Selective synthesis of cerebrosides: (2S, 3R, 4E)-1-O-β-d-galactopyranosyl-N-(2′R and 2′S)-2′-hydroxytetracosanoyl-sphingenine

The cerebrosides were first isolated by Thudicum in 1874 and the structures were established by Carteret al. in 1950 (for review, see [2]). In 1961 Shapiro and Flowers [3] reported the first total synthesis of a cerebroside1 (Fig. 1) which was identified with the natural sample, only through comparison of their i.r. data. In order to confirm the absolute configuration at C-2 of natural cerebroside1, we describe here an unambiguous synthesis of two stereoisomeric cerebrosides1 and2, and found that the¹H-NMR spectra of the synthetic1 (Fig. 2) was completely identical with that of the natural cerebroside reported recently by Dabrowskiet al. [4].In planning the synthetic route, the target structures1 and2 were disconnected at the dotted lines to give three key synthetic intermediates3, 4 and5 or6 (Fig. 1).Abbreviations Bu butyl - Ph phenyl - t-BuPh₂SiCl t-butyldiphenylsilyl chloride - MTPA -methoxy--trifluoromethylphenylacetic acid - THF tetrahydrofuran Part 36 in the series Synthetic Studies on Cell-surface Glycans, for part 35, see [1]     

Total synthesis of apigenin-4'-yl 2-O-(p-coumaroyl)-β-D-glucopyranoside

The first total synthesis of apigenin-4′-yl 2-O-(p-coumaroyl)-β-d-glucopyranoside, which exhibits good inhibitory activity against xanthine oxidase (XO), was accomplished in seven steps from a 1,2-blocked sugar unit and natural apigenin. A unique allyl protecting group, a phase-transfer-catalyzed (PTC) regioselective coupling reaction, and robustness in large-scale preparation are the merits of this synthetic strategy.     

Stereoselective Synthesis of 1- and 2-O-α-d-Cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols Related to Rhynchosporoside

The stereoselective synthesis of 1- and 2-O-α-d-cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols, which determined the structure of rhynchosporoside produced by Rhynchosporium secalis, and their phytotoxicity toward the host plant (Hordeum vulgare) are described in detail.     

Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2′-monomethyl-4-methyl- and 1′-thia-4-methyl-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs

In a continuing investigation into the pharmacophores and structure–activity relationship (SAR) of (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2′-monomethyl substituted 1′-oxa, 1′-thia, 1′-sulfoxide, and 1′-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2′S-monomethyl-4-methyl DCK (5a)³ and 2′S-monomethyl-1′-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC₅₀ values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2′R-monomethyl-4-methyl DCK (6) and 2′R-monomethyl-1′-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2′-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class.     

Stereocontrolled Facile Synthesis and Biological Evaluation of (3′S) and (3′R)-3′-Amino (and Azido)-3′-Deoxy Pyranonucleosides

This article describes the synthesis of (3 ′S) and (3 ′R)-3 ′-amino-3 ′-deoxy pyranonucleosides and their precursors (3 ′S) and (3 ′R)-3 ′-azido-3 ′-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 ′-amino-3 ′-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 ′-amino-3 ′-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.     

Syntheses and Biological Activities of (2S,2′ S)- and (2S,2′R)-Dimethyl 3-Phenyl-2,2′-oxydipropionate,Ether Analogues of a Plant-growth Regulator Isolated from Botrytis squamosa

Ether analogues of a plant growth regulator isolated from Botrytis squamosa, (2S,2′S)- and (2S,3′S)-dimethyl 3-phenyl-2,2′-oxydipro-pionate (1), were prepared by the Williamson synthesis, and the two diastereomers were separated. The absolute configurations of both diastereomers were determined by chemical transformation. The promoting effect of both synthesize analogues on lettuce seedling growth was similar to that of the natural plant growth regulator.     

Microbiological synthesis of 5-ethyl- and (E)-5-(2-bromovinyl)-2′-deoxyuridine

Summary The title compounds were prepared by an enzymatic transdeoxyribosylation from 2 dGuo or 2 dThd to the respective heterocyclic bases, 5-ethyluracil and (E)-5-(2-bromovinyl)uracil, using the whole bacterial cells ofEscherichia coli as a biocatalyst.     

Synthesis of 2-(3′-Azido- and 3′-Amino-3′-deoxy-β-D-ribofuranosyl)thiazole-4-carboxamide

Abstract

In view of biological activities of tiazofurin and azido or aminosugar nucleosides, novel azido- and amino-substituted tiazofurin derivatives (1 and 2) were efficiently synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose.     

Synthesis and Properties of Phosphorylated 3′-O-β-D-Ribofuranosyl-2′-deoxythymidine

Abstract

A strategy was developed for the synthesis of 3′-O-β-D-ribofuranosyl 2′-deoxythymidine derivatives using three different protecting groups, which allows the synthesis of a phosphoramidite building block for oligonucleotide synthesis. Likewise the 5′-O- and 5″-O-phosphorylated analogues were synthesized and their conformation was determined using NMR spectroscopy.     

