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Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity.

ABSTRACT: The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-(exo)-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for β,β'-disubstituted α,β-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (-)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all the isomers tested in cell culture, only (-)-parthenolide showed potent inhibition of microtubule detyrosination in living cells, confirming its exquisite selectivity on tubulin carboxypeptidase activity. On the other hand, the anti-inflammatory activity of the parthenolides was weaker and less selective with regard to compound stereochemistry.

SUBMITTER: Freund RRA

PROVIDER: S-EPMC6713873 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity.

Freund Robert R A RRA Gobrecht Philipp P Rao Zhigang Z Gerstmeier Jana J Schlosser Robin R Görls Helmar H Werz Oliver O Fischer Dietmar D Arndt Hans-Dieter HD

Chemical science 20190626 31

The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-(<i>exo</i>)-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for β,β'-disubstituted α,β-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (-)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all ...[more]

PMID: 31489157

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