Mono-Glycosylated 3-N-Alkylcatechols: Direct Synthesis from Glycosylacetates, 1H Nmr Analysis and Conformational Studies

ABSTRACT

The direct coupling of 3-n-alkyl catechols to the acetate or trichloroacetimidate derivatives of β-D- or α-D-glycosides (glucose, galactose, xylose, mannose and maltose) catalyzed by BF₃Ot₂ has been studied. β-Glycosides with an equatorial acetate group at position 2 formed exclusively β adducts with yields of 60–80%. α-Glycosides with an equatorial acetate group at position 2 formed β adducts, while β-glycosides with an axial acetate group formed α adducts when activated as trichloroacetimidates, with yields of 70–85%. This was applied to the coupling of 3-n-alkylcatechols of increasing chain length (up to C15) to sugar derivatives. The coupling position of glycosides on the catechol was determined either by differential NOE experiments and by the regioselective synthesis of 1-(O-β-D-glucopyranosyl)-3-pentadecylcatechol, a water soluble analogue of the poison ivy skin allergen. ¹H NMR of acetylated and deprotected compounds were investigated and the conformational preferences of the C₆ side chain determined using molecular modeling.     

Synthesis of a Tetrasaccharide Related to the Repeating Unit of the Antigen from Shigella dysenteriae Type 9 in the Form of Its 2‐(Trimethylsilyl)ethyl Glycoside

Abstract

Starting from D‐mannose, D‐galactose and D‐glucosamine hydrochloride, two disaccharide blocks were synthesized. Schmidt's inverse addition technique for trichloroacetimidate was utilized for the construction of a disaccharide with a β‐mannosidic linkage in good yield. The two disaccharides in the appropriate form were then allowed to react in the presence of N‐iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) to give the tetrasaccharide derivative from which removal of protecting groups gave the desired tetrasaccharide in the form of its 2‐(trimethylsilyl)ethyl glycoside.     

Synthesis of tetrahydropyridazino[1,2-a][1,2,4] benzotriazin-6-one derivatives. A novel heterocyclic system

Synthesis of pyridazino[1,2-a][1,2,4]benzotriazin-6-one derivatives involving reaction of either 1,2,3,6-tetra-hydropyridazine ( 9 ) or hexahydropyridazine 14 with 2-fluoro-5-nitrophenylisocyanate ( 5 ) to give, via intramolecular cyclization, 3a and 16 respectively is described. Compound 3a was converted to 18 via methylation and hydroxylation to give 20 followed by conversion to the acetonide derivative 18 . Both 16 and 18 were reduced to the amino derivatives 17 and 19 respectively.     

Synthesis of Two Tetrasaccharides Related to the O-Antigen from Azospirillum brasilense S17 and Azospirillum lipoferum SR65

Synthesis of two isomeric tetrasaccharides, β-D-Glup-(1→2)-α-L-Rhap-(1→3)-α-L- Rhap-(1→2)-α-L-Rhap (I) and β-D-Glup-(1→3)-α-L-Rhap-(1→3)-α-L-Rhap-(1→3)-α-L-Rhap (II), the repeating units from the lipopolysaccharides of the nitrogen-fixing bacterium Azospirillum brasilense S17 and Azospirillum lipoferum SR65, was achieved via assembly of the building blocks 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl trichloroacetimidate (2), p-methoxyphenyl 3,4-di-O-benzoyl-α-L-rhamnopyranoside (3), 3-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-L-rhamnopyranosyl trichloroacetimidate (6), 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl trichloroacetimidate (8), and p-methoxy phenyl 2,4-di-O-benzoyl-α-L-rhamnopyranoside (14). Condensation of 3 with 6 or 8 provided the disaccharides 9 or 11, respectively. Deallyloxycarbonylation of 11 gave the disaccharide aceptor 12, while removal of the p-methoxyphenyl group in 9 followed by trichloroacetimidation of the anomeric hydroxyl group afforded the disaccharide donor 10. Meanwhile, disaccharide donor 16 and acceptor 18 were prepared from 6, 8, and 14 similarly. Finally, condensation of 10 with 12 or 16 with 18, followed by deprotection, gave the target tetrasaccharides I or II, respectively.     

