses et réductions de sucres fonctionnels mono et diinsaturés

Attempts to prepare 1,2:5,6 and 2,3:5,6 di-unsaturated sugars starting from 3,4,6-tri-O-acetyl-1,5-anhydro-1,2-dideo xy-d-arabino-hex-1-enitol or from ethyl 4,6-di-O-acetyl-1,5-anhydro-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside led to 1,5-anhydro-1,2,6-trideoxy-l-threo-hex-5-enitol and its 3,4-diacetate. Hydrogenation and hydrogenolysis of the unsaturated chloro and fluoro derivatives afforded 1,5-anhydro-1,2,6-trideoxy-d-arabino-hexitol and ethyl 4-O-acetyl-2,3,6-trideoxy-α-d-erythro-hexopyranoside.     

Stereochemistry of D-galactal and D-galacto-octenitol hydration by coffee bean alpha-galactosidase: insight into catalytic functioning of the enzyme.

Green coffee bean alpha-galactosidase was found to catalyze the hydration of D-galactal and (Z)-3,7-anhydro-1,2-dideoxy-D-galacto-oct-2-enitol (D-galacto-octenitol), each a known substrate for beta-galactosidase. The hydration of D-galactal by the alpha-galactosidase in D2O yielded 2-deoxy-2(S)-D-[2-2H]galactose; the hydration of D-[2-2H]galacto-octenitol in H2O yielded 1,2-dideoxy-2(R)-D-[2-2H]galactooct-3-ulose. Thus, the enzyme protonated each substrate from beneath the plane of the ring, as assumed for alpha-D-galactosides. These results provide an unequivocal assignment of the orientation of an acidic catalytic group to the alpha-galactosidase reaction center. In addition, they reveal a pattern of glycal/exocyclic enitol/glycoside protonation by the enzyme that differs from the pattern reported for beta-galactosidase and from that reported for alpha-glucosidases. Further findings show that D-galacto-octenitol is hydrated by the coffee bean alpha-galactosidase to form the alpha-anomer of 1,2-dideoxy-D-galactooctulose and by Escherichia coli beta-galactosidase to form the beta-anomer. That each enzyme converts this enolic substrate to a product whose de novo anomeric configuration matches that formed from its D-galactosidic substrates provides new evidence for the role of protein structure in controlling the steric outcome of reactions catalyzed by these and other glycosylases. The findings are discussed in light of the concept that catalysis by glycosidases involves a "plastic" protonation phase and a "conserved" product configuration phase.     

Oxidation of 3-C-(2-amino-2-deoxy-D-glucopyranosyl)-1-propene compounds and the structure of 3-C-(2-amino-2-deoxy-D-glucopyranosyl)-1,2-propanediol derivatives for a synthesis of 2,3-didehydro-2,7-dideoxy-N-acetylneuraminic acid

Oxidation of 5-acetamido-4,8-anhydro-1,2,3,5-tetradeoxy-D-glycero-D-ido-non-1-enitol [3-C-(2-amino-2-deoxy-beta-D-glucopyranosyl)-1-propene] was studied to search for preparative routes to aminodeoxy didehydro nonulosonic acid derivatives. Since only moderate chiral induction was observed with osmium tetroxide dihydroxylation as well as with peracid epoxidation, the catalytic asymmetric dihydroxylation conditions were applied to give the stereocontrolled formation of 1,2-propanediol derivatives. The structures of these diastereoisomeric 1,2-propanediol derivatives were determined by X-ray crystallographic analyses. The formation of diastereoisomeric 1,2-propanediols also varied with the nature of 2-substituent on the aminodoexy glycosyl moiety. Thus 5-acetamido-4,8-anhydro-3,5-dideoxy-D-erythro-L-ido-nonitol [(2S)-3-C-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-1,2-propanediol] was obtained predominantly up to 70% from 3-C-(2-acetamido-2-deoxyglycosyl)-1-propene by the use of ADmixbeta reagent. The (2S)-propanediol derivative was transformed in a five-step reaction sequence to 2,3-didehydro-2,7-dideoxy-N-acetylneuraminic acid.     

Location of a proton-donating group at the re-face of a β-d-galactosidase-bound,diastereotopic substrate

(Z)-3,7-Anhydro-1,2-dideoxy-2-deuterio-d-galacto-oct-2-enitol (1) was used as a diastereotopic probe, in order to elucidate the stereochemistry of protonation by β-d-galactosidase. Compound 1 can be converted by the enzyme into 1,2-dideoxy-2-deuterio-d-galacto-3-octulopyranose (2), which was submitted to periodate degradation. Propanoic acid derived from C-1, 2, and 3 of 2 has the (S) configuration, which proved the enzymic protonation of 1 to have taken place exclusively from the re-face.     

