Intramolecular Didehydro-Diels–Alder Reaction and Its Impact on the Structure–Function Properties of Environmentally Sensitive Fluorophores.

Abstract

Reaction discovery plays a vital role in accessing new chemical entities and materials possessing important function.1 In this Account, we delineate our reaction discovery program regarding the [4 + 2] cycloaddition reaction of styrene-ynes. In particular, we highlight our studies that lead to the realization of the diverging reaction mechanisms of the intramolecular didehydro-Diels-Alder (IMDDA) reaction to afford dihydronaphthalene and naphthalene products. Formation of the former involves an intermolecular hydrogen atom abstraction and isomerization, whereas the latter is formed via an unexpected elimination of H2. Forming aromatic compounds by a unimolecular elimination of H2 offers an environmentally benign alternative to typical oxidation protocols. We also include in this Account ongoing work focused on expanding the scope of this reaction, mainly its application to the preparation of cyclopenta[b]naphthalenes. Finally, we showcase the synthetic utility of the IMDDA reaction by preparing novel environmentally sensitive fluorophores. The choice to follow this path was largely influenced by the impact this reaction could have on our understanding of the structure-function relationships of these molecular sensors by taking advantage of a de novo construction and functionalization of the aromatic portion of these compounds. We were also inspired by the fact that, despite the advances that have been made in the construction of small molecule fluorophores, access to rationally designed fluorescent probes or sensors possessing varied and tuned photophysical, spectral, and chemical properties are still needed. To this end, we report our studies to correlate fluorophore structure with photophysical property relationships for a series of solvatochromic PRODAN analogs and viscosity-sensitive cyanoacrylate analogs. The versatility of this de novo strategy for fluorophore synthesis was demonstrated by showing that a number of functional groups could be installed at various locations, including handles for eventual biomolecule attachment or water-solubilizing groups. Further, biothiol sensors were designed, and we expect these to be of general utility for the study of lipid dynamics in cellular membranes and for the detection of protein-binding interactions, ideal applications for these relatively hydrophobic fluorophores. Future studies will be directed toward expanding this chemistry-driven approach to the rational preparation of fluorophores with enhanced photophysical and chemical properties for application in biological systems.

The Cation−π Interaction Enables a Halo-Tag Fluorogenic Probe for Fast No-Wash Live Cell Imaging and Gel-Free Protein Quantification

“…Solvatochromic fluorophores are molecules with a delocalized aromatic π-system capped with an electron-donating group and an electron-withdrawing group. 28,29 They have been extensively utilized in the design of fluorogenic chemical probes for proteins because their quantum yield increases dramatically when they are embedded in hydrophobic protein interiors (Figure 1, bottom box). 30−32 Previous studies have demonstrated their general applicability in biological applications, in particular, live cell imaging.…”

Modern Synthetic Avenues for the Preparation of Functional Fluorophores

“…The use of didehydro‐Diels–Alder reactions for the preparation of environmentally sensitive probes (Figure 6 B) was recently summarized by Brummond and Kocsis 45. Such processes can afford dihydronaphthalene and naphthalene fluorophores resembling the solvatochromic dye Prodan.…”

Moderne Strategien zur Synthese funktioneller Fluorophore

“…Cycloadditionen mit hetero‐ oder carbocyclischen Partnern wurden im Zusammenhang mit der Fluorophorsynthese ebenfalls beschrieben. Die Verwendung von Didehydro‐Diels‐Alder‐Reaktionen zur Herstellung von umgebungsempfindlichen Sonden (Abbildung B) wurde kürzlich von Brummond und Kocsis zusammengefasst . Solche Prozesse können Dihydronaphthalin‐ und Napthalinfluorophore hervorbringen, die dem solvatochromen Farbstoff Prodan ähneln.…”