Synthesis of Methylene-Bridged Analogues of Nicotinamide Riboside,Nicotinamide Mononucleotide and Nicotinamide Adenine Dinucleotide

Abstract

5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-3(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose (11a) and ?3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (11b) were prepared by condensation of 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-erythro-3-pentulofuranose (10) with lithiated (LDA) 2-methylnicotinamide and 6-methylnicotinamide, respectively, and then deprotected to give 1,2-O-isopropylidene-3-(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose(12a) and 1,2-O-isopropylidene-3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (12b). Benzoylation as well as phosphorylation of compounds 12 afforded the corresponding 5-O-benzoate (13b) and 5-O-monophosphates (14a and 14b). Treatment of 13b with CF₃COOH/H₂O caused 1,2-de-O-isopropylidenation with simultaneous cyclization to the corresponding methylene-bridged cyclic nucleoside - 3′,6-methylene-1-(5-O-benzoyl-β-D-ribofuranose)-3-carboxamidopyridinium trifluoro-acetate (8b) - restricted to the “anti” conformation. In a similar manner compounds 14a and 14b were converted into conformationally restricted 2,3′-methylene-1-(β-D-ribofuranose)-3-carboxamidopyridinium-5′-monophosphate (9a - “syn”) and 3′,6-methylene-1-(β-D-ribofuranose)-3-carboxamido -pyridinium-5′monophosphate (9b - “anti”) respectively. Coupling of derivatives 12a and 12b with the adenosine 5′-methylenediphosphonate (16) afforded the corresponding dinucleotides 17. Upon acidic 1,2-de-O-isopropylidenation of 17b, the conformationally restricted P¹-[6,3′-methylene-1-(β-D-ribofuranos-5-yl)-3-carboxamidopyridinium]-P²-(adenosin-5′-yl)methylenediphosphonate 18b -“anti” was formed. Compound 18b was found to be unstable. Upon addition of water 18b was converted into the anomeric mixture of acyclic dinucleotides, i. e. P¹-[3(R)-nicotinamid-6-ylmethyl-D-ribofuranos-5-yl]-P²-(adenosin-5′-yl)-methylenediphosphonate (19b). In a similar manner, treatment of 17a with CF₃COOH/H₂O and HPLC purification afforded the corresponding dinucleotide 19a.

     

Synthesis and Herbicidal Activity of Phenoxypropionic Acid Derivatives with Imidazo[1,2-α]pyridine Moiety

Phenoxypropionic acid derivatives (Ia-s) with an imidazo[1,2-a]pyridine moiety were synthesized and their herbicidal activities were examined. The activities were affected dramatically by the substituents on the imidazo[1,2-a]pyridine ring, and good substituents to enhance the herbicidal activity were a cyano group at the 3-position and a chlorine atom at the 6-position. Among the compounds, n-propyl 2-[4-(6-chloro-3-cyano-2-imidazo[1,2-a]pyridinyloxy)phenoxy]propionate(Iq) was most active against gramineous weeds and the activity was comparable to that of the commercial herbicide fluazifop-butyl.     

Synthesis and conformational analysis of 1,2-cis fused bicyclic α-d-galactofuranosyl thiocarbamate from per-O-tert-butyldimethylsilyl-β-d-galactofuranosyl isothiocyanate

Per-O-tert-butyldimethylsilyl-α,β-d-galactofuranosyl isothiocyanate (4) was synthesized by the reaction of per-O-TBS-β-d-galactofuranose (1) with KSCN, promoted by TMSI. Upon O-desilylation (1,2-dideoxy-α-d-galactofuranoso)[1,2d]-1,3-oxazolidine-2-thione (6), the cis-fused bicyclic thiocarbamate was obtained as the only product. Conformational analysis, aided by molecular modelling, showed two stable twist forms (³T₄ and ⁴T_O) for the five-membered sugar ring in 6. In aqueous solution, the equilibrium favours the first conformation (3:1 ratio). On the other hand, this ratio decreases for less polar solvents.     