Reinvestigation of the iodocyclization of 4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-1,2,3-trideoxy-D-gluco-hept-1-enitol: unexpected formation of a 1,3-imino-heptitol derivative

The NIS-mediated iodocyclization of 4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-1,2,3-trideoxy-D-gluco-hept-1-enitol gave unexpectedly a 1,3-imino-heptitol derivative, namely 2-O-acetyl-N-benzyl-4,5,7-tri-O-benzyl-1,3-dideoxy-1,3-imino-D-glycero-D-ido-heptitol. This compound is a new example of a rare class of azetidine imino alditol derivatives which have interesting properties such as glycosidase inhibitors. The physical and spectral data for this imino heptitol were essentially identical to those reported for 2,6-anhydro-4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-3-deoxy-D-glycero-D-ido-heptitol, a derivative of C-(2-acetamido-2-deoxy-alpha-D-glucopyranosyl)methanol obtained from the same precursor [Lay, L.; Nicotra, F.; Panza, L.; Verani, A. Gazz. Chim. Ital. 1992, 122, 345-348]; these findings cast doubts on the structure reported for the latter product.     

Stereoselective synthesis of a C-glycosylic compound (a "methyl C-glycoside") through a regioselective free-radical ring-opening reaction. A single-crystal X-ray structure determination

Readily available 3,4,6-tri-O-acetyl-D-glucal was converted to 2,6-anhydro-5,7-O-benzylidene-1,3,4-trideoxy-D-arabino-hept-3-enitol, a methyl C-glycosylic compound. Cyclopropanation of 4,6-O-benzylidene-D-glucal, followed by tributylstannyl radical-mediated regioselective ring opening of the 1,2-cyclopropano sugar led to a 2,6-anhydro-1-deoxyheptose, (a "methyl C-beta-D-glycoside"). The stereochemistry of the 1,2-cyclopropano sugar and the "methyl C-glycoside" were confirmed by single-crystal X-ray diffraction studies.     

The synthesis of 3,4-dideoxyhex-3-enitols

Syntheses of (E)-3,4-dideoxy-erythro-, (Z)-3,4-dideoxy-D-threo- and (E)-3,4-dideoxy-D-threo-hex-3-enitols are described. The action of potassium selenocyanate on 1,2:5,6-di-O-isopropylidene-D-mannitol 3,4-di-p-toluenesulfonate has been reexamined. Epoxidation of (E)-3,4-dideoxy-1,2:5,6-di-O-isopropylidene-D-threo-hex-3-enitol affords 3,4-anhydro-1,2:5,6-di-O-isopropylidene-D-mannitol and -D-iditol in the approximate proportions of 3:1. The configurations of the two epoxides were assigned on the basis of the reaction of the latter compound with sodium methoxide to give 1,2:5,6-di-O-isopropylidene-4-O-methyl-D-altritol.     

A precursor to the beta-pyranosides of 3-amino-3,6-dideoxy-D-mannose (mycosamine).

SN2-type reaction of 3-O-(1-imidazyl)sulfonyl-1,2:5,6-di-O-isopropylidene-alpha-D-gluco furanose with benzoate gave the 3-O-benzoyl-alpha-D-allo derivative 2, which was hydrolysed to give the 5,6-diol 3. Compound 3 was converted into the 6-deoxy-6-iodo derivative 4 which was reduced with tributylstannane, and then position 5 was protected by benzyloxymethylation, to give 3-O-benzoyl-5-O-benzyloxymethyl-6-deoxy-1,2-O-isopropylidene-alpha -D- allofuranose (6). Debenzoylation of 6 gave 7, (1-imidazyl)sulfonylation gave 8, and azide displacement gave 3-azido-5-O-benzyloxymethyl-3,6-dideoxy- 1,2-O-isopropylidene-alpha-D-glucofuranose (9, 85%). Acetolysis of 9 gave 1,2,4-tri-O-acetyl-3-azido-3,6-dideoxy-alpha,beta-D-glucopyranose (10 and 11). Selective hydrolysis of AcO-1 in the mixture of 10 and 11 with hydrazine acetate (----12), followed by conversion into the pyranosyl chloride 13, treatment with N,N-dimethylformamide dimethyl acetal in the presence of tetrabutylammonium bromide, and benzylation gave 3-azido-4-O-benzyl-3,6-dideoxy-1,2-O-(1-methoxyethylidene)-alpha-D -glucopyranose (15). Treatment of 15 with dry acetic acid gave 1,2-di-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranose (16, 86% yield) that was an excellent glycosyl donor in the presence of trimethylsilyl triflate, allowing the synthesis of cyclohexyl 2-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranoside (17, 90%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluorinated acyclo-C-nucleoside analogues from glycals in two steps

