Inner- and Outer-Sphere Cross-Coupling of High Fsp3 Fragments.

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 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. 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 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.

Iron-Catalyzed Hydrobenzylation: Stereoselective Synthesis of (-)-Eugenial C.

Metal-hydride hydrogen atom transfer (MHAT) has emerged as a useful tool to form quaternary carbons from alkenes via hydrofunctionalization. Methods to date that cross-couple alkenes with sp3 partners rely on heterobimetallic catalysis to merge the two cycles. Here, we report an iron-only cross-coupling via putative MHAT/SH2 steps that solves a key stereochemical problem in the synthesis of meroterpenoid eugenial C and obviates the need for nickel. The concise synthesis benefits from a conformationally locked o,o'-disubstituted benzyl bromide and a locally sourced chiral pool terpene coupling partner.

Catalytic hydrogen atom transfer to alkenes: a roadmap for metal hydrides and radicals.

Hydrogen atom transfer from a metal hydride (MHAT) has emerged as a powerful, if puzzling, technique in chemical synthesis. In catalytic MHAT reactions, earth-abundant metal complexes generate stabilized and unstabilized carbon-centered radicals from alkenes of various substitution patterns with robust chemoselectivity. This perspective combines organic and inorganic perspectives to outline challenges and opportunities, and to propose working models to assist further developments. We attempt to demystify the putative intermediates, the basic elementary steps, and the energetic implications, especially for cage pair formation, collapse and separation. Distinctions between catalysts with strong-field (SF) and weak-field (WF) ligand environments may explain some differences in reactivity and selectivity, and provide an organizing principle for kinetics that transcends the typical thermodynamic analysis. This blueprint should aid practitioners who hope to enter and expand this exciting area of chemistry.

Functionalized Helical ß-Peptoids.

Peptidomimetic foldamers adopting well-defined three-dimensional structures while being stable toward proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science. Despite their backbone flexibility, ß-peptoids containing N-( S)-1-(1-naphthyl)ethyl ( Ns1npe) side chains can fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups onto robustly folded ß-peptoid helices by construction and incorporation of novel chiral building blocks. This is the first example of an X-ray crystal structure of a linear ß-peptoid containing more than one type of side chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side chains protruding perpendicular to the helical axis to provide a highly predictable display of functional groups. This work paves the way for development of ß-peptoid foldamers with a desired function, such as catalytic properties or as scaffolds enabling polyvalent display.