Retrosynthesis

RESEARCH HIGHLIGHTS

Nature Reviews Chemistry | Published online 6 Apr 2018; doi:10.1038/s41570-018-0152

RETROSYNTHESIS Computer says yes Retrosynthetic analysis is the way be automated has been debated ever patented, and the eighth a natural that organic chemists draw an imag- since its earliest applications: can a product (engelheptanoxide C) for There were a inary line from a target molecule to computer armed with sufficiently which a synthesis had not, at the time, few steps that available precursors. In addition to large databases of organic reactions been reported. functional group interconversions, and starting materials design a Chematica planned syntheses I did not really bonds may be disconnected or synthesis more effectively than a of each of these eight molecules, believe would rejoined in an attempt to find simpler human? Writing in Chem, Bartosz needing only 15–20 min for all work! That starting materials. Disconnecting a Grzybowski and co-workers describe except dronedarone, though this they did makes bond results in two synthons — either eight syntheses planned by computer retrosynthesis was performed using a pair of oppositely charged species or and then executed by the team in the an older and slower version of the me wonder two radicals. We then try to identify laboratory. software. “We are quite proud that about the synthetic equivalents that can stand Grzybowski’s group have been our algorithms can find syntheses advantages in for these hypothetical species in developing their retrosynthesis improving on previous approaches a forward reaction. This process planning software — Chematica — and on a timescale that would not offered by is repeated until readily available for over 10 years. “By 2012, we were irritate a practicing chemist,” says the ice cold starting materials are identified. quite proficient in using network Grzybowski. The software produces objectivity of Despite only being formalized in the algorithms to query synthetic paths and scores the proposed routes, which an algorithm past half-century — Elias J. Corey comprised of published reactions, but were then tested in the lab with pro- was awarded the 1990 Nobel Prize we were nowhere near tackling the de vision for only minor adjustments in in Chemistry for “his development novo retrosynthesis problem,” he says. reaction conditions (for example, to of the theory and methodology “It’s easy to imagine that this is simply the temperature, solvent or a specific of organic synthesis” — the retro a question of how many reaction rules reagent). In all eight syntheses, the synthesis process has become an we can input, but more rules means results exceeded those of previously integral part of the practice of organic more options. With our current reported routes. “There were a few chemistry. Whether the process might knowledge base of some 60,000 steps that I did not really believe reactions, there are, on average, 100 would work! That they did makes me OH legitimate options to choose from in wonder about the advantages offered each step and a rapidly intractable by the ice cold objectivity of an 100n options for an n-step synthesis.” algorithm over a human brain.” OMe O It took another 5 years and There are challenges ahead, how- joining forces with chemists at ever. “The molecules tackled so far HO OH MilliporeSigma/Merck KGaA to are industrially relevant but certainly tackle real retrosynthesis. “Our not of the highest synthetic complex- collaboration was important because ity,” says Grzybowski. “It will take a we were keen to get experimental few years for us to to add more rules, validation of the system and it was accelerate the algorithms, fine-tune essential that this included target our scoring functions and use more molecules selected by a third party,” CPU horsepower.” He also doesn’t says Grzybowski. Eight targets were believe that the use of such methods selected with different objectives in will limit creativity in designing com- mind for the new retrosyntheses. pletely new chemistry.“The program Six compounds were selected by the will not use, for example, a Wittig team at MilliporeSigma, each with reaction, if we do not first teach it the OH a market value of >US$100/mg and Wittig reaction,” states Grzybowski.

HO for which synthetic attempts yielded Stephen G. Davey little to no product or were not ORIGINAL ARTICLE Klucznik T. et al. Efficient OHC OMe OAc scalable. A seventh compound was an syntheses of diverse, medicinally relevant targets anti-arrhythmia drug (dronedarone, planned by computer and executed in the OH laboratory. Chem 4, 522–532 (2018) Macmillan Publishers Limited Sanofi-Aventis) whose synthesis was