The research program of the Fletcher group is focused on synthetic and physical organic chemistry with a special interest in dynamic systems, chirality and catalysis.

A major part of the program deals with the development of novel asymmetric synthesis methods. Overall we aim to develop new strategies for asymmetric synthesis, and use mechanistic insight to guide the process of discovering and improving new catalytic reactions. A theme of this program is to develop practical methods to convert simple starting materials into complex molecules in a straightforward manner.

A second part of the program is inspired by complex chemical phenomena observed in biological systems. The fundamental question of what “life” is and how living matter differs from other systems remains unanswered. We are working toward understanding how the most basic functions of life can be observed in purely synthetic systems by studying self-replicators that operate far-from-equilibrium, and mimicking engineering strategies seen in the biological world to develop smart materials.

Synthesis and Catalysis

Catalytic Asymmetric Methods

The ability to make carbon-based compounds is essential for the development of new medicines, fragrances, polymers and the study of biological and physical properties. Asymmetric C-C bond formation generates single enantiomer molecules at the same time as the molecular framework is assembled and is strategically powerful in synthesis design.

The addition of alkyl nucleophiles is often limited by the reactivity of the organometallic reagent and a lack of understanding of the mechanism and the roles of the catalyst and ligand used. Our lab is developing practical copper-catalysed methods which operate at room temperature and tolerate functional groups so that useful products can be obtained. We have developed a series of reactions where organometallic nucleophiles generated in situ are used in asymmetric additions and are expanding these C-C bond forming methods to work beyond simple bench-mark substrates.

Asymmetric additions of sp2-hybridized nucleophiles may serve as useful variations of C-C cross coupling reactions. Asymmetric Suzuki-Miyaura and related sp2-sp3 cross-coupling reactions promise to become incredibly useful tools for the construction of 3-dimensional molecules. We aim to develop asymmetric methods where cross-coupling complex heterocyclic structures to obtain drug-like molecules can be done routinely.

More generally we have an interest in unusual chiral phenomena, stereogenic features and dynamic processes and explore new approaches for asymmetric control of small molecules, supramolecular complexes and materials – and how chirality at these different scale lengths are interrelated.

Further reading:
Angew. Chem. Int. Ed. 2017, 563261–3265. 'Very Important Paper'
Nature Nanotechnol. 2017, 12, 410–419.
Chem. Commun. 2007, 2578–2580.
Adv. Synth. Catal. 2016, 358, 2489–2496.

Understanding enantioselectivity in asymmetric catalysis

The discovery of the appropriate chiral ligand for a desired transformation remains a formidable task. This is especially true for reactions where detailed mechanistic data are yet to be uncovered. As a consequence, chance, intuition, and screening all play an important role in the development of enantioselective catalytic reactions.

An essential component of our research is the use of mechanistic studies to probe our reactions and guide the optimization and further extension of our methods. An emerging research line is to understand how structure and enantioselectivity are related in metal catalysis by correlating selectivity against measured or calculated physical parameters. We are exploring this approach with Prof Rob Paton which promises to provide mechanistic information and enable the design of new reactions and more effective ligands for catalysis.

Correlation of experimentally observed and calculated enantioselectivity. (Chem. Sci. 2018, 9, 2628-2632)

Further reading:
ACS Catal. 2017, 76729–6737.
Chem. Sci. 2018, 9, 2628-2632.

New strategies in asymmetric catalysis

The vast majority of catalytic asymmetric C-C bond forming reactions rely on the use of prochiral starting materials, where the role of the catalyst is to guide bond formation to one face. We have shown that both Copper and Rhodium catalysed additions of non-stabilized nucleophiles to racemic electrophiles can give single enantiomer products with very high yields under easily accessible conditions.

We are currently expanding the range of asymmetric strategies applicable to non-stabilized nucleophiles and are developing dynamic kinetic transformations, kinetic resolutions, desymmetrizations of meso-compounds, and methods to control the stereochemistry of multiple centers in a single process.

