α-醯胺基碳自由基與矽基酮環化反應在合成(+)-Lentiginosine, (-)-Epiquinamide, (+)-Swainsonine及其他類似生物鹼之應用

Abstract

本論文是延續實驗室利用α-醯胺基碳自由基與矽基酮的環化反應來合成吡咯叻咭啶(pyrrolizidine)、吲哚叻咭啶(indolizidine)和喹叺叻咭啶(quinolizidine)等骨架的方法，進而企圖合成出(+)-Lentiginosine、(-)-Epiquinamide、(+)-Swainsonine及其它類似的生物鹼。生物鹼架橋上立體化學的建立，可透過環上取代基立體障礙的影響，使得環化過程只會從立障較小的一面進行，因此可得到單一立體化學的結果，而環化所形成的羥基則是以exo的產物為主。在這類的環化系統，當矽基為二苯基甲基矽基時的環化效率會比矽基為三甲基矽基時來得好，而且五圓環會比六圓環要來得有效率。 在第一部份，從文獻已知的2-二苯基甲基矽基-1,3-二硫環己烷化合物開始算至合成出(+)-Lentiginosine，經13個合成步驟，總產率為10.3%；至於將矽基酮的部分換成醛基時，自由基反應則無法進行。

在第二部分，我們完成了(-)-Epiquinamide的半合成，從2-二苯基甲基矽基-1,3-二硫環己烷化合物開始算，經13個合成步驟可合成到文獻已知的中間體，產率共10.9%，此中間體再經由4個步驟就可以得到(-)-Epiquinamide。

在第三部分，我們也完成了(+)-Swainsonine的半合成，從2-三甲基矽基-1,3-二硫環己烷化合物開始算，經12個步驟可合成到文獻已知的中間體，產率共16.5%，而此中間體再經由2個步驟就可以得到(+)-Swainsonine。此外，我們在同一個合成路徑上，也完成了(+)-1,8a-di-epi-lentiginosine的半合成以及(+)-1,2-di-epi-swainsonine的合成。透過另一個合成策略，從相同的起始物開始算到合成出(+)-Swainsonine，共17個步驟，總產率為6.1%。

在第四部分，關於控制立體化學的相關研究方面，均無法得到好的結果。對於硫醯亞胺與矽基酮的自由基反應，則是得到低產率的簡單環化產物，而不是預期的烯醇矽醚化合物。

Abstract

Using the methodology of radical cyclizations of α-acylamino radicals with acylsilanes to construct pyrrolizidine, indolizidine and quinolizidine skeletons, we were able to synthesize (+)-Lentiginosine, (-)-Epiquinamide, (+)-Swainsonine and other analogous alkaloids. In the cyclization process, α-acylamino radicals preferred to attack acylsilanes from the face opposite to the β-substituent, and the stereoselectivity of the bridgehead is excellent. The orientation of the hydroxy group formed in the cyclization process was mainly exo. In these systems, the cyclization efficiency of diphenylmethysilyl ketones was better than the corresponding trimethylsilyl compounds, and that of the five-membered ring system was better than the six-membered one.

This dissertation was divided into four sections. In the first part, starting from 2-diphenylmethysilyl-1,3-dithiane, the synthesis of (+)-Lentiginosine was accomplished in 13 steps, and the total yield is 10.3%. In contrast, switching the acylsilane functionality to an aldehyde, the radical cyclization failed.

In the second part, starting from 2-diphenylmethysilyl-1,3-dithiane, we accomplished a formal synthesis of (-)-Epiquinamide. The synthetic process included 13 steps in 10.9% yield, and the synthetic intermediate we approached was 4 steps away from (-)-Epiquinamide.

In part 3, we finished a formal synthesis of (+)-Swainsonine in 12 steps in 16.5% yield from commercially available 2-trimethysilyl-1,3-dithiane. The synthetic intermediate we reached was 2 steps away from (+)-Swainsonine. In this synthetic pathway, we also achieved a formal synthesis of (+)-1,8a-di-epi-lentiginosine and the synthesis of (+)-1,2-di-epi-swainsonine. We also developed a different approach for the synthesis of (+)-Swainsonine, the alkaloid was completed in 17 steps in 6.1% from the same starting material.

In the last part, the study of controlling the stereochemistry of the newly formed chiral centers was not successful. In another direction, the radical cyclization of thioimide with acylsilane produced simple cyclization product in low yield without expected enol silyl ether compound.