研究Benzylidene 開環及接續醣基化反應以應用於反應性導向的寡醣合成

Abstract

反應性導向的醣基化合成被廣泛的應用於多醣體的合成。此方法是從醣予體相對反應性值 (Relative reactivity value, RRV)資料庫中，按照醣予體反應性由大到小，依序加入來達到選擇性的活化。然而此方法會因醣體延長，隨著醣予體以及醣受體的活性差異越來越少，造成其活化選擇性下降，從而局限了反應性導向醣基化策略的應用。為此，我們嘗試對4,6-benzylidene的醣予體進行選擇性開環反應，形成具有4-OH，6-OBn 的醣予體來提高反應活性。例如: 從醣予體14 (RRV = 2239) 轉換成醣予體 19 (RRV = 7657)。因此，此論文著重在將醣基化反應與選擇性開環結合，應用於 [1 + 1 醣基化 接續 Benzylidene選擇性開環 接續 + 2 醣基化] 一鍋化合成策略，得到四醣體20。除此之外，透過選擇性開環後的醣體19不只可以增加反應活性，其裸露的四號羥基也可以進行醣基化反應；與高反應性岩藻糖21醣予體形成Lewis A三醣體22。在上述的例子中，我們以三步反應得到產率34 % 的四醣體20，以及產率38 % 的三醣體22。有趣的是，我們發現經由 [1 + 1 醣基化 接續 Benzylidene選擇性開環] 反應後會形成Benzaldehyde Diphenyl Dithioacetal副產物，而此副產物會影響之後醣基化反應。若改以[Benzylidene 選擇性開環 接續 + 2]則可以在本質上避免副產物的形成，並且提供有效的解決方法。而[Benzylidene選擇性開環 接續 + 2醣基化] 兩步可以得到58 % 產率的四醣體20。整體來說，Benzylidene 開環後接續醣基化反應提供有效地控制醣體使其同時做為醣予體以及醣受體。此雙重功能可以有效的為寡糖合成提供便利性

Reactivity based glycosylation are widely used as a chemoselectivity strategy by subjecting a mixture of the highest anomeric reactivity donor and the less anomeric reactivity donor based on the Relative Reactivity Values (RRV) database. However, the insufficient anomeric reactivity of the newly-formed donor causes low activation selectivity and limited this strategy during the subsequent glycosyl elongation. To overcome this challenge, we employed benzylidene selective ring-opening process, resulting in a donor with the 4-OH, 6-OBn functional groups. This approach enhances anomeric reactivity from donor 14 (RRV = 2239) to 19 (RRV = 7657). Our main goal is to combine selective benzylidene ring-opening and glycosylation in a one-pot reaction. This combination can be further applied in the synthesis of tetrasaccharide by using a [1 + 1 glycosylation then followed by selective ring-opening then 2 + 2 second glycosylation] approach. Besides, the formation of 4-OH, 6-OBn glycan can also act as a glycosyl acceptor. The newly-formed glycosyl acceptor 19 can further be glycosylated with fucosyl donor 21, leading to the Lewis A trisaccharide. With the combination of benzylidene ring-opening and glycosylation, we can successfully gain the tetrasaccharide 20 and trisaccharide 22 in 34 % and 38 % yields (in three steps), respectively. Interestingly, we found that the side product benzaldehyde diphenyl dithioacetal, which was generated after the one-pot of [1 + 1 then benzylidene ring-opening] may interfere the subsequent glycosylation. An alternative solution is substituted with the [benzylidene ring-opening then + 2 glycosylation] approach which can substantially prevent from the intrinsic problem caused by the side-product. The [benzylidene ring-opening then + 2 glycosylation] approach is accomplished in 58 % yield (two steps). Overall, the benzylidene ring-opening and in situ glycosylation present a critical method for the efficient synthesis of oligosaccharide serving a dual functionality as glycosyl donor and acceptor in glycan synthesis.