Application to target molecules

The discovery of new asymmetric methods promises to allow powerful new methods for synthesis and we often demonstrate our methods in the efficient synthesis of molecules of biological significance. Completed targets include mitsugashiwa lactone (ref/links org let 2004), hydnocarpic acid, chaulmoogric acid, anthelminthicin C (nature 2015), the breast cancer drug fulvestrant (Faslodex) (chem comm 2015), fragrances phenoxanol and hyroxycitronellal (chem comm 2017), muscone (org let 2016), the natural product isoanabasine, the antipsychotic preclamol and the recently approved anticancer agent niraparib (Zejula) (nature comm, 2017)

Reaction Networks and Complex Systems

Far-from-equilibrium systems

"…living matter, while not eluding the “laws of physics” as established up to date, is likely to involve “other laws of physics” hitherto unknown, which however, once they have been revealed, will form just as integral a part of science as the former."
–Erwin Schrödinger (What is Life? 1944)

A major part our program is to develop and understand complex non-equilibrium systems capable of a function. Currently there is only limited understanding of how to control information, energy flow and feedback in non-thermodynamically controlled systems and across length scales.


Autocatalysis is central to the propagation of life and intrinsic to many other biological processes. Organisms can be thought of as imperfect self-replicators, which produce closely-related species, allowing for selection and evolution. Autocatalytic chemical reactions have been studied for over a century, and it is widely accepted that they must have played a key role in the emergence of life. While much prebiotic research has focused on understanding the synthesis of building blocks and the self-replication of information polymers such as RNA, the fusion of simple molecules to give more complex products that spontaneously form dynamic functional systems remains poorly understood.

We are developing new autocatalytic reactions, characterizing the kinetics and dynamics of these systems, and using this information to rationally design new complex systems. Overall, these studies will contribute to understanding how complex cell-like systems can emerge from much simpler chemical components. In the long term, we want to develop ‘protocells’ that mimic living systems and allow the development of “bottom-up” approaches to synthetic biology.

Communication across scale-lengths

Using interferometric scattering microscopy (iSCAT) allows the very first visualizations of unlabeled vesicles and even micelles. We can watch the formation and dynamics of reaction aggregates, measure the kinetics of these systems, and quantify changes in nanoparticle distribution in time – such as micelle-to-vesicle transitions. Further we are able to observe a diverse range of complex supramolecular phenomena including vesicle fusion, the eruption of vesicles from the interface, the emergence of highly dynamic new phases along the interface, and other behavior that reveal the massive complexity of biphasic chemical reactions.

A selection of iSCAT movie stills from an autocatalytic reaction under kinetic control.

The challenge of developing nanoscale machines has inspired scientists for decades. However, synthetic molecular machines capable of useful function remain elusive, while nature uses nanoscale machines to drive every significant biological process. How to integrate synthetic machines into hierarchical assemblies so that they can perform work is virtually unexplored.

We have demonstrated that minimal synthetic engineering of all-trans-retinal can induce drastic changes in photochemisty and photophysics in solution so that isomerization can be controlled outside of an evolution optimized protein environment.

Model for backbone modified all-trans-retinal photochemistry (J. Am. Chem. Soc. 2014, 136, 2650-2658).

The development of functional nano-machines may allow for new approaches to convert light energy into work. Based on the general idea that helical deformations may occur in artificial systems, thus making them capable of producing mechanical work we are designing systems where molecular movement is translated to rotational movement across length-scales to form the basis of macroscopically functional materials. In collaboration with Nathalie Katsonis (University of Twente), we examined polymers organized into a helical orientation by a chiral dopant. A rich variety of chiral polymer shapes were observed, depending on the angle at which strips were cut – this proved to be a crucial parameter that determined the pitch, handedness and photo-response of the resultant helical ribbons.

Photo-actuation of helical polymers doped with azobenzenes. Winding, unwinding & helix inversion observed as dictated by initial shape (Nature Chem. 2014, 6, 229-235).

Further reading:
Watch this highlight video (Link)

Prof. Philipp Kukura (Oxford Chemistry): Ultrafast photochemistry and nanoscale spectroscopy
The collaboration with Dr Kukura is funded by the EPSRC grant “Do you need a protein for efficient photochemistry?”

Prof. Nathalie Katsonis (University of Twente, the Netherlands): Soft materials and microscopy
The collaboration with Dr Katsonis is funded by a Royal Society International Exchanges Grant

Prof. Tim Claridge (Oxford Chemistry): NMR spectroscopy

Prof. Mark Wallace (University of Edinburgh): Polymer chemistry

Prof. Rob Paton (Oxford Chemistry): Theoretical calculations