Total Synthesis of the Tridecasaccharide Motif from Angelica Sinensis APS‐1 II Polysaccharide with Anti‐Leukemia Activity and Structure‐Activity Relationship Studies

Abstract A polysaccharide APS‐1 II from a medicinal plant Angelica sinensis (Oliv.) Diels represents a potential therapeutic agent against leukemia. However, the synthetic accessibility of the highly branched and complex APS‐1 II polysaccharide with multiple 1, 2‐ cis ‐glycosidic linkages remains a difficult task, impeding the in‐depth structure–activity relationship biological studies and the development of carbohydrates‐based therapeutics against leukemia. Here, we report the first chemical synthesis of tridecasaccharide repeating unit together with shorter sequences 4‐mer, 6‐mer and 9‐mer from APS‐1 II polysaccharide via one‐pot orthogonal glycosylation strategy based on glycosyl ortho ‐(1‐phenylvinyl)benzoates, which precluded the potential issues such as aglycone transfer associated with one‐pot assembly with thioglycosides. The synthetic pathway also features the following aspects: 1) three contiguous and challenging 1, 2‐ cis ‐Fuc bonds were highly stereoselectively constructed via the newly developed stereoselective 1, 2‐ cis ‐fucosylation method; 2) several 1, 2‐ trans ‐glycosidic linkages were formed via neighboring group participation effect, while 1,2‐ cis ‐Glc linkage was stereoselectively assembled via N , N ‐dimethylformamide reagent modulation; 3) the final [1+1+2+9] one‐pot assembly of the target tridecasaccharide via strategic utilizations of glycosyl N ‐phenyltrifluoroacetimidates, ortho ‐alkynylbenzoates and ortho ‐(1‐phenylvinyl)benzoates. Biological studies revealed that human leukemia K562 and mouse L1210 cells could be effectively inhibited by tridecasaccharide repeating unit and substructure nonasaccharide.