Optimized Synthesis of Indole Carboxylate Metallo-β-Lactamase Inhibitor EBL-3183

Organic Process Research and Development 2023
Andrei Baran, Jevgenijs Kuzmins, Jevgenijs Kuznecovs, Alistair J M Farley, Tharindi panduwawala, Anete Parkova, Pavel A Donets, Jurgen Brem, Edgars Sūna, Cristopher J Schofield, Kirill Shubin

A new synthetic route for the preparation of the metallo-β-lactamase inhibitor pre-candidate EBL-3183 was developed and carried out on a kilogram scale. The described process starts from a commercially available indole-2-carboxylate and employs an Ellman auxiliary approach coupled with ruthenium-catalyzed stereoselective reduction for the introduction of chirality. The key spirocyclic cyclobutane motif was assembled utilizing an epoxide building block, which was conveniently obtained in diastereomerically pure form. The amount and quality of the prepared final target EBL-3183 were sufficient for the preclinical studies.

Keywords
Ellman auxiliary | epoxidation | indole carboxylates (InCs) | metallo-β-lactamase inhibitor | NDM-1 | spiro cyclobutane | Suzuki−Miyaura coupling | VIM-1
DOI
10.1021/acs.oprd.3c00002
Hyperlink
https://pubs.acs.org/doi/10.1021/acs.oprd.3c00002

Baran, A., Kuzmins, J., Kuznecovs, J., Farley, A., Panduwawala, T., Parkova, A., Donets, P., Brem, J., Sūna, E., Schofield, C., Shubin, K. Optimized Synthesis of Indole Carboxylate Metallo-β-Lactamase Inhibitor EBL-3183. Organic Process Research and Development, 2023, Vol. 77, No. 4, pp.692-706. ISSN 1083-6160. Available from: doi:10.1021/acs.oprd.3c00002

Publication language
English (en)