Periodic Reporting for period 2 - ChiCC (Chirality via Cross-Coupling: New Asymmetric C-C Bond Formations Driven by Atom and Step Economy)
Okres sprawozdawczy: 2022-03-01 do 2023-08-31
Over 60% of the world’s top selling small molecule drug compounds are chiral and, of these, approximately 80% are marketed as single enantiomers. Surprisingly, and despite the tremendous advances made in catalysis over the past several decades, the average “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time the “chiral complexity” of marketed drugs has increased. Consequently, there is now an urgent need to provide efficient processes that access directly privileged chiral “3D” building blocks. It is our philosophy that catalysis holds the key here and new processes should be based upon atom and step economical platforms that exert control over both absolute and relative stereochemistry. Palladium catalysed cross-coupling reactions or aryl (pseudo)halides with organo-nucleophiles (esp. the Suzuki coupling) have become mainstays of the pharmaceutical industry. Such processes predominantly provide planar “2D” structures and are not well suited to the production of chiral “3D” building blocks. Additionally, multiple “concession” steps are usually required to prepare the reaction partners, thereby detracting from atom and step economy. It would be much more efficient if feedstock precursors (e.g. alkenes and aryl C-H bonds) could be combined directly in enantioselective or enantiospecific C-C bond formations. Cross-couplings of this type would circumvent “concession” steps, thereby minimising cost, effort and waste; however, such processes are highly challenging because of issues associated with regio- and stereocontrol. Recently, we developed prototype catalyst systems that can address this. In the ERC project, these exciting preliminary results are being developed into a wider family of processes where asymmetric C-C bond formations are achieved directly by C-H activation. The new methods, which fulfil modern reaction ideals of atom and step economy, will likely find broad use in applied settings.
So far, we have published the following:
P. Cooper, A. G. Dalling, E. H. E. Farrar, T. P. Aldhous, S. Grélaud, E. Lester, L. J. Feron, P. D. Kemmitt, M. N. Grayson,* and J. F. Bower*; Atom and step economical synthesis of acyclic quaternary centers via iridium-catalyzed hydroarylative cross-coupling of 1,1-disubstituted alkenes. Chem. Sci. 2022, 13, 11183-11189.
P. Cooper, A. G. Dalling, E. H. E. Farrar, T. P. Aldhous, S. Grélaud, E. Lester, L. J. Feron, P. D. Kemmitt, M. N. Grayson,* and J. F. Bower*; Atom and step economical synthesis of acyclic quaternary centers via iridium-catalyzed hydroarylative cross-coupling of 1,1-disubstituted alkenes. Chem. Sci. 2022, 13, 11183-11189.
All the publications we will produce go beyond the sate of the art. We plan to submit the following manuscripts in the near future:
Publication 1: A method for the benzamide direct addition of C-H bonds across alkenes to generate tertiary stereocenters enantioselectively.
Publication 2: A method for the branch selective benzamide directed addition of aromatic C-H bonds across vinyl and allyl silanes.
Publication 3: A method where alkyl units are transferred from N to C under iridium catalyzed conditions.
Publication 4: A method for enantioselective enolate alkylation based upon the addition of alkyl C-H bonds across alkenes.
Publication 1: A method for the benzamide direct addition of C-H bonds across alkenes to generate tertiary stereocenters enantioselectively.
Publication 2: A method for the branch selective benzamide directed addition of aromatic C-H bonds across vinyl and allyl silanes.
Publication 3: A method where alkyl units are transferred from N to C under iridium catalyzed conditions.
Publication 4: A method for enantioselective enolate alkylation based upon the addition of alkyl C-H bonds across alkenes.