Pyridine-containing macrocycles via cobalt-mediated [2+2+2] cycloadditions of alpha,omega-bis-alkynes

We have been investigating the formation of macrocycles from alpha,omega-diynes in Co(I)-mediated co-cyclotrimerization reactions. In these metal-mediated [2 + 2 + 2] cycloadditions, long-chain alpha,omega-diynes were reacted with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)(2) (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, in the form of meta- and para-pyridinophanes (e.g., 5m/5p, 35m/35p, 41m/41p). The regioselectivity of these reactions was influenced by the length and type of linker unit between the alkyne groups, as well as by stereoelectronic factors. We developed an improved reaction protocol for these Co(I)-promoted [2 + 2 + 2] cycloadditions that offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield, at ca. 100 degrees C in 24 h, without photo-irradiation or syringe-pump addition. With this improved protocol, we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to effect a macrocyclic variant of the Vollhardt reaction (e.g., 6 + Pr-C=C-Pr --> 56p). We used our improved [2 + 2 + 2] cycloaddition method to synthesize some macrocyclic bis-indolemaleimides as potential protein kinase inhibitors. Thus, we prepared multiheterophanes 63p, 63m, and 64p and determined that they are potent, selective inhibitors of glycogen synthase kinase-3 beta (GSK- 3 beta).