Synthesis and functionalisation of a bifunctional normorphan 3D building block for medicinal chemistry

Abstract

A multi-gram-scale synthetic route to a novel, bifunctional normorphan 3D building block bearing orthogonally reactive vinyl MIDA boronate and N-2,4-dimethoxybenzyl (DMB) amide functional handles has been developed. Synthetic manipulation at each of the functional handles has been demonstrated including Suzuki-Miyaura cross-coupling, exo-diastereoselective hydrogenation, N-DMB group removal and lactam reduction. Normorphan cores derived from the building block satisfied AstraZeneca's ‘rule of 2’ for building blocks and had a high fraction of sp3 hybridised carbon atoms (Fsp3). A virtual lead-like library of 344 compounds derived from the building block had attractive lead-like properties. The 3D building block has been commercialised by Redbrick Molecular and is currently available for purchase.

Metadata

Item Type:	Article
Authors/Creators:	Gomez-Angel, Andres R. Donald, James R. https://orcid.org/0000-0002-2176-4902 Firth, James D. (jdf511@york.ac.uk) De Fusco, Claudia Ian Storer, R. Cox, Daniel J. O'Brien, Peter https://orcid.org/0000-0002-9966-1962
Copyright, Publisher and Additional Information:	This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Funding Information: This project was funded by The Royal Society (Industry Fellowship with AstraZeneca , INF∖R1∖191028 , POB), the EPSRC Impact Accelerator Account ( IAA ) ( JRD ) and the Higher Education Innovation Fund ( HEIF ) ( JRD ). We are grateful to AstraZeneca and Redbrick Molecular for their interest in this project, and we thank Sam Hart for X-ray crystallography and Andy Hogben (Redbrick Molecular) for useful discussions. Funding Information: This project was funded by The Royal Society (Industry Fellowship with AstraZeneca, INF?R1?191028, POB), the EPSRC Impact Accelerator Account (IAA) (JRD) and the Higher Education Innovation Fund (HEIF) (JRD). We are grateful to AstraZeneca and Redbrick Molecular for their interest in this project, and we thank Sam Hart for X-ray crystallography and Andy Hogben (Redbrick Molecular) for useful discussions. Publisher Copyright: © 2021 Elsevier Ltd
Keywords:	Building block,Lead-like compounds,Medicinal chemistry,Normorphan,Vinyl MIDA boronate
Dates:	Published: 12 March 2021 Published (online): 22 January 2021 Accepted: 18 January 2021
Institution:	The University of York
Academic Units:	The University of York > Faculty of Sciences (York) > Chemistry (York)
Depositing User:	Pure (York)
Date Deposited:	05 Mar 2021 16:40
Last Modified:	30 Mar 2025 00:09
Published Version:	https://doi.org/10.1016/j.tet.2021.131961
Status:	Published
Refereed:	Yes
Identification Number:	10.1016/j.tet.2021.131961
Related URLs:	http://www.scopus.com/inward/record.url?...
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:171880

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Synthesis and functionalisation of a bifunctional normorphan 3D building block for medicinal chemistry

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