达玛烷皂苷Ginsenoside Re与Notoginsenoside R1的全合成

摘要

采用汇聚式合成的方式,充分利用原人参三醇各羟基活性的差异,采用高效的区域选择性保护策略,并以Au(Ⅰ)催化的糖苷化反应对达玛烷20位大位阻酸敏感羟基和6位羟基及6-O-Glc'糖基2位羟基连续三次糖苷化,以最长线性13步分别以5.1％和4.5％的收率合成了天然双糖基达玛烷皂苷Ginsenoside Re (1)和Notoginsenoside R1 (2).%Ginsenoside Re (1) and Notoginsenoside R1 (2) are two representative dammarane type protopanaxatriol-6,20-O-bisglycosides occurring widely founded in Panaxginseng.Ginsenoside Re (1) showed potent antioxidative,antiinflammatory and antihyperlipemia activities,and Notoginsenoside R1 (2) showed potent antioxidative and antiinflammatory activities,so it would be helpful to synthesize these homogeneous natural products in appreciable amounts by accelerating their structure-activity relationship study.As a persistent effort on the chemical syntheses of the diverse ginsenosides in our group,we report herein the efficient syntheses of these two complex natural products.Thus,based on the reactivity sequence of the four hydroxyl groups (i.e.,12-OH＞3-OH＞6-OH＞＞20-OH) of the protopanaxatriol aglycon,an orthogonal and efficient protecting group strategy was applied to distinguish these hydroxyl groups.The subsequent installation of the 6,20-O-bisglycosides are challenging,given the poor reactivity of the secondary 6-OH and tertiary 20-OH,moreover,with the latter being labile toward acidic conditions.Taking advantage of the neutral conditions of the Au(Ⅰ)-catalyzed glycosylation reaction (0.3 equiv.Ph3PAuNTf2,4 A MS,CH2Cl2,r.t.),the glycosylation of the acid-labile 20-hydroxyl group was achieved effectively in a high 84％ yield firstly.To be convergent for the syntheses of these two ginsenosides,the 6-O-disaccharide residues were installed in a stepwise manner.For the glycosylation of the 6-OH of protopanaxatriol,a higher loading of the catalyst Ph3PAuNTf2 (0.5 equiv.) was employed in order to increase the glycosylation yield while reduce the orthoester formation,thus,the desired 6β-O-glucosides were prepared in satisfactory yields (77％～83％).Both terminal a-L-Rha/β-D-Xyl moieties at the 2'position of 6-O-glc were installed efficiently under 0.2 equiv.Ph3PAuNTf2 catalyzing condition (ClCH2CH2Cl,5 A MS,40 ℃) with 86％ and 81％ yields,respectively.After global deprotection,Ginsenoside Re (1) and Notoginsenoside R1 (2) were synthesized with the longest 13 linear steps in 5.1％ and 4.5％ overall yields,respectively.