Inner- and Outer-Sphere Cross-Coupling of High F_sp3 Fragments

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Natural product research originates from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful and creative problem solving. Often this means bold disconnections that would simplify access to complex structures, if only the methods existed to bridge these theoretical gaps. Whereas biological interrogations provide long-term intellectual value and impetus, methods come as attractive fringe benefits of natural product synthesis. This Account describes strategic, methodological solutions to the syntheses of natural products [(−)-eugenial C, Galbulimima alkaloids GB18, GB22, GB13, and himgaline] featuring new, convergent disconnections as important problemsolving steps, which themselves were inspired by recent methods that arose from our group. Each target required the invention of first-row transition metal-catalyzed cross-coupling procedures to satisfy the biological goals of the project. In these cases, synthetic strategy identified the methodological gap (the absence of stereoand chemoselective couplings of appropriate fragments), but the tactical advantage conferred by first-row metals met the challenge. These methods were competent to handle the dense, sterically encumbered motifs common to natural products due to, in many cases, elementary steps that did not require bond formation between the hindered substrate and the metal center. Instead, these sterically lenient reactions appeared to involve metal−ligand−substrate reactions (i.e., outer-sphere steps), in contrast to the metal− substrate, coordinative reactions of precious metals (i.e., inner-sphere steps). Key observations from our previous studies, combined with the observations in seminal publications from other laboratories (Mattay, Weix, and MacMillan), led to the optimization of ligand-controlled, stereoselective reactions and the introduction of complementary catalytic cycles that revealed new modes of reactivity and generated novel structural motifs. Optimized access to bioactive natural product space accelerated our timeline of biological characterization, fulfilling a common premise of natural products research. The integration of methodology, complex natural product synthesis, diversification, and bioassay into a single Ph.D. dissertation would have been unmanageable in a prior era.The unique ability of first-row transition metals to effect Csp 3 −Csp 3 cross-coupling with high chemo-and stereoselectivity has significantly lowered the barrier to reach the avowed goal of natural product synthesis and reduced the burden (real or perceived) of integrating natural products into functional campaigns.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling

“…A simple and predictable method to form quaternary C’s akin to classic N quaternization would be an appealing transformation. Our previous studies have demonstrated how radical methods can be leveraged to cross-couple olefins with other olefins or alkyl/aryl halides ( 6 , 7 ). In many cases, quaternary C synthesis can be achieved through such methods.…”

Metal-Hydride C–C Cross-Coupling of Alkenes Through a Double Outer-Sphere Mechanism

“…Both of these stoichiometric reactions have now given way to catalytic variants with higher chemoselectivity and broader functional group tolerance. Particularly important examples involve Markovnikov-selective hydrofunctionalizations that form quaternary carbons via merger of complex, high F sp 3 fragments . Such fragment couplings form the backdrop to this short Synopsis.…”