Organic Pseudometals to Sustain and Transform Small-Molecule Drug Synthesis

Transition metals are elements with unique reactivity that have changed the trajectory and success rate of small-molecule drug discovery and manufacturing over the past decades. A quarter of the top 20 most used reactions in medicinal chemistry are catalyzed by noble metals, and the majority of the top 200 selling small- molecule drugs now contain either a biaryl or arylamine linkage (motifs easily accessible by Pd-catalyzed cross- coupling). The dependence of medicine on transition metals is alarming, as most of the important metals are toxic, expensive, environmentally damaging, and, most importantly, increasingly scarce, with several facing effective extinction in the next century. Accordingly, there has been an urgent need to discover strategies to force other more available and benign elements to substitute for transition metals in these essential chemical processes. As an alternative, we ask whether, rather than using a single element, we might use entire organic molecules (or fragments) as oversized surrogates for metals (“pseudometals”). First, we aim to show that organic, metal-free catalysts can be capable of performing processes traditionally considered only possible with transition metals, with special emphasis on oxidative addition and reductive elimination. We will then assemble these elementary steps into catalytic mechanisms to achieve mimicry of cross-couplings, the most important class of metal-catalyzed reactions in drug discovery. Second, we will extend the pseudometal concept from mimicry to unprecedented reactivity, realizing metal-like transformations that are impossible with conventional, periodic-table metals. These new cross-couplings will enable access to desirable chemical space for accelerated drug discovery and more rapid construction of bioactive small-molecule agents. Finally, in a parallel direction, we will investigate the combination of electrochemistry with rationally tailored redox-active organic molecules to generate very weak X–H bonds akin to first-row metal hydrides, with the goal of functionalizing ubiquitous alkenes and alkynes through a biologically-inspired hydrogen-atom transfer process. This research goal will establish the potential of organic pseudometals to cover the whole range of transition-metal reactivity and beyond, providing a roadmap for the design of efficient and enabling catalytic transformations to sustain biomedical research in a transition-metal-free future. Project Number: 1DP2GM164340-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Richard Liu | Institution: HARVARD UNIVERSITY, CAMBRIDGE, MA | Award Amount: $1,516,500 | Activity Code: DP2 | Study Section: Special Emphasis Panel[ZRG1 IIDB-Q (71)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11172015