Synthesis of 1-O-(2′,4′-Dichlorophenoxyacetyl)-d-glucopyranose

1-O-Glucosyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) were easily prepared from 4,6-O-benzylideneglucose. The configuration of 1-O-ester linkage was affected by pH at the end of the reaction, that is, β-type was a major product at a neutral or acidic condition and α-type at an alkaline condition. Both of the anomers showed the same biological activities as sodium salt of 2,4-D.     

Synthesis of 2-(p-trifluoroacetamidophenyl)ethylO-α-l-fucopyranosyl-(1–3)-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl) (1–3)-O-β-d-galactopyranosyl-(1–4)-β-d-glucopyranoside,a tetrasaccharide fragment of a tumour-associated glycosphingolipid

The tetrasaccharide 2-(p-trifluoroacetamidophenyl)ethylO-α-l-fucopyranosyl-(1–3)-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1–3)-O-β-d-galactopyranosyl-(1–4)-β-d-glucopyranoside was synthesized from thioglycoside intermediates. The key step was a methyl triflate promoted glycosidation of a lactose-derived 3′,4′-diol with a disaccharide thioglycoside to give a β(1–3)-linked tetrasaccharide derivative in 67% yield.     

Concise syntheses and HCV NS5B polymerase inhibition of (2′R)-3 and (2′S)-2′-ethynyluridine-10 and related nucleosides

(2′R)-Ethynyl uridine 3, and its (2′S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5′-O-triphosphates. Subsequently, this lead to the discovery of the 2′-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.     

Synthetic mucin fragments. Methyl 6-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,methyl 3,4-di-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,and methyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1 å 3)-O-β-D-galactopyranosyl-(1 å 3)-O-(2-acetamido-2-deoxy-β- D-glucopyranosyl)-(1 å 3)-β-D-galactopyranoside

Condensation of methyl 2,6-di-O-benzyl-β-d-galactopyranoside with 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-d-glucopyrano)-[2,1,-d]-2-oxazoline (1) in 1,2-dichloroethane, in the presence of p-toluenesulfonic acid, afforded a trisaccharide derivative which, on deacetylation, gave methyl 3,4-di-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2,6-di-O-benzyl-β-d- glactopyranoside (5). Hydrogenolysis of the benzyl groups of 5 furnished the title trisaccharide (6). A similar condensation of methyl 2,3-di-O-benzyl-β-d-galactopyranoside with 1 produced a partially-protected disacchraide derivative, which, on O-deacetylation followed by hydrogenolysis, gave methyl 6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-β-d-glactopyranoside (10). Condensation of methyl 3-O-(2-acetamido-4,6-O-benzylidene-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-benzyl-β-d- galactopyranoside with 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide in 1:1 benzene-nitromethane in the presence of powdered mercuric cyanide gave a fully-protected tetrasaccharide derivative, which was O-deacetylated and then subjected to catalytic hydrogenation to furnish methyl O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-O-β-d-galactopyranosyl-(1å3)-O-(2-acetamido-2-deoxy- β-d-glucopyranosyl)-(1å3)-β-d-galactopyranoside (15). The structures of 6, 10, and 15 were established by ¹³C-n.m.r. spectroscopy.     

Synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d-galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol

Stereo- and regio-selective synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d- galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol by use of 1,2-di-O-tetradecyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-galactopyranosyl)-sn-glycerol as a key intermediate is described.     

Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents

Thirteen novel seco-DCK analogs (4–16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC₅₀ value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC₅₀: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.     

A convenient synthesis of 2-deoxy-2-[(R)-1-hydroxytetradecanamido]-3-O-[(R)-3-hydroxytetradecanoyl]-α-d-glucopyranose 1-phosphate (lipid X)

The crystalline tris(hydroxymethyl)aminomethane (“Tris”) salt of 2-deoxy-2-[(R)-3-hydroxytetradecanamido]-3-O-[(R)-3-hydroxytetradecanoyl]-α-d-glucopyranose 1-phosphate (lipid X) has been synthesised from 2-amino-2-deoxy-d-glucose hydrochloride in five steps in ∼ 50% overall yield. The key step was 1-O-(dibenzyl) phosphorylation of 4,6-O-benzylidene-2-[(R)-3-benzyloxytetradecanamido]-2-deoxy-d-glucopyranose, catalysed by butyl-lithium. The product was then 3-(R)-3-benzyloxytetradecanoylated, and the benzyl and benzylidene groups were removed by catalytic hydrogenation.     

Synthesis of (2′S)-1-(2-C-Azidomethyl-2-deoxy and 2-C-Cyanomethyl-2-deoxy-β-D-arabinofuranosyl)cytosines

Abstract

2′-C-Cyanomethyl-2′-deoxy-arabinosylcytosine 3 and 2′-C-azidomethyl-2′-deoxy-arabinosylcytosine 4 were synthesized from uridine. The antineoplastic activities of these compounds were evaluated.