Chemists can now insert and remove individual atoms from the core of a molecule.

For organic chemists, the ability to swap atoms within a molecular scaffold holds intrinsic appeal. Richmond Sarpong of the University of California, Berkeley—a leading figure in the field of skeleton editing—says: “These transformations are now possible—it’s like magic.” Yet this capability also serves a highly practical purpose. Drug discovery begins with identifying promising molecules, followed by preparing hundreds of slightly modified variants to improve efficacy or reduce toxicity. Altering substituent groups on the periphery of a molecule is relatively straightforward for generating such variants. Editing the core, however, typically requires de novo synthesis—building the modified scaffold entirely from scratch. This is both costly and time-consuming, and in practice severely limits the structural diversity that pharmaceutical companies can screen and test. Reliable skeleton editing could dramatically accelerate this process. Currently, many such methods apply only to specific molecules or operate inefficiently during editing. Researchers are excited about this emerging field but remain cautious about overhyping it. Nevertheless, chemists at pharmaceutical companies—including Pfizer and Merck—are already testing various skeleton-editing reactions. David Blakemore, Head of Synthetic Chemistry, Inflammation, Immunology, and Anti-Infectives at Pfizer, states: “We recognize this could be a transformative approach. It’s still early days, but I believe we’re not far from being able to deploy some of these methods.” To the layperson, organic chemistry appears as an incomprehensible parade of pictographic symbols—zigzags and hexagons whirling across the page. Yet these diagrams constitute a visual vocabulary rich in information about the molecules they represent. Each vertex in the drawing stands for a carbon atom (accompanied by implicit hydrogen atoms), and the lines between them represent chemical bonds. Additionally, letters denoting atoms such as oxygen, nitrogen, or sulfur are scattered throughout the scaffold and periphery. When chemists aim to synthesize a specific molecule, they first sketch its structure in this manner. Then, working backward, they systematically cleave bonds that can be reliably formed via known reactions—breaking the diagram into smaller fragments that can either be purchased from chemical suppliers or synthesized de novo. Adding reliable skeleton-editing reactions to chemists’ toolkits introduces an entirely new set of bond-cleavage strategies, enabling more efficient synthesis and access to previously inaccessible compounds. Junqi Li, an organic chemist at Iowa State University, remarks: “This represents a fundamentally different paradigm shift from how we’ve traditionally viewed synthesis.” The potential rewards are immense. Novel chemical reactions for synthesizing molecules have already revolutionized drug discovery. The 2005 Nobel Prize in Chemistry was awarded in part to researchers who, in the 1990s, developed highly efficient catalysts for olefin metathesis—the reaction that welds carbon–carbon double bonds together. This transformation proved essential for constructing large macrocyclic structures found in hepatitis C drugs. The 2010 Nobel Prize in Chemistry honored researchers who, in the 1960s and 1970s, developed palladium-catalyzed cross-coupling reactions—a powerful method for forging carbon–carbon bonds in drug molecules.

Nanjing University, Science! Nitrogen-atom insertion via skeleton editing.

In medicinal chemistry, six-membered rings containing five carbon atoms and one nitrogen atom (e.g., piperidines) are extremely common; by contrast, analogous six-membered rings bearing two adjacent nitrogen atoms and four carbon atoms—though highly attractive—rarely appear in drug discovery programs. This disparity likely stems from synthetic challenges associated with introducing an additional nitrogen atom. Recently, two research teams have reported complementary synthetic strategies: the Puriņš group employed a photochemical approach to cleave six-membered pyridine rings, inserting nitrogen while expelling a carbon atom; the Li group started from five-membered pyrrolidines and introduced nitrogen via ring-expansion. Background Single-atom skeleton editing is a transformative strategy accelerating the reconstruction of molecular frameworks—especially cyclic scaffolds—without requiring de novo synthesis. By enabling atomic-level modifications of existing structures, this approach significantly simplifies retrosynthetic analysis, reduces synthetic burden, and unlocks chemical space inaccessible via conventional methods—particularly valuable for late-stage functionalization. Given the ubiquity of nitrogen-containing heterocycles in biologically active molecules, nitrogen insertion into saturated ring systems represents an efficient yet underexplored strategy for scaffold hopping in drug discovery. Research Objective This study reports a skeleton-editing method that directly inserts a nitrogen atom into pyrrolidine rings under mild, operationally simple conditions using readily available O-diphenylphosphinylhydroxylamine, converting them into tetrahydropyridazine scaffolds. The method exhibits broad substrate scope and excellent functional-group tolerance, enabling late-stage editing of complex molecules. Furthermore, simple redox modulation allows conversion of the tetrahydropyridazine products into either saturated piperazine scaffolds or aromatized diazine structures—nitrogen-rich frameworks of high value in medicinal chemistry yet notoriously difficult to synthesize. This work establishes a general platform for nitrogen-atom skeleton editing of pyrrolidines, enriching the synthetic toolbox of medicinal chemistry. Key Points: 1. Nitrogen-containing heterocycles (N-heterocycles) are among the most advantageous and versatile scaffolds in medicinal chemistry, playing critical roles in modulating molecular recognition, pharmacokinetics, and physicochemical properties. Between 1938 and 2013, 59% of small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) contained at least one N-heterocycle; this proportion rose to 82% between 2013 and 2023, with over half of newly approved drugs featuring multiple nitrogen heterocycles (Figure 1A). Among these, six-membered pyridine and piperidine rings, five-membered pyrrolidines, and diazine-containing scaffolds such as piperazines and pyrimidines are most prevalent. Given their widespread occurrence and structural diversity, developing direct editing strategies for N-heterocycles holds both fundamental scientific value and practical significance. In this context, atom-level skeleton editing of N-heterocycles offers an innovative route to novel N-heterocyclic architectures. Such methods become especially attractive if they enable rapid construction of target molecules from naturally scarce yet pharmaceutically valuable scaffolds. 2. Among single-atom skeleton-editing strategies, nitrogen-atom (N-atom) insertion has emerged as a particularly important tool due to its profound influence on molecular stability, polarity, and biological activity. Recent studies have demonstrated the feasibility of N-atom insertion into N-heteroaromatic systems: the Morandi, Ackermann, and Sharma groups independently achieved late-stage conversion of indoles to quinolines using nitrene intermediates; meanwhile, the Ghiazza and Zheng groups developed a photocatalytic editing strategy—converting pyridines to diazepines—via aminopyridinium salts (Figure 1B).

New 'Mousane' Scaffold Enters Medicinal Chemist’s Toolbox

Oct 16, 2026

A new hydrocarbon scaffold named mousane has been developed to add rigidity to drug candidates, potentially improving their properties. The research, published as a preprint, was led by teams from Bristol Myers Squibb and Harvard University.

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New 'Mousane' Scaffold Enters Medicinal Chemist’s Toolbox