Novel Cyclic Reaction Networks Based on Transition Metal Catalysis for the Deracemisation of Biaryl Atropisomers

Abstract

Atropisomers are key structural motifs in many commonly used ligands and catalysts and are
increasingly found in drug molecules. As a result, the development of synthetic methods to
access enantioenriched atropisomers is an active area of synthetic chemistry research. As the
interconversion of atropisomers, or atropisomerisation, inherently involves rotation around the
stereogenic axis, asymmetric resolution and desymmetrisation methods which selectively
control an atropisomer’s rotational energy barrier and bias rotation around the stereogenic axis
have emerged as powerful strategies in atroposelective synthesis. Nonetheless, these methods
are limited to maximum yields of 50% of the enantioenriched starting material, or to
structurally modified enantioenriched products. Atropisomer deracemisation is a
complementary approach to resolution and desymmetrisation methods, which can lead, in
theory, to 100% yields of a single atropisomer, with improved atom economy. Only three
examples of atropisomer deracemisation have (very recently) been reported. These examples,
like all deracemisation processes, comprise sets of opposing and mechanistically distinct
reactions whose concurrent operation is driven by a coupled, enthalpically favoured, reaction
in a cyclic reaction network (CRN). Almost all reported examples of deracemisation employ
photochemically or biocatalytically derived CRNs, with only two examples of chemocatalysed
deracemisation so far reported. Herein are described the studies undertaken to achieve two
novel chemocatalysed CRNs, underpinned by palladium catalysis, and explores their
application to the deracemisation of atropisomers.
We begin by describing the development of a CRN which operates through the interconversion
of carbon–hydrogen and carbon–palladium bonds (referred to as the C–H/C–Pd CRN), via non
microscopically reverse C–H activation and reductive elimination. We successfully
demonstrate the stoichiometric operation of the C–H/C–Pd CRN in an achiral biaryl compound
using deuterium labelling studies. Later, we describe studies towards the development of the
C–H/C–Pd CRN with an atropisomeric biaryl compound, and examine the challenges
encountered in the process. Thereafter, we describe the development of a CRN which operates
through the interconversion of carbon–boron and carbon–palladium bonds (referred to as the
C–B/C–Pd CRN), via non-microscopically reverse transmetalation and reductive elimination.
We successfully demonstrate catalytic C–B/C–Pd CRN operation in a configurationally
unstable atropisomer. Studies to identify a configurationally stable atropisomer which can be
deracemised via the C–B/C–Pd CRN are underway. Finally, we conclude by summarising the
results of our investigations and discuss potential areas for future study. In particular, we discuss strategies to make the C–H/C–Pd CRN operate catalytically and its potential to achieve
a catalytic ortho deuteration methodology, as well as exploring potential avenues through
which to achieve C–H/C–Pd CRN-mediated deracemisation.

Date of Award	17 Mar 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Beatrice Collins (Supervisor) & Natalie Fey (Supervisor)