转自：康龙化成

Thianthrenium-enabled Modular Synthesis of Bicyclo[1.1.1]pentanes

Zibo Bai , Zikuan Wang , Thomas Hin-Fung Wong & Tobias Ritter*

Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

—Nat. Synth., 2025, doi: org/10.1038/s44160-025-00821-8.

Recommended by Bingbing Chang_MC5

KEY WORDS:Photo chemistry, SN2 reaction (反应类型), C(sp3)–C(sp3), C(sp3)–C(sp2), C(sp3)–S, C(sp3)–O, C(sp3)–Se, C(sp3)–N (成键类型), iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT+) (原料), bicyclo[1.1.1]pentanes,BCP (产物)

ABSTRACT: The incorporation of three-dimensional small-ring scaffolds into bioactive molecules can enhance metabolic stability and solubility. Over the last decade, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres for para-substituted benzene rings in drug discovery. However, BCP synthesis typically requires de novo synthesis from volatile [1.1.1]propellane, whereas more stable BCP reagents, such as alkyl BCP iodides, allow modification at only one end, limiting their application to end groups. Prof. Tobias Ritter et al. describe a stable, bifunctional iodobicyclo[1.1.1] pentylmethyl thianthrenium (IBM-TT+) reagent for modular BCP bioisostere production. The cationic thianthrenium group at the neopentyl site of IBM-TT+ facilitates chemoselective substitutions through electrostatic interactions, overcoming the high energy barriers of bimolecular nucleophilic substitution (SN2) at neopentylsites. The retained BCP iodide functionality serves as a second versatile handle for metal-halogen exchange, photoredox chemistry or transition-metal catalysis.The dual reactivity of IBM-TT+ allows synthesis of a multitude of BCP bioisosteres for benzyl amines, ethers, esters,thioethers and diarylmethanes.

Background and Synthesis of IBM-TT+ reagent 2 a) State-of-the-art of 1,3-disubstituted bicyclo[1.1.1]pentanes. b) Representative benzyl-containing drugs. c) Modular synthesis of methylene bicyclo[1.1.1]pentanes enabled by a thianthrenium-based reagent

Substrate scope

Synthesis of BCP pharmaceutical analogues

Prof. Tobias Ritter et al. developed a stable bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium reagent, IBM-TT+. By exploiting the distinct reactivity of thianthrenium and iodine groups, this reagent enables the efficient and modular introduction of various functional groups onto BCP scaffolds that can now be used as core structure, to be functionalized at both termini, as opposed to currently available BCP end groups. They have efficiently synthesized BCP analogues of known benzyl-containing pharmaceuticals, highlighting the potential of reagent 2 in drug development. Moving forward, They envision that enhancing the practical application of their modular approach using reagent 2through methods such as continuous-flow chemistry and the development of analogues of 2 that lack or incorporate substituted methylene groups will be a promising avenue for future research.

（转自：康龙化成）