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By Sander Kluwer, InCatT B.V.
The conversion of feedstocks to useable chemical compounds is at the heart of chemistry and the chemical industry. Many catalytic transformations have been developed in the last decades to mature processes. Despite numerous efforts, there were always a number transformations that remained a tough nut to crack. One such conversion is the direct functionalization of remote sp3 C-H groups where only one single C-H is activated in a stereochemical manner to produce chiral product with high enantiomeric excess. Until now, such highly selective transformations were only reserved for enzymatic reactions.
Figure 1. The site-selective and stereocontrolled activation of carboxylic acid derivates using a supramolecular iridium catalyst.
In this light, the achievements published by Professor Masaya Sawamura and coworkers in Science (DOI: 10.1126/science.abc8320) are a breakthrough as they developed a catalyst that can just do that. The authors show that it indeed possible to convert simple aliphatic esters and amides to the gamma functionalized alkylboronate or corresponding alcohol with astonishing enantioselectivities up to 99.9%.
Figure 2. The active catalyst which creates the enzyme-like cavity (Left), and the substrate pre-organization by the pyridine-urea ligand.
The active catalyst is a iridium complex consisting of a bulky chiral phosphite ligand, three Bpin moieties (Bpin = pinacolboryl) and pyridine-urea ligand creating an enzyme-like cavity. The pyridine-urea acts a supramolecular docking station to bind the substrate carbonyl group and effectively positions the substrate toward the iridium reactive site. Multiple non-covalent interactions between the catalyst ligands (p-p interactions between phosphite napthyl and pyridine-urea ligands), and the incoming substrate and ligands (hydrogen bonds between C-H of the substrate and the O of the phosphite and O of the Bpin groups) allows for a selective pre-organization of the substrate in such way that only one of the C-H bonds at the g-position is activated leading to the R-isomeric product. An extensive substrate scope is covered of aliphatic carboxylic acids (such as (alkyl, aryl) amines and various ester) that constitute one of the most fundamental and widespread compound classes in nature and serve as major feedstock chemicals. The importance of this breakthrough is highlighted producing the pharmacologically interesting (R)-g-alkyl-g-aminobutyric acid (GABA) derivative in just two chemical steps.
Related to this publication, Amsterdam researchers at the group for Homogeneous, Supramolecular and Bio-inspired catalysis led by Prof. Joost Reek have previously applied their concept of substrate orientation to develop CH activation protocols for the important class of amide containing aromatic rings. This concept was inspired by the working principles of natural enzymes that bind molecules in well-defined pockets close to their active sites and thereby use pre-organization as a strategy to induce selectivity. The authors succeeded in designing a relatively simple iridium catalyst that is functionalized with an indole amide binding site. It properly organizes the amide substrate for ortho selective CH activation, a selectivity that cannot be achieved with just ligand design.
Figure 3. The supramolecular substrate orientation approach allows selective C-H borylation, an important new reaction for sustainable synthesis.
In their publication, published in Angewandte Chemie International Edition, the researchers present their novel supramolecular iridium catalyst. By combining experimental data and DFT calculation, they were able to elucidate the reaction mechanism and demonstrate that the hydrogen bonds are important for the pre-organization and activation. Substrate organization takes place via the formation of three hydrogen bonds between the substrate and the catalyst. If not all three hydrogen bond can be formed, the selectivity for the reaction drops substantially.
Importantly, in both approaches the fundamental principles of enzyme controlled selective catalysis is stripped down to relatively simple ligand designs. Such strategies therefore allow easy scale up application at larger scale for applied catalysis.
Ronald L. Reyes, Miyu Sato, Tomohiro Iwai, Kimichi Suzuki, Satoshi Maeda,Masaya Sawamura, Science, 2020, 369, 970–974. DOI: 10.1126/science.abc8320
Shaotao Bai, Charles Bheeter and Joost N. H. Reek: Angew.Chem. Int.Ed. 2019, 58,13039 –13043. DOI:10.1002/anie.201907366