A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

Abstract

Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy-substituted isoquinolines at C-1, followed by reaction with iodine. Subsequent Suzuki cross-coupling of the resulting 1-iodoisoquinolines to methyl 2-(isoquinolin-1-yl)benzoates and intramolecular acylation of the corresponding carboxylic acids with Eaton’s reagent afforded five alkaloids of the oxoisoaporphine type. The yield of the cyclization step strongly depends on the electrophilic properties of ring B. An alternative cyclization protocol via directed remote metalation of ester and amide intermediates was investigated thoroughly, but found to be not feasible. Two of the alkaloids showed strong cytotoxicity against the HL-60 tumor cell line.

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

“…Inspired by reports of Knochel’s [19–20] and our group [21–23] on direct metalation of substituted isoquinolines at C-1 and in continuation of our recent work on the synthesis of aromatic oxoaporphine, oxoisoaporphine and pyridoacridine alkaloids [17–18 21–22] using direct ring metalations of heterocycles with the hindered amide base TMPMgCl∙LiCl as crucial step, the Knochel–Hauser base was again the metalation reagent of our choice.…”

Isoquinoline-based biaryls as a robust scaffold for microtubule inhibitors

“…The required isoquinoline building blocks were then synthesised by a modified Pomeranz-Fritsch reaction according to Reimann 23 . These were directly metalated at C-1 using Knochel-Hauser base 24 similarly to our previously published procedure 25 , and Suzuki coupled with appropriately-substituted phenylboronic esters 26 to deliver the target compounds IQTub1-5 and IQTub8. Methylating IQTub3 and IQTub4 yielded IQTub7 and IQTub6 respectively.…”

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

“…Numerous methods have been published over the decades for the construction of highly substituted isoquinolines [4]. Alternatively, subsequent functionalization of isoquinolines is feasible, e.g., via Pd-catalyzed C–H functionalization [5] or regioselective direct ring metalation (at C1) [6–8]. General aspects of the direct methylation of electron-deficient N -heterocycles have been reviewed [9].…”

“…Our new strategy was fueled by our previous findings in the course of new approaches to benzylisoquinoline, oxoaporphine [7], and oxoisoaporphine alkaloids [8], where we could demonstrate the power of regioselective direct ring metalations of isoquinolines at C1 with sterically hindered amide bases like TMPMgCl∙LiCl (Knochel–Hauser base) [6]. For our present purpose, an appropriate 1-metalated isoquinoline species was to be converted into the corresponding 1-methyl product.…”