Synthesis of a Single Repeat Unit of Type VIII Group B Streptococcus Capsular Polysaccharide 1

Abstract

We have synthesized a single repeat unit of type VIII Group B Streptococcus capsular polysaccharide, the structure of which is {L-Rhap(β1→4)-D-Glcp(β1→4)[Neu5Ac(α2→3)]-D-Galp(β→4)}_n. The synthesis presented three significant synthetic challenges namely: the L-Rhap(β→4)-D-Glcp bond, the Neu5Ac(α2→3)-D-Galp bond and 3,4-D-Galp branching. The L-Rhap bond was constructed in 60% yield (α:β 1:1.2) using 4-O-acetyl-2,3-di-O-benzoyl-α-L-rhamnopyranosyl bromide 6 as donor, silver silicate as promotor and 6-O-benzyl-2,3-di-O-benzoyl-1-thio-β-D-glucopyranoside as acceptor to yield disaccharide 18. The Neu5Ac(α2→3) linkage was synthesized in 66% yield using methyl [phenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-glycero-D-galacto-nonulopyranosid]onate as donor and triol 2-(trimethylsilyl) ethyl 6-O-benzyl-β-D-galactopyranoside as acceptor to give disaccharide 21. The 3,4-D-Galp branching was achieved by regioselective glycosylation of disaccharide diol 21 by disaccharide 18 in 28% yield to give protected tetrasaccharide 22. Tetrasaccharide 22 was deprotected to give as its 2-(trimethylsilyl)ethyl glycoside the title compound 1a. In addition the 2-(trimethylsilyl)ethyl group was cleaved and the tetrasaccharide coupled by glycosylation (via tetrasaccharide trichloroacetimidate) to a linker suitable for conjugation.

     

SYNTHESIS OF 6-AMINO-6-DEOXY-2,3,4,5- TETRA-O-METHYL-D-GALACTONIC ACID,A KEY PRECURSOR OF A STEREOREGULAR POLYAMIDE[1]

The title compound (17) was synthesized by two alternative sequences, starting from D-galactose diacetonide (1) and from methyl 6-O-tosyl-α-D-galactopyranoside (9). Compound 1 was converted into the 6-bromo-6-deoxy derivative 2 or mesylated to 3. Nucleophilic substitution of the leaving group in 2 and 3 by sodium azide led to the 6-azido-6-deoxy derivative 4, which on treatment with methanol under acidic conditions afforded a mixture of the corresponding methyl β-furanoside (5) and α-pyranoside (6). Methylation of the free hydroxyl groups of 5 and 6 gave the respective per-O-methyl derivatives 7 and 8. In order to maintain the size of the sugar ring during the sequence, compound 8 was alternatively prepared from 9, by acetylation, substitution by azide and per-O-methylation. Hydrolysis of the glycoside followed by oxidation and further 5-O-methylation afforded the 6-azido-6-deoxy carboxylic acid 16 which was converted into 17 (38% overall yield from 9) by hydrogenolysis of the azide function.     

Synthesis of 6α-methyl-16α,17α-cyclohexano-19-norprogesterone from a 19-methyl-6-desmethyl precursor

After prolonged refluxing of 19-tosyloxy-16α,17α-cyclohexanopregn-5-en-3β-ol-20-one (3) with NaI in 2-propanol, the initially formed 19-iodo derivative (4) undergoes supraface migration of the CH₂I group from the C(10) atom to the C(6) atom, probably through involvement of a homoallyl cation. The resulting 6β-iodomethyl-16α,17α-cyclohexano-19-norpregn-5(10)-en-3β-ol (5) was transformed in three steps into 6α-methyl-16α,17α-cyclohexano-19-norprogesterone (6α-methyl-19-nor-D′ ₆-pentarane,8). The transformation of compound5 into the target product8 also gave a side product, a pentarane with aromatic ringA (10), which was isolated and characterized by spectroscopic methods. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1688–1691, September, 1997.     

Synthesis of the 4-Deoxy-2-Deutero-4-Fluoro Analog of Methyl O-β-D-Galactopyranosyl-(1→6)-β-D-Galactopyranoside

ABSTRACT

Methyl 4-deoxy-4-fluoro-6-O-(β-D-galactopyranosyl)-(2-²H)-β-D-galactopyranoside was prepared by the condensation of 2,3,4,6-tetra-O-benzoyl-α-D-galactopyranosyl bromide and methyl 2-O-benzoyl-3-O-benzyl-4-deoxy-4-fluoro-(2-²H)-β-D-galactopyranoside (17), followed by deprotection. The introduction of deuterium at C-2 in an intermediate methylhexopyranoside was achieved by a double inversion, brought about by oxidation of C-2 of a derivative of methyl α-D-glucopyranoside, to give the corresponding ketone, and subsequent reduction thereof with NaBD₄, to give a derivative with the D-manno configuration (8). Inversion of the configuration at C-2 of the latter was achieved by displacement with sodium benzoate of the O-trifluoromethanesulfonyl (triflyl) group in the 2-O-triflyl derivative of 8. The resulting synthon was converted, conventionally, to methyl 2-O-benzoyl-3-O-benzyl-6-O-trityl-(2-²H)-β-D-glucopyranoside. Its conversion into the 6-O-trityl derivative of 17, unsuccessful by treatment with dimethylaminosulfur trifluoride, was readily accomplished by the displacement of the triflyl group with fluoride ion contained in an ion-exchange resin.     

