An approach to hyperolactone C and analogues using late stage conjugate addition on an oxonium ylide-derived spirofuranone

Abstract

A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the anti-HIV agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.

Predictive Model for Oxidative C–H Bond Functionalization Reactivity with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

“…The enhanced rate of enamides and vinyl sulfides relative to allylic amides and sulfides, , for example, further illustrates the role of oxidation potential on the activation barrier. The disparate reactivities of enolsilanes in carbocycles, where nucleophilic addition occurs, and heterocycles, where C–H bond cleavage dominates, , illustrate the importance of cation stability on the reaction pathway. The facile oxidation of transiently generated enamines to form α,β-unsaturated iminium ions demonstrates the role of both factors.…”

Intramolecular Oxonium Ylide Formation–[2,3] Sigmatropic Rearrangement of Diazocarbonyl-Substituted Cyclic Unsaturated Acetals: A Formal Synthesis of Hyperolactone C

“…Following precedent on a closely related system ( 8b with R 3 = H) in our recent synthesis of hyperolactone C ( 4 ), a phenyl group was introduced into dimethylated spirofuranone 8b by conjugate addition–oxidation, giving spirofuranone 8d in 78% yield (Scheme ). Alternatively, as mentioned in the Introduction, the phenyl group could, in principle, be present prior to the ylide chemistry.…”

“…Hyperolactone C ( 4 ) forms part of a small family of related lactones, originally isolated from the leaves and stems of Hypericum chinese L . It is an attractive target for fundamental and structure–activity relationship synthetic studies, due to a combination of structural complexity and potential as a lead in anti-HIV research. , We have previously reported approaches to hyperolactone C ( 4 ) using tandem oxonium ylide formation–[2,3]-sigmatropic rearrangements ( 1 → 3 , Scheme , R′ = Ph or H, R′′ = alkyl). − However, our earlier studies did not fully control the relative stereochemistry and required post-rearrangement oxidation to introduce the furanone double bond. The present work sought to address both of these latter issues, by constraining the allylic ether as part of a cyclic unsaturated acetal 5 (Scheme ).…”

“…An initial aim of the current work was, therefore, to establish whether bicyclic acetal 7a could undergo acid-catalyzed rearrangement with loss of methanol to directly generate the spirofuranone framework 8 of the hyperolactones. In the context of the specific substitution pattern of hyperolactone C ( 4 ), further challenges identified at the outset that would need to be subsequently addressed were the viability of the sequence from cyclic acetal 5 to spirofuranone 8 with (a) R 1 = Ph (noting that late-stage conjugate addition offers flexibility to introduce this group after rearrangement), and (b) R 2 = Me (to forge the adjacent quaternary stereocenters), and R 3 either = Me (then requiring a late-stage demethylation) or = H (requiring selection between nonequivalent acetal oxygen atoms in the oxonium ylide formation–rearrangement).…”

Spiroacetal Formation through Telescoped Cycloaddition and Carbon–Hydrogen Bond Functionalization: Total Synthesis of Bistramide A

“…The sequence was completed by protodesilylation with p-TsOH·H 2 O to deliver the spiroacetal 6 in 78 % yield upon isolated with 91 % ee. The oxygen atom in the ring appears to be essential for promoting rapid oxidation in consideration of the studies from Guo and Mayr, [11] who showed that carbocyclic enolsilanes add to DDQ rather than form enones.…”