| The transition metal mediated [2+2+2] cyclotrimerization reaction of alkynes is a highly convergent approach to the synthesis of polysubstituted carbo- and heterocyclic aromatic ring systems. However, few examples of the application of cyclotrimerization reactions in natural product synthesis have been reported. In order to supplement the understanding of various aspects of the cyclotrimerization chemistry such as reactivity, regioselectivity, and chemoselectivity of advanced diyne intermediates, we explored the development of the [2+2+2] cyclotrimerization reaction towards benzene and pyridine derivatives as well as its application to the total synthesis of natural products.;As an approach to solve the chemoselectivity issues associated with the cyclotrimerization reaction, a solid supported cyclotrimerization reaction was utilized as the key step in the regioselective synthesis of an indanone natural product in only 11 steps. The development of microwave assisted nickel catalyzed cyclotrimerization reactions allowed for the rapid synthesis of fused benzene ring systems and led to the total synthesis of the isoquinoline natural product illudinine in only eight steps. Several strategies towards the synthesis of anthraquinone and anthracycline natural products were investigated. The efficiency of these reactions was sensitive to both the electronic and steric properties of the investigated diynes. A novel approach to the tricyclic cannabinoid ring structure via the cyclotrimerization reaction was developed and led to the total synthesis of three cannabinoid natural products all in >20% overall yield. Furthermore, easy access to cannabinoid analogues is possible with this strategy. Initial investigations into the synthesis of four neolignan natural products from a common precursor were accomplished. The cyclotrimerization reaction successfully provided the core structures; however, subsequent steps to yield the natural products are needed.;With respect to pyridine derivatives, the syntheses of the Streptomyces anticancer natural products streptonigrin and lavendamycin were explored. Several model routes, including the use of ynamides, were initiated to access the core structures, and further examination into the substitution of the diynes is necessary to realize the total synthesis of these two natural products. Attempts to synthesize two lycopodium alkaloids, lycopladine A and lycodine, via the cyclotrimerization reaction of alkyne-nitriles have been studied. However, access to the requisite alkyne-nitriles for the cyclotrimerization reaction has been problematic. |
