Diastereoselective synthetic approaches to functionalised tetrahydropyrrolo[3,4-a] carbazole derivatives

Abstract

The heterocyclic carbazoles are privileged scaffolds present in many biologically active naturally occurring and synthetic compounds. Herein, we disclose our investigations into new approaches towards the diastereoselective synthesis of highly functionalised tetrahydropyrrolo[3,4-a] carbazole derivatives, and the subsequent evaluation of their biological activities. Our synthetic methodology is based on an initial intermolecular Diels-Alder (D-A) reaction between a substituted 3-vinyl-1H-indole 1, containing an electron withdrawing N-protecting group, and a range of dienophiles. This key step allows access to a variety of the D-A cycloadducts 2 in good yields (64-85%) and as single diastereomers, arising from an endo selective D-A cycloaddition (Scheme 1). Scheme 1. D-A reaction of N-protected, substituted 3-vinyl-1H-indole 1 The new alkene bond generated in the D-A reaction is highly reactive towards electrophiles and has a propensity towards migration, to rearomatise the indole ring. Thus we decided to exploit this reactivity to generate our target pyrrolo[3,4-a]carbazoles using a number of different approaches (Scheme 2). Route 1: D-A cycloadducts 2 was further functionalised using an intermolecular ene reaction to afford the tetrahydropyrrolo[3,4-a]carbazoles 3. Route 2: Alternatively intramolecular carbonyl-ene reactions of D-A cycloadducts 2 were investigated as a route to polycyclic tetrahydropyrrolo[3,4-a]carbazoles 4. Abstract Page iii Route 3: Finally bromination of the reactive alkene followed by in situ trapping with a nucleophilic amines gave access to amine functionalised tetrahydropyrrolo[3,4-a]carbazoles 5. These could in turn be deprotected via a PtO2 catalysed hydrogenation to give a focussed library of biologically active molecules 6. Scheme 2. Synthetic approaches towards functionalised pyrrolo[3,4-a]carbazole