Stereoselective synthesis of D-glycero-D-manno-heptose-1ß,7-bisphosphate (HBP) from D-mannurono-2,6-lactone.

The synthesis of D-glycero-D-manno-heptose-1ß,7-bisphosphate (HBP) from D-mannose is described. This synthetic approach is notable for the elongation of the seventh carbon, employing mannurono-2,6-lactone, the substrate-controlled establishment of the C-6 configuration, and the nucleophilic introduction of phosphate at the C-1 position through the utilization of 4,6-O-benzylidene-α-triflate.

Conformationally restricted donors for stereoselective glycosylation.

In nucleophilic reactions using sugars as electrophiles, i.e., glycosyl donors, their conformation affects the generation rate or stability of the glycosyl cation intermediates and determines at which side of the SN2-SN1 borderline and at what rate the reaction occurs. In addition, changes in the conformation create the steric or stereoelectronic effects of the substituents, which also change the reaction rate and stereoselectivity. Bulky silyl protecting groups, uronic acid esters, and transannular structures have been utilized to change the conformation. Consequently, reactions with unique reactivities and stereoselectivities have been developed. In this chapter, a discussion of the reaction mechanisms relating stereoselectivity to conformation is provided.

Selective alkylation of T-T mismatched DNA using vinyldiaminotriazine-acridine conjugate.

The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T-T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)-acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T-T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T-T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT-acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1.

α-Methylphenacyl thioesters as convenient thioacid precursors.

α-Methylphenacyl (Mpa) thioesters are described as precursors of thioacids. Mpa thioesters are accessible via the condensation of carboxylic acids and phenacyl thiol, which is easily prepared without column chromatography. The Mpa thioesters are selectively deprotected by reduction with zinc dust in the presence of conventional thioacid protecting groups. In addition, the Mpa group exhibits orthogonal reactivity to the Boc group. These features are expected to facilitate the preparation of complex thioacids, including those in peptides.

ß-Stereoselective Mannosylation Using 2,6-Lactones.

ß-Stereoselective mannosylation using donors bearing the 2,6-lactone moiety is described. In general, glycosylation is a nucleophilic substitution reaction between an alcoholic nucleophile and a sugar moiety containing a leaving group at the anomeric position. Owing to stereoelectronic effects, the reaction tends to proceed via an SN1 mechanism to afford α-glycosides. We found that the introduction of a 2,6-lactone bridge can circumvent the competing SN1 reaction, affording ß-glycosides with stereoinversion via SN2(-like) mechanisms. Glycosyl trichloroacetimidates are particularly efficient when activated by a combined catalyst of AuCl3 and 3,5-bis(trifluoromethyl)phenyl thiourea. In addition, the product stereoselectivity was highly dependent on the concentration of the reaction. Moreover, even when the reaction proceeds via an SN1 mechanism, the corresponding glycosyl cation appears to present sterically a ß-directing nature. Overall, 2,6-lactones were promising structures for achieving ß-mannosylations.

Pterin-7-carboxamides as a new class of aldose reductase inhibitors.

Aldose reductase is related to the onset and progression of diabetic complications, such as neuropathy, retinopathy, angiopathy, and so on: therefore molecules that are capable of inhibiting the enzyme are potential drugs for treatment of diabetic complications. Epalrestat is the sole aldose reductase inhibitor that is clinically used, but still has some drawbacks. Thus, the development of new aldose reductase inhibitors is still desired. We have synthesized a series of new pterin-7-carboxamides, and evaluated their in vitro inhibitory activities against human aldose reductase. All newly synthesized compounds exhibited the inhibitory activity. Among them, 1a having a glycine side chain exhibits the highest activity comparable to that of sorbinil, a highly active aldose reductase inhibitor. Molecular docking of 1a on the active site of the enzyme indicated this compound interacts with amino acid residues that are specific to the enzyme and related to suppressing side effects. Based on these results, we proved perin-7-carboxamides to be a new class of aldose reductase inhibitors, and particularly compound 1a was found to be a good candidate for further biological investigations as a drug for treatment of diabetic complications with fewer side effects.

Total synthesis of vineomycin B2.

The first total synthesis of vineomycin B2 (1) has been accomplished. The aglycon segment, a vineomycinone B2 derivative, and the glycon segment, an α-L-acurosyl-L-rhodinose derivative, were prepared via C-glycosylation using an unprotected sugar and powerful chemoselective O-glycosylation using a 2,3-unsaturated sugar, respectively, as the key steps. Furthermore, effective and simultaneous introduction of the two glycon moieties to the aglycon part by concentration-controlled glycosylation led to the total synthesis of 1.

Exploration of an imide capture/N,N-acyl shift sequence for asparagine native peptide bond formation.

Imide capture of a C-terminal peptidylazide with a side-chain thioacid derivative of an N-terminally protected aspartyl peptide leads to the formation of an imide bond bringing the two peptide ends into close proximity. Unmasking of the N(α) protecting group and intramolecular acyl migration results in the formation of a native peptide bond to asparagine.

Exploring the potential of the ß-thiolactones in bioorganic chemistry.

