Total Synthesis of Nakadomarin A und Manzamine A

Nakadomarin A and Manzamine A are two naturally occurring alkaloids with a hexa- and pentacyclic skeleton, respectively, bearing 4 to 5 carbon stereocentres, one of them being quarternary, around which all further stereocentres are allocated in close vicinity. Both molecules have a very promising bioactivity profile, ranging from antituberculosis over anti-HIV to antimalarial activity. Due to this pharmacological activity, an efficient synthesis of these complex structures is imperative to determine reliable structure-activity relationships, synthesise derivatives and finally generate drug candidates based on these natural products. In this proposal, we describe an organocatalysed entry to these structures in an enantioselective, convergent manner. Avoiding unnecessary protection/deprotection steps is a key concept to keep our synthesis as short as possible. Chirality shall be introduced to the system by a chiral counterion controlled acyl iminium cyclisation to yield the central 8-ring fused pyrrolidine. The coupling of this fragment with a Michael acceptor can be achieved in an organocatalysed 1,4-addition. Due to the mild conditions in organocatalysed reactions, protecting group are not necessary in this step and the product can be functionalised further without any additional manipulation.