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

TETRAHEDRON

卷:83

Article

Gomez-Angel, Andres R.¹  Donald, James R.¹  Firth, James D.¹  De Fusco, Claudia²  Storer, R. Ian²  Cox, Daniel J.³  O'Brien, Peter¹ 

[1] Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England

[2] AstraZeneca, Struct Biophys & Fragments, Discovery Sci, BioPharmaceutial R&D, Cambridge, England

[3] Redbrick Mol Ltd, Innovat Ctr, 217 Portobello, Sheffield S1 4DP, S Yorkshire, England

关键词: Normorphan;    Vinyl MIDA boronate;    Building block;    Medicinal chemistry;    Lead-like compounds;   

DOI  :  10.1016/j.tet.2021.131961

来源: Elsevier

【 摘 要 】

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 sp(3) hybridised carbon atoms (Fsp(3)). 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. (C) 2021 Elsevier Ltd. All rights reserved.

【 授权许可】

Free