The Study of the Synthesis of Two Different Types of Alkaloids. Synthesis of Aporphinoids- Lirioferine and BoldineI. Synthesis of Chiral Piperidines via Radical Cyclization of Acylsilanes
Date Issued
2009
Date
2009
Author(s)
Chu, Fang-Lan
Abstract
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.
Subjects
aporphine
lirioferine
boldine
acylsilanes
radical
piperidine
Type
thesis
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