Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

Whereas most organic molecules can be synthesized from progressively simpler substrates, syntheses of complex organic targets often involve counterintuitive sequence of steps that first complexify the structure but, by doing so, open up possibilities for pronounced structural simplification in subsequent, downstream steps. Such complexifying/simplifying reaction sequences, called tactical combinations (TCs), can be quite powerful and elegant but also inherently hard to spot—indeed, only some 500 TCs have so far been cataloged, and even fewer are routinely used in synthetic practice. This paper describes computer-driven discovery of large numbers of viable TCs (over 46,000 combinations of reaction classes and ∼4.85 million combinations of reaction variants), the vast majority of which have no prior literature precedent. Examples—including a concise wet lab synthesis of a small natural product—are provided to illustrate how the use of these newly discovered TCs can streamline the design of syntheses leading to important drugs and/or natural products. [Display omitted] •Only ∼500 synthetically powerful “tactical combinations” have been cataloged to date•Computer discovers millions of such elegant, useful, and viable reaction sequences•Examples illustrate how the newly discovered combinations streamline synthetic planning Although computers have recently made remarkable progress in autonomous synthetic planning, their ability to strategize over multiple steps, essential for the synthesis of complex targets, is still limited. One form of such “strategizing” is the so-called tactical combinations (TCs)—which are sequences of steps that first complexify the target but, by doing so, enable elegant and simplifying downstream disconnections. TCs are often counterintuitive even to human experts and, over several decades, only about 500 of them have been cataloged. Here, we show that computers can systematically discover much larger numbers (millions) of previously unreported yet valid TCs that unlock new and elegant synthetic approaches. These results and accompanying experimental demonstrations indicate that computers can now assist chemists not only by processing and adapting existing synthetic approaches (e.g., via artificial intelligence tools learning from prior art) but also by uncovering new ones. Tactical combinations (TCs) are two-step reaction sequences that first, in a retrosynthetic direction, complexify the target structure but, by doing so, enable signi