A convenient two-step strategy is reported for the synthesis of fluorinated optically pure acyclo-C-nucleoside analogues starting from simple glycals. In the first step, benzyl- or p-methoxybenzyl-protected glycals are treated with trifluoroacetic anhydride, bromodifluoroacetyl chloride, trichloroacetyl chloride, and perfluorooctanoyl chloride, respectively, in the presence of Et3N. This one-pot procedure yields 1,2-unsaturated sugars (1,5-anhydro-3,4,6-tri-O-benzyl (or p-methoxybenzyl) 2-deoxy-2-perhalogenoacyl-D-arabino / lyxo-hex-1-enitols 4-9) acylated at C-2. In the second step, a selective ring transformation is induced by treatment of the C-acylated glycals with bis-nucleophiles (hydrazine, phenylhydrazine, o-phenylenediamine, hydroxylamine). In particular, 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trifluoroacetyl-D-arabino-hex-1-enitol (4) and 1,5-anhydro-2-deoxy-2-trifluoroacetyl-3,4,6-tri-O-(p-methoxybenzyl)-D-arabino-hex-1-enitol (8) were reacted with these nucleophiles generating the final C-nucleoside analogues of pyrazole (10, 11, and 12), diazepine (13), and isoxazole (15), respectively, containing a carbohydrate side chain linked to the heterocyclic ring.     

Reactions of sugar nitro-alkenes with 3-aminocrotonic esters

3,4,5,6,7-Penta-O-acetyl-1,2-dideoxy-1-nitro-d-gluco- and -d-galacto-hept-1-enitol and 3,4,5,6-tetra-O-acetyl-1,2-dideoxy-1-nitro-d-xylo-hex-1-enitol react with 3-aminocrotonic esters, yielding mixtures of the epimeric Michael adducts. These are thermally stable, and do not cyclize to pyrroles. The structures, configurations, and conformations of these compounds were established on the basis of their spectroscopic and X-ray crystallographic data. The intramolecularly bonded, (Z) configuration was deduced for all of them. Mild hydrolysis of adducts with acid yields the corresponding 2-(nitromethylpolyacetoxyalkyl)acetoacetates.     

Synthesis and antitumor activity of 3'-C-methyl-daunorubicin

Reaction of 1,5-anhydro-4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoro-acetami no-L-lyxo-hex-1-enitol with daunomycinone in the presence of anhydrous toluene-p-sulfonic acid in benzene, followed by removal of the N- and O-protecting groups under mild conditions, gave 3'-C-methyldaunorubicin. The antitumor activity of the new anthracycline glycoside has been evaluated.     

The interaction of per-O-acetylated acyclic 1-(1-butylindol-3-yl)-1-deoxy-ketoses with silylated uracil

The per-O-acetylated open chain derivatives of 1-(1-butylindol-3-yl)-1-deoxy-1-L-sorbose and 1-(1-butylindol-3-yl)-1-deoxy-L-tagatose, which are readily available by alkaline degradation of 1-butylascorbigen followed by acetylation, were used in a nucleoside-type synthesis. The interaction of these ketoses derivatives with bis-(trimethylsilyl)-uracil yielded in each case a mixture of (E)-2,4,5,6-tetra-O-acetyl-1-(1-butylindol-3-yl)-1,3-dideoxy-3-(uracil-1-yl)-L-xylo-hexa-1-enitol and (E)-2,4,5,6-tetra-O-acetyl-1-(1-butylindol-3-yl)-1,3-dideoxy-3-(uracil-1-yl)-L-lyxo-hexa-1-enitol, which were separated by preparative HPLC. The deacetylation of each of these compounds by MeONa in MeOH produced a mixture of 1-(1-butylindol-3-yl)-1,3-dideoxy-4-O-methyl-3-(uracil-1-yl)-alpha-L-sorbopyranose and 1-(1-butylindol-3-yl)-1,3-dideoxy-4-O-methyl-3-(uracil-1-yl)-beta-D-fructopyranose, which were also separated by HPLC, the structures were confirmed by NMR.     

