Second-Generation Synthesis of the Northern Fragment of Mandelalide A: Role of π-Stacking on Sharpless Dihydroxylation of cis-Enynes

J Org Chem. 2019 Jul 19;84(14):9196-9214. doi: 10.1021/acs.joc.9b01153. Epub 2019 Jul 2.

Abstract

The development of a π-stacking-based approach for increased stereoselectivity in Sharpless asymmetric and diastereomeric dihydroxylation of cis-enynes is disclosed. The use of neighboring, electron-rich benzoate esters proved key to the success of this process. Density functional theory study suggests that the substrate benzoate ester group rigidifies the dihydroxylation transition states by forming a favorable π-stacking interaction in both Major-TS and Minor-TS. The energetic preference for the Major-TS was found in part because of the favorable eclipsing conformation of the alkene substituent as opposed to the disfavored bisecting conformation found in the Minor-TS. The application to a second-generation synthesis of the C15-C24 northern portion of mandelalide A is demonstrated.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.