Akihiro Ishiwata

Recent advances in stereoselective glycosylation through intramolecular aglycon delivery

Methodology toward the stereoselective 1,2-cis glycoside linkage using intramolecular aglycon delivery (IAD) has been extensively developed. In the last two decades, progress has been made using various mixed acetal linkages and a number of glycosyl donor moieties to develop novel IAD strategies, mainly based on formation of acetal linkages. This account summarizes the newest naphthylmethyl (NAP) ether-mediated IAD as well as all the types of mediations for stereospecific construction of various 1,2-cis linkages, not only for beta-mannopyranoside, but also for other linkages almost without exception, including beta-L-rhamnoside.

Synthesis of docosasaccharide arabinan motif of mycobacterial cell wall.

Mycobacterial arabinan is a common constituent of both arabinogalactan (AG) and lipoarabinomannan (LAM). In this study, synthesis of β-Araf containing common arabinan docosasaccharide motif (22 Araf monomer units) of mycobacterial cell wall was achieved. Our synthetic strategy toward arabinan involves (1) the stereoselective β-arabinofuranosylation using both 3,5-O-TIPDS-protected and NAP-protected arabinofuranosyl donors for straightforward intermolecular glycosylation and intramolecular aglycon delivery (IAD), respectively, and (2) the convergent fragment coupling with branched fragments at the linear sequence using thioglycoside donor obtained from the corresponding acetonide at the reducing terminal of each fragment through a three-step procedure. Because the acetonide at the reducing terminal of all fragments would be converted to thioglycoside as the glycosyl donor, and mainly Bn ether protections were used, our strategy will be readily applicable to the synthesis of more complex arabinan, arabinogalactan, and arabinomycolate derived from mycobacterial CWS.

A NOVEL TOTAL SYNTHESIS OF (+)-HIMBACINE, A POTENT ANTAGONIST OF THE MUSCARINIC RECEPTOR OF M2 SUBTYPE

Abstract The title total synthesis was achieved by a method featuring highly stereoselective intermolecular Diels-Alder reaction of the tetrahydroisobenzofuran 5 with the chiral butenolide 6 as the key step. The cycloadduct 4 was converted to the title alkaloid by way of the known sulfone 2 in 17 steps. The title total synthesis was achieved by a method featuring highly stereoselective intermolecular Diels-Alder reaction as the key step. Download full-size image

Stereoselective Synthesis of β-l-Rhamnopyranosides

Stereoselective construction of 1,2-cis-beta-L-rhamnopyranoside was achieved by our effective methodology using naphthylmethyl (NAP) ether-mediated intramolecular aglycon delivery (IAD). The complete stereoselective synthesis of the bacterial extracellular polysaccharide, alpha-L-Rhap-(1-->3)-beta-L-Rhap-(1-->4)Glcp from Sphaerotilus natans, was successfully accomplished, clearly demonstrating that the NAP-IAD methodology is highly versatile.

Synthetic studies of himbacine, a potent antagonist of the muscarinic M2 subtype receptor 1. Stereoselective total synthesis and antagonistic activity of enantiomeric pairs of himbacine and (2′S,6′R)-diepihimbacine, 4-epihimbacine, and novel himbacine congeners

Abstract Total synthesis of an enantiomeric pair of himbacine 1 and ent-1 was achieved in a highly stereoselective manner by employing an intermolecular Diels–Alder reaction of tetrahydroisobenzofuran 8 with chiral furan-2(5H)-one (S)-9 and (R)-9 , respectively, as a key step. An enantiomeric pair of (2′S,6′R)-diepihimbacine 24 and ent-24 , 4-epihimbacine 4-epi-1 , and novel himbacine congeners bearing the same tricyclic moiety as that of 1 were also successfully prepared by utilizing the key synthetic intermediates for 1 , establishing the convergency and flexibility of the explored synthetic route. All of the synthesized compounds used were subjected to muscarinic M2 subtype receptor binding affinity assay, disclosing novel aspects of the structure–activity relationships for 1 .

