Convergent Synthesis of Fostriecin via Selective Alkene Couplings and Regioselective Asymmetric Dihydroxylation

Abstract

A highly convergent synthesis of fostriecin is described, featuring sequential palladium-catalyzed Negishi cross couplings to form the C7-C8 bond and C8-methyl bond, followed by late-stage regio- and stereoselective dihydroxylation of C8-C9.

Catalytic Enantioselective Allylations of Acetylenic Aldehydes via 2-Propanol-Mediated Reductive Coupling

“…Optimal results were obtained using the catalyst ( S )-Ir- I modified by ( S )-Cl-MeO-BIPHEP. The optical rotation of 3f matched the literature value, 11 and its absolute stereochemical assignment is consistent with the enantiofacial preference generally observed in related aldehyde allylations catalyzed by ( S )-Ir I and ( S )-Ir- II . 6d,10…”

Total Synthesis of Kingianin A

“…Stork-Zhao olefination provided the (E, Z)-iododiene 6 . The required vinyl boronic ester 9 was prepared in two steps as described in the literature 14 and coupled with iododiene 6 under Suzuki conditions. The expected mixture of bicyclo octadienes 11 and 12 was isolated from this reaction.…”

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

“…Even base-sensitive compounds are tolerated under these conditions as the basic TBAF can be buffered and the cross-coupling reaction still proceeds. McDonald’s synthesis of fostriecin 150 also highlights the way in which cross-coupling can be used to disconnect at positions that are not sp 2 -hybridized. This strategy uses a “hidden alkene” in the retrosynthetic analysis to unite both the lactone portion and the C8 methyl group to the fostriecin core, and then a dihydroxylation to functionalize this alkene to the desired set of stereocenters at C8 and C9.…”

“…150 Though cross-coupling has been widely used to install the triene portion of the molecule, McDonald envisioned using this technology to unite a central fragment to the lactone portion of the molecule, as well as the methyl group at C8. These disconnections yield a highly convergent strategy.…”