Research Projects

Tertiary alcohols are useful functional motifs present in various natural products and pharmaceutically active molecules. For the generation of tert-alcohols, traditionally, organic chemists mostly rely on the 2e- approach, where strongly nucleophilic organometallic reagents like R-MgX and R-Li are added to the carbon-based electrophiles. Despite the robustness of this protocol, many natural product syntheses require multiple steps involving protection-deprotection phenomena that make the overall synthesis cumbersome. Retrosynthetically, one can envision a umpolung 1e- approach where a ketyl radical (generated from ketone via reduction) will act as a nucleophile and can combine with an olefin to produce a tert-hydroxyl motif. Olefin functionalization is a compelling and constantly growing strategy in organic synthesis due to its potential to construct complex molecular architecture starting from simple, abundant feedstock chemicals. Transition metal-catalyzed cross-coupling reactions have emerged as an essential tool for olefin functionalization. However, stereoselective di-functionalization remained underdeveloped due to the associated reactivity and selectivity challenges. Our current goal is to develop an olefin difunctionalization protocol for accessing complex tert-hydroxyl architecture via the stereoselective addition of two different classes of electrophiles across an olefin. To affect this transformation, we envision the use of a nickel catalyst because of its slower rate of -H elimination and its unique ability to operate through both one-electron and two-electron processes in the presence of a terminal reductant under mild reaction conditions. During this process, a stereospecific C–[Ni] bond will be generated, which could be intercepted with different carbon and heteroatom-based electrophiles, expanding the chemical space further. Several dearomatization protocols and intramolecular variants leading to the spirocycles could also be generated via this protocol. To probe the mechanistic details of the reaction, e.g., identification of the rate-determining step and exact nature of the nickel species involved, several control experiments and kinetic profiling could be performed. A thorough understanding of the catalytic cycle could enable the use of alternative metal catalysts. Next, a formidable task would be to render this process enantioselective, which could be achieved by designing a new class of chiral ligands as well as performing a thorough screening of the existing library to access the enantioenriched products containing three consecutive stereogenic centers in a single operation. This envisioned strategy would foster the smoother and short-route enantioselective synthesis of various bioactive molecules relevant to pharmaceutical and agrochemicals, previously either non-accessible or achieved by low-yielding long synthetic sequences.