From toluene to triquinanes: formal total syntheses of the sesquiterpenoid natural products (−)-hypnophilin and (−)-coriolin

Establishing the True Structure of the Sorbicillinoid‐Derived Isolate Rezishanone C by Total Synthesis

“…Rezishanone C, in any of its structurally proposed or plausible alternate forms, embodies a polyfunctionalized and homochiral bicyclo[2.2.2]octane core bearing a bridgehead methyl group, a structural motif that we have been able to assemble by chemoenzymatic means during the course of our studies on the total synthesis of various terpenoids . Accordingly, and given the absence of any prior studies as well as the ambiguities associated with its structure, we were attracted to rezishanone C as a synthetic target.…”

“…The opening stages of the synthesis are shown in Scheme and involved converting, under standard conditions, the readily available, enzymatically derived and homochiral cis ‐1,2‐dihydrocatechol 5 into the corresponding and previously reported acetonide 6 . Compound 6 was itself engaged in a thermally induced Diels–Alder cycloaddition reaction with α‐chloroacrylonitrile, and the epimeric mixture of ortho adducts thus obtained were hydrolyzed using potassium hydroxide in tert ‐butanol to give the known bicyclo[2.2.2]octenone 7 (53 % from 5 ). Cleavage of the acetonide moiety within the last compound was achieved using acidified AG‐50W‐X8 resin in hot aqueous methanol, but this process was accompanied by a retro‐aldol/aldol sequence that led to the production of the trans ‐diol 8 (86 %).…”

“…3 Rezishanone C, in any of its structurally proposed or plausible alternate forms, [4] embodies ap olyfunctionalized and homochiral bicyclo[2.2.2]octane core bearing ab ridgehead methyl group, as tructuralm otif that we have been able to assemble by chemoenzymatic means duringt he course of our studies on thet otal synthesis of various terpenoids. [5] Accordingly,a nd given the absence of any prior studies [6] as well as the ambiguities associated with its structure, we were attracted to rezishanone Ca sas ynthetic target. As ap relude to undertaking synthetic studies,w ec arried out dispersion-corrected DFT calculations to determine the transition state energies associated with the various possible modes of Diels-Alder cycloaddition that couldt ake place between sorbicillinol (2)a nd ethyl vinyl ether.T hese suggestedt hat the reactionp athway leadingt oc ompound 4 (rather than congener 1 or the 7R epimeric form of 2)i st he most energeticallyf avorable one (see the Supporting Information).…”

Linear Triquinane Sesquiterpenoids: Their Isolation, Structures, Biological Activities, and Chemical Synthesis

“…In 2013, Bon and co-workers accomplished the formal total syntheses of (−)-hypnophilin ((−)- 8 ) and (−)-coriolin ((−)- 2 ) [ 72 ]. In particular, they reported the synthesis of compound 159 , an advanced intermediate related with previously reported syntheses of both compounds (−)- 8 and (−)- 2 .…”

Studies on the Photochemical Rearrangements of Enantiomerically Pure, Polysubstituted, and Variously Annulated Bicyclo[2.2.2]octenones

“…While various methods are available for the synthesis of such systems, a particularly useful approach involves the facially selective intermolecular cycloaddition of dienophiles to enantiomerically pure cis -1,2-dihydrocatechols such as 5 (Figure ) that are readily obtained through the whole-cell biotransformation of the corresponding arene (toluene in the case of compound 5 ) . Indeed, we have exploited such adducts in the photochemically mediated total synthesis of a range of sesquiterpenoid natural products including various triquinanes, protoilludanes, and the structure assigned to a sterpurene . In seeking to extend such studies for the purposes of preparing new molecular scaffolds, including those of use in drug discovery, we became interested in establishing the degree to which the bicyclo[2.2.2]­octenone framework could be substituted and/or annulated and continue to engage in the above-mentioned photochemical processes.…”