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

Andrei Baran; Jevgenijs Kuzmins; Jevgenijs Kuznecovs; Alistair J.M. Farley; Tharindi Panduwawala; Anete Parkova; Pavel A. Donets; Jürgen Brem; Edgars Suna; Christopher J. Schofield; Kirill Shubin

doi:10.1021/acs.oprd.3c00002

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

Andrei Baran^*
, Jevgenijs Kuzmins
, Jevgenijs Kuznecovs
, Alistair J.M. Farley
, Tharindi Panduwawala
, Anete Parkova
, Pavel A. Donets
, Jürgen Brem
, Edgars Suna
, Christopher J. Schofield^*
, Kirill Shubin^*

^*Corresponding author for this work

Latvian Institute of Organic Synthesis
University of Oxford

Research output: Contribution to journal › Review article › peer-review

3 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	692-706
Number of pages	15
Journal	Organic Process Research and Development
Volume	27
Issue number	4
DOIs	https://doi.org/10.1021/acs.oprd.3c00002
Publication status	Published - 21 Apr 2023
Externally published	Yes

Keywords

Ellman auxiliary
epoxidation
indole carboxylates (InCs)
metallo-β-lactamase inhibitor
NDM-1
spiro cyclobutane
Suzuki−Miyaura coupling
VIM-1

Access to Document

10.1021/acs.oprd.3c00002

Cite this

@article{405d33ebcbea419cb9d3c3d942176a9e,

title = "Optimized Synthesis of Indole Carboxylate Metallo-β-Lactamase Inhibitor EBL-3183",

abstract = "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",

author = "Andrei Baran and Jevgenijs Kuzmins and Jevgenijs Kuznecovs and Farley, \{Alistair J.M.\} and Tharindi Panduwawala and Anete Parkova and Donets, \{Pavel A.\} and J{\"u}rgen Brem and Edgars Suna and Schofield, \{Christopher J.\} and Kirill Shubin",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2023",

month = apr,

day = "21",

doi = "10.1021/acs.oprd.3c00002",

language = "English",

volume = "27",

pages = "692--706",

journal = "Organic Process Research and Development",

issn = "1083-6160",

publisher = "American Chemical Society",

number = "4",

}

TY - JOUR

T1 - Optimized Synthesis of Indole Carboxylate Metallo-β-Lactamase Inhibitor EBL-3183

AU - Baran, Andrei

AU - Kuzmins, Jevgenijs

AU - Kuznecovs, Jevgenijs

AU - Farley, Alistair J.M.

AU - Panduwawala, Tharindi

AU - Parkova, Anete

AU - Donets, Pavel A.

AU - Brem, Jürgen

AU - Suna, Edgars

AU - Schofield, Christopher J.

AU - Shubin, Kirill

PY - 2023/4/21

Y1 - 2023/4/21

N2 - 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.

AB - 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.

KW - Ellman auxiliary

KW - epoxidation

KW - indole carboxylates (InCs)

KW - metallo-β-lactamase inhibitor

KW - NDM-1

KW - spiro cyclobutane

KW - Suzuki−Miyaura coupling

KW - VIM-1

UR - https://www.scopus.com/pages/publications/85151329123

U2 - 10.1021/acs.oprd.3c00002

DO - 10.1021/acs.oprd.3c00002

M3 - Review article

AN - SCOPUS:85151329123

SN - 1083-6160

VL - 27

SP - 692

EP - 706

JO - Organic Process Research and Development

JF - Organic Process Research and Development

IS - 4

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this