학술논문
Organometallic Bridge Diversification of Bicyclo[1.1.1]pentanes.
Document Type
Academic Journal
Author
Anderson JM; Medicinal Chemistry, GSK, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, UK, SG1 2NY.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK, G1 1XL.; Poole DL; Medicinal Chemistry, GSK, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, UK, SG1 2NY.; Cook GC; Medicinal Chemistry, GSK, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, UK, SG1 2NY.; Murphy JA; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK, G1 1XL.; Measom ND; Medicinal Chemistry, GSK, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, UK, SG1 2NY.
Source
Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 9513783 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3765 (Electronic) Linking ISSN: 09476539 NLM ISO Abbreviation: Chemistry Subsets: PubMed not MEDLINE; MEDLINE
Subject
Language
English
Abstract
Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1-electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron "late stage" approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched "chiral-at-BCP" bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.
(© 2023 Wiley-VCH GmbH.)
(© 2023 Wiley-VCH GmbH.)