Photochemical addition of 2-propanol and of acetone to 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal

Irradiation of a solution of 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal (1) in 1:200 acetone-2-propanol with a high-pressure mercury-lamp gave 4,5,6,8-tetra-O-acetyl-3,7-anhydro-1-deoxy-2-C-methyl-D-glycero-D-gulo-octitol (2) (51.2%), -D-glycero-D-ido-octitol (3) (16.2%), and-D-glycero-D- galacto-octitol (4) (21.0%). The irradiation of 1 in 1:1 acetone-2-propanol gave 5,6,8-tri-O-acetyl-3,7-anhydro-1-deoxy-4-C-(1-hydroxy-1-methylethyl)-2-C-methyl-D-glycero-D-(gluco or manno, etc.)-octitol 2,4,4¹-orthoacetate (17%) and a 2:1:1 mixture of 2, 3, and 4 (64%). Moreover, the irradiation of 1 in 1:9 acetone-tert-butyl alcohol gave 2 (15%), 3 (9%), 4 (7%), and (4S)-4,5,6,8-tetra-O-acetyl-2,4:3,7-dianhydro-1-deoxy-2-C-methyl-D-gluco-octos-4-ulose (14%).     

Stereoselective synthesis of a ketohexofuranose from an aldohexopyranose by a [6+1-1] strategy

Ozonolysis of 2-acetoxymethyl-1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hex-1-enitol gave 1-O-acetyl-3,4,6-tri-O-benzyl-4-O-formyl-D-arabino-hex-2-ulose (5). Subsequent hydrolysis and acetylation of 5 provided 1,2-di-O-acetyl-3,4,6-tri-O-benzyl-D-fructofuranose 6 in excellent yield. This methodology allows specific deuteration at C-1 of a protected D-fructofuranose derivative. This approach therefore could serve as [6+1-1] formulation for hexose series inter-conversion, that is, aldohexopyranose to ketohexofuranose.     

Fluorinated carbohydrates as potential plasma membrane modifiers and inhibitors. Synthesis of 2-acetamido-2,6-dideoxy-6-fluoro-D-galactose

Reaction of benzyl 2-acetamido-3,4-di-O-benzyl-2-deoxy-6-O-mesyl-alpha-D-galactopyran oside with cesium floride gave benzyl 2-acetamido-3,6-anhydro-4-O-benzyl-2-deoxy-alpha-D-galactopyranoside instead of the desired 6-fluoro derivative. Acetonation of benzyl 2-acetamido-2-deoxy-6-O-mesyl-alpha-D-galactopyranoside gave the corresponding 3,4-O-isopropylidene derivative. The 6-O-mesyl group was displaced by fluorine with cesium fluoride in boiling 1,2-ethanediol, and hydrolysis and subsequent N-acetylation gave the target compound. In another procedure, treatment of 2-acetamido-1,3,4-tri-O-acetyl-2-deoxy-alpha-D-galactose with N-(diethylamino)sulfur trifluoride gave 2-acetamido-1,3,4-tri-O-acetyl-2,6-dideoxy-6-fluoro-D-galactose which, on acid hydrolysis followed by N-acetylation, gave 2-acetamido-2,6-dideoxy-6-fluoro-D-galactose.     

Synthesis of 1,3-Dl-O-Acetyl-5-O-Benzoyl-2-O -(O-Carboran-1-Ylmethyl)- D-Ribofuranose. A General Precursor for the Preparation of Carborane-Containing Nucleosides for Boron Neutron Capture Therapy

Abstract

An eight-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-O-(o-carboran-1-ylmethyl)-D-ribofuranose 9 was carried out from 1,2:5,6-O-isopropylidene-α-D-allofuanose 1. Condensation of 9 with trimethylsilyl protected uracil in the presence of trimethylsilyl trifluoro-methanesulfonate, and subsequent deblocking of the resulting 1-[3-O-acetyl-5-O-benzoyl-2-O-(o-carboran-1-ylmethyl)-D-ribofuranosyl]uracil 10 (>95& β-configuration) by alkaline hydrolysis, yielded 1-[2-O-(o-carboran-1-ylmethyl)-β-D-ribofuranosyl]uracil 11.