合成胺基神經醯胺醇之類似物作為核心化合物以建構醯胺化生物分子庫

Synthesis of amino sphingosine analogue as a core compound for contructing a solution-phase derived library

張凱翔(Kai-Hsiang Chang)

指導教授 ： 俞鐘山

國立清華大學/原子科學院/生醫工程與環境科學系/碩士(2009年)

摘要

The aim of the study is to synthesize the analogue of phytosphingosine as a core amine compound, which is going to be coupled with a variety of carboxylic acids via amide bond formation to construct a library for screening experiment.
The synthesis of Garner’s aldehyde started from L-Serine via Wittig reaction, Sharpless dihydroxylation, and protection of the hydroxyl groups with benzyl groups in 14% yield. After the adequate protection of the amino group with the azido group, the primary alcohol was attempted to substitute by azido group via the intermediate of triflate. However, it failed to provide the product but only the cyclized Jaspine B.
An alternative synthetic route via tosylate did successfully generate the desired diazido phytosphingosine analogue in 74% yield,
((2S,3S,4R)-1,2-diazidoheptadecane-3,4-diyl)bis(oxy)bis(methylene. The concommitant deprotection of the amino groups and benzyl groups using hydrogen atmosphere at 50 psi under catalytic condition of either Pd/C or Pd(OH)2/C failed to provide the target compound but only a smear of spots was observed in TLC. An alternative condition using trichloroborane could be successfully to provide the product, (2S,3S,4R)-1-amino-2-azidoheptadecane-3,4-diol.
The subsequent construction of the library and the corresponding in-situ bioassay are in progress.

關鍵字

神經醯胺醇 ； 核心化合物 ； 生物分子褲 ； 合成

並列摘要

本論文之研究目的為合成神經醯胺醇之類似物，作為核心化合物與各種類之酸耦合形成醯胺鍵後，以之建立分子庫篩選實驗。 以絲胺酸作為起始物，經五步合成獲得Garner’s aldehyde，而後以Wittig reaction、Sharpless dihydroxylation。再將裸露之雙醇基以Benzyl基保護，接著除去Boc及acetonide保護基，形成神經醯胺醇之結構((2S,3S,4R)-2-amino-3,4-bis(benzyloxy)heptadecan-1-ol)。以TfN3將胺基轉換成azido基後，欲將官能基轉換(1°OH→NH2)時，以triflate作為離去基， 卻無法得到目標物，反而形成五員環之Jaspin B類似物。而後改用tosylate作為離去基時，以吡啶及二氯甲烷(體積比為一比一)作為溶劑下成功地將醇基轉換為tosylate。再以疊氮化鋰將tosylate取代為azido基，最後嘗試一系列之氫化條件，欲將兩個azido基及benzyl基一併去除，但無法達成，benzyl基無法完全還原。故改用以三氯化硼的條件，欲先除去兩個benzyl基，在此條件下，不僅成功地還原了兩benzyl基，另外亦還原其一azido基，總計十三步合成，產率4%。 未來此化合物將與各式羧酸經由活化條件來進行耦合提供生物上細胞活性實驗，以期能篩選出具有潛力之化合物。

並列關鍵字

synthesis ； sphingosine

參考文獻

(1) Ogretmen, B.; Hannun, Y. A. Nat. Rev. Cancer 2004, 4, 604-616.

(2) Snook, C. F.; Jones, J. A.; Hannun, Y. A. Biochim. Biophys. Acta 2006, 1761, 927-946.

(8) Inagaki, M.; Isobe, R.; Higuchi, R. Eur. J. Org. Chem. 1999, 771-774.

(11) Chang, Y. T.; Choi, J.; Ding, S.; Prieschl, E. E.; Baumruker, T.; Lee, J. M.; Chung, S. K.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1856-1857.

(12) Howell, A. R.; Ndakala, A. J. Curr. Org. Chem. 2002, 6, 365-391.