[Show abstract][Hide abstract] ABSTRACT: We have built a new isonucleoside derivative on a 2,6-dioxobicyclo[3.2.0]heptane skeleton as a potential anti-HIV agent. To synthesize the target compound, an acetal-protected dihydroxyacetone was first converted to a 2,3-epoxy- tetrahydrofuran derivative. Introduction of an azide group, followed by the formation of an oxetane ring, gave a pseudosugar derivative with a 2,6-dioxobicyclo[3.2.0]heptane skeleton. The desired isonucleoside was obtained by constructing a purine base moiety on the scaffold, followed by amination.
[Show abstract][Hide abstract] ABSTRACT: A series of α-1-C-4'-arylbutyl-l-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a-e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.
[Show abstract][Hide abstract] ABSTRACT: As a part of our ongoing studies of structure–activity re-lationships regarding cyclohexenyl nucleosides, we were prompted to synthesize a dihydropyranonucleoside as a potential anti-HIV agent. The synthesis of a glycal moiety started from but-2-enediol, which was converted into a di-PMB derivative in several steps. The introduction of an allyl group followed by ring-closing metathesis gave a dihydropyran derivative. After isomerization of the double bond catalyzed by Wilkinson's catalyst, the resulting glycal, 2,3-bis[(4-methoxybenzyloxy)methyl]-3,4-dihydro-2H-pyran, was subjected to an oxidative glycosylation reaction mediated by hyper-valent iodine. Treatment of 2,3-bis[(4-methoxybenzyloxy)methyl]-3,4-dihydro-2H-pyran with (PhSe) 2 /PhI(OAc) 2 /TMSOTf (cat.) gave the desired pyranyluracils as a mixture of anomers that were converted into the final target, dihydropyranocytidine, after several manipulations and separation of the anomers.
[Show abstract][Hide abstract] ABSTRACT: Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2-en-1-yl methyl carbonates were investigated. The relative position of the 2,5-substituents of the resulting pyrrolidines was found to be controlled by using both enantiomers ( and ) of the appropriate chiral ligand, demonstrating a simple and highly stereodivergent synthetic protocol. Selected trans- and cis-2,5-disubstituted 3-hydroxypyrrolidines ( and ) were converted to (+)-bulgecinine () and (+)-preussin (), respectively.
[Show abstract][Hide abstract] ABSTRACT: The synthesis of a novel nucleoside phosphonate constructed on a branched-threo-tetrofuranose scaffold, as a potential antiviral agent, is described. The pseudosugar moiety served as the nucleoside skeleton was produced starting from 2-butyne-1,4-diol in 10-steps. Glycosylation with the pseudosugar involved stereoselective neighboring group participation of p-anisyl group and gave the nucleoside derivative in 94% yield. After manipulating the protecting group and introduction of a methylenephosphate unit, the synthesis of the target novel cytidine phosphonate was achieved. The resulting nucleoside, a synthetic intermediate of the nucleoside phosphonate, would also be expected to serve as a useful building block for the synthesis of novel antisense/antigene derivatives.
[Show abstract][Hide abstract] ABSTRACT: An asymmetric synthesis of 1-alkyl-2-deoxyiminofuranoses was achieved in which the Ir-catalyzed intramolecular cyclization was the key step. The diastereoselective cyclization converted an allylic carbonate into pyrrolidine derivatives. The alpha-glucosidase inhibitory activities of the prepared 2-deoxyiminofuranoses were also investigated.
[Show abstract][Hide abstract] ABSTRACT: Synthesis of beneficial protected meso-DAP 9 by cross metathesis of the Garner aldehyde-derived vinyl glycine 1b with protected allyl glycine 2 in the presence of Grubbs second-generation catalyst was performed. Preparation of lipophilic N-acyl iE-DAP as potent agonists of NOD 1-mediated immune response from 9 is described.
