Free radical cyclizations onto -C=N-R acceptors: Kinetics and synthetic applications and synthesis of taxoid mimics.

Abstract

The kinetics for the 5-exo cyclizations of secondary alkyl radicals onto various imine acceptors (alkyl-, aryl-, benzoylhydrazones, oxime ethers, etc) have been determined. The preparation of a series of halo C=N containing "bis imine" systems (182 a--i ) for use in kinetic studies has been described. The rate constants have been established by competitive "internal radical clock" type cyclizations on the basis of the known rate constants for alkene and N,N-diphenylhydrazone systems. In refluxing benzene the rate constants for these 5-exo cyclizations fall within the range of 4 x 107 to 16 x 107 s-1 depending on the electron withdrawing capacity of the imine acceptor. These rate constants are approximately 200 times faster than those for the corresponding 5-exo cyclizations onto alkenes. The fastest rate constants were observed for the N,N-diphenylhydrazones and N-benzoylhydrazones. N,N-Diphenylhydrazones were further employed in the formation of nitrogen containing bicyclic systems via tandem radical cyclizations. Tandem products were obtained for 5,5- and 6,5-bicyclic systems. Attempted synthesis of 5,6- and 6,6-bicyclic systems via tandem cyclizations resulted only in the formation of monocylized products 284 and 285 respectively. A new chiral auxiliary 327 was synthesized for use in the study of asymmetric induction in radical cyclizations in the presence of chiral auxiliaries in systems such as 328b. In search of "taxoid mimics" with less functionality and better therapeutic profile as compared to the anti cancer drug "Taxol", small taxol like compounds 350 and 351 were synthesized and their biological activity was evaluated.