Studies on the stereoselective synthesis of a protected α-d-Gal-(1→2)-d-Glc fragment

A novel 1,2-cis stereoselective synthesis of protected α-d-Gal-(1→2)-d-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-α-d-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-β-d-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-thio-β-d-galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl-α-d-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-β-d-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis α-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of α selectivity. In particular, higher α/β stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a β-CH₃ at C-1 and benzoyl groups at C-4 and C-6.     

Synthesis of 3′-Thioribouridine, 3′-Thioribocytidine,and Their Phosphoramidites

Abstract

3′-Thio-3′-deoxyribonucleosides (U and C) have been synthesized via Vorbruggen-type glycosylation with 3-S-benzoyl-5-O-toluoyl-1,2-O-diacetylfuranose, which was obtained from 1,2-O-isopropylidene-5-O-toluoyl-3-O-trifluoromethanesulfonyl-α-D-xylofuranose. 3′-Thio-3′-deoxyuridine has been converted to its phosphoramidite.     

A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.     

Synthesis of a Base-Protected α-L-LNA Guanine Nucleoside

Abstract

Synthesis of (1R,3R,4S,7R)-7-hydroxy-1-hydroxymethyl-3-(2-N-isobutyroylguanin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane (12), a protected α-L-LNA guanine nucleoside, has been accomplished using a convergent synthetic strategy starting from 1,2-di-O-acetylfuranose 4.     

Flavonoids and other constituents of Hymenostegia afzelii (Caesalpiniaceae)

Phytochemical investigation of the stem bark and leaves of Hymenostegia afzelii resulted in the isolation of three new flavonoids, named afzelin A-C (1–3), together with five known compounds: 7,6-(2″,2″-dimethylpyrano)-3,5,4′-trihydroxyflavone, apigenin, 3-O-α-l-rhamnopyranosylcincholic acid, 3-O-β-d-glucopyranosylcincholic acid, and dodecanoic acid 1,1′-[(1S)-1-(hydroxymethyl)-1,2-ethanediyl] ester. The structures of 1–3 were determined by means of spectroscopic methods. Compounds 1–3 were tested in vitro for their preliminary cytotoxicity using the Artemia salina assay.     

Synthesis of octyl S-glycosides of tri- to pentasaccharide fragments related to the GPI anchor of Trypanosoma brucei

The three oligosaccharide octyl-S-glycosides Man-α1,6-Man-α1,4-GlcNH₂-α1,S-Octyl (19), Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (27) and Man-α1,2-Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (37), related to the GPI anchor of Trypanosoma brucei were prepared by a stepwise and block-wise approach from octyl 2-azido-2-deoxy-3,6-di-O-benzyl-1-thio-α-d-glucopyranoside (8) and octyl 2-O-benzoyl-4,6-O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-α-d-mannopyransoside (9). Glucosamine derivative 8 was obtained from 1,3,4,6-tetra-O-acetyl-2-azido-2-desoxy-β-d-glucopyranose (1) in five steps. Mannoside 9 was converted into the corresponding imidate 12 and coupled with 8 to give disaccharide octyl-S-glycoside 13 which was further mannosylated to afford trisaccharide 19 upon deprotection. Likewise, mannoside 9 was galactosylated, converted into the corresponding imidate and coupled with 8 to give trisaccharide 25. Mannosylation of the latter afforded tetrasaccharide 27 upon deprotection. Condensation of 25 with disaccharide imidate 35 gave, upon deprotection of the intermediates, the corresponding pentasaccharide octyl-S-glycoside 37. Saccharides 19, 27 and 37 are suitable substrates for studying the enzymatic glycosylation pattern of the GPI anchor of T. brucei.     

