The Application of α-Acylamino Carbon Radical Cyclizations with Acylsilanes in the Synthesis of (+)-Lentiginosine, (-)-Epiquinamide, (+)-Swainsonine and Other Alkaloid Analogues
Date Issued
2007
Date
2007
Author(s)
Chen, Ming-Jen
DOI
zh-TW
Abstract
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.
Subjects
α-醯胺基碳自由基
矽基酮
自由基環化反應
生物鹼
α-Acylamino
Radical Cyclization
Acylsilane
Lentiginosine
Epiquinamide
Swainsonine
Alkaloid
Type
thesis
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