Phosphate Tether-Mediated, One-Pot Metathesis Processes: Application in Small Molecule Synthesis.

摘要

The focus of this dissertation is to utilize the empowering ability of phosphate tethers to mediate a series of reactions towards the synthesis of bioactive molecules by exploiting several salient features inherent to organophosphates, including (i) orthogonal stability under acid conditions, (ii) possessing leaving group ability, (iii) multivalent activation of carbinol centers, (iv) protecting group attributes, and serving as a (v) temporary tether that can be removed under various conditions. Taken collectively, the reported bicyclo[4.3.1]phosphate (both enantiomers) undergoes several selective transformations to access polyol building blocks that are present in a number of bioactive natural products. Application of this method to the total synthesis of the pancreatic lipase inhibitor (--)-tetrahydrolipstatin (THL) is reported. THL is a currently marketed as an anti-obesity drug under the generic name OrlistatRTM. The concise approach to this molecule invokes cross-metathesis, chemoselective hydrogenation, regio- and diastereoselective cuprate addition and Mitsunobu esterification as key synthetic transformations. Additionally, a phosphorodiamidite coupling and one-pot, sequential RCM/CM/chemoselective hydrogenation sequence was developed to obtain the final molecule in 9 steps from dienediol. The reported versatile three-step, one-pot, sequential RCM/CM/chemoselective protocol in THL was further optimized to improve the overall and average yields. Both type I and type II olefins with varied electronics and functionalities participate in this one-pot reaction, where chemoselectivity is governed by stereoelectronic properties innate to phosphate tethers. This efficient method allows access to advanced polyol synthons present in several bioactive natural products. Furthermore, synthetic studies towards macrolactone core of marine natural product (+)-neopeltolide, following a phosphate tether methodology has revealed the stereochemical implications on the RCM of medium- sized ring systems. The planned route involves the installation of all the stereocenters by a single asymmetric reaction, the Noyori Hydrogenation, and potential to integrate other phosphate mediated one-pot processes.