Organocatalytic methods that efficiently transform simple racemic mixtures into complex enantioenriched products are critical components of modern organic synthesis but remain scarce. Stereodivergent processes with racemic substrates represent an underutilized strategy toward enantioenriched products, whereby each enantiomer of the starting material reacts with a catalytically generated intermediate activated by a single chiral catalyst to furnish separable, non-enantiomeric products. Furthermore, the paucity of synthetic strategies that expeditiously access fully separable stereoisomeric complement of a given complex scaffold is crucial for natural product-inspired diversity-oriented synthesis to drug discovery. Although many examples of stereodivergent reactions catalyzed by enzymes are known, cases with small-molecule organocatalysts are uncommon. Herein, we describe the first organocatalytic stereodivergent Diels-Alder-Lactonization cascade that converts simple racemic dienes into diverse complex polycyclic ?-lactones in a single operation guided by unusual chiral dienophiles, in situ generated a,�-unsaturated acylammoniums derived from commodity acid chlorides and a readily accessible chiral isothiourea catalyst. This simple and efficient methodology enables the construction of two C-C bonds, one C-O bond, two rings, and up to five contiguous stereogenic centers delivering complex fused, polycyclic ?-lactones with high levels of diastereo- and enantiocontrol. Given the prevalence of fused polycyclic ?-lactones in naturally occurring and biologically active terpenoids and pharmaceutical agents, we envisage that the described method will offer rapid diverse synthetic entry to these intriguing structural motifs.

Unusual class of chiral dienophiles guiding stereodivergent Diels-Alder-mediated organocascades

247th National Meeting (2014)

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