Diversity-Oriented Synthesis of Highly Fluorescent Fused Isoquinolines for Specific Subcellular Localization

Abstract

A multicomponent diversity-oriented synthesis of new highly emissive tetracyclic isoquinolines that target specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi fourcomponent reaction, followed by either an intramolecular alkyne hydroarylation and subsequent alkene isomerization or through a Pomeranz−Fritsch-type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of these compounds using green channel confocal microscopy revealed remarkable and distinctive distribution patterns in live cells, showing an unprecedented high selectivity and imaging contrast. The differentiated organelle visualizationincluding localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum, and plasma membranewas achieved by varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting Ugi reaction.

Synthesis of Tetrahydro‐4H‐pyrido[1,2‐b]isoquinolin‐4‐ones from Ugi 4‐CR‐Derived Dihydroisoquinoline‐Xanthates**

“…Then, 10 a-d were directly submitted to the previously reported Au-catalyzed hydroarylation conditions with JohnPhosAu(MeCN)SbF 6 (5 mol%) in chloroform at room temperature. [14] Thus, after 2.5 h of stirring under open-flask conditions, TLC analysis showed the complete transformation of 9 a-d into the cyclic intermediates 17 a-d (Scheme 2). It is worth mentioning that the use of electron-rich benzaldehydes is necessary to promote the complete transformation of the propargylic-derived Ugi adduct into the desired tetrahydroisoquinoline core.…”

“…[12] In this context, as part of our ongoing program for developing Diversity-Oriented protocols for the rapid construction of different heterocyclic scaffolds, [13] we recently described a multicomponent approach for the synthesis of highly emissive fused-dihydroisoquinolines which found application as organelle targeting-fluorescent molecular probes in live HeLa cells. [14] In this early work, the dihydroisoquinoline skeleton was constructed by a gold-catalyzed hydro-arylation reaction of propargyl-containing Ugi 4-CR adducts 9, followed by an acidcatalyzed double bond isomerization (exo!endo) and a subsequent intramolecular Heck reaction with o-halo(hetero)arenes to furnish the tetracyclic-fused isoquinolines of type 10 (Scheme 1). This schematic approach led to the idea that the change of the acid in the Ugi reaction would be an important point of diversification to broaden the scope of the method.…”

Dual-State Emission (DSE) in Organic Fluorophores: Design and Applications

“…Restricting motions by changing the viscosity of the surrounding media is a well-known strategy that has been used to increase the fluorescence of the molecules in solution . This approach offers an opportunity to detect biomolecular interactions, and more recently, it has been used to evaluate microenvironments in subcellular organelles. , However, the precise assessment of the rotational frequencies in the solid state is a less documented aspect, due in part to the different motion regimes. Nevertheless, their relevance has been evidenced in qualitative models like the restriction of intramolecular rotations (RIR) or restriction of intramolecular vibrations (RIV). ,,, …”

Annulation of the Ugi Products Using Palladium Catalysts

“…The authors of an intriguing study [53] wanted to synthesize fluorescence fused isoquinolines, so they use two special functions in the Ugi substrates. The first is the use of an especial amine; a 2,2‐dimethoxyethylamine 91 moiety in the structure of Ugi adducts promotes the Pomeranz–Fritsch cyclization [54] in the presence of an Au complex as a catalyst to give isoquinoline 92 ; or upon introduction of propargyl amine 57 into the structure of Ugi product, a Brønsted acid‐mediated intramolecular alkyne hydroarylation/alkene isomerization (exo → endo) is occurred to achieve the corresponding isoquinolines 92 .…”

“…The second function was the use of 2‐halobenzoic or phenylacetic acids 91 to perform an intramolecular Heck reaction, furnishing the desired fluorescent fused isoquinolines 93 (Scheme 31). The importance of this research was the subcellular localization studies of fluorophores 93 for targeting lysosomes to be used as the organelle‐targeted probes [53] …”