Application of the Wittig rearrangement of N-butyl-2-benzyloxybenzamides to synthesis of phthalide natural products and 3-aryl-3-benzyloxyisoindolinone anticancer agents

R Alan Aitken; Francesca K. Cooper; Andrew David Harper; Ryan A. Inwood; Elizabeth A. Saab; Ewan J. Soutar

doi:10.3390/molecules29194722

Application of the Wittig rearrangement of N-butyl-2-benzyloxybenzamides to synthesis of phthalide natural products and 3-aryl-3-benzyloxyisoindolinone anticancer agents

R Alan Aitken^*, Francesca K. Cooper, Andrew David Harper, Ryan A. Inwood, Elizabeth A. Saab, Ewan J. Soutar

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO₂ provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

Original language	English
Article number	4722
Number of pages	16
Journal	Molecules
Volume	29
Issue number	19
DOIs	https://doi.org/10.3390/molecules29194722
Publication status	Published - 6 Oct 2024

Keywords

[1,2]-Wittig rearrangement
3-arylphthalides
3-aryl-3-hydroxyisoindolinones
Natural products
Anticancer agents

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10.3390/molecules29194722Licence: CC BY

Aitken-2024-Application-of-the-Wittig-Molecules-29-04722-CCBY
Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/4.0/).
Final published version, 2.11 MBLicence: CC BY

Application of the Wittig Rearrangement of N-Butyl-2-benzyloxybenzamides to Synthesis of Phthalide Natural Products and 3-Aryl-3-benzyloxyisoindolinone Anticancer Agents (dataset)
Aitken, R. A. (Creator), Cooper, F. K. (Creator), Harper, A. D. (Creator), Inwood, R. (Creator), Saab, E. A. (Creator) & Soutar, E. J. (Creator), University of St Andrews, 6 Oct 2024
DOI: 10.17630/10d97ec3-6df2-4c00-80f2-7b814fc3c99e
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title = "Application of the Wittig rearrangement of N-butyl-2-benzyloxybenzamides to synthesis of phthalide natural products and 3-aryl-3-benzyloxyisoindolinone anticancer agents",

abstract = "Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.",

keywords = "[1,2]-Wittig rearrangement, 3-arylphthalides, 3-aryl-3-hydroxyisoindolinones, Natural products, Anticancer agents",

author = "Aitken, {R Alan} and Cooper, {Francesca K.} and Harper, {Andrew David} and Inwood, {Ryan A.} and Saab, {Elizabeth A.} and Soutar, {Ewan J.}",

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doi = "10.3390/molecules29194722",

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T1 - Application of the Wittig rearrangement of N-butyl-2-benzyloxybenzamides to synthesis of phthalide natural products and 3-aryl-3-benzyloxyisoindolinone anticancer agents

AU - Aitken, R Alan

AU - Cooper, Francesca K.

AU - Harper, Andrew David

AU - Inwood, Ryan A.

AU - Saab, Elizabeth A.

AU - Soutar, Ewan J.

PY - 2024/10/6

Y1 - 2024/10/6

N2 - Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

AB - Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

KW - [1,2]-Wittig rearrangement

KW - 3-arylphthalides

KW - 3-aryl-3-hydroxyisoindolinones

KW - Natural products

KW - Anticancer agents

U2 - 10.3390/molecules29194722

DO - 10.3390/molecules29194722

M3 - Article

SN - 1420-3049

VL - 29

JO - Molecules

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M1 - 4722

ER -

Application of the Wittig rearrangement of N-butyl-2-benzyloxybenzamides to synthesis of phthalide natural products and 3-aryl-3-benzyloxyisoindolinone anticancer agents

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Keywords

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Application of the Wittig Rearrangement of N-Butyl-2-benzyloxybenzamides to Synthesis of Phthalide Natural Products and 3-Aryl-3-benzyloxyisoindolinone Anticancer Agents (dataset)

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