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

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.

A Quarter Century of Marine Biodiscovery in Algoa Bay, South Africa

“…66,67,69−71 Two additional synthetic strategies were reported in 2019. 72,73 The cytotoxicity reported for synthetic 38 against 11 different cancer cell lines (including H1229 lung cancer) was disappointingly at variance 4,66,67 with the potent cytotoxicity originally reported for the natural product. 53 While Furstner et al 67 erroneously attributed this discrepancy in cytotoxicity to an impure/contaminated natural product used for testing, this broader testing of synthetic 38 against cancer cell lines with varied metabolic backgrounds provided early clues to the biological mechanism of the mandelalides.…”

“…The reassigned macrocycle configuration, with the tetrahydrofuran moiety and two adjacent chiral centers inverted, was subsequently deemed correct for 39 – 41 as well, based on quantum mechanical NMR chemical shift predictions, although no synthesis of these butyrolactone-containing mandelalides has been reported to date. Within four years, five prominent international synthetic chemistry research groups had synthesized, and tested, the corrected absolute structure of 38 . ,,− Two additional synthetic strategies were reported in 2019. , …”