"以1,4-醣內酯為起始物有效合成3種亞環胺糖"

Abstract

亞環胺醣 (iminocyclitols) 為廣泛應用的醣水解酶及醣合成轉移酶抑制物，其分子結構中之氮原子容易在生理狀態下被質子化，此情況可以模擬酵素催化反應過渡狀態的鎓陽離子 (oxocarbenium transition state) 所具備正電荷的性質，成為良好的酵素抑制物。因此亞胺醣具備藥物開發之價值而受到學術界高度的重視。舉例而言，作為α-葡萄糖苷水解酶抑制物，Miglitol™已是第二型糖尿病藥物之一；Miglustat™則是用於治療基因失調而導致的高雪氏症 (Gaucher’s disease)。 先前本實驗室已報導利用此概念而研發出岩藻醣水解酶 (α-L-fucosidase) 具有良好抑制效果之亞胺糖，相關的合成使用1,4-內酯 (L-gulono-1,4-lactone) 為起始物，製備出一系列以1-β-substituted fuconojirimycin (FNJ) 為核心結構的不同官能基修飾衍生物。本論文則是利用兩種在5號碳上具有不同組態 (configuration) 羥基的1,4-內酯，包括L-gulono-1,4-lactone以及D-mannono-1,4-lactones，目的在合成出3種亞胺醣。它們分別是：1-α/β-aminomethyl FNJs, 以及1-α-hydroxymethyl rhamnojirimycin (可作為α-L-鼠李醣苷酶抑制物)。這些合成具有類似的路徑，皆是在1號碳位置引入甲基以及5號碳位置引入疊氮基後，再利用還原胺化反應(reductive amination)建構出含氮原子之六碳亞環胺糖。 經由實驗測試，我們能夠以7步總產率19 %及13 %方式合成出1-β-aminomethyl FNJ A及1-α-aminomethyl FNJ B，另外我們也以L-gulono-1,4-lactone開始，經由12步總產率3.3%方式合成出去氧亞環胺醣前驅物C，將來我們會將化合物C去保護及進行相關活性測試。

Iminocyclitols are known as potent glycosidase and glycosyltransferase inhibitors. One major merit is the fact that the ring nitrogen is protonated at physiological pH to mimic the positive-charge feature of the oxocarbenium transition state. Several iminocyclitols have been utilized for therapeutic intervention, e.g., Miglitol™ and Miglustat™, as for therapeutics of type II diabietes and Gaucher’s disease, respectively, explaining the reason why they have drawn much attention. We previously developed a series of α-L-fucosidase inhibitors, including 1-β-substituted fuconojirimycin (FNJ) derivatives. The synthesis started from commercial available L-gulono-1,4-lactone. This thesis research aimed at the synthesis of three iminocyclitols starting from two sugar lactones. They are L-gulono-1,4-lactone and D-mannono-1,4-lactones that differ in C5-stereochemical configuration. We developed synthetic approaches to prepare 1-α/β-aminomethyl FNJs (B/A), and 1-β-hydroxymethyl rhamnojirimycin (as an α-L-rhamnosidase inhibitor). In general, the syntheses utilize a common strategy, relying on the introduction of an azide to C5 of the sugar lactone (to introduce the ring nitrogen) and the nucleophilic addition of a methyl group to C1 (the lactone). The subsequent reductive amination represents the key step to construct six-membered iminocyclitols. Finally, we efficiently synthesized inhibitors A and B in 7 steps from L-gulono-1,4-lactone/D-mannono-1,4-lactones, with 19%/13% total yields. We also synthesized compound C in 12 steps with 3.3% total yield, as the precursor of the other target iminocyclitol.