Synthesis of (+)-Manoalide via a Copper(I)-Mediated 1,2-Metalate Rearrangement

Abstract

An enantiospecific synthesis of the phospholipase A(2) inhibitor (+)-(4R)-manoalide is reported in which all 25 carbons of the sesterterpenoid skeleton are constructed from 3-furaldehyde, trimethylalane, oxirane, CO, beta-ionone, and propargyl bromide. The overall yield for the longest linear sequence (12 steps) is 12%. Key steps include (a) a zirconium-catalyzed carboalumination reaction to construct the C10-C11 trisubstituted alkene, (b) a Cu(I)-mediated 1,2-metalate rearrangement to construct the C6-C7 trisubstituted alkene, (c) a Sharpless kinetic resolution to secure the (4R)-stereochemistry, (d) generation of a 5-stannyl-2,3-dihydrofuran by Mo-catalyzed cycloisomerization of a homopropargylic alcohol, and (e) construction of the hydroxyfuranone ring by photooxidation of a silylfuran.

New Methods for Medicinal Chemistry - Universal Gene Cloning and Expression Systems for Production of Marine Bioactive Metabolites

“…Although numerous syntheses of manoalide have been reported [70][71][72][73][74] including enantiospecific syntheses [75,76], low synthetic yields are not viable to sustain a large-scale market supply. Other than the elucidation of the antiinflammatory, diterpene glucoside pseudopterosin (18) [77][78][79] produced by symbiotic Symbiodinium sp.…”

Five‐Membered Heterocycles: Furan

“…2-Furylcuprate 190, as shown in Scheme 6.88, was recently discovered to undergo a 1,2-metalate rearrangement to form 191 [165]. A similar dyotropic rearrangement of 2-furylzirconocene complexes has also been reported [166].…”

Synthetic Approaches to α,β‐Unsaturated δ‐Lactones and Lactols

“…This compound was then transformed into the corresponding lactone by a palladium-catalyzed carbonylation in which the acylpalladium intermediate was intramolecularly trapped by the δ-hydroxy group. [49] …”