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A Novel Synthetic Approach to (±)-Desoxynoreseroline


Mekhael, Maged K G; Heimgartner, Heinz (2003). A Novel Synthetic Approach to (±)-Desoxynoreseroline. Helvetica Chimica Acta, 86:2805-2813.

Abstract

(±)-Desoxynoreseroline (3), the basic ring structure of the pharmacologically active alkaloid physostigmine (1), was synthesized starting from 3-allyl-1,3-dimethyloxindole (9). The latter was prepared from the corresponding 2H-azirin-3-amine 6 by a BF3-catalyzed ring enlargement via an amidinium intermediate 7 (Scheme 1). An alternative synthesis of 9 was also carried out by the reaction of N-methylaniline with 2-bromopropanoyl bromide (12), followed by intramolecular Friedel-Crafts alkylation of the formed anilide 13 to give Julian's oxindole 11. Further alkylation of 11 with allyl bromide in the presence of LDA gave 9 in an excellent yield (Scheme 3). Ozonolysis of 9, followed by mild reduction with (EtO)3P, gave the aldehyde 14, whose structure was chemically established by the transformation to the corresponding acetal 15 (Scheme 4). Condensation of 14 with hydroxylamine and hydrazine derivatives, respectively, gave the corresponding imine derivatives 16a - 16d as a mixture of syn- and anti-isomers. Reduction of this mixture with LiAlH4 proceeded by loss of ROH or RNH2 to give racemic 3 (Scheme 5).

Abstract

(±)-Desoxynoreseroline (3), the basic ring structure of the pharmacologically active alkaloid physostigmine (1), was synthesized starting from 3-allyl-1,3-dimethyloxindole (9). The latter was prepared from the corresponding 2H-azirin-3-amine 6 by a BF3-catalyzed ring enlargement via an amidinium intermediate 7 (Scheme 1). An alternative synthesis of 9 was also carried out by the reaction of N-methylaniline with 2-bromopropanoyl bromide (12), followed by intramolecular Friedel-Crafts alkylation of the formed anilide 13 to give Julian's oxindole 11. Further alkylation of 11 with allyl bromide in the presence of LDA gave 9 in an excellent yield (Scheme 3). Ozonolysis of 9, followed by mild reduction with (EtO)3P, gave the aldehyde 14, whose structure was chemically established by the transformation to the corresponding acetal 15 (Scheme 4). Condensation of 14 with hydroxylamine and hydrazine derivatives, respectively, gave the corresponding imine derivatives 16a - 16d as a mixture of syn- and anti-isomers. Reduction of this mixture with LiAlH4 proceeded by loss of ROH or RNH2 to give racemic 3 (Scheme 5).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2003
Deposited On:11 Sep 2013 14:26
Last Modified:05 Apr 2016 16:58
Publisher:Wiley-Blackwell
ISSN:0018-019X
Funders:F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1002/hlca.200390231

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