Prediction of High-Yielding Single-Step or Cascade Pericyclic Reactions for the Synthesis of Complex Synthetic Targets

Abstract

Pericyclic reactions, which involve cyclic concerted transition states without ionic or radical intermediates, have been extensively studied since their definition in the 1960s, and the famous Woodward–Hoffmann rules predict their stereoselectivity and chemoselectivity. Here, we describe the application of a fully automated reaction-path search method, that is, the artificial force induced reaction (AFIR), to trace an input compound back to reasonable starting materials through thermally allowed pericyclic reactions via product-based quantum-chemistry-aided retrosynthetic analysis (QCaRA) without using any a priori experimental knowledge. All categories of pericyclic reactions, including cycloadditions, ene reactions, group-transfer, cheletropic, electrocyclic, and sigmatropic reactions, were successfully traced back via concerted reaction pathways, and starting materials were computationally obtained with the correct stereochemistry. Furthermore, AFIR was used to predict whether the identified reaction pathway can be expected to occur in good yield relative to other possible reactions of the identified starting material. In order to showcase its practical utility, this state-of-the-art technology was also applied to the retrosynthetic analysis of a natural product with a relatively high number of atoms (52 atoms: endiandric acid C methyl ester), which was first synthesized by Nicolaou in 1982 and provided the corresponding starting polyenes with the correct stereospecificity via three pericyclic reaction cascades (one Diels–Alder reaction as well as 6π and 8π electrocyclic reactions). Moreover, not only systems that obey the Woodward–Hoffmann rules but also systems that violate these rules, such as those recently calculated by Houk, can be retrosynthesized accurately.

A 21st Century View of Allowed and Forbidden Electrocyclic Reactions

“…These enzymes seem to follow Pauling’s vision of enzymes: complementary to transition states, but in a noncovalent way. While in general the mechanisms of enzyme catalysis are much more complicated than this, the original Pauling model is now being manifested in pericyclases. ,,− …”

“…There are None!”, , were Woodward and Hoffmann just provocative? Psychologically perceptive for suretheir categorical locution immediately engaged the organic chemistry community, and continues to do so, even today, more than 50 years later. ,,− …”

“…While in general the mechanisms of enzyme catalysis are much more complicated than this, the original Pauling model is now being manifested in pericyclases. 99 , 104 , 133 − 136 …”

Quantum chemical data generation as fill-in for reliability enhancement of machine-learning reaction and retrosynthesis planning

“…Maeda and coworkers have long highlighted the value of reaction exploration software for retrosynthetic applications. 44–48 In particular, they presented an approach in which an exploration is started from the desired end product, i.e. , the compound which is to be synthesized.…”

“…Maeda and coworkers have long highlighted the value of reaction exploration soware for retrosynthetic applications. [44][45][46][47][48] In particular, they presented an approach in which an exploration is started from the desired end product, i.e., the compound which is to be synthesized. Then, an exploration soware is taking advantage of automatic identication of possible reaction pathways leading to this compound.…”