Alternate Approaches to the Synthesis of 2′-O-Me Nucleosides

Abstract

Three different approaches to the synthesis of 2′-O-methyl nucleosides starting from the corresponding nucleoside or commercially available 1,2:5,6-di-O-isopropylidene-α-D-allofuranose 1 are described.     

Furanoditerpenes from Arcangelisia flava (L.) Merr. and their antifungal activity

Two furanoditerpenes, 2α,3α-epoxy-2,3,7,8α-tetrahydropenianthic acid methyl ester (1) and 2α,3α-epoxy-2,3-dihydropenianthic acid methyl ester (2) were isolated and identified from the root of Arcangelisia flava (L.) Merr. The configuration of 1 was determined by X-ray crystallographic analysis and two-dimensional NMR. Fibraurin (3), fibleucin (4), 2β, 3α-dihydroxy-2,3,7,8α-tetrahydropenianthic acid-2,17-lactone (5), p-hydroxybenzaldehyde and vanillin were also isolated and identified by NMR and EI-MS or FAB-MS. The 2β, 3α-dihydroxy-2,3,7,8α-tetrahydropenianthic acid-2,17-lactone (5) showed the highest antifungal activity of the isolated five furanoditerpenes against a white-rot fungus (Trametes versicolor) and a brown-rot fungus (Fomitopsis palustris).     

Ganoderiol A and B,New Triterpenoids from the Fungus Ganoderma lucidum (Reishi)

Two new lanostane-type triterpenoids, ganoderiol A (1) and ganoderiol B (2) were isolated from the fruiting bodies of Ganoderma lucidum, together with known ganodermanontriol (3) and ganodermatriol (4). The compounds were identified as 5α-lanosta-7,9(11)-dien-3β,24,25,26-tetraol (1), 15α,26,27-trihydroxy-5α-lanosta-7,9(11),24-trien-3-one (2), 24,25,26-trihydroxy-5α-lanosta-7,9(11)-dien-3-one (3) and 5α-lanosta-7,9(ll),24-trien-3β,26,27-triol (4), respectively.     

Microbial hydroxylation of epiandrosterone by Aspergillus candidus

In this work, Aspergillus candidus MRC 22634 converted epiandosterone 1 into 10 hydroxylated metabolites. A. candidus has been shown to hydroxylate 1 predominantly at C-11α, C-1α, and C-15β with minor hydroxylations occurring at C-14α and C-7α. Oxidation at C-3, reduction at C-17, and C-3 epimerization of some of the remaining substrate have also been shown. 15β-Hydroxylation and C-3 epimerization of 1 by a fungus were reported for the first time. Two of the metabolites, 1α,3α-dihydroxy-5α-androstan-17-one 4 and 15β,17β-dihydroxy-5α-androstan-3-one 7, were identified as new compounds.     

Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)¹ 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.     

Herbicidal Activity of N-(2,3-Epoxypropyl)benzenesulfonamide Derivatives

N-Acyl- and N-sulfonyl-N-(2,3-epoxypropyl)benzenesulfonamide derivatives were synthesized and their herbicidal activities were tested against barnyardgrass and rice plants by the pot and the petri dish tests in order to examine the structural requirements for herbicidal activity in N-(2,3-epoxypropyl)benzenesulfonamide derivatives. The N-sulfonylbenzenesulfonamide derivatives exhibited higher activity against barnyardgrass than the N-acylbenzenesulfonamide derivatives, and were found to be as active as N-(2,3-epoxypropyl)-N-(α-methylbenzyl)benzenesulfonamide. Some of the N-sulfonylbenzenesulfonamide derivatives showed high selectivity towards barnyardgrass and rice plants at their germination stage.     

