1,6-Anhydro-N-acetyl-β-D-glucosamine in the oligosaccharide syntheses: I. Synthesis of 3-acetate and 3-benzoate of 1,6-anhydro-N-acetyl-β-D-glucosamine via the 4-O-trityl derivative

3-O-Acetyl and 3-O-benzoyl derivatives of 1,6-anhydro-N-acetyl-β-D-glucosamine were synthesized via its selective tritylation followed by the 3-O-acylation and removal of the trityl protective group. Tritylium trifluoromethanesulfonate, which can easily be prepared by mixing solutions of triphenylcarbinol and trimethylsilyl trifluoromethanesulfonate in an equimolar ratio, was suggested as a reagent for the effective tritylation of a secondary hydroxyl group. This paper is dedicated to the 70th birthday of Prof. A. Ya. Khorlin.     

Synthesis of capsular polysaccharide of Streptococcus pneumoniae type 14. 3. Synthesis of a monomer for polycondensation

Synthesis of a tritylated tetrasaccharide 1,2-O-(1-cyano) ethylidene derivative is described by glycosylation of 3,6-di-O-benzoyl-4-O-(2,4,6-tri-O-benzoyl-beta- D-galactopyranosyl)-1,2-O-[1-(exo-cyano)ethylidene]-alpha-D- glucopyranose with 6-O-acetyl-3-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-beta- D-galactopyranosyl)-2-deozy-2-phthalimido-D-glucopyranosyl. bromide followed by selective deacetylation and tritylation.     

Facile synthesis of a D-galactono-1,6-lactone derivative, a precursor of a copolyester

2,3,4,6-Tetra-O-methyl-d-galactonic acid (5) was readily prepared from d-galactono-1,4-lactone (1) in 47% yield. The sequence involves tritylation of HO-6 of 1, followed by O-permethylation and deprotection. Lactonization of 5 led to the per-O-methyl-d-galactono-1,6-lactone, which was copolymerized with epsilon-caprolactone by ring-opening polymerization catalyzed by scandium triflate. The incorporation of the sugar comonomer into the polyester chain was about 10%.     

Synthesis of 5-chloro-1-(2,3-dideoxy-3-fluoro-beta-D-glycero-hex-2- enopyranose-4-ulosyl)uracil as potential anticancer/antiviral agent

Peracetylated alpha-D-glucose was coupled with silylated 5-chlorouracil. The product (2) was deacetylated and 4',6'-hydroxyls were then protected with 4',6'-O-isopropylidene group. Fluorine was introduced at the 3'-position, followed by acetylation, deprotection, tritylation, oxidation and deritylation of subsequent compounds gave the target compound (10).     

SYNTHESIS OF 5-CHLORO-1-(2,3-DIDEOXY-3-FLUORO-β-D-GLYCERO-HEX-2-ENOPYRANOSE-4-ULOSYL)URACIL AS POTENTIAL ANTICANCER/ANTIVIRAL AGENT

Peracetylated α-D-glucose was coupled with silylated 5-chlorouracil. The product (2) was deacetylated and 4′,6′-hydroxyls were then protected with 4′,6′-O-isopropylidene group. Fluorine was introduced at the 3′-position, followed by acetylation, deprotection, tritylation, oxidation and deritylation of subsequent compounds gave the target compound (10).

     

Synthesis of methyl glycosides of beta-(1----6)-linked D-galactobiose, galactotriose, and galactotetraose having a 3-deoxy-3-fluoro-beta-D-galactopyranoside end-residue

Methyl 2,4-di-O-acetyl-3-deoxy-3-fluoro-beta-D-galactopyranoside was synthesized by sequential tritylation, acetylation, and detritylation of methyl 3-deoxy-3-fluoro-beta-D-galactopyranoside, and used as the initial nucleophile in the synthesis of methyl beta-glycosides of (1----6)-beta-D-galacto-biose, -triose (20), and -tetraose (22) having a 3-deoxy-3-fluoro-beta-D-galactopyranoside end-residue. The extension of the oligosaccharide chains, to form the internal units in 20 and 22, was achieved by use of 2,3,4-tri-O-acetyl-6-O-bromoacetyl-alpha-D-galactopyranosyl bromide as a glycosyl donor, and mercuric cyanide or silver triflate as the promotor. While fewer by-products were formed in the reactions involving mercuric cyanide, the reactions catalyzed by silver triflate were stereospecific and yielded only the desired beta (trans) products.     

