DIASTEREOSELECTIVE ADDITION OF H-PHOSPHINATES TO ALKENYL KETONES UNDER PHASE-TRANSFER CONDITIONS AND SYNTHESIS OF BRIDGED BICYCLIC COMPOUNDS FOR BIOLOGICAL EVALUATION

In the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer chemistry leading to phosphinate compounds. In this method, phosphinate nucleophiles were added to various alkenyl ketones as Michael acceptors using crown ethers as phase transfer agents to obtain highly diastereoselective products with the generation of a carbon-based quaternary centers. A closed transition state mechanism is proposed to describe the diastereoselectivity observed in the reactions that is consistent with product outcome as established by X-ray crystallography. Analysis using the 31P NMR technique is also reported to ascertain the diastereomeric ratios in product formation. Using products obtained with the newly developed method, we disclose for the first time a novel phospha-heterocycle with high control of stereochemistry. Relative stereochemistry of the phosphorus containing heterocycle was reported using 2D NMR analysis. In Chapter two focus is placed on the use of acrylates as Michael acceptors in both the diastereoselective and enantioselective studies of phospha-Michael addition. In the asymmetric method development, screening of various chiral catalysts and development of HPLC method to quantify the enantiopurity of products obtained under reaction conditions are reported. The role of crown ether catalysts towards diastereoselectivity is reported.