Studies on Geobacillus stearothermophilus – Part V: Transformation of 11α-hydroxyprogesterone

The influence of a hydroxyl group on the biotransformation of 11α-hydroxyprogesterone mediated by the thermophile Geobacillus stearothermophilus, was investigated. Bacterial transformation of 11α-hydroxyprogesterone resulted in the formation of previously reported six hydroxylated progesterone metabolites, identified as 11α-hydroxy-5α-pregnane-3, 6, 20-trione 1, 11α, 20α-dihydroxypregnene-3-one 2, 11α, 6β-dihydroxyprogesterone 3, 11α, 6α-dihydroxyprogesterone 4, 11α, 6β, 20α-trihydroxypregnene-3-one 5, 11α, 6α, 20α-trihydroxypregnene-3-one 6. All transformation products were identified through their spectral data and comparison with reference compounds.     

Synthesis of Branched-Chain and Bicyclic Thiosugar Nucleosides

Abstract

The synthesis of strategically protected nucleosides bearing β-mercaptoethyl chains at the α-C-3′ position from 1,2-di-O-acetyl-2′-S-acetyl-5-t?butyldiphenylsilyl-3-deoxy-3-C-(2′-mercaptoethyl)-α-D-ribofuranose 1 is described. It was found that treatment of the 5-O-methanesulfonyl sugar 19 or nucleoside 5 with either benzylmercaptan or methoxide resulted in rapid cleavage of the thiolester followed by intramolecular cyclization. This was used to prepare the novel trans?fused oxathiahydrindane nucleosides 7 and 27 as well as the cAMP analogue 29.     

Novel steroidal saponins from Liriope graminifolia (Linn.) Baker with anti-tumor activities

Phytochemical investigation of the underground parts of Liriope graminifolia (Linn.) Baker resulted in the isolation of two new steroidal saponins lirigramosides A (1) and B (2) along with four known compounds. The structures were determined by extensive spectral analysis, including two-dimensional (2D) NMR spectroscopy and chemical methods, to be 3-O-{β-d-xylopyranosyl-(1→3)-α-l-arabinopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→4)]-β-d-glucopyranosyl-(25S)-spirost-5-ene-3β,17α-diol (1), 1-O-[α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl]-(25R)-ruscogenin (2), 1-O-β-d-xylopyranosyl-3-O-α-l-rhamnopyranosyl-(25S)-ruscogenin (3), 3-O-α-l-rhamnopyranosyl-1-O-sulfo-(25S)-ruscogenin (4), methylophiopogonanone B (5), and 5,7-dihydroxy-3-(4-methoxybenzyl)-6-methyl-chroman-4-one, (ophiopogonanone B, 6), respectively. Compound 1 has a new (25S)-spirost-5-ene-3β,17α-diol ((25S)-pennogenin) aglycone moiety. The isolated compounds were evaluated for their cytotoxic activities against Hela and SMMC-7721 cells.     

Two New Gibberellins A50 and A52 in Seeds of Lagenaria leucantha

Two new gibberellins A₅₀ and A₅₂ were isolated from seeds of Lagenaria leucantha Rusby var. clavata Makino. Their structures were shown to be ent-2α,3α,10,llα-tetrahydroxy-20-norgibberell-16-ene-7,19-dioic acid 19,10-lactone (1) and ent-2α,3α,11β20-tetrahydroxy-gibberell-16-ene-7,19-dioic acid 19,20-lactone (10), respectively.     

A New Apparatus for Preparative Gel Electrophoresis

Syntheses of two carbonyl derivatives of hydantocidin 1, a potent, naturally occurring herbicide, and their herbicidal activity are described. Spiroimidazolidinone 2, the descarbonyl compound at C9, was prepared by employing reductive demethylsulfurization with tri-n-butyltin hydride as the key step. Another derivative, spiroimidazolinone 10, was obtained from α-azidoamide 8 and benzyl isocyanate via the aza-Wittig reaction. 2 had lost almost all herbicidal activity, whereas 10 retained herbicidal activity against such dicotyledonous weeds as ragweed and cocklebur, but lost activity against monocotyledonous weeds. These results imply the possibility that proper modification of the carbonyl group at C7 of the parent compound would afford hydantocidin analogues possessing crop selectivity.