Cycloadditions with constrained dienes

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

The Cj - and 54-symmetric tetraesters of tricyclo[3.3.0.0 ]octane (430 and 431) have been prepared by oxidation of diene 429 To access the parent hydrocarbon (435), acid chloride 432 was transformed to the derived ketene which undergoes intramolecular [2+2] cycloaddition The resulting cyclobutanone (433) serves as precursor to perester 434 whose thermal decomposition proceeds with chain transfer in competition with cleavage The unique arrangement of the carbon atoms in 435 is such that the smallest rings are all five-membered. The highly symmetric structure may be viewed as a constrained cisoid bicyclo[3.3.0]octane (as well as the symbol of NATO). 

A (4 + 2) cycloaddition can take place between singlet oxygen and conjugated dienes that are free (or constrained) to adopt an s>c/s conformation (2.93). When such a reaction occurs with an aryl-conjugated alkene (2.94), the first-formed cycloadduct is itself a conjugated triene, and the overall reaction produces a bis-(4 + 2) adduct. 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

The Brummond research group also illustrated that the stereoselectivity of these reactions can be controlled by tethering the first dienophile to the dendralene [22, 23]. In one such example, ester 84 underwent an e do-selective intramolecular DA reaction to provide the tricyclic diene 85 (Scheme 12.17). In this reaction, the dienophile is constrained to the bottom face of the molecule, thus controlling the it-diastereofacial selectivity of the cycloaddition. Piperidine 85 was then subjected to an ewdo-selective intermolecular DA reaction with NPhM to provide the pentacycle 86 in excellent yield. 

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