Synthesis of cyclopropanes via hydrogen borrowing catalysis Jessica L. Crompton 1 , James R. Frost 1 , Sam M. Rowe 2 , Kirsten E. Christensen 1 and Timothy J. Donohoe 1 1 University of Oxford, UK, 2 GSK Medicines Research Centre, UK Cyclopropanes are a useful motif within drug discovery; the fragment can improve both the potency and the pharmacokinetic profile of the resulting compound and has been employed to this end in a number of drug candidates and FDA-approved drugs. 1 Classical methods for the cyclopropane synthesis often require the use of toxic alkyl halide or pseudohalide-derived reagents and therefore generate large amounts of hazardous waste. Hydrogen borrowing (HB) catalysis is a powerful method which utilises reversible oxidation state changes to enable the formation of C(sp 3 )‒C(sp 3 ) bonds. 2 This method is also highly “green,” making use of renewable feedstock alcohols and producing water as the sole by‑product, vastly reducing the waste produced compared to its classical alternatives. The Donohoe group has demonstrated that hindered ketones can be alkylated efficiently using HB catalysis to give a range of both α‑ and β‑branched products. 3, 4 The process works by employing a transition metal catalyst, which abstracts hydrogen from the alcohol to generate a metal‑hydride species and the corresponding carbonyl compound. This reactive carbonyl species is then able to undergo an aldol condensation with the ketone to give the corresponding enone, which is subsequently reduced by the metal-hydride species. The final reduction step of this catalytic cycle results in the delivery of a hydrogen atom to both the α‑and β-positions, and therefore precludes the synthesis of spirocycles at these positions using the HB method. We therefore present our strategy to synthesise α-cyclopropyl ketones within the HB manifold. We have shown that by careful consideration of both the ketone and alcohol substrates employed, a specialised α‑branched ketone intermediate can be formed via established HB alkylation chemistry. This intermediate can subsequently cyclise in situ via the corresponding enolate to give a cyclopropane directly. Most importantly, the key Ph × protecting group can easily be cleaved from these fragments to give synthetically useful carboxylic acid derivatives bearing an α-cyclopropyl group. References 1. Talele, T. T., J. Med. Chem. 2016, 59 (19), 8712-8756. 2. Reed-Berendt, B. G.; Latham, D. E.; Dambatta, M. B.; Morrill, L. C., ACS Cent. Sci. 2021, 7 (4), 570-585. 3. Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F.; Stevenson, N. G.; Donohoe, T. J., J. Am. Chem. Soc. 2015, 137 (50), 15664-7. 4. Akhtar, W. M.; Cheong, C. B.; Frost, J. R.; Christensen, K. E.; Stevenson, N. G.; Donohoe, T. J., J. Am. Chem. Soc. 2017, 139 (7), 2577-2580.
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