[Show abstract][Hide abstract] ABSTRACT: Cyclonucleosides which are fixed in a specific conformation around the glycosyl bond by a carbon and heteroatom chain constitute a unique category of nucleoside derivatives. Because they are structural analogs, cyclonucleosides and oligodeoxynucleotides containing them would be useful tools for investigating the biological functions and conformations of DNA, RNA as well as their steric interactions with proteins. C-Cyclonucleosides bridged by a carbon chain between the base and sugar moieties are the most attractive from the synthetic points of view as well as for use as biological tools. In this review, recent progress of the synthesis of C-cyclonucleosides is surveyed. Among the C-cyclonucleosides, 5',8-C-cyclodeoxyadenosine is one of the well-known derivatives of which the first practical synthesis was reported over 30 years ago. Recently, 5',8-C-cyclodeoxyadenosine has attracted considerable interest as a biomarker, since its formation in oxidatively-damaged DNA is considered to be related to various diseases and aging. Another important analogue of cyclonucleosides is a unique thymidine phosphate dimer, a so-called spore photoproduct, which has been found in photo-damaged DNA. Recent advances in the synthesis, mechanism-studies, and stereochemical preference of repairing enzymes related to 5',8-C-cyclodeoxyadenosine and spore photoproducts are also reviewed.
[Show abstract][Hide abstract] ABSTRACT: We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. α-1-C-Butyl-LAB was potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. MALDI-TOF MS analysis revealed that this compound differed from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase (ntMGAM) suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol were clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compound that can improve postprandial hyperglycemia.
[Show abstract][Hide abstract] ABSTRACT: Oxidative coupling of persilylated uracil with allylsilane or dihydropyran is performed in the presence of PhI(OAc)2 and TmsOTf to give N-substituted derivatives.
[Show abstract][Hide abstract] ABSTRACT: An asymmetric synthesis of 2-propylisofagomine 5 using allylic hydroxy group accelerated ring-closing enyne metathesis (AHA-RCEM) was conducted with high diastereoselectivity in 13% overall yield starting from the commercially available (E)-hex-2-ol.
[Show abstract][Hide abstract] ABSTRACT: In continuation of our previous study, oxidative coupling reactions of uracil with allylsilane or enol ethers were examined using diacetoxyiodobenzene. The reaction of persilylated uracil with 3,4-dihydro-2H-pyran in the presence of TMSOTf and PhI(OAc)(2) resulted in the formation of a dihydropyranyluracil derivative, although the yield was low. In an extension of the oxidative coupling reaction, a novel glycosylation reaction using glycal derivatives as substrates was also developed. The treatment of persilylated uracil and 3,4-dihydro-2H-pyran with (PhSe)(2) and PhI(OAc)(2) in the presence of a catalytic amount of TMSOTf gave a 2,3-anti-derivative of 1-(3-phenylselanyltetrahydropyran-2-yl) uracil stereoselectively and in good yield.
[Show abstract][Hide abstract] ABSTRACT: We have developed a novel method for the synthesis of the β-anomer of 4'-thio-C-ribonucleosides from 3,5-O-(di-tert-butylsilylene)-4-thiofuranoid glycal. Palladium-catalyzed coupling of 1-tributylstannyl-4-thiofuranoid glycal with iodobenzene or a heteroaryl halide gave 1-C-phenyl- or 1-C-heteroaryl-glycals. Hydroboration of these glycals proceeded at the α-face, and subsequent alkaline hydrogen peroxide treatment of the resulting 2'-α-borane furnished the respective β-anomer of 4'-thio-C-ribonucleosides. These results demonstrate that this synthetic method has a wider scope in terms of heterocyclic base structure. During this study, unexpected Markovnikov-oriented hydroboration has been observed to lead to the respective 1'-α-boranes. These 1'-boranes were converted into either the ring-opened structure or the 2'-deoxy derivatives depending upon their stability.
The Journal of Organic Chemistry 11/2011; 76(21):8658-69. DOI:10.1021/jo201100n · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the structure–activity relationship of a series of D-, and L-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, D-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. L-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC50 value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of D-3-epi-isofagomine in the binding site was similar to that of D-isofagomine, while D-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that D-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease.
[Show abstract][Hide abstract] ABSTRACT: As a part of our ongoing efforts to identify new anti-HIV agents, a 5'-thiopyrano-nucleoside derivative 4, designed based on 4'-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated.
[Show abstract][Hide abstract] ABSTRACT: The asymmetric synthesis of 1-C-alkyl-L-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC50 values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC50 = 0.032 μM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.