Computationally‐Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions

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  • Toshinobu Korenaga
    Department of Chemistry and Biological Sciences, Faculty of Science and Engineering Iwate University 4-3-5 Ueda Morioka, Iwate 020-8551 Japan
  • Ryo Sasaki
    Department of Chemistry and Biological Sciences, Faculty of Science and Engineering Iwate University 4-3-5 Ueda Morioka, Iwate 020-8551 Japan
  • Toshihide Takemoto
    Central Research Laboratory, Technology and Development Division Kanto Chemical Co., Inc., Soka Saitama 340-0003 Japan
  • Toshihisa Yasuda
    Central Research Laboratory, Technology and Development Division Kanto Chemical Co., Inc., Soka Saitama 340-0003 Japan
  • Masahito Watanabe
    Central Research Laboratory, Technology and Development Division Kanto Chemical Co., Inc., Soka Saitama 340-0003 Japan

Bibliographic Information

Published
2018-01-11
Resource Type
journal article
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  • http://onlinelibrary.wiley.com/termsAndConditions#vor
DOI
  • 10.1002/adsc.201701191
Publisher
Wiley

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<jats:title>Abstract</jats:title><jats:p>A chiral ligand for the rhodium‐catalyzed asymmetric 1,4‐addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6‐31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron‐poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)<jats:sub>2</jats:sub> decomposition (protodeboronation). The computationally‐designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one‐hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram‐scale synthesis of the urological drug, (<jats:italic>R</jats:italic>)‐tolterodine (<jats:sc>l</jats:sc>)‐tartrate, was demonstrated without the need of intermediate purification.</jats:p><jats:p><jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/adsc201701191-toc-0001-m.png"><jats:alt-text>magnified image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p>

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