Intermolecular cyclization of cinnamoyl isothiocyanate: A new synthetic entry for pyrimidine,triazine, and triazole candidates

An efficient and facile protocol for the synthesis of azine and azole ring systems was reported. Whereas, reaction of cinnamoyl isothiocyanate with N-nucleophile containing compounds (namely, p-aminophenol (2), N¹-phenylbenzene-1,4-diamine (5) and p-aminoacetophenone (8)) tolerated thiourea derivatives 3, 6, and 9, respectively. The later compounds underwent intramolecular cyclization upon treatment with EtONa to give pyrimidinethiones 4, 7, and 10, respectively, in moderate yield (74–79%). Compound 9 underwent intramolecular cyclization and condensation upon reaction with NaOH and benzaldehyde to give pyrimidinethione 12. Thiosemicarbazides 14 and 19 were obtained through reaction of heteroallen 1 with 2,4-dinitrophenylhydrazine 13 and hydrazone 18, respectively. Compound 14 was cyclized to pyrimidinethione 15 and triazine derivatives 17 through its reaction with EtONa at room temperature and refluxing temperature, respectively. Finally, base mediated and oxidative cyclization of thiourea derivative 19 with EtONa, Br₂/AcOH, and Pb(OAc)₂ afforded thiadiazole 20, benzothiazolotriazole 21, and triazolethione 22 derivatives, respectively.     

Synthesis of Lacto‐ and Neolacto‐series Ganglioside Analogs Containing N‐Glycolylneuraminic Acid: Probes for Investigation of Specific Receptor Structures Recognized by Influenza A Viruses

Sialic acids are essential components of host‐cell surface receptors for infection of influenza virus. To investigate the specific receptor structures recognized by various influenza A viruses, a series of lacto‐ and neolacto‐series ganglioside analogs containing N‐glycolylneuraminic acid (Neu5Gc) have been synthesized. The pentasaccharide structures of Neu5Gc‐α‐(2→3)/(2→6)‐lactotetraose (IV³⁽⁶⁾Neu5GcLcOse) and Neu5Gc‐α‐(2→3)/(2→6)‐neolactotetraose (IV³⁽⁶⁾Neu5GcnLcOse) were constructed by glycosylation of the suitably protected trisaccharide acceptors (2A and 2B) with the Neu5Gc‐α‐(2→3)/(2→6)‐Gal trichloroacetimidate donors (1 and 21), respectively. Transformation of the 2‐(trimethylsilyl)ethyl group at the reducing end in 4, 11, 23, and 30 into the trichloroacetimidate group gave a series of Neu5Gc‐α‐(2→3)/(2→6)‐lacto‐ and neolactotetraose donors (7, 13, 26, and 33), which were coupled with 2‐(tetradecyl)hexadecanol (8), to give the corresponding glycolipids (9, 14, 27, and 34). Finally, the complete removal of the O‐acyl groups and saponification of the methyl ester group gave the desired ganglioside analogs (10, 15, 28, and 35).     

Dichloro‐cyanoacetimidates as Glycosyl Donors

Transformation of 1‐O‐unprotected glucose and galactose derivatives (1a–d) into O‐glycosyl dichloro‐cyanoacetimidates (2a–d) was performed with dichloro‐cyanoacetonitrile in the presence of DBU as base. Reaction with different acceptors (3a–d) under TMSOTf catalysis afforded glycosides 4 in high yields. Competition experiments with O‐glucopyranosyl trichloroacetimidate 10a, bearing a 4‐tert‐butylbenzyl group at 6‐O, and O‐glucopyranosyl dichloro‐cyanoacetimidate 10b, bearing a 4‐methylbenzyl group at 6‐O, displayed similar reactivities for these two types of glycosyl donors.     

