Kinetic resolution chemistry
Research

There is a current drive towards more diversity in drug collections and away from 'flat' molecules that typically dominate drug collections to create molecules with more three-dimensional shape. This can lead to improved pharmacokinetic properties and bioavailability. Molecules with 3D shape often have a number of stereocentres that need to be controlled in a particular configuration. This project is exploring an efficient approach to heterocycles that have one or more substituents next to the ring nitrogen atom.

In particular, we are studying the preparation of carbamates, the rate of rotation of the carbonyl group by VT-NMR spectroscopy and by DFT studies, the lithiation of the carbamates followed by trapping with electrophiles, and their kinetic resolution. In addition, we are studying the lithiation-trapping of the enantioenriched carbamates.

We have discovered that lithiation can be used to resolve racemic starting materials to give highly enantiomerically enriched compounds such as 2-arylpiperidines. The simple base n-butyllithium was used with the chiral ligand sparteine and this chiral base system selectively removes a proton from one mirror image of the starting material.

An example is shown in Scheme 2 for the kinetic resolution of a racemic 2-arylpiperidine. The partially lithiated intermediate is reacted with an electrophile so that the starting material can be separated from the quenched product. This gave the recovered piperidine starting material in 41% yield and with enantiomer ratio (er) 96:4. This compound can be treated with a base and an electrophile to give 2,2-disubstituted products without loss of selectivity, thereby providing an approach to chiral amines with a fully substituted alpha centre that are often difficult to access by other means.

The carbamate starting materials exist as a mixture of rotamers. We have determined the barrier to rotation using VT-NMR spectroscopy and DFT studies and have found that the rate of rotation is fast (in comparison with the rate of lithiation). Therefore although only one rotamer (with the carbonyl oxygen atom pointing towards the benzylic proton) undergoes lithiation, the other rotamer equilibrates easily in these piperidines. 

We are applying this chemistry to other ring systems to prepare different enantiomerically enriched substituted nitrogen-containing heterocycles. As examples, this project has led to the synthesis of substituted indolines and benzoxazines (Scheme 3).

Publications from this project

A. Choi, A. Das, A. J. H. M. Meijer, I. Proietti Silvestri, I. Coldham, Org. Biomol. Chem. 2024, 22, 1602–1607.

'Synthesis of Enantioenriched Spirocyclic 2-Arylpiperidines via Kinetic Resolution'

DOI: 10.1039/D4OB00011KD

S.-H. Yeo, A. Choi, S. Greaves, A. J. H. M. Meijer, I. Proietti Silvestri, I. Coldham, Chem. Eur. J. 2023, 29, e202300815.

'Kinetic Resolution of 2-Aryldihydroquinolines using Lithiation – Synthesis of Chiral 1,2- and 1,4-Dihydroquinolines'

DOI: 10.1002/chem.202300815

A. Das, A. Choi, I. Coldham, Org. Lett. 2023, 25, 987–991.
'Photocatalysis and Kinetic Resolution by Lithiation to give Enantioenriched 2-Arylpiperazines'
DOI: 10.1021/acs.orglett.3c00074

A. Choi, A. J. H. M. Meijer, I. Proietti Silvestri, I. Coldham, J. Org. Chem. 2022, 87, 8819–8823.
'Kinetic Resolution of 2-Aryl-4-methylenepiperidines toward Enantioenriched Functionalizable Piperidine Fragments'
DOI: 10.1021/acs.joc.2c00862

A. El-Tunsi, N. Carter, S.-H. Yeo, J. D. Priest, A. Choi, C. M. Kobras, S. Ndlovu, I. Proietti Silvestri, A. K. Fenton, I. Coldham, Synthesis 2022, 54, 355–368.
'Kinetic Resolution by Lithiation: Highly Enantioselective Synthesis of Substituted Dihydrobenzoxazines and Tetrahydroquinoxalines'
DOI: 10.1055/a-1638-2478

A. Choi, A. El-Tunsi, Y. Wang, A. J. H. M. Meijer, J. Li, X. Li, I. Proietti Silvestri, I. Coldham, Chem. Eur. J. 2021, 27, 11670–11675.
'Asymmetric Synthesis of 2-Arylindolines and 2,2-Disubstituted Indolines by Kinetic Resolution'
DOI: 10.1002/chem.202101248