Although biomimetic approaches have proven capable of converting resveratrol (1) concurrently into many of the more complex oligomers produced by plants throughout the world (such as 2-10), methods to access single members of the family have proven far more difficult to identify. Herein is described a strategy-level solution based on the use of a common building block, one distinct from Nature's starting material, that can participate in a variety of highly selective, reagent-controlled reaction cascades. These endeavors have led to the controlled synthesis of 25 natural products and analogues, molecules whose architectures encompass nearly all the carbogenic diversity of the resveratrol family.

The power of the Diels-Alder reaction was expanded recently through the discovery by Li and Danishefsky that cyclobutenone is an unusually reactive dienophile; importantly, the adducts can be converted to products that are formally the Diels-Alder adducts of unreactive dienophiles.[1] We have determined the origin of the special reactivity of cyclobutenone and quantitate the origins of the unusually high reactivity of strained enones. Cyclopropenones, the DielsAlder reactions of which were studied earlier by Breslow and co-workers, [2] are also highly reactive dienophiles. We show that the ease of out-of-plane distortion of strained cycloalkenones contributes to their high reactivity.Ross and Danishefsky have compared the reactivity of four-, five-, and six-membered cycloalkenones with cyclopentadiene and other dienes.[3] New experimental results (see the Supporting Information) are summarized in Scheme 1.The reactivities of different dienes with cyclobutenone have been measured as well. Scheme 2 gives results of standard reaction conditions. Experimental details for these and other conditions are given in the Supporting Information.The reactions of pent-3-en-2-one, cyclohex-2-enone, cyclopent-2-enone, cyclobutenone, and cyclopropenone with three cyclic dienes have been explored with M06-2X, a density functional that we have shown to give relatively accurate activation and reaction energies for cycloadditions. [4] B3LYP and CBS-QB3, [5] a high-accuracy composite method, were also used (see the Supporting Information for a full comparison) and gave the same trends as discussed here. [6] Herein, we interpret the activation barriers of these reactions by using the distortion/interaction model [7] (or activation strain model).[8] This model relates the activation energy to the energy required for the geometrical deformation to achieve the transition structure, and to the favorable interactions between the two distorted reactants. Figure 1 shows the transition structures for reactions of cyclopentadiene with these dienophiles. The endo transition states are favored, except with cyclopropenone. The predicted relative rates are given below each structure. Cyclobutenone and cyclopropenone are 1000 to 100 000 times more reactive than cyclohexenone at room temperature. [9] These reactions are asynchronous concerted processes, except that of the symmetrical cyclopropenone. Cyclohexenone and cyclopentenone have high activation barriers and low predicted rate constants, approximately like those of the acyclic analogue. By contrast, cyclobutenone has a considerably lower activation barrier and, accordingly, higher rate constants for reaction. Cyclopropenone is predicted to be even more reactive. [*] Dr.

Intramolecular Diels–Alder (IMDA) reactions of cyclobutenone and larger cycloalkenones are described. High levels of endo addition attained from Lewis acid catalysis translate to trans hydrindene junctions upon fragmentation of the tricyclic adducts.

Halocycloalkenones are demonstrated to function as potent dienophiles in inter- and intramolecular Diels-Alder cycloadditions. We have found 2-brominated cycloalkenone dienophiles to be both highly endo selective and significantly more reactive than their non-halogenated parent compounds. A method for the facile conversion of brominated cyclobutanone DA adducts to synthetically useful cyclopropyl functional handles is described.

A polycyclic collapse: Use of a carefully designed acyclic intermediate provided the means to execute a cascade-based construction which formed the entire core of the polyketide-derived dalesconols in a single flask. A number of additional and carefully controlled synthetic operations completed an expeditious synthesis of both of these highly bioactive natural products as well as structural congenors.