C45- and C50-Carotenoids Part7 Total synthesis of (all-E,2R,6R,2′R,6′R)- and (all-E,2R,6S,2′R,6′S)-2,2′-Bis(4-hydroxy-3-methylbut-2-enyl)-γ,γ-carotene (sarcinaxanthin)

The synthesis of sarcinaxanthin ((2R,6R,2′R,6′R)- 1 ), a symmetrical C₅₀-carotenoid with two γ-end groups, isolated from Sarcina lutea and from Cellulomonas biazotea as major pigment, was based on the strategy C₂₀ + C₁₀ + C₂₀ = C₅₀ using camphoric acid as starting material for the C₂₀-end group 3. The key step of the synthesis is a ring enlargement of the cyclopentane derivative 10 with 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one (TBCO) to give the cyclohexane derivative 11 (Scheme 1). The spectroscopic data of the synthetic compound are in full agreement with the data of the isolated product and give the final proof for the (2R,6R,2′R,6′R) chirality of natural sarcinaxanthin.     

Synthetic Studies on Sialoglycoconjugates 88: Synthesis of Ganglioside GM3 and GM4 Analogs Containing 2- OR 3-Branched Fatty-Alkyl Residues in Place of Ceramide

ABSTRACT

Each of four ganglioside GM₄ and GM₃ analogues containing 2- or 3-branched fatty alkyl residues in place of ceramide have been synthesized. Coupling of O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-(2→3)-2,4,6-tri-O-benzoyl-α-D-galactopyranosyl trichloroacetimidate (13) or O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-glacto-2-nonulopyranosylonate)-(2→3)-O-(2,4-di-O-acetyl-6-O-benzoyl-β-D-galactopyranosyl)-(1→4)-3-O-acetyl-2,4-di-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate (14) with 2- or 3-branched fatty-alkyl-1-ols (9-12), prepared from the corresponding branched fatty acids by methyl esterification and reduction, using BF₃Ot₂ gave the corresponding ganglioside analogues (15, 17, 19, 21, 23, 25, 27, 29) in good yields, which were coverted, via O-deacylation and de-esterification, into the title compounds.     

Synthesis of Sialyl Lewis X Ganglioside Analogs Containing A Variable Length Spacer Between the Sugar and Lipophilic Moieties 1

Abstract

Five sialyl Lew is X ganglioside analogs containing 4-(2-tetradecylhexadecanoylamino)benzyl group in place of ceramide and a variety of lengths of ethylene glycol chains as the spacer, have been synthesized. Glycosidation of O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-glacto-2-nonulopyranosylonate)-(2→3)-O-(4-O-acetyl-2,6-di-O-benzoyl-β-D-galactopyranosyl)-(1→4)-O-[(2,3,4-tri-O-acetylα-L-fucopyranosyl)-(1→3)]-2,4-di-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate (13) with oligo ethyleneglycol monobenzyl ether derivatives 9, 10, 11 and 12, prepared from the corresponding oligo ethyleneglycols by 4-nitrobenzylation, reduction and N-acylation with 2-tetradecylhexadecanoic acid, using boron trifluoride etherate gave the corresponding glycolipid derivatives 14, 15, 16 and 17. A similar glycosidation of 13 with 4-nitrobenzyl alcohol gave the 4-nitrobenzyl glycoside 18, which was converted via reduction of nitro group and N-acylation into the corresponding glycolipid derivative 19. Compounds 14-17 and 19 were transformed into the title compounds by O-deacylation and hydrolysis of methyl ester group in good yields.

     

Synthesis of Disaccharides Containing 6-Deoxy-a-L-talose as Potential Heparan Sulfate Mimetics

A 6-deoxy-a-L-talopyranoside acceptor was readily prepared from methyl a-L-rhamnopyranoside and glycosylated with thiogalactoside donors using NIS/TfOH as the promoter to give good yields of the desired a-linked disaccharide (69-90%). Glycosylation with a 2-azido-2-deoxy-D-glucosyl trichloroacetimidate donor was not completely stereoselective (a:b = 6:1), but the desired a-linked disaccharide could be isolated in good overall yield (60%) following conversion into its corresponding tribenzoate derivative. The disaccharides were designed to mimic the heparan sulfate (HS) disaccharide GlcN(2S,6S)-IdoA(2S). However, the intermediates readily derived from these disaccharides were not stable to the sulfonation/deacylation conditions required for their conversion into the target HS mimetics.     

