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

Andres R. Gomez-Angel, James R. Donald, James D. Firth, Claudia De Fusco, R. Ian Storer, Daniel J. Cox, Peter O'Brien*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number131961
Number of pages9
JournalTetrahedron
Volume83
Early online date22 Jan 2021
DOIs
Publication statusPublished - 12 Mar 2021

Bibliographical note

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

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