What is Editing?

Abstract

Published as part of Accounts of Chemical Research special issue “Skeletal and Stereochemical Editing”. Organic chemistry has an intimate connection with its applications, as synthesis remains the primary tool by which chemical space is navigated in the optimization of functional molecules. Medicinal chemists, for example, will prepare hundreds, if not thousands, of derivatives of promising lead compounds through iterative, parallel synthesis in order to identify the ideal compound to advance to the clinic. In the context of natural products, which have often proven to be valuable starting places for drug discovery, (1,2) the role of synthesis has been central, enabling the preparation of non-natural analogues inaccessible through semisynthesis by diverting from a totally synthetic route. This idea was eloquently captured by Danishefsky, who coined the term “molecular editing” to describe the synthesis of such analogues, essentially advocating for the application of medicinal chemistry principles even in targets as complex as epothilone B. (3) Szpilman and Carreira subsequently wrote an influential review which was responsible for the further proliferation of this coinage, bringing the original term into even broader circulation. (4) Recently, this term-of-art has taken on a very different valence─causing no small amount of confusion─because of a perspective shift in the role of chemical reactions in molecular optimization campaigns. (5−8) Parallel synthesis, though successful, has a fundamental mismatch with the underlying thought process that drives it, as even small changes to a target structure typically require de novo synthesis. This tension has brought on a simple question: can we develop chemical reactions that represent direct analogues to common design strategies? This new movement has also taken on the mantle of “molecular editing”, with distinct forms of optimization-mimicry developing into subfields in their own right: C–H functionalization, functional group interconversion, stereochemical modulation, and skeletal modification have all been encompassed under this redefined heading as flavors of editing, especially when such transformations can be conducted with specificity on complex, late-stage compounds or at nontraditional sites of reactivity. (9−11) A challenge in this vernacular is that, taken at face value, the term molecular editing is synonymous with chemical reaction. It should be clear to even the most cynical reader, however, that not all reactions should be called edits. The above history is instructive here: the reactions that hew closest to the editing ideal are those whose changes are interpretable from a structure–activity relationship perspective. The starting material and product should form a matched molecular pair that a chemist could test to learn something about the landscape of their optimization. (12) The more changes made at once, the further one moves from interpretability. That is, editing is ultimately about simplicity. (13) In this issue of Accounts of Chemical Research, cutting edge research that embodies this movement is surveyed across a wide range of chemical modalities, including transition metal catalysis (including contributions from Ning Jiao, Hao Wei, Xihe Bi, and Guangbin Dong), photochemistry (including contributions from David Sarlah, Frank Glorius, Alison Wendlandt, Ryan Gilmour, and Rob Knowles), and reagent development (including contributions from Hideki Yorimitsu, Manuel Alcarazo, Hongjian Lu, Armido Studer, and Ohyun Kwon). These methods have been applied from small molecules (including site-specific applications highlighted by Scott Miller) to total synthesis (including contributions from Mingji Dai and Richmond Sarpong) and polymers (including a contribution from Aleksandr Zhukovitskiy). Together, these approaches enable useful and often surprising transformations. We thank the authors of each of the contributions that are presented herein, which highlight many of the emerging thought processes that continue to shape this exciting and evolving direction for chemical synthesis research. We are also grateful to Associate Editor Prof. Abigail Doyle, Editor-in-Chief Prof. Christopher Chang, and the rest of the editorial team at Accounts of Chemical Research for proposing this timely special issue. This collection of exciting contributions makes clear that not only can reactions be devised that begin to mimic the creative process of navigating chemical space but that we are also at an inflection point for such methods; as this toolbox grows, the discovery campaigns of tomorrow will be empowered to reduce their vision to practice, one molecular edit at a time. This article references 13 other publications. This article has not yet been cited by other publications.