Stereoselective synthesis of 2-O-MEM-2,3-unsaturated-β-O-glycosides and elaboration to useful synthetic tools

The glycosylation of alcohols by the new 2-O-MEM-substituted d-galactal-derived allyl epoxide affords the corresponding alkyl 2-O-MEM-3-deoxy-β-d-threo-hex-2-enopyranosides through a completely 1,4-regio- and a highly to completely substrate-dependent stereoselective glycosylation processes. The glycosides obtained can be regioselectively transformed into corresponding 3-deoxy-β-O-glycosides, 3-deoxy-β-d-threo-hexopyranosid-2-uloses, and 3,4-dideoxy-β-d-glycero-hex-3-enopyranosid-2-uloses, which are useful synthetic tools for further transformations.     

Intervention of catalytic amounts of water in the allylic rearrangements of glycal derivatives

It is confirmed that tri-O-acetyl-d-glucal with thiophenol in the presence of BF₃·OEt₂ as catalyst gives the allylically rearranged S-phenyl 4,6-di-O-acetyl-2,3-dideoxy-1-thio-α- and β-d-erythro-hex-2-enopyranosides as the main products, and now demonstrated that the presence of catalytic proportions of water diverts the reaction in favour of the isomeric S-phenyl 4,6-di-O-acetyl-2-deoxy-3-phenylthio-1-thio-d-arabino- and -d-ribo-hexopyranosides. It is proposed that these products are formed from an intermediate enal.     

Enantiospecific synthesis of a glycoside of d-epi-purpurosamine

2-Propyl d-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α-d-erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl 4,6-diazido-2,3,4,6-tetradeoxy-α-d-threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative 13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).     

Synthesis and Conformational Studies of Unnatural Pyrimidine Nucleosides

ABSTRACT

Starting from 3,4-di-O-acetyl-L-rhamnal (6) and thymine (7) the unsaturated nucleosides 1-(2′,3′,6′-trideoxy-4′-O-acetyl-α- and β-L-erythro-hex-2′-enopyranosyl)-thymine (8a and 8b) were prepared in anomerically pure form. In solution 8a was shown to be present in the ⁵ H _o and ⁰ H ₅ conformations, whereas the predominant conformation of 8b was ⁵ H _o. Chemical transformation of 8a and 8b led to the saturated nucleosides 1-(2′,3′,6′-trideoxy-α- and β-L-erythro-hexopyranosyl)thymine (10a and 10b, respectively), which were converted into 1-(4′-azido-2′,3′,4′,6′-tetradeoxy-α- and β-L-threo-hexopyranosyl)thymine (12a and 12b). Preliminary biological studies showed that 9b was inactive against the HIV-1 and HIV-2 viruses.     

3″-De-O-methyl-2″,3″-anhydro-lankamycin,a New Macrolide Antibiotic from Streptomyces violaceoniger

A further examination of the products from fermentation broths of Streptomyces violaceoniger has yielded small quantities of several lankamycin related antibiotics and metabolites. One of the antibiotics has been characterized as 3″-de-O-methyl-2″,3″-anhydro-lankamycin. The anhydro sugar of the new lankamycin, 3-methyl-4-O-acetyl-2,3,6-trideoxy-α-L -threo-hex-2-enepyranoside was also isolated as the ethyl glycoside from fermentation broths of the same organism.     

Synthesis of 2,3-UNSATURATED 4-Amino Sugars and Cyclohexyl 2,3-Di-O-Acetyl-4,6-Di-O-Methyl-α-D-Manno-Pyranoside from Cyclohexyl 4,6-Di-O-Acetyl-2,3-Dideoxy-α-D-erythro-Hex-2-Enopyranoside

ABSTRACT

The synthesis of three 2,3-unsaturated 4-amino sugars 2-4 and cyclohexyl 2,3-di-O-acetyl-4,6-di-O-methyl-α-D-mannopyranoside 8 starting from cyclohexyl 4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside 1 is described. The amino sugars were prepared by allylic substitution using a palladium catalyst.     

Self-sacrificing acetylation observed during attempted desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine

Desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine (4) with Bu₄NF/THF, when carried out at room temperature, gave four products. Among these, there were 1-[3-O-acetyl-4-benzenesulfonyl-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine (7) and thymine. A possible reaction mechanism is proposed, which suggests the origin of 3′-O-acetyl group of 7 and thymine as well as structures of the other two products (9a and 9b).     