A series of novel peptide-based ß-thiolactones were synthesized and assayed for cytotoxicity against several human cancer cell lines, where they showed greater activity than the corresponding ß-lactones and ß-lactams. Several of the ß-thiolactones prepared showed strong inhibitory activity in vitro against human cathepsins B and L.

Facile amide bond formation from carboxylic acids and isocyanates.

A wide variety of carboxylic acids in the form of their salts condense with aryl isocyanates at room temperature with loss of carbon dioxide to give the corresponding amides in high yield. Application of the reaction to acyl isocyanates gives unsymmetric imides. The reaction is compatible with hydroxyl groups and both Fmoc and Boc protecting groups for amines and is applicable to aliphatic, aromatic, and heteroaromatic acids.

Influence of protecting groups on the reactivity and selectivity of glycosylation: chemistry of the 4,6-o-benzylidene protected mannopyranosyl donors and related species.

The genesis and development of the 4,6-O-benzylidene acetal method for the preparation of ß-mannopyranosides are reviewed. Particular emphasis is placed on the influence of the various protecting groups on stereoselectivity and these effects are interpreted in the framework of a general mechanistic scheme invoking a series of solvent-separated and contact ion pairs in dynamic equilibrium with a covalent α-glycosyl trifluoromethanesulfonate.

Cyclic peptide synthesis with thioacids.

C-Terminal amino acid 9-fluorenylmethylthioesters may be carried through Boc chemistry solution phase peptide synthesis sequences. After insertion of the final residue in the form of an Fmoc carbamate, treatment with piperidine releases a seco-peptide as a C-terminal thioacid that on treatment with Sanger's reagent undergoes cyclization to a cyclic peptide. Cyclic penta- and hexapeptides have been synthesized in this manner, as has a cyclic glycopeptide. Functional group compatibility with alcohols and carboxylic acids is demonstrated.

Effective and chemoselective glycosylations using 2,3-unsaturated sugars.

Glycosyl donors containing a double bond between C2 and C3 were designed by mimicking the reaction mechanism of lysozyme-initiated hydrolysis of mucopolysaccharides. It was found that, under various glycosylation conditions, the reactivities of 2,3-unsaturated glycosyl acetates were significantly higher, while those of the corresponding 2,3-unsaturated-4-keto glycosyl acetates were much lower than those of the corresponding 2,3-dideoxy (2,3-saturated) glycosyl acetates. Based on these results, chemoselective glycosylations were effectively realized via combinatorial techniques in short-steps using three types of glycosyl donors to construct several types of deoxyoligosaccharides. Furthermore, the highly reactive 2,3-unsaturated glycosyl acetates were found to be useful in the synthesis of the O-glycosides of low reactive tertiary alcohols.

Chemoselective glycosylations using 2,3-unsaturated-4-keto glycosyl donors.

2,3-Unsaturated-4-keto glycosyl acetates were found to exhibit low reactivity under several glycosylation conditions. Chemoselective glycosylations were effectively performed using 2,3-unsaturated glycosyl and 2,3-dideoxy glycosyl acetates as armed glycosyl donors, and 2,3-unsaturated-4-keto glycosyl acetates as disarmed glycosyl donors.

Reaction of thioacids with isocyanates and isothiocyanates: a convenient amide ligation process.

Thiocarboxylates, prepared conveniently by cleavage of 9-fluorenylmethyl or trimethoxybenzyl thioesters, react at room temperature with isocyanates and isothiocyanates to give amide bonds in good to excellent yield. A carboxylate salt is also shown to react with an electron-deficient isocyanate to give the corresponding amide in excellent yield at room temperature.

One-pot syntheses of dissymmetric diamides based on the chemistry of cyclic monothioanhydrides. Scope and limitations and application to the synthesis of glycodipeptides.

Opening cyclic monothioanhydrides by amines provides a convenient entry into amido thioacids that can be trapped in situ by 2,4-dinitrobenzenesulfonamides, by electron-deficient azides, or by amines in the presence of Sanger's reagent leading, in each case, to dissymmetric diamides in what can be considered a one-pot, three-component coupling sequence. The use of monothiomaleic anhydride and bifunctional nucleophiles such as amino thiols provides access to heterocyclic amides. The low reactivity of cyclic monothioanhydrides toward alcohols enables the use of methanol as solvent and obviates the need for the protection of alcohols in the various reaction components. Reaction of N-benzyloxycarbonyl-l-aspartic monothioanhydride with unprotected glycosyl amines, followed by capture of the thioacid intermediate with N-sulfonyl amino acid derivatives results in a three-component convergent synthesis of glycosylated peptides.

Environmentally benign beta-stereoselective glycosidations of glycosyl phosphites using a reusable heterogeneous solid acid, montmorillonite K-10.

Environmentally benign and stereoselective beta-glycosidations of glycopyranosyl phosphites and alcohols using a reusable heterogeneous solid acid, montmorillonite K-10, as an activator have been developed. By these glycosidations, beta-gluco-, 2-deoxy-beta-gluco-, and beta-mannopyranosides were selectively produced in good to high yields.