Preparation of Reduced Pyrazino[2,1-a]isoquinoline Derivatives: Important Heterocycles in the Field of Bioactive Compounds

Partially hydrogenated pyrazino[2,1-a]isoquinoline derivatives, such as praziquantel, have been the subject of significant research efforts in the field of medicinal chemistry, thanks to their antihelmintic, antiprotozoal, and antifungal activities. Nevertheless, methods for their efficient synthesis (and especially for their stereoselective preparation) can be traced back to just a few general procedures. In this short review we will summarize the approaches developed so far to access pyrazino[2,1-a]isoquinolines, with a particular focus on bioactive derivatives, and will highlight their features and weaknesses, aiming to stimulate further investigations in the preparation of this important class of heterocyclic compounds. 1 Introduction 2 Different Approaches to the Synthesis of Pyrazino[2,1-a]isoquinolines 2.1 1-(Aminomethyl)tetrahydroisoquinoline Ring Closure 2.2 Diketopiperazine Reduction/Cyclization 2.3 N-Acyliminium Ion Cyclizations 2.4 Radical Cyclizations 2.5 Multicomponent Reactions 2.6 Miscellaneous Routes 3 Access to Enantiomerically Pure Praziquantel 4 Conclusions