Nephritogenoside, isolated from the basement membrane of rats, is a nephritogenic glycopeptide whose structure 1 was determined by S. Shibata et al. in 1988. In the molecule of nephritogenoside, the trisaccharide containing three glucose moieties is linked with the peptide composed of 21 amino acids via N-glycoside bond on the asparagine residue. We planned the synthetic study of this glycopeptide in order to confirm the proposed structure and to elucidate the structure-activity relationship. In our synthetic strategy, allyloxycarbonyl group which is removable by palladium complex under neutral conditions was chosen as the final protecting group, taking account of general unstability of glycopeptide under acidic and basic conditions. Trisaccharide 4 was synthesized from heptaacetylisomaltosyl fluoride and 2,3,4-triacetylglucopyranosyl azide. The compound 4 was reduced followed by acylation with Aloc-Asp(OH)-O^tBu to give N-glycoside 5. After replacement of acetyl group with Aloe group, the coupling with the eicosapeptide (2-21) was attempted. However, N-hydroxysuccinimide active ester (7) did not react with the peptide but cyclized itself to give the succinimide derivative of 7. Therefore, we then tried a coupling of the active ester of glycosyldipeptide (1-2) (10) with nonadecapeptide (3-21). This reaction gave us a desirable protected nephritogenoside. After deprotection of all Aloc group by palladium complex, the crude product was purified by HPLC to give free nephritogenoside. In this study, we established the synthetic strategy for glycopeptide with relatively long peptide chain. The glycodipeptide was coupled with an appropriate peptide using Aloc group as the final protecting group and an active ester method for the coupling.

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Somamide A (1) is a unique cyclic depsipeptide having the 3-amino-6-hydroxy-2-piperidone (Ahp) unit, 2-amino-2-butenoic acid (Abu), and sulfoxide. It was isolated from assemblages of the marine cyanobacteria Lyngbya majuscula and Schizothrix sp. in Fijian Islands by Gerwick and coworkers. As an extension of our interests on the synthesis of biologically and structurally intriguing aquatic natural products, we succeeded in the total synthesis of somamide A (1). For the synthesis of the Abu-containing depsipeptide fragment of somamide A, we chose the stereospecific dehydrative elimination of the corresponding N-acyl thereonine ester. After several trials utilizing thionyl chloride, Burgess reagent, and DAST, we finally found out that Martin's sulfurane (dephenyl bis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propyl)sulfurane) was quite effective for the stereospecific dehydration to give the Abu residue. The synthesis of the building blocks, the depsipeptide 4, dipeptide 5, and 5-hydroxynorvaline derivative 6 was efficiently accomplished. After assembling these three fragments, the linear precursor 22 was simultaneously deprotected at the C- and N-terminals and subjected to macrolactamization using pentafluorophenyl diphenylphosphinate (FDPP, Ph_2P(O)OC_6F_5) to give the macrocyclic depsipeptide 23 in 64% yield. Removal of the TBS group from 23 followed by treatment with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) then TBAF afforded somamide A (1) as the major product (50%) together with the minor product 24 (39%). The latter was slowly and spontaneously transformed to 1 in air at room temperature. Oxidation of 24 with aqueous hydrogen peroxide also afforded 1 in 57% yield. Thus we could complete the total synthesis of somamide A (1) and indicate that 24 will be a true natural product whereas 1 will be an artifact. Our strategy for the construction of the Ahp moiety will be useful for the synthesis of the Ahp-containing natural products. Furthermore, we have found that martin's sulfurane is a powerful reagent for the dehydrative elimination of the N-acyl-β-hydroxy-α-amino acid esters to the α,β-dehydroamino esters.

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CS-0777 (4) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (25) acts as a selective S1P₁ receptor agonist, which is known as a novel mechanism of action to be able to provide a potent immunosuppressant agent. We report herein the primary synthetic route of CS-0777 and CS-0777-P using asymmetric desymmetrization of prochiral-diol precursor as a key reaction along with the biological activity of those compounds, and in the later part of the manuscript, we also describe an extensive process research effort to establish the scalable synthetic method to prepare CS-0777 at tens of kilogram scale.

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A lithium amide conjugate addition approach to the synthesis of β-amino acid derivatives is described. Lithium amides derived from α-methylbenzylamine, such as lithium (α-methylbenzyl) benzylamide undergo highly diastereoselective 1, 4-conjugate addition to a variety of α, β-unsaturated carbonyl compounds. The benzyl substituents on the amino group can be readily removed by hydrogenolysis to afford a wide range of β-amino acid derivatives. The enolate intermediate can be trapped by electrophiles such as alkylhalides and (camphorsulphonyl) oxaziridine to give α-alkyl and α-hydroxy-β-amino acids in a highly stereocontroled fashion. The synthetic utility of the methodology is demonstrated by the syntheses of numbers of natural products and other important synthetic intermediates such as taxol C-13 side chain, cispentacin, and (+) -negamycin. The origin of the stereoselectivity is briefly discussed.

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After graduating with a master’s degree from Faculty of Pharmaceutical Sciences, Hokkaido University in 1983, I worked in medicinal chemistry for 37 years at a pharmaceutical company and 4 years at a university. On this occasion of my retirement, I would like to summarize the memorable reactions from my life in research over more than 40 years. This includes an overview of my drug discovery research at pharmaceutical companies covering practical and effective synthetic methods of key intermediates for renin inhibitors, 1β-methylcarbapenem, neurokinin receptor antagonists and sphingosine-1-phosphate receptor agonists. I have also described microbial transformation reactions for phosphorylation and glucuronidation, as well as antibacterial cyclic peptide and ogipeptins. During this time, two years of studying at the Scripps Research Institute and three years of working in India were also very valuable experiences. Finally, I have summarized the results of synthetic research on indole and azaindole derivatives conducted at the Health Sciences University of Hokkaido over a period of four years.

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糖鎖生物学および糖鎖工学に対する注目は増大している。筆者は主として複合糖質糖鎖の合成と機能解析を目指した研究を行ってきた。このミニレビューでは、過去12年を振り返り、その間の研究を総括したい。代表的なテーマとして、1)アスパラギン結合型糖鎖の合成、2)新規糖タンパク質構造の合成、3)高分子担体を用いる糖鎖合成法、4)糖タンパク質関連化合物の合成における新規手法の開発、 5)糖タンパク質の合成研究、 6) 糖タンパク質プロセシングと品質管理過程の解析、7)糖転移酵素阻害物質の合成、8)生物活性糖脂質の合成、9)結核菌表層構造体の合成と生物活性、を取り上げる。

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