Novel Chemoselectivity and Stereochemical Aspects of Nickel-Catalyzed [2 + 2 + 2] Cycloadditions

Metal-catalyzed cyclotrimerizations are well-precedented with a range of substrate classes and with a variety of metal catalysts.1,2 Features that are shared by nearly all variants include a high propensity for the incorporation of alkynes over alkenes and a high degree of stereospecificity in cases in which alkenes are incorporated. While investigating the role of organozinc structure in determining selectivities between reductive and alkylative pathways in nickel-catalyzed cyclizations of alkynyl enones,3,4 we found that an unexpected dimerization involving a formal [2 + 2 + 2] cycloaddition process was observed as a side reaction in some instances. A control experiment demonstrated that the organozinc component was not required for the [2 + 2 + 2] cycloaddition to occur, and that nearly quantitative yields of the [2 + 2 + 2] product were obtained upon exposure of alkynyl enones to Ni(COD)2 and PPh3 (Table 1). In addition to the inherent interest in a reaction that assembles two rings and four contiguous stereocenters in a completely stereoselective fashion from an acyclic, achiral substrate, several additional features were perhaps even more intriguing. First, the reaction chemoselectivity was quite unusual. The formal dimerization by a [2 + 2 + 2] reaction of an alkynyl enone requires that three unsaturated groups are incorporated while one is left unchanged, and an alkyne is the one functional group that does not participate in the cyclization. This chemoselectivity was confirmed to be quite general since treatment of alkynyl enone (E)-1 with Ni(COD)2 in the presence of 5 equiv of a variety of internal and terminal alkynes all led to efficient formation of dimer 4 without incorporation of the simple alkyne. For the alkyne unit to remain unaffected during this process goes against all expectations based on earlier investigations of related processes.5 This general trend was particularly well demonstrated in the early cobalt-catalyzed cyclotrimerizations of Vollhardt,2 and numerous related observations have been reported.6-10 The structurally distinct case of the nickel-catalyzed homo-Diels-Alder reaction of norbornadienes largely explored by Lautens is a rare example in which multiple alkene units are selectively incorporated in a metal-catalyzed [2 + 2 + 2] cycloaddition process.11 A second intriguing feature is that the initial trans stereochemistry of the starting enone (E)-1 was cleanly inverted in product 4 at the position adjacent to the ring juncture. This unexpected stereochemistry was confirmed by single-crystal X-ray analysis.12 Metal-catalyzed cycloadditions typically display high stereospecificities with alkene stereochemistry being maintained during the process. This issue has been well demonstrated in several related contexts.13-15 In a study of palladium-catalyzed [2 + 2 + 2] cycloadditions involving enyne additions to alkynes, Trost demonstrated that Z enynes underwent completely stereospecific couplings, whereas E enynes displayed moderate stereospecificity.13 In a study of nickel-catalyzed [4 + 2] cycloadditions, Wender demonstrated that both E,E-dienes and E,Z-dienes added to alkynes in a completely stereospecific fashion.14 However, we observed that treatment of enone (Z)-1 to the dimerization conditions led to the same single stereoisomer as that seen in the dimerization of enone (E)-1 (eq 1). Recovered starting material