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Development of indolizidine alkaloid as glycosidase inhibitor : Total syntheses of (+)-Castanospermine & (+)-6-Epicastanospermine 원문보기

  • 저자

    서우덕

  • 학위수여기관

    경상대학교

  • 학위구분

    국내석사

  • 학과

    농화학전공

  • 지도교수

  • 발행년도

    2004

  • 총페이지

    iii, 77장.

  • 키워드

    glycosidase inhibitor indolizidine alkaloi;

  • 언어

    kor

  • 원문 URL

    http://www.riss.kr/link?id=T10081976&outLink=K  

  • 초록

    Catanospermine and 6-epicastanospermine are plant natural indolizidine alkaloids. These alkaloids have been attracted continued interest by synthetic and medicinal chemists for its inhibitory action toward various glucosidase enzymes and its promising effects against disease such as diabetes, cancer and viral replication. Therefore, in recent years much effort has been devoted to the synthesis of target molecules (1 and 20). Most practical route is starting from carbohydrate because of minimizing the need to create the requisite stereoisomers. The efficiency of any synthetic protocol to castanospermine from carbohydrate would be largely depended on how chiral induction of C-1 is carried out. In this paper, we report a total synthesis of highly stereoselective of castanospermine and 6-epicastanospermine from D-glucono-δ-lactone. This study highlighted the synthetic utility of stereocontrol by indium mediated allylation in the presence of (+)-cinchonine as a chiral promotor. The results were summarized as follows. 1) Synthesis of (+)-castanospermine (1) In our retrosynthesis, As starting material, we chose D-glucono-δ-lactone which supplies the complete C-unit, stereochemistry and functionalities of each final compounds (6. 7. 8. 8a). Each stereochemistry of target compounds was used one of C2, C3, C4, C5 in starting material. ◁그림 삽입▷(원문을 참조하세요) We chose the 9-phenylfluoren-9-yl (Pf) group for protection of amine since this protecting group has been shown to inhibit deprotonation at the α-position of α-aminoaldehyde. The azido mannonate (4) was prepard from D-glucono-δ-lactone. Using precooled (-20℃) solution of trifluoromethane sulfonic anhydride in CH_(2)Cl_(2) at triflation step and sodium azide in DMF at azidation step. The azido mannonate (4) was hydrogenated in presence of palladium on charcoal, and then corresponding amine was protected with PfBr to give mannonate (6) in 87% yield. (6) with LAH in THF, the resulting mannitol (7) was swern oxidation and reaction of the resulting aldehyde (8) was treated with allylbromide and indium in the presence of (+)-cinchonine as a chiral promotor to give syn-aminoalcohol (9) in a 50:1 ratio in 90 % yield. The secondary hydroxy group of (9) was easily protected with TBDMS-Cl to give silylate (10) in 98 % yield. The terminal olefin group was ozonized with anticipation of aldehyde product, but this reaction kept running directly to intramolecular amination to give corresponding hemiaminal with palladium hydroxide in EtOH cleaved Pf group, and subsequently produced pyrrole (11) in 63 % yield from (11). The pyrrole (11) was protected with benzyl chroloformate (CbzCl) in quantitative yield (12). Diisopropylidene (12) under acidic condition, Dowex 50W X8 was treated with in 90 % MeOH to give diol (13) in 93 % yield. The primary hydroxy group of (13) was selectively protected with TBDMS-Cl to give (14), and secondary hydroxy group of (14) was mesylated to give (15) in 92 % yield. The inversion of stereochemistry at C3 in (15) was accomplished by tetrabutylammonium fluoride (TBAF) in THF at room temperature and then treated with K_(2)CO_(3) in MeOH to give epoxide (16) in 90 % yield. Hydrogenolysis of epoxide (16) in the presence of 10 % Pd/C and NaOAc removed the Cbz group to give indolizidine (17) in 65 % yield. (+)-castanospermine (1) was easily obtain by treatment of (17) with Dowex 50W-X8 in THF-H_(2)O (3:1) in nearly quantitative yield without further purification. 2) Synthesis of (+)-6-Epicastanospemine Diol (13) was treated with mesylchloride under CH_(2)Cl_(2) at -40 % to give monomesylate (18) selectively in 86 % yield. (18) was hydrogenated in presence of 10 % Pd/C and NaOAc to remove Cbz group, and led to direct intramolecular cyclization to give indolizidine (19) 85 % yield. (19) was refluxed with Dowex 50W-X8 and afford enantiomerically pure (+)-6-epicastanospermine (20) in 90 % yield. Here, we report the diastereoselective synthesis of (+)-castanospermine and (+)-6-epicastanospermine from D-glucono-δ-lactone.


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