兩種生物鹼類化合物之合成研究 I. 阿樸吩類衍生物-鵝掌楸啡鹼與波兒丁鹼之全合成 II. 透過矽基酮自由基環化反應合成具光學活性之哌啶類化合物

The Study of the Synthesis of Two Different Types of Alkaloids I. Synthesis of Aporphinoids- Lirioferine and Boldine II. Synthesis of Chiral Piperidines via Radical Cyclization of Acylsilanes

朱芳蘭(Fang-Lan Chu)

指導教授 ： 蔡蘊明

國立臺灣大學/理學院/化學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.03114

摘要

本篇論文中探討了兩種不同種類植物鹼的合成，在A部分中，我們針對阿樸吩(aporphine)類天然物中的鵝掌楸啡鹼(lirioferine)與波兒丁鹼(boldine)做了各自的全合成研究；在B部分中，我們發展了一種自由基環化策略運用在含多羥的哌啶(piperidine)類化合物之合成上。
研究顯示，阿樸吩類天然物對於生物體中的5-HT7受體具有很好親合力，所以在醫療與藥物合成上具有很高的研究價值。為了發展一套實用的合成方法，我們首先製備於苯環上具有不同種取代基的苯乙醯胺，接著透過Bischler-Napieralski反應進行分子內合環，並利用釕金屬對亞胺中間體進行不對稱的還原反應，建立出產物中唯一的光學活性中心，最後再利用Heck反應連結兩個苯環，就可以順利得到具有光學選擇性的阿樸吩類天然物。我們從可購買到的癒創木酚當起始物，經過十四步，可得到總產率9%、光學純度70% e.e.的鵝掌楸啡鹼。另外，利用異香草醛當起始物，經過十四步，可得到總產率6%、光學純度62% e.e.的波兒丁鹼。
另一部分，我們利用L-絲胺酸當掌性模板，建立一個具有光學活性的矽基酮當做自由基環合前驅物，並在氮上引入Boc保護基，利用A1,3 strain的關係迫使鄰位上的酯基位於軸向上，當自由基與矽基酮行分子內環化及重排後產生的矽氧基自由基要抓取氫原子時，會因為有1,3雙軸排斥的效應，使得反應傾向從軸向抓取氫原子，而得到具有順式為主的產物。研究過程中，成功克服了先前在環合前驅物的製備上所遇到的困難，利用苯硒基取代溴基做為產生自由基的官能基
，另外，也透過氯化汞順利水解1,3-二硫環己烷以得到矽基酮官能基，而不影響到苯硒基官能基，最後進行自由基的環化反應後，得到含有氮的六員環。總共經過十步得到總產率26%的多羥基哌啶類化合物，與氮上放置甲苯磺醯基的體系比較，順反式的選擇性也從先前的3：1提升到3.6：1。

關鍵字

阿樸吩類化合物 ； 鵝掌楸啡鹼 ； 波兒丁鹼 ； 矽基酮 ； 自由基 ； 哌啶類化合物

並列摘要

We discussed the syntheses of two different types of plant alkaloids in this thesis. In part A, we aimed at total syntheses in two kinds of aporphine alkaloids, lirioferine and boldine. In part B, we developed a tactic about radical cyclization in polyhydroxylated piperidine synthesis.
According to recent research, high affinities between aporphine alkaloids and 5-HT7 receptor were observed. In order to develop an useful synthestic process, we have synthesized amides with various substitutents. The isoquinoline skeleton was constructed through Bischler-Napieralski reaction, followed by asymmetric reduction of the imine intermediates with a Ru complex to form the only chiral center. Finally, we connected the two phenyl groups by Heck reaction and effectively obtained optically active aporphine alkaloids. Thus, starting from commercially available material, guaiacol, we successfully produced lirioferine with 9% yield and 70% e.e. in fourteen steps. Similarly, starting from isovialine, we successfully produced boldine with 6% yield and 62% e.e. in fourteen steps.
In another direction, we used L-serine as a chiral template to synthesize a chiral acylsilane as radical cyclization precursor. We uesd a “Boc” group for the protection of the amino group. Because of A1,3 strain, the neighboring ester group was pushed into an axial position in the radical cyclization chair transition state. After intramolecular radical cyclization and Brook-rearrangement, the resulting silyloxy substituted cyclohexyl radical preferred to abstract H atom from equatorial position to avoid the axially oriented ester group. We obtained the cis isomer as major product. During our research, we used phenyl selenenyl group to replace bromide to overcome the difficulties of synthesizing the cyclization precursor. Moreover, we used mercury (II) chloride for hydrolyzing 1,3-dithiane protecting group selectively to yield acylsilane with no influence on the phenyl selenenyl group. Eventually, we successfully produced polyhydroxylated piperidine with 26% yield in ten steps. Furthermore, comparing with the system with a tosyl group on nitrogen, the cis-trans selectivity was raised to 3.6:1 from 3:1.

並列關鍵字

aporphine ； lirioferine ； boldine ； acylsilanes ； radical ； piperidine

參考文獻

1. Guinaudeau, H.; Leboeuf, M.; Cavé, A. J. Nat. Prod. 1994, 57, 1033−1035.

Med. Chem. 2007, 50, 171−181.

4. Menon, R.; Stacy, M. Expert Opin. Pharmacother 2007, 8, 1941−1950.

Fitoterapia. 2003, 74, 493−496.

Biol. Chem 1993, 268, 23422−23426.