Direct arylation of vinyl halides and triflates and synthesis of Liver X receptor ligands.

摘要

Palladium-catalyzed arylation has been established as a good route for the synthesis of aryl-aryl bonds; however the use of vinylic halides and pseudohalides has not been explored much. Studying an intramolecular version of direct arylation of vinylic halides and triflates would provide access to carbo- and heterocycles with endocyclic double bonds, which are not readily obtained via the traditional Heck reaction.;We developed an efficient procedure for cyclization of vinyl triflate to afford five-membered carbocycles with an endocyclic double bond. During the course of this work several significant variations in the reaction yield have been observed. Investigating the cause of these variations, the addition of water or cesium pivalate slows reaction rate and prevents catalyst decomposition thus affording higher yields.;Expanding upon the derived model system, attention turned to synthesis of six-membered heterocyclic systems through the implementation of palladium-catalyzed direct arylation. Optimization of the model system for the synthesis of 1,2-dihydrochromenes using vinyl bromides has been completed.;The Liver X receptor regulates transcription of genes involved in the efflux of cholesterol and the synthesis of triglycerides. The binding of small molecule ligands to the Liver X receptor is required for this activity. We are synthesizing a library of ligands based on a trisubstituted alkene scaffold. The ligands are assembled in modular fashion using various bromoallylic alcohols as core scaffolds. While investigating the synthesis of the (Z)-3-bromoallylic alcohol core scaffold an interesting side product, the (Z)-3-bromoacrolein was isolated and the reaction conditions were optimized to synthesize this compound as an additional scaffold. Once optimized the reaction was applied to the synthesis of different type A and B ligands. These ligands will be used to determine the binding activities within the four binding pockets of the LXR receptor. Currently, there is investigation into the synthesis of other bromoallylic alcohol scaffolds, such as (Z)-2-bromoallylic systems, which can be made through hydrostannylation.