Natural Product Synthesis via [2+2+2] Cyclotrimerization Reactions

Abstract

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. Here we explore the development of [2+2+2] cyclotrimerization reactions towards benzene derivatives applicable to the regioselective synthesis of indanone, isoquinoline, anthraquinone, cannabinoid, and neolignan based natural products. In addition, the development of [2+2+2] cyclotrimerization reactions towards pyridine derivatives applicable to the synthesis of the Streptomyces antitumor natural products streptonigrin and lavendamycin and several Lycopodium alkaloids has been explored. Optimization of the key cyclotrimerization events involved investigation of the alkyne (diyne or monoyne) and nitrile substitution pattern, the catalyst system employed, and conventional heating versus microwave irradiation.