Application of Ring-Closing Metathesis for the Synthesis of Benzo[3,4]azepino[1,2-b]isoquinolin-9-ones

Abstract

NoteIn order to heal cancer, chemotherapeutic treatments have been investigated over the last several decades.1,2) Conformation studies and synthesis of medium-sized heterocyclic compounds, which have been investigated as the scaffolds of many biologically interesting structures, have received more attention.3-5) Recently, we studied the synthesis of 3-arylisoquinoline derivatives such as indeno [1,2-c] 10) as constrained structures through molecular modeling to find plausible antitumor agents. The diversely rigidified 3-arylisoquinoline analogs exhibited promising cytotoxicities and topoisomerase I inhibitory activities.11) We also reported the convenient synthesis of protoberberines using ring-closing metathesis (RCM) as shown in Fig. 1. 12)Seven-membered heterocyclic rings are considered attractive molecules due to the points of structural determination of natural products as well as their interesting pharmacological actions. [3][4][5] In this paper we applied RCM [13][14][15][16][17][18][19][20][21][22][23][24][25][26] for the formation of seven-membered benzo [3,4]azepino[1,2-b]isoquinolinone 5, and the retrosynthetic pathway of benzo [3,4]azepino [1,2-b]isoquinolinone 5 is depicted in Chart 1. The coupling reaction of toluamide 7 with benzonitrile 8 afforded the 3-arylisoquinolinone 6, which could be modified to diene 4 as a key intermediate for the RCM reaction.The synthetic approach of using the RCM reaction to prepare the seven-membered ring was based on the synthesis of 3-arylisoquinolines 4 that contain olefins at the appropriate positions. To synthesize the 3-arylisoquinoline 6a, a coupling reaction between N,N-diethyl-o-toluamide 7a and benzonitrile 8a was performed (Chart 2).10) Generally, the chemical yield of this reaction is low (33 to 49%) due to the unknown side product and it is quite dependent on the substitution pattern of aromatic rings of the starting materials.10) As a part of our continuous research on natural alkaloids synthesis, including biological evaluation of 3-arylisoquinolines, the coupling reaction of o-toluamides with benzonitriles was utilized to provide the desired molecules.27) Significant increases in the topoisomerase I inhibitory activities of these compounds were observed through conversion of flexible 3-aryl rings to rigid forms such as isoindolo[2,1-b]isoquinolinones, benz-[b]oxepines, 12-oxobenzo[c]phenanthridinones and indeno-[1,2-c]isoquinolines, and molecular docking studies were used to explain the potency of these compounds.11) The above coupling reaction has advantages as a synthetic tool for the construction of 3-arylisoquinolines because it is easily adaptable to starting materials with diverse aromatic ring substitutions and it is a one-pot procedure for the construction of all essential carbon atoms in the desired molecules. Cycloaddition reaction between toluamides and benzonitriles was applied to prepare the 3-arylisoquinolines, and their chemical transformation to the dienes 4 was performed. The ring-closing metathesis (RCM) reaction afforded the desir...