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Dissertation Title: New approach to the synthesis of some Iboga alkaloids
[Neuer Zugang zu den Iboga-Alkaloiden]
Author: Frauenfelder, Christine
School: EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH (SWITZERLAND) (0663)
Degree: Drscnat Date: 1999 pp: 249
Source: DAI-C 61/02, p. 526, Summer 2000
Subject: CHEMISTRY, ORGANIC (0490)
The family of the Iboga-alkaloids comprises over sixty, structurally closely related members. Interestingly, representatives of both antipodal series are naturally occurring. Some of the simple structures like ibogaine (1) and ibogamine (2) have been synthesized before. So far, an efficient approach to the numerous oxidized members of this alkaloid family does not exist. The present thesis discloses a novel flexible approach to these biologically extremely interesting alkaloids.
Following their biosynthesis, the Iboga-alkaloids were retrosynthetically divided in an isoquinuclidine- and an indole-building block. The isquinuclidine part was built up by an intramolecular 1,3-dipolar cycloaddition. In this reaction, the stereochemical relations between three centers are defined and at the same time an oxygen substituent is positioned at center C(19).
The alpha-methylene ester 172 required for that purpose was synthesized via Claisen-rearrangement in four steps or via Wittig-Horner-synthesis in two steps. A Michael-addition of methyl cyanoacetate to alpha-methylene ester 172 was followed by the selective reduction of the nitrile and subsequent cyclisation to lactam 178. Transformation of 178 into piperidine derivative 151 was accomplished in five steps.
The oxidation of 151 to the nitrone 149 proved to be more complicated than expected. A tungsten-catalyzed hydrogen peroxide oxidation was finally successful. The immediately following 1,3-dipolar cycloaddition to isoquinuclidine 147 and subsequent reductive cleavage with zinc in glacial acetic acid produced the isoquinuclidine building block 209 in good yield.
For the assembly of the indole part several possibilities have been considered. The synthesis of N-boc-2-(3-bromopropyl)-aniline (156), 2-(3 prime-bromopropyl)-nitrobenzene (156), N-Boc-1-(2-aminophenyl)-prop-2-en-1-one (156) and N-(p-MBS)-3-indolylacetaldehyde (156) caused no difficulties, neither did their condensation with isoquinuclidine 209.
Ring-closure by ortho-metallation of 229 failed as well as a McMurry-coupling of lactam 242 to epiheyneanine (68).
Transformation of 248 to 250 by Hunsdiecker -reaction, followed by Friedel-Crafts-alkylation could still lead to a successful ring closure, resulting in epiheyneanine (68).
Several synthetic strategies leading to piperidine derivative 151 among others via derivatisation of malonic ester 258, oxime 301 or Hetero-Diels-Alder product 333 had to be abandoned for lack of success.
"Whatever there is to learn has to be learned the hard way."
Castaneda's teacher Don Juan Matus
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Is iboga (the plant) legal in the USA?