Transannular cyclization reactions: a shortcut in the total synthesis of natural products (4 h)

The natural compounds are an endless source of ideas for the discovery of new drugs to treat diseases, and the total synthesis of complex natural products still represents a big challenge for the organic chemist. While many strategies applied to the synthesis of complex natural products are based on the construction of individual rings or fragments of the natural products followed by a unification step, or by the iterative annulation of one ring onto a preexisting ring, an efficient alternative strategy could be represented by the transannular cyclization reactions. Transannular reactions are defined as “those reactions which lead to the formation of covalent bond between atoms on opposite sides of the ring compound”. They usually occur in macrocyclic compounds that, to minimize transannular strain (Prelog strain), are constricted in rigid conformations that force some functional groups to be close to each other. This intimacy between functional groups confers entropic advantages “to enable transformations that are otherwise difficult in intermolecular and intramolecular settings”, making transannular reactions a highly efficient tool for the construction of complex polycyclic architectures. Transannular reactions are classified according to the reaction type involved in the cyclization process [Diels-Alder (TADA), ene reaction, [2+2] and other cycloadditions, Michael addition, aldol condensation, Mannich and miscellaneous reaction]. The transannular cyclisation process is the result of a series of cascade reactions that allow us to obtain a complex polycyclic architecture from an easily accessible macrocyclic compound, representing a shortcut in the synthesis of complex natural products. The entire process can be highly influenced by several factors such as the conformation of the macrocycle and the activation strategy. This course will outline the main features and the applications of transannular ring closure reactions and examples will be given to validate this approach as a versatile, efficient and flexible strategy to access new polycyclic structures on the way to the synthesis of important natural products.


A. Minassi


organic chemistry