Inner- and outer-sphere cross-coupling of high Fsp3 fragments

Natural products research derives from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful, strategic, and creative problem solving. Often this means bold and unprecedented disconnections that would simplify access, 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 methodological solutions to the syntheses of natural 1 products—(–)-eugenial C, Galbulimima alkaloids GB18, GB22, GB13, and himgaline— featuring new, convergent disconnections as important problem-solving 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 stereo- and 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 (i.e. inner-sphere steps), instead engaging metal ligands (i.e. outer-sphere steps). Optimized access to bioactive natural product space led to an accelerated timeline of biological characterization, fulfilling a common promise of natural products research. The integration of complex natural product synthesis, diversification and bioassay into a single PhD dissertation would have been unmanageable in a prior era. The unique ability of first row transition metals to effect Csp3- Csp3 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.