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透過分子內變旋異構端的合環保護進行空腸曲桿菌 (C. Jejuni) NCTC11168 的夾饃多醣體單元全合成

Total Synthesis of Campylobacter jejuni NCTC11168 Capsular Polysaccharide via the Intramolecular Anomeric Protection Strategy

JACS 2023, DOI: 10.1021/jacs.3c00102
Chun-Hong Yeh, Ya-Jou Chang, Tsung-Juin Lin, and Cheng-Chung Wang*

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Organic synthesis is a greatly important field in chemistry as it is an indispensable pathway and tool to procure complicated molecules nowadays. Campylobacter jejuni is a typical foodborne pathogen, and its infection results in a significant diarrhea disease, which is highly fatal to young children in unindustrialized countries. Although antibiotic treatment is available, it is urgent to develop an alternative therapy considering that antibiotic resistance increase gradually. A potential solution in focus is to devise a carbohydrate-conjugating vaccine, which can against specific bacteria and has less toxicity. Herein, we described a total synthesis of a C. jejuni NCTC11168 capsular polysaccharide repeating unit containing a linker moiety via an intramolecular anomeric protection (iMAP) strategy. Applying the iMAP strategy efficiency reduces the reaction steps of configuration modification to furanoside structure and the following regioselectivity protection. Therefore, we successfully concisely synthesize a rare sugar, heptose, in a six-steps manner from D-galactose, and generate the desired furanosyl galactosamine building block after 2 steps from a commercial galactosamine. Accordingly, we construct the target tetrasaccharide in merely 28 steps using [2 + 1 + 1] glycosylation strategy and accomplish the required substitutive modification and global deprotection, including the preparation of all the building blocks. Our research provides the first synthesis study on this complex tetrasaccharide structure, and the amine of linker moiety is capably conjugated with carrier protein for further vaccination study.

有機合成是化學中一門非常重要的領域,是現今取得各種複雜分子不可或缺的途徑和方法。空腸彎曲桿菌是一種典型的食源性病原體,其感染會導致嚴重的腹瀉症狀,對於已開發或開發中國家的幼兒來說高度致命。儘管我們可以使用抗生素治療這樣的細菌感染,但考慮到抗生素耐藥性逐漸增加,相關的替代療法也迫切需要開發。 發展碳水化合物結合疫苗是一個備受關注且具有潛力的解決方案,它可以對抗特定的細菌且毒性較小。在本合成研究中,我們描述了經由醣單元分子內變旋異構保護 (iMAP) 策略合成空腸彎曲菌 NCTC11168 莢膜多醣重複單元,包含接頭部分的全合成。 應用 iMAP 策略有效的減少了呋喃醣苷的建構以及後續的區域選擇性保護所需要的反應步驟。 因此,我們能以六步的方式從 D-半乳醣成功簡明地合成出稀有的”庚醣”,並由購得的半乳醣胺經過 2 步後即生成了所需的呋喃糖基半乳醣胺結構單元。我們使用 [2 + 1 + 1] 醣基化策略僅需 28 步即可構建目標四糖,並完成所需的取代修飾和全去保護,其中包括所有構建塊的製備。這是對這種複雜四醣結構的首次合成研究,產物接頭部分的胺基能與載體蛋白進行結合,並用於後續的疫苗接種研究。