Synthesis of optically active 1-acyl-2-O-alkyl-sn-glycero-3-phosphocholine via 1-O-benzyl-sn-glycerol 3-arenesulfonate

A stereocontrolled route to 1-palmitoyl-2-O-hexadecyl-sn-glycero-3-phosphocholine from (R)-glycidyl tosylate is described. This method gives very high enantioselectivity (93-96% enantiomeric excess) and can be used to prepare 3-acyl-2-O-alkyl-sn-glycero-1-phosphocholines from (S)-glycidyl tosylate. The key step is the preparation of 1-O-benzyl-sn-glycerol 3-tosylate by the boron trifluoride etherate catalyzed regio- and stereo-specific opening of the epoxide ring with excess benzyl alcohol. The alkyl group is introduced using alkyl trifluoromethanesulfonate in the presence of excess 2,6-di-tert-butyl-4-methylpyridine. Debenzylation gives 2-O-alkyl-sn-glycerol 3-arenesulfonate, which is acylated and then converted into the phosphocholine. The use of chiral glycidyl derivatives as starting materials for the synthesis of glycerophospholipids is discussed.     

Exomethylene pyranonucleosides: efficient synthesis and biological evaluation of 1-(2,3,4-trideoxy-2-methylene-beta-d-glycero-hex-3-enopyranosyl)thymine

A new series of unsaturated pyranonucleosides with an exocyclic methylene group and thymine as heterocyclic base have been designed and synthesized. d-Galactose (1) was readily transformed in three steps into the corresponding 1-(beta-d-galactopyranosyl)thymine (2). Selective protection of the primary hydroxyl group of 2 with a t-butyldimethylsilyl (TBDMS) group, followed by specific acetalation, and oxidation gave 1-(6-O-t-butyldimethylsilyl-3,4-O-isopropylidene-beta-d-lyxo-hexopyranosyl-2-ulose)thymine (5). Wittig reaction of the ketonucleoside 5, deprotection and tritylation of the 6'-hydroxyl group gave 1-(2-deoxy-2-methylene-6-O-trityl-beta-d-lyxo-hexopyranosyl)thymine (9). Exomethylene pyranonucleoside 9 was converted to the olefinic derivative 10, which after detritylation afforded the title compound 1-(2,3,4-trideoxy-2-methylene-beta-d-glycero-hex-3-enopyranosyl)thymine (11). These novel synthesized compounds were evaluated for antiviral activity against rotaviral infection and cytotoxicity in colon cancer. As compared to AZT, compounds 1-(2-deoxy-2-methylene-beta-d-lyxo-hexopyranosyl)thymine (7) and 1-(beta-d-lyxo-hexopyranosyl-2-ulose)thymine (8) showed to be more efficient, in rotavirus infections and in treatment of colon cancer.     

Simultaneous regioselective protection of phenyl 1-thioglucosides at the C-3 and C-6 or at the C-2 and C-6 hydroxy groups

Simultaneous regioselective 3,6- or 2,6-selective protection of 1-thio-beta- or alpha-D-glucopyranosides is described. The C-3 and C-6 hydroxy groups of the beta-thioglucoside were selectively protected with triisopropylsilyl or tert-butyldiphenylsilyl trifluoromethanesulfonate. The C-2 and C-6 hydroxy groups of the alpha-thioglucoside were selectively protected with tert-butyldiphenylsilyl trifluoromethanesulfonate.     

Synthesis of methyl O-(3-deoxy-3-fluoro-β- -galactopyranosyl)-(1→6)-O-β- -galactopyranosyl-(1→6)-3-deoxy-3-fluoro -β- -galactopyranoside and related n.m.r. studies

Sequential tritylation, benzoylation, and detritylation of methyl 3-deoxy-3-fluoro-β- -galactopyranoside gave crystalline methyl 2,4-di-O-benzoyl-3-deoxy-3-fluoro-β- -galactopyranoside (9), which was used as the initial nucleophile in the synthesis of the target oligosaccharide (16). Treatment of 9 with 2,3,4-tri-O-benzoyl-6-O-bromoacetyl-α- -galactopyranosyl bromide gave the corresponding disaccharide derivative 13, having a selectively removable blocking group at O-6′. Debromoacetylation of 13 afforded the disaccharide nucleophile 14 which, when treated with 2,4,6-tri-O-benzoyl-3-deoxy-3-fluoro-α- -galactopyranosyl bromide, gave the fully protected trisaccharide 15. Debenzoylation of 15 gave the title glycoside 16. Condensation reactions were performed with silver trifluoromethane-sulfonate as a promoter in the presence of sym-collidine under base-deficient conditions, and gave excellent yields of the desired β-(trans)-products. Analyses of the ¹H- and ¹³C-n.m.r. spectra, as well as determination of the J_CF and J_HF coupling constants, were made by using various one- and two-dimensional n.m.r. techniques.     

Improved synthesis of 5-hydroxylysine (Hyl) derivatives.

