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Computationally‐Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions
Author(s) -
Korenaga Toshinobu,
Sasaki Ryo,
Takemoto Toshihide,
Yasuda Toshihisa,
Watanabe Masahito
Publication year - 2018
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201701191
Subject(s) - chemistry , rhodium , ligand (biochemistry) , catalysis , substrate (aquarium) , combinatorial chemistry , enantioselective synthesis , hydrolysis , decomposition , computational chemistry , stereochemistry , organic chemistry , biochemistry , receptor , oceanography , geology
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) 2 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, ( R )‐tolterodine ( l )‐tartrate, was demonstrated without the need of intermediate purification.