臺灣博碩士論文加值系統

人參是五加科多年生植物Panax ginseng C. A. Meyer之乾燥根。其主要成分是saponin類化合物和一些sesquiterpene類化合物。除此之外，最近也有一些在天然物中較不尋常的polyacetylene化合物被分離出來，具有抗腫瘤活性及細胞毒性，panaxytriol是其中之一。本論文中提出一個較簡易的構想利用不對稱合成方法來合成panaxytriol，藉此一方面可以幫助確認其立體結構，另外也可以用來更廣泛更深入的研究其抗腫瘤活性。
本論文以trans-2-decenal為起始物，加入DIBAL-H被還原成trans-dec-2-en-1-ol，然後再與PBr3反應轉變成trans-1-bromodec- 2-ene。乙炔和n-butyllithium及CuCN反應後加入trans-1-bromo- dec-2-ene，即可獲得coupling之產物trans-dodec-4-en-1-yne。再與AD-mix-β進行Sharpless asymmetric dihydroxylation後就可產生合成panaxytriol所需之一前驅物(4R,5R)-dodec-1-yne-4,5-diol。
而另一前驅物5-iodopent-1-en-4-yn-3-ol的合成，本論文嘗試使用下列兩種方法。其中一方法以propenal為起始物，加入trimethylsilylacetylene和n-BuLi中，產生5-trimethylsilylpent-1-en -4-yn-3-ol，再與NIS和AgNO3反應，即能得到5-iodo-pent-1-en-4- yn-3-ol。最後若再與(4R,5R)-dodec-1-yne-4,5-diol，利用CuI進行coupling之後，將可以獲得立體結構為3R,9R,10R和3S,9R,10R之panaxytriol。而另一方法以methyl 3,4-O- isopropylidene-L-threonate當作起始物，加入imidazole和tert-butyldimethylsilyl chloride，形成methyl (2R)-2-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-2-[(4R)-2,2- dimethyl-1,3-dioxolan-4-yl]acetate後再加入DIBAL-H還原成(2R) -2-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-2-[(4R)-2,2-dimethyl-1,3-di-oxolan-4-yl]acetaldehyde，然後和dimethyl 1-diazo-2- oxopropylphosphonate反應，即可獲得tert-butyl({(1S)-1-[(4R)- (2,2-dimethyl-1,3-dioxolan-4-yl)]prop-2-ynyl}oxy)dimethylsilane。若經由periodic acid進行dehomologation水解並氧化acetonide產生aldehyde，再經過Wittig reaction將可生成tert-butyl(1-ethynyl- allyloxy)dimethylsilane，再和NIS、AgNO3反應可以得到(R) form的iodoacetylene，然後再與(4R,5R)-dodec-1-yne-4,5-diol利用CuI進行coupling之後，將可以獲得(3R,9R,10R)-panaxytriol。
本論文利用不對稱合成之方法順利完成(4R,5R)-dodec-1-yne- 4,5-diol之合成，其步驟遠比文獻上的方法要短，而且也提出利用methyl 3,4-O-isopropylidene-L-threonate來合成(R)-5-iodopent-1- en-4-yn-3-ol之構想，以縮減合成panaxytriol之步驟。

Panax ginseng has been considered as one of the most important and valuable medicinal plants in traditional oriental medicine. It was reported to have numerous biological activity, including effects on the cardiovascular, immune, and nervous systems, and activity as an antidote, antitumor agent, or antitumor adjuvant and as an antidiabetic. Although ginseng has been used for thousands of years, its chemical constituents were gradually isolated until 1960s. In the last two decades, many unusual polyacetylene compounds were isolated from this traditional medicine and showed to suppress the in vitro growth of cultured tumor cells. Panaxytriol is one of these new type of antitumor agents. In this thesis, the asymmetric synthesis of panaxytriol was investigated.
We started with trans-2-decenal, which was reduced to trans- dec-2-en-1-ol by DIBAL. Phosphorus tribromide converted the alcohol into an allyl bromide and the bromide coupled with lithium acetylide in the presence of copper(I) cyanide to give trans-dodec- 4-en- 1-yne. Sharpless asymmertric dihydroxylation with AD-mix-β transformed the enyne into (4R,5R)-dodec-1-yne-4,5-diol,which was one of the precursors for the synthesis of panaxytriol.
The other precusor, 5-iodopent-1-en-4-yn-3-ol, was syn- thesized by two approaches. One approach started with propenal, which reacted with lithium trimethylsilylacetylide to produce 5- trimethylsilylpent-1-en-4-yn-3-ol. The reaction of this enynol with N-iodosuccinimide and AgNO3 gave 5-iodopent-1-en-4-yn-3-ol. Finally, if the iodoacetylene couples with (4R,5R)-dodec-1-yne-4,5- diol using Cadiot-Chodkiewicz procedure, panaxytriol will be obtained, which has the configuration of 3R,9R,10R and 3S,9R,10R. The other approach started with methyl 3,4-O-iso- propylidene-L-threonate. After protection of the hydroxyl group with tert-butyldimethylsilyl chloride, the ester was reduced by DIBAL to give an aldehyde, which reacted with dimethyl 1-diazo-2- oxopropylphosphonate to afford an alkyne. Finally, the alkyne will be converted into (R)-5-iodopent-1-en-4-yn-3-ol in three steps and then couple with (4R,5R)-dodec-1-yne-4,5-diol by Cadiot- Chodkiewicz procedure to give (3R,9R,10R)-panaxytriol.
In this synthetic study of panaxytriol, 5-iodopent-1-en-4-yn-3- ol and(4R,5R)-dodec-1-yne-4,5-diol were successfullys ynthesized. In addition to racemic 5-iodopent-1-en-4-yn-3-ol, the synthesis of (R)-5-iodopent-1-en-4-yn-3-ol was also attempted. The precursor for the synthesis of panaxytriol, (4R,5R)-dodec-1-yne-4,5-diol, was synthesized via only four steps, which was much fewer than the procedures reported in the synthesis of the alkynediol precursor.

目 錄
中文摘要-------------------------------------------------------i
英文摘要-----------------------------------------------------iii
壹、緒論------------------------------------------------------01
貳、合成所需之儀器與材料------------------------------------- 09
儀器------------------------------------------------------09
材料------------------------------------------------------10
溶劑之純化------------------------------------------------11
參、研究方法--------------------------------------------------13
Scheme 1--------------------------------------------------16
Scheme 2--------------------------------------------------17
Scheme 3--------------------------------------------------18
Scheme 4--------------------------------------------------19
肆、合成實驗部分----------------------------------------------20
伍、結果與討論------------------------------------------------34
陸、參考文獻--------------------------------------------------37
柒、附錄------------------------------------------------------40

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