The synthesis of 5-hydroxylysine (Hyl) derivatives for incorporation by solid-phase methodologies presents numerous challenges. Hyl readily undergoes intramolecular lactone formation, and protected intermediates often have poor solubilities. The goals of this work were twofold: first, develop a convenient method for the synthesis of O-protected Fmoc-Hyl; secondly, evaluate the efficiency of methods for the synthesis of O-glycosylated Fmoc-Hyl. The 5-O-tert-butyldimethylsilyl (TBDMS) fluoren-9-ylmethoxycarbonyl-Hyl (Fmoc-Hyl) derivative was conveniently prepared by the addition of tert-butyldimethylsilyl trifluoromethanesulfonate to copper-complexed Hyl[epsilon-tert-butyloxycarbonyl (Boc)]. The complex was decomposed with Na+ Chelex resin and the Fmoc group added to the alpha-amino group. Fmoc-Hyl(epsilon-Boc, O-TBDMS) was obtained in 67% overall yield and successfully used for the solid-phase syntheses of 3 Hyl-containing peptides. The preparation of Fmoc-Hyl[epsilon-Boc, O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)] was compared for the thioglycoside, trichloroacetimidate and Koenigs-Knorr methods. The most efficient approach was found to be Koenigs-Knorr under inverse conditions, where Fmoc-Hyl(epsilon-Boc)-OBzl and peracetylated galactosyl bromide were added to silver trifluoromethanesulfonate in 1,2-dichloroethane, resulting in a 45% isolated yield. Side-reactions that occurred during previously described preparations of glycosylated Hyl derivatives, such as lactone formation, loss of side-chain protecting groups, orthoester formation, or production of anomeric mixtures, were avoided here. Research on the enzymology of Lys hydroxylation and subsequent glycosylation, as well as the role of glycosylated Hyl in receptor recognition, will be greatly aided by the convenient and efficient synthetic methods developed here.     

A mild and environmentally friendly scandium(III) trifluoromethanesulfonate-catalyzed synthesis of bis(3'-indolyl)alkanes and bis(3'-indolyl)-1-deoxyalditols

Bis(3'-indolyl)alkanes and bis(3'-indolyl) derivatives containing a 1-deoxyalditol moiety were synthesized in the presence of 5 mol% of scandium(III) trifluoromethanesulfonate [Sc(OTf)3] in CH3CN or EtOH-H2O mixture as a solvent from room temperature to 70 degrees C in good yields (78-97%).     

Synthesis of 5 alpha-androstane-3 alpha,17 beta-diol 3- and 17-glucuronides

The glucuronidation of 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) was carried out by three different methods: The Koenigs-Knorr reaction using methyl-2,3,4-tri-O-acetyl-1 alpha-bromo-1-deoxy-beta-D-glucuronate, by employing methyl-2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-alpha-D-gl ucopyranuronate (imidate procedure), and by the reaction of 2,3,4-tri-O-acetyl-alpha-D-glucopyranuronate catalyzed by trimethylsilyl trifluoromethanesulfonate (triflate method). The Koenigs-Knorr method gave the beta-anomers of both the 3- and 17-glucuronides. The imidate procedure also resulted in the beta-anomers of the 3- and 17-glucuronides, but in lower yield. The triflate method, however, yielded only the alpha-anomers of the 3- and 17-glucuronides. The structural assignments of these compounds were made from NMR spectral data obtained with a 500 mHz instrument.     

Synthesis of methyl glycosides of β-(1→6)-linked -galactobiose, galactotriose, and galactotetraose having a 3-deoxy-3-fluoro-β- -galactopyranoside end-residue

Methyl 2,4-di-O-acetyl-3-deoxy-3-fluoro-β- -galactopyranoside was synthesized by sequential tritylation, acetylation, and detritylation of methyl 3-deoxy-3-fluoro-β- -galactopyranoside, and used as the initial nucleophile in the synthesis of methyl β-glycosides of (1→6)-β- -galacto-biose, -triose (20), and -tetraose (22) having a 3-deoxy-3-fluoro-β- -galactopyranoside end-residue. The extension of the oligosaccharide chais, to form the internal units in 20 and 22, was achieved by use of 2,3,4-tri-O-acetyl-6-O-bromoacetyl-α- -galactopyranosyl bromide as a glycosyl donor, and mercuric cyanide or silver triflate as the promotor. While fewer by-products were formed in the reactions involving mercuric cyanide, the reactions catalyzed by silver triflate were stereospecific and yielded only the desired β (trans) products.     

Debenzylation and detritylation by bromodimethylborane: synthesis of mono-acid or mixed-acid 1,2- or 2,3-diacyl-sn-glycerols.

