硫酸乙醯肝素是屬於葡胺巨醣的一種生物分子，它們廣佈於細胞表面及胞外纖維組織裡，在生物系統中扮演非常重要的角色，包括病毒感染、細胞成長及癌細胞轉移等等，其生合成過程主要是經由核蛋白的絲胺酸餘基以□方式鏈結一特定四醣體後，再依序交錯以□1□4方式連接氮–乙醯基D式葡萄胺醣(GlcNAc)及□1□4方式連接D式葡萄醣酸(GlcA)，其中D式葡萄醣酸第五號碳的位置可被第五號碳異構酶轉變成L式艾杜醣酸，而形成-□-1,4-GlcNSO3-(6-OSO3)-□-1,4-IdoA(2-OSO3)-重複單元。到目前為止已經被發現有許多生理反應或病毒的感染皆是透過和硫酸乙醯肝素的鍵結，但由於缺乏適合的分離或合成方法，硫酸乙醯肝素在結構上和生物巨分子辨識間的關係仍是個謎，為了徹底了解這個問題，我們開發了一個新的方法可以有效地合成硫酸乙醯肝素寡醣體，並且探討了它們對登革病毒感染的抑制作用。
本論文共分為三部份，第一部份是探討D式葡萄糖的一鍋化組合保護反應。在計量的醋酸酐為試劑的條件下，利用0.5 mol%鈧三氟甲磺酸酯催化D式葡萄糖40的乙醯化反應，可得到高產率的化合物59，接著經由三項步驟的官能基轉換獲得起始物61，在三甲矽基三氟甲磺酸酯的催化下，可分別進行二、三或四個循環的一鍋化組合保護反應，分別得到完全保護或具有三個保護基的2­、3­、4­或6­醇的化合物。

第二部份是研究L式艾杜醣的製備方法。以雙丙酮□-D葡萄糖1為起始物，在第三號氧位置先進行苯甲基保護反應，隨後在醋酸水溶液作用下得到雙醇化合物90，接著一鍋化將第六及第五號氧位置分別引進苯甲醯基和甲磺醯基，產生化合物91 (81%)，然後加入異丁基氧化鉀，待形成環氧化合物後，再加入0.2 N硫酸水溶液及2–甲氧乙基醚，將溫度升高至160度，可一鍋化得到1,6­無水L式艾杜哌喃醣衍生物89 (52%)，進一步選擇性酯化反應，得到單一的4–醇產物96，可作為我們的合成策略中一個非常重要的建構單元。

第三部份是探討硫酸乙醯肝素寡醣體的合成研究。以D式葡萄胺醣21為起始物，經八項步驟可獲得亞胺化合物103，進一步與醣受體96進行醣鏈結反應，產生雙醣體104□，接著利用銅三氟甲磺酸酯催化進行乙醯酐開環反應及一系列官能基轉換反應，得到雙醣建構單元139，然後與D式葡萄胺醣衍生物126進行偶合反應，產生三醣體140，接著以2,3–二氯–5,6–二氰–1,4–苯醌將2–萘甲基移除得到另一個醣受體並進一步與化合物139反應，重複此步驟一至三次，可分別產生五(141)、七(142)及九醣體143，接著經由六步的官能基轉換，順利得到硫酸乙醯肝素最終產物150-153。

Heparan sulfate (HS), ubiquitously distributed on the cell surface and in the extracellular matrix, play significant roles in a diverse set of biological processes, including virus infection, cell growth, tumor metastasis, and so on. Biosynthesis of HS involves the formation of an initial glycosaminoglycan structure, comprised of alternating N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcA) jointed by 1,4-linkages. The structure may be modified through a series of enzymatic reactions that ultimately result in the formation of -□-1,4-GlcNSO3-(6-OSO3)-□-
1,4-IdoA(2-OSO3)- sequences. The L-iduronic acid (IdoA) is the C5-epimerization product of D-glucuronic acid (GlcA). With the discovery of increasing numbers of HS-binding proteins, there was a need to characterize the molecular properties, within the proteins and HS, responsible for specific recognition. To tackle this problem, we have developed new and efficient methodologies to synthesize various HS-oligosaccharides and studied their inhibitory activity with dengue virus.

In the first part of this thesis, we focus on the investigation of first regioselective combinatorial one-pot protection of D-glucopyranosides. A high-yielding per-O-acetylation of D-glucose 40 with stoichiometric amount of acetic anhydride to D-glucopyranosyl pentaacetate 59 employing 0.5 mol% Sc(OTf)3 as an efficient catalyst was successfully developed. A three-stepped transformation of the ester 59 led to the corresponding O-silylated thioglycoside 61, which was subjected to one-pot protection strategy in the presence of TMSOTf as the catalyst to provide the fully protected derivatives and the individual 2-, 3-, 4-, as well as 6-alcohols, respectively.

A novel synthesis of L-idopyranosyl sugars from diacetone □-D-glucose 1 in four straightforward steps is described in the second part. The 5,6-diol 90, generated from 1 via sequential 3-O-benzylation and removal of the 5,6-O-isopropylidene group, underwent one-pot benzoylation-mesylation to yield the corresponding furanose 91 (81%) as a single isomer. Treatment of compound 91 with t-BuOK in t-BuOH followed by addition of a 1:2 mixture of 0.6 N H2SO4(aq) and diglyme and subsequent heating temperature (160 oC) for 16 h gave 1,6-anhydro-3-O-benzyl-□-L-idopyranose 89 (52%) in a one-pot manner. Regioselective benzoylation of the diol 89 exclusively furnished the corresponding 2-ester 96 (85%), which could be used as a valuable synthon for our purpose.

In the last part, we have summarized our strategy toward the synthesis of HS-oligosaccharides. The trichloroacetimi-

date 103, prepared from D-glucosamine hydrochloride 21 in eight steps, was coupled with the acceptor 96 to deliver the desired □-disaccharide 104□, which upon acetolysis catalyzed by Sc(OTf)3 and a series of reactions successfully furnish the imidate 139, a disaccharide building block. Coupling of 139 with the alcohol 126, derived from D-glucosamine, afforded the trisaccharide 140, which was treated with DDQ and further glycosylation with 139 ( a two-stepped elongation cycle) to produce the penta- (141), hepta- (142), and nonasaccharides 143. The expected HS target molecules 150-153, respectively, were smoothly obtained from 140-143 via functional group transformation in six consecutive steps, respectively.

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