Abstract
The Castagnoli–Cushman reaction of 3,4-dihydroisoquinolines with glutaric anhydride, its oxygen and sulfur analogues was investigated as a one-step approach to the benzo[a]quinolizidine system and its heterocyclic analogs. An extension towards the pyrrolo[2,1-a]isoquinoline system was achieved with the use of succinic anhydride. The results are evidence of an unexplored method for the access of the aforementioned tricyclic annelated systems incorporating a bridgehead nitrogen atom. The structures and relative configurations of the new compounds were established by means of 1D and 2D NMR techniques. The reactions between 1-methyldihydroisoquinoline and glutaric, diglycolic and succinic anhydrides yielded unexpected isoquinoline derivatives containing an exocyclic double bond. The compounds prepared bear the potential to become building blocks for future synthetic bioactive molecules.
Highlights
The benzo[a]quinolizidine ring system is an important heterocyclic framework found in natural products and prospective pharmaceuticals [1]
A comparative study on novel classes of anticancer drugs identified benzo[a]quinolizines 3 and 4 (Figure 1) to be useful for a specific inhibition of heat shock response in cancer cells, which strongly enhances the treatment by sensitizing cancer cells to anticancer drugs [5]
Our synthetic strategy relied on the possibility to form ring C of the target ring system using the Castagnoli–Cushman reaction between 6,7-dimethoxy-3,4-dihydroisoquinoline (18) and its 1-substituted derivatives 19 and 20, and the anhydrides 5–8
Summary
The benzo[a]quinolizidine ring system is an important heterocyclic framework found in natural products and prospective pharmaceuticals [1]. A comparative study on novel classes of anticancer drugs identified benzo[a]quinolizines 3 and 4 (Figure 1) to be useful for a specific inhibition of heat shock response in cancer cells, which strongly enhances the treatment by sensitizing cancer cells to anticancer drugs [5] The presence of such structural pattern has Beilstein J. The purpose of the present investigation was to explore the much less studied reaction between monocyclic anhydrides 5–8 and cyclic imines (such as 6,7-dimethoxy-3,4-dihydroisoquinoline (18) and its 1-alkyl derivatives 19 and 20) as a potential one-step route towards substituted benzo[a]quinolizidinones and pyrrolo[2,1-a]isoquinolinones. This reaction would allow the construction of bioisosteric oxygen and sulfur derivatives of the target heterocyclic framework
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