2-Deoxy-2-C-(2,3-dideoxy-α-d-erythro-hexopyranosyl)-β-d-glucopyranoses: Reinvestigation of Synthesis,Use in Glycosylation,and Conformational Analyses by NMR

Abstract

Conformational investigations using 1D TOCSY and ROESY ¹H NMR experiments on 1,3,4,6-tetra-O-acetyl-2-C-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexopyranosyl)-2-deoxy-β-D-glucopyranose (8) and related disaccharides showed that for steric reasons the C-linked hexopyranosyl ring occurs in the usually unfavoured ¹C₄ conformation and reconfirmed the structure of 1,3,4,6-tetra-O-acetyl-2-C-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranosyl)-2-deoxy-β-D-glucopyranose (5). Glycosylation of 2,3,6-tri-O-benzyl-α-D-glucopyranosyl 2,3-di-O-benzyl-4,6-(R)-O-benzylidene-α-D-glucopyranoside (13) with acetate 8 using trimethylsilyl triflate as a catalyst afforded the α-D-linked tetrasaccharide 14. A remarkable side product in this reaction was the unsaturated tetrasaccharide 2,3,6-tri-O-benzyl-4-O-[4,6-di-O-acetyl-2,3-dideoxy-2-C-(4,6-di-O-acetyl-2,3-dideoxy-β-D-erythro-hexopyranosyl)-α-D-erythro-hex-2-enopyranosyl]-α-D-glucopyranosyl 2,3-di-O-benzyl-4,6-(R)-O-benzylidene-α-D-glucopyranoside (16) where in the C-linked hexopyranosyl ring an isomerization to the β-anomer had taken place to allow for the favoured ⁴C₁ conformation. The tetrasaccharide 14 was deacetylated and hydrogenolyzed to form the fully deprotected tetrasaccharide 18. The ¹ C ₄ conformation of the C-glycosidic pyranose of this tetrasaccharide was maintained as shown by an in depth NMR analysis of its peracetate 19.     

Palladium(0)-Mediated Synthesis of Acetylated Unsaturated 1,4-Disaccharides

Abstract

Alkylation of ethyl 6-O-tert-butyldiphenylsilyl-4-O-methoxycarbonyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (1) with various peracetylated 1-hydroxy sugars in the presence of a catalytic amount of palladium(O) gave the corresponding unsaturated 1,4-disaccharides and trisaccharides. In all cases the reaction is regio- and stereospecific according to the unsaturated moiety, alkylation occuring only at C-4 of the unsaturated carbohydrate, with overall retention of configuration.     

Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.     

Strukturelle Abwandlungen an partiell silylierten Kohlenhydraten mittels Triphenylphosphin/Azodicarbonsäure-diäthylester. 3. Mitteilung [1]

Structural Modification on Partially Silylated Carbohydrates by Means of Triphenylphosphine/Diethyl Azodicarboxylate Reaction of methyl 2, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1a ) with triphenylphosphine (TPP)/diethyl azodicarboxylate (DEAD) and Ph₃P · HBr or methyl iodide yields methyl 3-bromo-2, 6-bis-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 3a ) and the corresponding 3-deoxy-3-iodo-alloside 3c (Scheme 1). By a similar way methyl 2, 6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2a ) can be converted to the 4-bromo-4-deoxy-galactoside 4a and the 4-deoxy-4-iodo-galactoside 4b . In the absence of an external nucleophile the sugar derivatives 1a and 2a react with TPP/DEAD to form the 3,4-anhydro-α- or -β-D -galactosides 5 and 6a , respectively, while methyl 4, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1b ) yields methyl 2,3-anhydro-4, 6-bis-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 7a , s. Scheme 2). Even the monosilylated sugar methyl 6-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2b ) can be transformed to methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 8 ; 56%) and 3,4-anhydro-α-D -alloside 9 (23%, s. Scheme 3). Reaction of 1c with TPP/DEAD/HN₃ leads to methyl 3-azido-6-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 10 ). The epoxides 7 and 8 were converted with NaN₃/NH₄Cl to the 2-azido-2-deoxy-altrosides 11 and 13 , respectively, and the 3-azido-3-deoxy-glucosides 12 and 14 , respectively (Scheme 4 and 5). Reaction of 7 and 8 with TPP/DEAD/HN₃ or p-nitrobenzoic acid afforded methyl 2,3-anhydro-4-azido-6-O-(t-butyldimethylsilyl)-4-deoxy-α- and -β-D -gulopyranoside ( 15 and 17 ), respectively, or methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-4-O-(p-nitrobenzoyl)-α- and -β-D -gulopyranoside ( 16 and 18 ), respectively, without any opening of the oxirane ring (s. Scheme 6). - The 2-acetamido-2-deoxy-glucosides 19a and 20a react with TPP/DEAD alone to form the corresponding methyl 2-acetamido-3,4-anhydro-6-O-(t-butyldimethylsilyl)-2-deoxy-galactopyranosides ( 21 and 22 ) in a yield of 80 and 85%, respectively (Scheme 7). With TPP/DEAD/HN₃ 20a is transformed to methyl 2-acetamido-3-azido-6-O-(t-butyldimethylsilyl)-2,3-didesoxy-β-D -allopyranoside ( 25 , Scheme 8). By this way methyl 2-acetamido-3,6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 19b ) yields methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-α-D -galactopyranoside ( 23 ; 16%) and the isomerized product methyl 2-acetamido-4,6-bis-O-(t-butyldimethylsilyl)-2-deoxy-α-D -glucopyranoside ( 19d ; 45%). Under the same conditions the disilylated methyl 2-acetamido-2-deoxy-glucoside 20b leads to methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-β-D -galactopyranoside ( 24 ). - All Structures were assigned by ¹H-NMR. analysis of the corresponding acetates.     

