Stereoselective Annulation Reactions for the Asymmetric Synthesis of Tricyclic Guanidine Natural Products and Related Polycyclic Alkaloids.

Abstract

Natural products and molecules derived from natural products have historically been one of the primary sources of new pharmaceuticals including antibiotics, antimalarials and anticancer drugs. However, many natural products cannot be isolated in sufficient quantities for commercialization due to insufficient natural resources, elevated costs of extractions and/or environmental factors; thus, pharmaceutical companies attempt to synthetically generate these compounds on scales large enough in order to serve the public. Tricyclic guanidine alkaloids are a class of natural products that exhibit a wide range of interesting biological properties including anti-HIV, antibacterial and anti-tumor activity but face practical isolation challenges. Unfortunately, current methods for the synthesis of these molecules suffer from an inability to provide access to stereochemically different cores and fail to facilitate the synthesis of analogs in a straightforward manner. To address these limitations, the research outlined in this thesis focused on the development of annulation strategies that can be utilized for the synthesis of polycyclic guanidines of any given stereochemical configuration and that are amenable to rapid analog construction. In all, this dissertation describes the synthesis of tricyclic guanidine natural products and structurally related alkaloids from bicyclic ureas and sulfamides that were prepared in a concise and stereocontrolled manner via Pd-catalyzed carboamination reactions. Chapters 2 and 3 of this dissertation detail the development of Pd-catalyzed carboamination reactions that are believed to proceed via syn-aminopalladation. This chemistry was utilized to accomplish the first total synthesis of (+)-merobatzelladine B. Additionally, an asymmetric variant of this methodology allows for the construction of bicyclic ureas via the desymmetrization of meso-pyrrolidinyl ureas, in good yields, diastereo- and enantioselectivities. The utility of the desymmetrization methodology was demonstrated by transforming one of the bicyclic urea products into 9-epi-batzelladine K. In an effort to synthesize the natural stereoisomer of batzelladine K, Pd-catalyzed carboamination reactions that are believed to proceed via anti-aminopalladation were explored. The optimization of this chemistry, along with the scope and limitations of the methodology, is described in chapter 4. Lastly, the final chapter of this dissertation details the application of the carboamination methodology developed in chapters 2-4 towards the total synthesis of the tetraponerine alkaloids.