(-)-Harveynone

The enantiomerically pure and readily available metabolites 10-12 have been converted over four simple steps into the epoxyquinol derivatives 22-24, respectively. Compounds 23 and 24 or their immediate precursors have been exploited in efficient total syntheses of (-)-bromoxone (ent-1), (-)-epiepoformin (ent-2), (-)-harveynone (4), (+)-panepophenanthrin (6), and (+)-hexacyclinol (9).

A tandem reaction sequence involving relay metathesis-induced enyne RCM and metallotropic [1,3]-shift is an effective tool to construct cyclic alkenes with embedded 1,5-dien-3-yne moieties from acyclic precursors containing a 1,3-diyne. Total syntheses of (+)-asperpentyn, (-)-harveynone, and (-)-tricholomenyn A have been accomplished by implementing this metathesis-based tandem reaction sequence as the key step.

Exploitation of the beta-hydroxysulfoxide fragment present in a number of enantiomerically pure (SR)- and (SS)-[(p-tolylsulfinyl)methyl]-p-quinols allowed chemo- and stereocontrolled conjugate additions of different organoaluminium reagents to the cyclohexadienone moiety. The same fragment was also shown to act as an efficient chiral masking carbonyl group, after oxidation to sulfone and retroaddition in basic medium, with elimination of methyl p-tolyl sulfone. Through the use of both transformations as key steps, enantiocontrolled syntheses of different natural products-such as the two enantiomers of dihydroepiepoformin, (-)-gabosine O, (+)-epiepoformin, (-)-theobroxide and (+)-4-epigabosine A (an epimer of the natural product gabosine A)-has been achieved. The presence of the beta-hydroxy sulfone moiety makes the cyclic structures rigid, allowing a number of stereoselective transformations such as carbonyl reductions, enone epoxidations or cis-dihydroxylations, en route to the natural structures. The observed selectivities were dependent on the particular substitution in each substrate, providing evidence of a strong influence of remote groups on the preferred approach of the reactants to the reactive conformations. An advanced precursor of natural (+)-harveynone was also synthesized, but the isolation of the natural product was not possible because of the instability of the corresponding enone, containing a triple bond, under the basic conditions necessary to eliminate the beta-hydroxy sulfone. This demonstrated that the limitations of the use of the beta-hydroxy sulfoxide as a chiral protecting carbonyl group were dependent on the relative stabilities of the final targets in the presence of the required base.