Multicomponent reactions (MCRs) are highly atom-economic syntheses in which three or more substrates are combined to form product in one pot without isolating the intermediates. Compared to traditional sequential syntheses, MCRs quickly achieve complex molecules by multiple-bond formation while significantly reduce time of preparation, purification, as well as labor and cost. Despite their tremendous advantages, there are only a handful of multicomponent methods developed since its birth 100 years ago, and the number of asymmetric MCRs is much less. Utilizing the underexplored reactive a,�-unsaturated acylammonium intermediate, we set out to access 6,4-bicyclic �-lactones in a multi-component fashion. Such motif has been found in the natural products such as rubesanolide A, B, and papyriogenin G. We envisioned 6,4-bicyclic �-lactones system could be obtained from an unsaturated acylammonium formed in situ and a 1,5-dicarbonyl compound which could be easily accessed through a Michael addition between a �-ketoester and an activated alkene. To this end, a catalytic, enantioselective one-pot three-component reaction was carried out to quickly gain access to �-lactone 5  . During this process, an in situ generated Michael adduct (�)-4,  from �-ketoester 1  and 2-methylenemalonate 2,  underwent Michael-aldol-�-lactonization cascade to form 5,6,4-tricyclic �-lactone (+)-5  in 53% yield, dr>19:1 and 93%ee. With four contiguous stereocenters, diastereoselectivity of the reaction was remarkably controlled by the A1,3 and high ring strains associated with the fused trans-5,6-bicyclic system. Details of the work will be presented.

Rapid constructions of complex hetero [4.2.0]-bicyclic system via asymmetric multicomponent reaction

247th National Meeting (2014)

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