Synthetic Study and Structural Analysis of the Antifreeze Agent Xylomannan from Upis ceramboides

The novel antifreeze factor, xylomannan, first isolated from the freeze-tolerant Alaskan beetle Upis ceramboides , demonstrates a high degree of thermal hysteresis, comparable to that of the most active insect antifreeze proteins. Although the presence of a lipid component in this factor has not yet been verified, it has been proposed that the glycan backbone consists of a β-D-mannopyranosyl-(1→4)-β-D-xylopyranose-disaccharide-repeating structure according to MS and NMR analyses. In this contribution, we report the stereoselective synthesis of the tetrasaccharide β-D-mannopyranosyl-(1→4)-β-D-xylopyranosyl-(1→4)-β-D-mannopyranosyl-(1→4)-D-xylopyranoside, a structural component of xylomannan. Our synthesis features the use of 2-naphthylmethyl (NAP)-ether-mediated intramolecular aglycon delivery (IAD) as the key reaction in obtaining β-mannopyranoside stereoselectively. Various donors for NAP-IAD were tested to determine the most suitable for the purposes of this synthesis. Fragment coupling between a disaccharyl fluoride and a disaccharide acceptor obtained from a common β-D-mannopyranosyl-(1→4)-β-D-xylopyranoside derivative was successfully carried out to afford the desired tetrasaccharide in the presence of Cp(2)HfCl(2)-AgClO(4). Structural analysis of the resulting synthetic tetrasaccharide using NMR techniques and molecular modeling was performed in order to demonstrate the presence of the proposed xylomannan linkages in this molecule.

Synthesis of the highly glycosylated hydrophilic motif of extensins.

Extensin, the structural motif of plant extracellular matrix proteins, possesses a unique highly glycosylated, hydrophilic, and repeating Ser1Hyp4 pentapeptide unit, and has been proposed to include post-translational hydroxylation at proline residue and subsequent oligo-L-arabinosylations at all of the resultant hydroxyprolines as well as galactosylation at serine residue. Reported herein is the stereoselective synthesis of one of the highly glycosylated motifs, Ser(Galp1)-Hyp(Araf4)-Hyp(Araf4)-Hyp(Araf3)-Hyp(Araf1). The synthesis has been completed by the application of 2-(naphthyl)methylether-mediated intramolecular aglycon delivery to the stereoselective construction of the Ser(Galp1) and Hyp(Araf(n)) fragments as the key step, as well as Fmoc solid-phase peptide synthesis for the backbone pentapeptide.

Chemoselective peptide bond formation using formyl-substituted nitrophenylthio ester

A novel method for peptide bond formation utilizing amino acid 2-formyl-4-nitrophenylthio ester has been developed. The reaction can be performed in water-containing media and is compatible with various types of amino acid side-chain functional groups. Use of N-methylmaleinimide as an additive is essential for the reaction to proceed with high efficiency. It captures liberated formyl-substituted thiophenol through 1,4-addition followed by aldol cyclization.

A novel and convenient synthesis of 2-aryl-4-methylenetetrahydrofurans from 2-(trimethylsiloxymethyl)allytrimethylsilane and acetals

Abstract The reaction of acetals with 2-(trimethylsiloxymethyl)allyltrimethylsilane under the influence of the combined use of a catalytic amount of tin(II) halide and acetyl halide affords the corresponding 2-aryl-4-methylenetetrahydrofurans in good yields.

Regiospecific Syntheses of 6α-(1R-hydroxyoctyl)penicillanic acid and 6β-(1R-hydroxyoctyl)penicillanic acid as Mechanistic Probes of Class D β-Lactamases

The unique hydrophobic surface patches in class D beta-lactamases presented an opportunity for designing two compounds, 6alpha-(1R-hydroxyoctyl)penicillanic acid and 6beta-(1R-hydroxyoctyl)penicillanic acid, as mechanistic probes of these enzymes. In a sequence of three synthetic steps from benzhydryl 6,6-dibromopenicillanate, the targeted compounds were prepared in a stereospecific manner.