Studies on catalytic macrocyclization towards the synthesis of macrocyclic ketones macrolactones and macrolactams

Abstract

Nature is the biggest source of bioactive macrocyclic compounds, which have an indispensable impact on human lives. Currently, many approved drugs feature a macrocycle moiety as their bioactive core. Furthermore, macrocycles play an important role in supramolecular chemistry, catalysis, nanotechnology and various other fields. Although macrocyclic compounds are important in diverse applications, their synthesis is a long-standing challenge for organic chemists as it is an entropically forbidden process. Despite the challenges associated with macrocyclization, numerous synthetic methods have been developed for the synthesis of macrocycles. The conventional synthetic methods include stoichiometric amounts of coupling reagents and alkyl halides as electrophiles, resulting in copious waste. Consequently, there are very few catalytic methods have been developed for macrocyclization that avoid toxic and halogenated waste. However, diversity and specially designed substrates are required for these catalytic macrocyclizations. Therefore, the development of general, effective, and efficient catalytic strategies for macrocyclization is always an important theme of research in synthetic chemistry. Thus, we have studied macrocyclization by utilizing the borrowing hydrogen catalysis and acceptorless dehydrogenation. Intriguingly, these methods use easily accessible/available alcohols, produce environmentally benign (H2O and H2 as) byproducts and follow many of the green chemistry principles. In the initial part of the research, we studied Ru-MACHO catalyzed domino macrocyclization reaction using diols and amino acetophenones for the simultaneous construction of C-C and C-N bonds with the removal of water as the only byproduct. This method is diversified with several substrates and investigated the mechanism by experimental evidences.