Synthetic/Catalytic Studies Towards Construction of Macrocycles Under Batch and Continuous Flow Conditions

Abstract

Macrocyclic compounds are large-sized cyclic structures constituted by more than 12 atoms and are found as important scaffolds in medicine, materials, sensors, and catalysis applications. Macrocycles are also important scaffolds in many natural products. Broader applications and less abundance of these macrocycles fascinated researchers to develop synthetic approaches using stoichiometric reagents or catalysts. Since macrocyclisation is an entropically challenging process, it requires high-dilution conditions. The catalytic macrocyclisation has several advantages, including green chemistry matrices over the conventional methods using stoichiometric reagents. However, very limited catalytic approaches are available for macrocyclisation, which uses specially designed substrates. Another important challenge in macrocyclisation is the handling of high dilution and scalability. In this direction, our research is focused on the development of catalytic approaches for efficient macrocyclisation under batch/flow conditions. The initial study involved the catalytic borrowing hydrogen concept for the synthesis of macrocyclic ketones using alcohols and ketones through intramolecular borrowing macrocyclic alkylation. This domino process proceeds through oxidation, condensation, and reduction which gives water as a sole by-product. Further, this macrocyclisation is extended to the synthesis of natural products like engelhardione, acerogenin, and their analogues. Next, to address the scalability and high dilution condition, the macrolactonisation was investigated under a continuous flow module using dicarboxylic acids with diols for inter-molecular macrolactonization and intra-molecular macro-lactonization of various seco-acids using Mukaiyama reagent as an acid activator. To avoid the stoichiometry reagent, a reusable heterogeneous catalyst was prepared for the dehydrative macrolactonisation. Several seco-acids were prepared and studied the macrolactonisation using a Ru-zeolite as a heterogeneous catalyst under continuous flow chemistry to afford the diverse macrocyclic lactone with different ring sizes (12 to 19). This continuous-flow catalysis was also studied for intramolecular dehydrative coupling of diols for the synthesis of macrocyclic ether using Ni-Zeolite. Finally, we performed our studies towards catalytic dehydrative macrocyclic olefination under continuous flow using primary alcohols and secondary alcohols. Among a series of catalysts, the Ni-zeolite catalyst was found robust and efficiently dehydrates unsymmetric diols to furnish various macrocyclic alkenes. All the above studies were investigated with several substrates and the appropriate mechanism was justified by detailed experimentation in the thesis book.