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Automatic chemical reaction prediction: now in stereo

The automated reaction pathway search method predicts the correct stereochemistry of pericyclic reactions using only the target molecular structure.

The AFIR method traces the reaction of a 52-atom natural product, endiandric acid C methyl ester, to the starting materials using only quantum chemical calculations. (Tsuyoshi Mita et al. JACS. 30 November 2022)

Researchers at the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) have demonstrated extended use of a computational method called the Artificial Force-Induced Reaction (AFIR) method, which predicts Pericyclic reactions with accurate stereoselectivity based solely on information about the target product molecule. . Accurate prediction of the stereochemistry of a molecule, i.e. the 3-dimensional arrangement of the atoms that compose it, is unprecedented for this type of automatic reaction pathway search. This work serves as proof that the AFIR method has the potential to discover new reactions with specific stereochemistry.

In this study, AFIR was used to calculate retrosynthetic or reverse reactions from product molecules to starting materials. Previously, AFIR was used to predict small, simple reactions, but accurate stereochemistry estimates were out of reach, limiting the technique’s applicability. In this study, the researchers overcame this hurdle by using the AFIR method on the main class of chemical reactions commonly found in biological processes, called pericyclic reactions, including Vitamin D synthesis.

An image showing that, given a product molecule, AFIR can predict the most likely reactants required to obtain that product.

General scheme for constructing retrosynthetic reaction pathway networks using the AFIR method. (Tsuyoshi Mita et al. Journal of the American Chemical Society. November 30, 2022)

An important feature of pericyclic reactions is that they have the same stereochemical relationship whether the reaction occurs in the forward or reverse direction. This allowed the team to use the calculated stereochemistry for the backward reaction to accurately predict the stereochemistry for the forward reaction. In particular, AFIR was able to accurately predict the stereochemistry for a reaction that broke the Woodward-Hoffman rules that typically govern the behavior of pericyclic reactions. The ability of this technique to predict exceptions to these standard rules demonstrates the potential to use this automated method to discover unintuitive reactions that might otherwise be overlooked.

Pericyclic reactions are also advantageous for computational work because they are coherent, meaning that all bond breaking and bond formation takes place in a single step. Because such reactions do not go through ionic intermediates, it is difficult for solvent molecules to modify the reaction, allowing researchers to ignore solvent effects in their calculations. Such calculations are simpler to perform and therefore allow more complex molecules to be handled. In this study, AFIR successfully processed molecules up to 52 atoms, which is more than 2.5 times the molecular size in previous studies.

More importantly, the only information needed to use AFIR is the structure of the desired product molecule, so researchers can input a molecule they want to make and effectively hit the rewind button to find promising starting materials. Extending the use of AFIR to larger molecules and stereospecific processes opens new avenues for automated reaction discovery.

Lead author Tsuyoshi Mita was also impressed by the importance of using an automated approach to recreate historically significant reactions.

«The Woodward-Hoffmann Rules were created in the 1960s, and I think it’s very important that 60 years later, with stereochemistry following these rules, we can use automated reaction path searching methods to predict the starting materials for a reaction,» said lead author Tsuyoshi. mita “Endiandric Acid C was synthesized by Nicolau in 1982 based on Black’s biosynthetic hypothesis and I am very pleased that in this work we were able to recreate what was in their head using quantum chemical calculations. I am both an organic synthetic chemist and a user of the AFIR method, and the power of the AFIR method on this project has struck me once. more reminded.»

Photograph of researchers from WPI-ICReDD of Hokkaido University.  Top Row, Left to Right: Yu Harabuchi, Wataru Kanna, Hideaki Takano, Hiroki Hayashi.  Bottom row, left to right: Satoshi Maeda, Tsuyoshi Mita.  Photo courtesy of ICReDD.

WPI-ICReDD, members of the research team at Hokkaido University. Top Row, Left to Right: Yu Harabuchi, Wataru Kanna, Hideaki Takano, Hiroki Hayashi. Bottom row, left to right: Satoshi Maeda, Tsuyoshi Mita. (Photo Credit: ICReDD)

original article:

Tsuyoshi Mita, Hideaki Takano, Hiroki Hayashi, Wataru Kanna, Yu Harabuchi, Kendall N. Houk and Satoshi Maeda. Prediction of High-Efficiency Single-Step or Stepped Pericyclic Reactions for Synthesis of Complex Synthetic Targets. Journal of the American Chemical Society. 30 November 2022.

DOI: 10.1021/jacs.2c09830


This work was financially supported by the Japan Science and Technology Agency Advanced Technology Discovery Research (JST-ERATO) grant (JPMJER1903), the Japan Science Promotion Association (JSPS) World Premier Initiative (WPI), and the JSPS Grants-in. Help for Challenging Research (Discovery) (21K18945), Scientific Research (B) (22H02069), Transformative Research Areas (A) (Digitization-driven Transformative Organic Synthesis (Digi-TOS)) (22H05330) and Young Scientists (22K14673). It has also been supported by the Fugaku Medical Research Foundation, the Uehara Memorial Foundation, the Naito Foundation, and the US National Science Foundation (CHE-1764328). All calculations were performed using the Fugaku supercomputer provided by the RIKEN Center for Computational Science, as well as the supercomputer system at the Information Enterprise Center at Hokkaido University, Sapporo, Japan. Use of GRRM and Gaussian programs on the supercomputer Fugaku

Enabled with support from HPC Systems, Inc.

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