Hiroki Takahata

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.

We are studying the medicinal synthetic chemistry of biomolecular component mimics such as carbohydrates, nucleosides, amino acids, and peptides. In this review, the synthesis and biological activities of iminosugars as carbohydrate mimics are discussed. Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. Hence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. We synthesized all of the stereoisomers of polyhydroxypiperidines such as fagomine, 1-deoxynojirimycine, and isofagomine. In addition, their both enantiomers, as substrates for a variety of glycosidases were evaluated. Secondly, the asymmetric synthesis of α-1-C-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, RCM, and Negishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms 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 towards intestinal sucrase of α-1-C-L-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs.

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, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC₅₀ values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are 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 compounds that can improve postprandial hyperglycemia.

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.

Nucleoside antimetabolites act an important role in the fields of cancer and viral chemotherapies. To search new agents effective for tumor and virus, many attempts were made for synthesizing novel nucleoside derivatives. Construction of the glycosidic bond is a key reaction to synthesize new nucleoside derivatives. We have been focused the synthesis of novel biologically active nucleoside derivatives by developing novel “glycosylation” reactions. Our first successful example was the synthesis of 4′-thionucleoside by using the Pummerer-type thioglycosylation reaction. As a result, we found potent antineoplastic nucleoside, 4′-thioFAC, and some novel 4′-thionucleosides possessing antiherpes virus activities. Secondary, we developed a new entry to isonucleosides in which the Mitsunobu reaction with neighboring sulfur assistance was employed as a nucleobase introducing reaction. We also developed a conceptually new method for synthesizing carbocyclic nucleosides based on hypervalent iodine chemistry. The mechanism of this oxidative coupling reaction was investigated.

An asymmetric synthesis of all stereoisomers of piclavines A1-4 using an iterative asymmetric dihydroxylation An asymmetric synthesis of all stereoisomers of piclavines A1-4 using an iterative asymmetric dihydroxylation