Synthesis,Reactions, and Characterization of 6-Amino-4-(Benzo[b]Thiophen-2-YL)-2-Thioxo-1, 2-Dihydropyridine-3, 5-Dicarbonitrile

Abstract

Benzothiophene -2- carbaldehyde 1 reacted with 2-cyanoethanethioamide 2 in 1:2 molar ratios to give the corresponding 6-amino-4-(benzo[b]thiophen-2-yl)-2-thioxo-1, 2-dihydropyridine-3,5-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents to afford the corresponding thieno[2,3-b]pyridine derivatives 11a,b, 14, 16, and 19. Also, compound 6 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 21. Compound 21 condensed with 4-(2-thienyl)benzaldehyde to afford pyrazolo[3,4-b]pyridine derivative 23. Structural elucidation of all the newly synthesized heterocyclic compounds was based on elemental analyses, IR, ¹H NMR, and mass spectra.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Pyridazine Derivatives and Related Compounds,Part 1. Some Reactions with 4-Cyano-5,6-Diphenyl-2,3-Dihydropyridazine-3-One

4-Cyano-5,6-diphenyl-2,3-dihydropyridazine-3-onc 1 reacts with phosphorous oxychloride to give 70% of the corresponding 3-chloro derivative 2. Treating 2 with anthranilic acid in butanol, 4-cyano-2,3-diphenyl-10H-pyridazino[6,1-b]quinoxaline-10-one, 3 was obtained. Compound 1 reacts with phosphorous pentasulphide to give 3-mercapto derivative 4, which was converted by acrylonitrile to S-(2-cyanoethyl)pyridazine derivative 5. Compound 4 reacts with ethyl bromoacetate and with phenacyl bromide gave the corresponding thieno[2,3-c] pyridazine derivatives 8, 9, Alkylation of 1 with ethyl chloroacetate afforded 3-0-carbethoxymethyl derivative 10. Compound 10 reacts with amines (aniline, hydrazine) to give the corresponding amide and acid hydrazide 13, 12 respectively. Hydrolysis of 10 with sodium hydroxide gave the corresponding acid derivative 11. Treating 1 with methyl iodide, 3-0-methyl derivative 14 was obtained, which was converted by ammonium acetate/acetic acid to 3-amino-4-cyano-5,6-diphenyl pyridazine 15. Compound 1 reacts with methyl magnesium iodide gave 4-acetyl derivative 16, which was reacted with hydrazine, phenyl hydrazine and with hydroxylamine to give the substituted I H pyrazolo [3,4-c] pyridazine 17 a,b and isoxazolo [5,4-c] pyridazine 18 derivatives respectively.     

N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis: A Facile Synthesis of Nicotinamide,Thieno[2,3-b]pyridine,and Bi- or Tricyclic Annulated Pyridine Derivatives Containing Naphthyl Moiety

N-1-Naphthyl-3-oxobutanamide (1) reacts with arylidinecyanothioacetamide 2a–c in ethanol/piperidine solution under reflux to yield the pyridine-2(1H)-thiones 6a–c. Compound 6a reacts with α-haloketones 7a–e to give the 6-thio-N-1-naphthyl-nicotinamides derivatives 8a–e, which cyclized to thieno[2,3-b]pyridine derivatives 9a–e. The reaction of compound 9a with hydrazine hydrate and formamide gives the thieno[2,3-b]pyridine carbohydrazide derivative 10 and pyridothienopyrimidine derivative 11, respectively. Reaction of 9a with benzoyl isothiocyanate gave thiourea derivative 12. Compound 12, upon treatment with alcoholic NaOH, gave pyridothienopyrimidine 13. Saponifications of 9a gave the amino acid 15, which affords 16 when refluxed in Ac₂O. Treatment of compound 16 with AcONH₄/AcOH gave 17. Diazotization and self-coupling of 9b gave the pyridothienotriazine 18. Also, diazotization of the ortho-aminohydrazide 10 give the corresponding azide 19, which was subjected to Curtius rearrangement in boiling xylene to give imidazothienopyridine 20. Reaction of 10 with either formic acid or triethylorthoformate and phenyl isothiocyanate gave the corresponding pyridothienotriazepines 22 and 23, respectively. The interaction of 10 with acetylacetone furnished the pyrazolyl derivative 24. The structures of the synthesized compounds were established from their analytical and spectral data.     

Preparation of 2-Azido-4-O-benzoyl-2,6-dideoxy-3-O-methyl-β-D-allopyranose and Its Disaccharide Derivative

Abstract

2-Azido-4-O-benzoyl-2,6-dideoxy-3-O-methyl-D-allopyranose, needed as one of the building blocks for construction of a novel cyclodextrin-like compound, was prepared in the form of crystalline β-anomer 6 from methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-allopyranoside 1. As a model of α-glycosidation necessary for formation of a cyclic structure, 6 was converted into the corresponding β-glycosyl trichloroacetimidate and coupled with methyl 6-O-benzyl-2,3-di-O-methyl-α-D-glucopyranoside 8, giving α(1→4)-linked disaccharide derivative 9.     

Aza-Claisen Rearrangement: Synthesis of 5′-branched 5′-aminothymidines

The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH₂CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b , respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted Pd^II-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17 , whose structure was confirmed by X-ray analysis.