Development of Aryl Siloxane Cross- Coupling Technology and Its Application to the Synthesis of Colchicine and Allocolchicine Derivatives

Title of Dissertation: DEVELOPMENT OF ARYL SILOXANE CROSSCOUPLING TECHNOLOGY AND ITS APPLICATION TO THE SYNTHESIS OF COLCHICINE AND ALLOCOLCHICINE DERIVATIVES William Michael Seganish, Doctor of Philosophy, 2005 Dissertation directed by: Professor Philip DeShong Department of Chemistry and Biochemistry One of the most versatile methods for the formation of aryl-aryl bonds is the palladium-catalyzed cross-coupling reaction. Previous work in the DeShong laboratory has demonstrated the utility of aryl siloxanes for the palladium-catalyzed cross-coupling of aryl iodides, bromides, and chlorides, as well as new synthetic methods for the formation of aryl siloxanes. The work reported herein details (1) the synthesis of aryl siloxanes using ortho-metallation techniques (2) the coupling of aryl bis(catechol) silicates with aryl triflates, and (3) the application of aryl siloxane coupling technology to the synthesis of colchicine and allocolchicine derivatives. The synthesis of aryl siloxanes had previously been performed using either metal-halogen exchange, or transition metal-catalyzed silylation. These techniques necessitate the use of an aryl halide as the starting material. The application of orthometallation conditions avoids this requirement and allows for the synthesis of siloxanes directly from the unfunctionalized arene. Using this approach, ortho-ether and carbamate siloxanes were prepared in good yields, however, o-benzamide siloxanes could not be prepared using this method. The coupling of aryl triflates with aryl siloxanes had previously proven problematic due to competitive hydrolysis of the triflate. The use of aryl bis(catechol) silicates as siloxane surrogates facilitated the coupling of aryl triflates and iodides bearing a range of functional groups in excellent yield. Additionally, aryl bromides could be successfully coupled by switching from conventional heating to microwave irradiation. The use of aryl siloxanes in the synthesis of the natural products colchicine and allocolchine was explored. It was found that the carbocyclic framework of colchicine could be constructed using an aryl siloxane coupling reaction; however, the reaction required the use of a stoichiometric amount of the palladium “catalyst.” This amount of catalyst was required because of the competition between a slow oxidative addition step, and a fast protodesilylation pathway that lead to the decomposition of the siloxane. The synthesis of the allocolchicine carbocyclic framework was successful utilizing a siloxane coupling reaction, and a phenanthrol ring expansion protocol as the key steps. DEVELOPEMENT OF ARYL SILOXANE CROSS-COUPLING TECHNOLOGY AND ITS APPLICATION TO THE SYTHESIS OF COLCHICINE AND ALLOCOLCHICINE DERIVATIVES By William Michael Seganish Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, College Park in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2005