Gold(Ⅰ)-Catalyzed β-Glycosylations With Mannopyranosyl Ortho-Hexynylbenzoates And Its Applications

Oligosaccharides and glycoconjugates play an extremely important role in the biological process, and their synthesis has gained increasing attention recently. β-Mannopyranosyl unit is an essential constituent of naturally occurring bioactive oligosaccharides and glycopeptides. Formation of β-mannosidic linkages has long been considered one of the most difficult and challenging targets in carbohydrate chemistry because of both anomeric effects and the axial C2-O2 substituent favoring α-mannosides when the mannosyl donors function as glycosylation reagents. In this paper, A mild and convenient protocol for direct synthesis of β-mannosides via glycosylations with mannopyranosyl ortho-hexynylbenzoates has been developed, and this reaction was applied to the total synthesis of acremomannolipin A and Kakelokelose trisaccharide.We prepared orthogonally-protected mannosyl ortho-hexynylbenzoates 39 and 42 as donors. To test their β-mannosylations, a series of glycosylations were explored and 10 glycosides were obtain in high yields (62%-93%) and with exclusive β-stereoselectivity. This method is operationally simple because the reaction were performed at 0 ℃ to r.t. and without the necessity of preactivation of the glycosyl donors. Successful β-glycosylations of the orthogonally protected mannosyl donors open up prospect for diverse synthesis of oligosaccharides and nutural products containing β-glycosidic bond, and provide additional protocol for synthesis of β-mannosides.After establishing the protocol for construction of β-mannoside via gold(I)-catalyzed glycosylations with mannopyranosyl ortho-hexynylbenzoates, we set out to synthesize natural products. Acremomannolipin A was isolated in 2012 from Acremonium strictum and is a potential calcium signal modulator. Acremomannolipin A is a novel glycolipid composed of mannitol and peracylated mannopyranosyl moiety through a β-glycosidic linkage.The key β mannoside 79 was obtained with 85% yield and β/α=14:1, using the establishing the protocol. Finally we accomplished the total synthesis of acremomannolipin A in 10 steps and a 15% overall yield with mannitol as starting material. To demonstrate the versatility of our synthesis and facilitate in-depth investigation into structure-activity relationships, we intended to install different acyl groups onto the mannosyl unit of acremomannolipin A. Thus, acremomannolipin A analogue 89 was obtained in 12 steps for 16% overall yield. During the synthesis of acremomannolipin A and 89, difficulty in selective cleavage of Nap protection group in the presence of benzyl groups was overcome.Kakelokelose was isolated in 1996 from the Pacific Tunicate Didemnum molle, and shows in vitro anti-HIV activity. Kakelokelose is a sulphated homopolymer consisting of 2,3-di-O-sulfated mannose through β-(1,6)-glycosidic linkage. So far no synthesis of oligosaccharide derived from Kakelokelose has been reported. So we set out to synthesize the first synthesis of Kakelokelose trisaccharide using the method we developed for β-mannoside. Finally, Kakelokelose trisaccharide 90 was obtained in 23% overall yield thorough a linear stepwise synthesis strategy, with glycosyl ortho-alkynyl benzoates 42 as donor.