부산대학교 도서관

1. Stereoselective Total Synthesis of Neuraminic Acid via Chiral 1,3-OxazineNeuraminic acid and its derivatives have important roles in the influenza infection. The influenza virus infection on the respiratory system produces severe cold like symptoms. Neuraminidase, a surface glycoprotein of the influenza virus membrane, assists disintegration between virus and host cell. For example, Relenza®(zanamivir) that was firstly identified as a potent neuraminidase inhibitor in 1989. In addition, Tamiflu®(oseltamivir phosphate) are widely prescribed for the effective treatment of influenza. Despite the significance of synthesis of neuraminic acid, the effective synthetic investigations have not been explored. Here we report the total synthesis of neuraminic acid 1 based on our previously described oxazine strategy.On the basis of our previous research, we anticipated that the palladium(0)-catalyzed oxazine formation of a γ-allyl benzamide with a benzoyl substituent as N-protecting group in the presence of Pd(PPh3)4, NaH, and n-Bu4NI might procced with a high stereoselectivity. The bulkiness of the protecting group of the secondary alcohol is responsible for controlling the diastereoselectivity in the oxazine ring formation.The synthetic utility of anti,syn-oxazines as chiral building blocks has been demonstrated by their successful application to the synthesis of biologically active natural products, i. e., glucosidase inhibitors such as phytosphingosines and deoxynojirimycins. As part of the expansion of chirality of anti,syn-oxazines, we have also been exploring the development of a novel strategy for the concise total synthesis of neuraminic acid. We envisioned neuraminic acid could be generated by the acid catalyzed O-cyclization of α-keto ester. α–Keto ester would be induced via the OsO4-mediated dihydroxylation followed by TEMPO oxidation of homoallylic alcohol. Homoallylic alcohol would come from the chelation-controlled Sakurai reaction of diol. Diol could be prepared by stereoselective OsO4-mediated dihydroxylation of anti,syn-oxazine.2. Study of Stereoselective Allylation of α-Alkoxy, β-Amino AldehydesOur laboratory has synthesized various amino alcohols such as phytosphingosine, pyrrolidine, piperidine and pyrrolizidine etc. using chiral trans-oxazoline and chiral 1,3-oxazine as chiral building blocks. Calystegines include nortropane ring framework and continuous chirality of amino alcohol. In particular, acetylnorloline, oseltamivir, agelastatine and manzacidines show interesting structural feature such as chiral diamino moiety. For these reasons, arduous efforts have been made for the formation of these complicated bioactive natural compounds. For the expansion of research and development of methods for controlling chirality, the progressive research of chirality generation via Lewis acid mediated stereoselective allylation with various aldehydes and aldimines has been designed. Study of addition reaction to α-alkoxy; β-alkoxy; α-alkyl, β-alkoxy; α-amino; β-amino aldehyde (and alimine) which have single chirality is being progressed. Study of addition reaction to α-alkoxy, β-alkoxy; α-alkoxy, β-amino; α-amino, β-alkoxy; α-amino, β-amino aldehyde (and alimine) which have two continuous chiral centers is advanced research for syntheses of various aminopolyol compounds. Regulation of protection of amines (Cbz and BnCbz) and alkoxy (TBS, Bn, BOM) can provide efficient stereoselectivity control of each reaction steps.