Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations

Vindoline and catharanthine are the major alkaloids of <i>Catharanthus roseus</i> and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine ma...

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Autores principales:	Shamsher Ali, Eric Hénon, Ritchy Leroy, Georges Massiot
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	vindoline benzoquinone atropoisomerism cytotoxicity Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/77269905e27844e98c6ca2a01266463a
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spelling	oai:doaj.org-article:77269905e27844e98c6ca2a01266463a2021-11-11T18:25:09ZAddition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations10.3390/molecules262163951420-3049https://doaj.org/article/77269905e27844e98c6ca2a01266463a2021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6395https://doaj.org/toc/1420-3049Vindoline and catharanthine are the major alkaloids of <i>Catharanthus roseus</i> and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as <i>syn</i> (minor) and <i>anti</i> (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the <i>syn-anti</i> interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between <i>syn</i> and <i>anti</i> isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.Shamsher AliEric HénonRitchy LeroyGeorges MassiotMDPI AGarticlevindolinebenzoquinoneatropoisomerismcytotoxicityOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6395, p 6395 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	vindoline benzoquinone atropoisomerism cytotoxicity Organic chemistry QD241-441
spellingShingle	vindoline benzoquinone atropoisomerism cytotoxicity Organic chemistry QD241-441 Shamsher Ali Eric Hénon Ritchy Leroy Georges Massiot Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
description	Vindoline and catharanthine are the major alkaloids of <i>Catharanthus roseus</i> and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as <i>syn</i> (minor) and <i>anti</i> (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the <i>syn-anti</i> interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between <i>syn</i> and <i>anti</i> isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.
format	article
author	Shamsher Ali Eric Hénon Ritchy Leroy Georges Massiot
author_facet	Shamsher Ali Eric Hénon Ritchy Leroy Georges Massiot
author_sort	Shamsher Ali
title	Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
title_short	Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
title_full	Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
title_fullStr	Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
title_full_unstemmed	Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations
title_sort	addition of vindoline to <i>p</i>-benzoquinone: regiochemistry, stereochemistry and symmetry considerations
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/77269905e27844e98c6ca2a01266463a
work_keys_str_mv	AT shamsherali additionofvindolinetoipibenzoquinoneregiochemistrystereochemistryandsymmetryconsiderations AT erichenon additionofvindolinetoipibenzoquinoneregiochemistrystereochemistryandsymmetryconsiderations AT ritchyleroy additionofvindolinetoipibenzoquinoneregiochemistrystereochemistryandsymmetryconsiderations AT georgesmassiot additionofvindolinetoipibenzoquinoneregiochemistrystereochemistryandsymmetryconsiderations
_version_	1718431829341503488

Addition of Vindoline to <i>p</i>-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations

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