Chemo- and bio-catalytic methods towards chiral dihalocyclopropanes

In recent years, gem-dihalocyclopropanes have garnered much attention in the pharmaceutical industry due to increased metabolic stability, lipophilicity and being bioisosteric to epoxides attributed to the unique chemical and biological properties. The overarching aim of this project is to develop novel synthetic routes for the synthesis of difficult to access enantiomerically pure dihalocyclopropanes.

As systematic methods towards enantioenriched gem-dihalocyclopropanes would be transformative for the pharmaceutical, agrochemical and fine chemical industries, we envisage that through the development of novel dihalocarbene precursors, streamlined chemo- and bio-catalytic approaches converting simple and readily available olefins into value-added chiral gem-dihalocyclopropanes will be achievable in one step.

To date many highly efficient synthetic methods for dihalocyclopropanation of olefins have been developed, and current state-of-the-art methodologies centres around two main approaches 1) addition of free-dihalocarbene and 2) Michael-induced ring closure (MIRC) using trihalomethyl anions. Despite these efficient approaches, there is a paucity in the approaches towards the synthesis of chiral gem-dihalocyclopropanes, attributed to the extremely fast (and unproductive) racemic background reaction.

Our approach will be exemplified through the application of two different types of dihalocyclopropanation reagents developed within the Willcox group; 1) a novel N-sulfonylhydrazone, which will act as a stable diazo precursor and 2) a sulfoximinium reagent (first reported by Olah) which will act as an ylide precursor. Both of these reagents will be utilized independently in chemo- and bio-catalysis.

The chemocatalytic approach will focus on transferring the dihalocarbene (generated in situ from the hydrazone) to a wide range of olefins, using classical carbene transfer reagents (eg Rh2(O2CR)4, Fe(TPP)Cl and Co(TPP)) [4,5]. The sulfoximinium ylide will be employed in MIRC chemistry using either organocatalysis or chiral-at-metal catalysis to facilitate the addition to electron-deficient olefins.[6] The biocatalytic approach will explore olefin dihalocyclopropanations using a series of de novo heme enzymes developed in the Green lab in collaboration with Prof.

David Baker. In parallel, we will explore several mechanistic strategies to accelerate the MIRC reaction within designed enzymes; 1. Lewis acid catalysis. 2.

Dual hydrogen bonding catalysis and 3. Iminium ion catalysis. Here we can take advantage of new genetically encodeable functional components developed within the Green lab (e.g.

Nature 2019, 570, 219). Having identified promising designs with desired activity, we will use directed evolution to optimize catalytic performance and reaction selectivity. Optimized designs will then be structurally and biochemically characterized to gain insights into the origins of improved activity in order to guide future enzyme designs efforts.

The work conducted in the Willcox group will provide training in reagent design, ligand design and synthesis, synthesis of new metal complexes, reaction optimization, and general synthetic manipulations and reaction purification. Techniques include: Schlenk methods, X-ray crystallography, NMR, EPR and FTIR spectroscopies, mass spectrometry, transition metal catalysis and chromatography (preparative and chiral GC/HPLC).

The work conducted in the Green group will provide training in enzyme design, directed evolution, stop codon suppression, mechanistic enzymology and structural biology.

The absence of any effective chemo- and bio- catalytic method to prepare enantiomerically enriched dihalocyclopropance means that this project enables access to previously unattainable chiral derivatives. A new dihalocyclopropanation paradigm would place the UK at the leading edge of a new global economic sector enhancing quality of life, health and creative output in this niche.