How cycloalkane fusion enhances the cycloaddition reactivity of dibenzocyclooctynes

Dennis Svatunek, Anton Murnauer, Zhuoting Tan, K. N. Houk, Kathrin Lang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Dibenzoannulated cyclooctynes have emerged as valuable compounds for bioorthogonal reactions. They are commonly used in combination with azides in strain-promoted 1,3-dipolar cycloadditions. They are typically, however, unreactive towards 3,6-disubstituted tetrazines in inverse electron-demand Diels-Alder cycloadditions. Recently a dibenzoannulated bicyclo[6.1.0]nonyne derivative (DMBO) with a cyclopropane fused to the cyclooctyne core was described, which showed surprising reactivity towards tetrazines. To elucidate the unusual reactivity of DMBO, we performed density functional theory calculations and revealed that a tub-like structure in the transition state results in a much lower activation barrier than in the absence of cyclopropane fusion. The same transition state geometry is found for different cycloalkanes fused to the cyclooctyne core albeit higher activation barriers are observed for increased ring sizes. This conformation is energetically unfavored for previously known dibenzoannulated cyclooctynes and allows tetrazines and azides to approach DMBO from the face rather than the edge, a trajectory that was hitherto not observed for this class of activated dieno- and dipolarophiles.

Original languageEnglish
Pages (from-to)2229-2235
Number of pages7
JournalChemical Science
Volume15
Issue number6
DOIs
StatePublished - 8 Jan 2024
Externally publishedYes

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