A novel method of deprotecting primary alcohols protected with either benzyl or trityl groups by using bromodimethylborane under mild reaction conditions (dichloromethane, -20 to 5 degrees C) has been applied to the synthesis of optically pure mono-acid or mixed-acid 1,2- or 2,3-diacyl-sn-glycerols. This method was particularly useful for the synthesis of long saturated acyl (C12 to C24) as well as unsaturated diacyl-sn-glycerols since little or no acyl migration occurred during deprotection. Diacylation of 3-benzyl-sn-glycerol or 1-benzyl-sn-glycerol followed by bromodimethylborane debenzylation gave mono-acid 1,2- or 2,3-diacyl-sn-glycerols, respectively. The mixed-acid 1,2- or 2,3-diacyl-sn-glycerols were prepared from 1-acyl-sn-glycerols or 3-acyl-sn-glycerols, respectively, by tritylation, acylation with a different fatty acid, followed by detritylation with bromodimethylborane.     

Synthesis of arylated coumarins by Suzuki–Miyaura cross-coupling. Reactions and anti-HIV activity

Arylated coumarins were prepared by site-selective Suzuki–Miyaura cross-coupling reaction of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin. Triarylated coumarins were prepared by Suzuki–Miyaura cross-coupling reactions of 3-bromo-4-methyl-2-oxo-2H-chromene-6,7-diylbis(trifluoromethanesulfonate). The in vitro anti-HIV activity of the products was investigated. Two lead structures with considerable activities were identified.     

3-benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists and their efficient synthesis

A series of novel 3-benzhydryl-4-piperidone derivatives were identified as potent tachykinin neurokinin-1 (NK(1)) receptor antagonists. An efficient and versatile synthesis of this series was achieved with a coupling reaction of 1-benzylpiperidones with benzhydryl bromides or benzhydrols in the presence of trifluoromethanesulfonate and a condensation reaction of piperidones with benzyl alcohols using ethyl o-phenylenephosphate. The 3-benzhydryl-4-piperidone skeleton, which has a 1,1-diphenylmethane moiety that is a known privileged substructure targeting G-protein coupled receptors, can be used for chemical library synthesis because of chemical accessibility and diversity.     

Direct C-glycosylation of indole with unprotected mono-, di-, and trisaccharides: a one-pot synthesis of 1-deoxy-1,1-bis(3-indolyl)alditols

1-Deoxy-1,1-bis(3-indolyl)alditols were synthesized by reacting 2.5equiv of indole with 1equiv of the following seven monosaccharides (D-galactose, D-mannose, D-allose, 2-deoxy-D-arabinohexose (2-deoxy-D-glucose), D-arabinose, L-arabinose, D-xylose), two disaccharides (D-lactose, D-maltose), and a trisaccharide (D-maltotriose) in 1:1 EtOH-H(2)O at room temperature, or at 40 or 50 degrees C, in the presence of 5 mol% scandium(III) trifluoromethanesulfonate [Sc(OTf)(3)], in a one-pot reaction, in 36-95% yields.     

Metabolism of glucose 1,6-P2--III. Partial purification and characterization of glucose 1,6-P2 synthase from pig skeletal muscle

1. Glycerate 1,3-P2-dependent glucose, 1,6-P2 synthase has been purified 2000-fold from pig skeletal muscle, with a yield of 75%. 2. The enzyme possesses fructose 1,6-P2-dependent glucose 1,6-P2 synthase and phosphoglucomutase activities, which represent 0.1 and 60% of the main activity, respectively. 3. Both glucose 1-P and glucose 6-P can act as acceptors of the phosphoryl group from glycerate 1,3-P2. 4. The Km values are 19 microM and 67 nM for glucose 1-P and glycerate 1,3-P2, respectively. 5. The enzyme is inhibited by glycerate 2,3-P2, fructose 1,6-P2, glycerate 3-P, phosphoenolpyruvate and lithium, the inhibition pattern varying with the compound.     

Synthesis of 3′-Fluoro-3′-Deoxyribonucleosides; Anti-HIV-1 and Cytostatic Properties

Abstract

It has generally proven difficult to synthesize ribonucleosides with sugar modifications at the 3′ position. We now present a practical route for the synthesis of ribonucleosides with a 3′ fluorine substituent. Nucleosides with the xylo configuration were prepared by sugar-base condensation. Tritylation of the unprotected nucleosides gave a mixture of 2′,5′ and 3′,5′ bistritylated nucleosides which were difficult to characterize. Therefore the necessary precursors were synthesized in a step-wise fashion, starting with selective deprotection of the 2′-acyl group, followed by tritylation. This gave the 2′,5′-tritylated xylonucleosides in good yield. Reaction with diethylaminosulfur trifluoride and deprotection with 80 % acetic acid provided the 3′-fluoro-3′-deoxyribonucleosides 1, 2 and 4. The cytidine derivative was synthesized from 1 by reaction with trifluoromethanesulfonic anhydride followed by ammonia. Treatment of 4 with adenosine deaminase yielded 5.