Selective synthesis of Neu5Ac2en and its oxazoline derivative using BF3·Et2O

Application of the Lewis acid BF₃·Et₂O to the selective synthesis of 5-acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enonic acid (Neu5Ac2en) and the related oxazoline, methyl 7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-2,3-didehydro-2,3-trideoxy-4′,5′-dihydro-2′-methyloxazolo[5,4-d]- d-glycero-d-talo-non-2-enonate is described.     

Steric course of some cyclopropanation reactions of L-threo-hex-4-enopyranosides

Completely protected 4-deoxy-α-L-threo-hex-4-enopyranosides 1c,d undergo the dichlorocarbene addition affording exclusively diastereomeric adducts 5c,d with the cyclopropane ring anti to the C-3 alkyloxy substituent, while the reaction with 3-unprotected derivatives 1a,b affords a mixture of syn and anti derivatives. Under the Simmons-Smith cyclopropanation adducts 2a-d with a syn stereochemistry are obtained. Starting from 5b, the cyclopropanated sugar 3b is obtained by reduction with LiAlH₄, thus the two diastereomers 2b and 3b can be stereoselectively obtained through the two different pathways. For a useful comparison, 4-deoxy-β-L-threo-hex-4-enopyranoside 1e was also subjected to the above two cyclopropanation methods affording the expected cycloadduct 2e and a diastereomeric mixture of dichlorocycloadducts 4e and 5e (4e/5e=2.8:1).     

Enantiospecific synthesis of a glycoside of -epi-purpurosamine

2-Propyl -epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α- -erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl 4,6-diazido-2,3,4,6-tetradeoxy-α- -threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative 13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).     

Ring Opening of Benzyl β-D-Galactoside Cyclic Sulfates into Galactose Monosulfates. New Access to 6-Deoxy-Galacto-Hex-5-Enopyranoside and 4-Deoxy-3-Ketogalactopyranoside.

ABSTRACT

The behavior of 3,4- and 4,6-cyclic sulfates derived from benzyl 2,6- and 2,3-di-O-benzyl-β-D-galactopyranosides toward hydrolysis has been studied using aqueous sodium hydroxide under various conditions. Starting from benzyl 2,6-di-O-benzyl-3,4-O-sulfuryl-β-D-galactopyranoside (5), the reaction with aq NaOH in THF gave both 3- and 4-monosulfates 7 and 8 (83%, in 68:32 ratio), while the reaction in DMF led unexpectedly to the 4-deoxy-3-keto derivative 10 in 77% yield after acidic hydrolysis of the intermediate enolester 9. On the other hand, when benzyl 2,3-di-O-benzyl-4,6-O-sulfuryl-β-D-galactopyranoside (6) was treated with aq NaOH in THF, a mixture of benzyl 2,3-di-O-benzyl-6-deoxy-4-O-(sodium sulfonato)-α-L-arabino-hex-5-enopyranoside (11) and benzyl 2,3-di-O-benzyl-4-deoxy-6-O-(sodium sulfonato)-α-L-threo-hex-4-enopyranoside (12) (in 65:35 ratio) was obtained in 93% yield, giving a new and rapid access to 11, a potential precursor of L-sugars derivatives. Alternatively, BzONBu₄ gave a regiospecific opening reaction of 6 and led to the 6-O-benzoate 4-O-sulfate derivative (13) in excellent yield.     

Zur Synthese von Sialylglykosiden (Darstellung von Methyl-6-O-benzyl-(4,7,8,9-tetra-O-acetyl-5-acetylamino-3,5-didesoxy-D-glycero-α bzw. β-D-galacto-2-nonulopyranosäure-methylester)-α bzw. β-D-glucopyranosid)

Silver triflate promoted condensations of 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β-D-glycero-D-galacto-2-nonulopyranosidonic acid methylester with methyl-2,3,4-tri-O-benzyl-α or β-D-glucopyranoside to the title products are reported.     

Application of Phenyl 1-Selenoglycosides in the Synthesis of a Cell-Wall Tetrameric Fragment of Proteus Vulgaris Strain 5/43

Abstract

DAST-assisted rearrangement of 3-O-allyl-4-O-benzyl-α-l-rhamnopyranosyl azide followed by treatment of the generated fluorides with ethanethiol and BF₃·OEt₂ gave glycosyl donor ethyl 3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-1-thio-α/β-l-glucopyranoside. Stereoselective glycosylation of methyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucopyranoside with ethyl 3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-1-thio-α/β-l-glucopyranoside, under the agency of NIS/TfOH afforded methyl 3-O-(3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-α-l-glucopyranosyl)-4,6-O-benzyli-dene-2-deoxy-2-phthalimido-β-D-glucopyranoside. Removal of the allyl function of the latter dimer, followed by condensation with properly protected 2-azido-2-deoxy-glucosyl donors, in the presence of suitable promoters, yielded selectively methyl 3-O-(3-O-[6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl]-2-azido-4-O-benzyl-2,6-dideoxy-α-l-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucopyranoside. Deacetylation and subsequent glycosylation of the free HO-6 with phenyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside in the presence of NIS/TfOH furnished a fully protected tetrasaccharide. Deprotection then gave methyl 3-O-(3-O-[6-O-{β-D-glucopyranosyl}-2-acetamido-2-deoxy-β-D-glucopyranosyl)-2-acetamido-2,6-dideoxy-α-L-glucopyranosyl)-2-acetamido-2-deoxy-β-D-glucopyranoside.     

A case of oligomerization on attempted chlorination of an α-hydroxy acetal with the triphenylphosphine tetrachloromethane reagent

Treatment of methyl 3,5-dideoxy-β-$\text{D}$-$\text{erythro}$-pentofuranoside $\text{8}$ with the Ph₃P-CCl₄ reagent gave none of the expected 2-chloro derivative but a mixture of l→2 linked oligosaccharides, $\text{9}$, $\text{10}$ with some higher homologues, terminated by αa 2-chloro-2,3,5-trideoxy-α-$\text{D}$-$\text{threo}$-pentofuranosyl unit at the non reducing end.     

SYNTHESIS OF BRANCHED-CHAIN HEXULOSE DERIVATIVES AS MODEL FOR THE SYNTHESIS OF TALAROMYCINS

The synthesis of 3,5-dideoxy-1,2-O-isopropylidene-5-C-hydroxymethyl-β-D-erythro- (1) and α-L-threo-hexulopyranose (2) from 3-deoxy-1,2-O-isopropylidene-β-D-erythro-hexulopyranose (5) from D-fructose is described, as well as their respective transformation into 3,5-dideoxy-1,2-O-isopropylidene-5-C-hydroxymethyl-β-D-threo-(3) and -α-L-erythro-hexulopyranose (4) by inversion of configuration at C-4.     

Heterocyclic N-glycosyl derivatives—XI: Synthesis and NMR conformational study of N-glycosyl benzotriazoles from acetylated glycals

Acid-catalyzed reaction of benzotriazole, 5,6-dimethylbenzotriazole and 5,6-dichlorobenzotriazole with di-O-acetyl-d-xylal in ethyl acetate afforded 1-(4′-O-acetyl-2′,3′-dideoxy-d-glycero-pent-2′-enopyranosyl)benzotriazole derivatives and small amounts of 1,2,3-trideoxy-4-O-acetyl-3-(benzotriazolyl)-d-threo-pent-1-enopyranose derivatives. The reactions using di-O-acetyl-l-arabinal led to the formation of the corresponding 1- and 2-(3′,4′-di-O-acetyl-2′-deoxy-l-erythro-pentopyranosyl)benzotriazole derivatives. In addition the enantiomers of the above 2′, 3′-unsaturated N-glycosyl compounds were also obtained. The configurations and conformations of the products obtained were determined by NMR spectroscopy.