Research Projects

Macrocycles are often considered as potential candidates in drug discovery due to their conformational flexibility, like helix and turn structures, resulting in selective binding to the surface of large protein structures, metabolic stability and passive membrane permeability. Among various macrocyclic structures, cyclic peptides, cyclophane-braced cyclic peptides or cyclophanes are common. The macrocyclic skeletons are often furnished mainly through macrolactonization, macroaldolizations, macrolactamizations, internal disulfide bonding, ring-closing metathesis, cyclic click reactions, template-directed cyclisation and Ugi-based multicomponent macrocyclization. However, limitations like structural pre-organisation, functional group protection–deprotection steps, high dilution conditions and application of exclusive coupling reagents forced the synthetic community to search for alternative, straightforward and unconventional pathways to explore the new synthetic macrocycles in drug discovery. The planar and axial chirality in macrocyclic molecules is immensely important due to its occurrence in natural products and utility in asymmetric catalysis. However, the atroposelective macrocyclizations are limited compared to the asymmetric synthesis of other types of chiral compounds, especially via the induction of asymmetry during the macrocyclization step. Metal-carbenes generated from diazo compounds have noteworthy potential in the construction of heterocycles/carbocycles or heterocycle/carbocycle functionalizations via site-selective, chemoselective or stereoselective functionalizations. However, their use in transition metal-catalysed macrocyclization is limited. To the best of our knowledge, macrocyclic scaffolds with axially or planar chiral skeletons have hardly been explored via metal-carbene insertion. We propose the design of the substrates with suitably positioned diazo to offer underexplored synthetic cyclophane-braced peptidic or cyclophane macrocycles through unconventional insertion/migratory insertion of metal carbene. Further, the methodical screening of transition metal-based chiral catalytic systems will afford the synthetically challenging planar and axial chiral macrocycles via C-C, C-N and N-N bond formations. Axially chiral macrocyclic binaphthyldiol, azabinaphthyldiol, diazabinaphthyldiol, and their corresponding biphenyl disphosphine ligands bearing carbon chain bridges or polyether-type linkages have recently gained significant attention due to their applications in various asymmetric transformations. There is hardly any known method of preparation of this class of axially chiral macrocyclic diphosphine ligands in an asymmetric manner. We propose that the axial chiral macrocyclic binaphthyl, azabinaphthyl, diazabinaphthyl diols can be directly synthesised using the corresponding ortho-hydroxy enaminone tethered diazonaphthoquinone via C-C bond activation and subsequent migratory rearrangement under suitable chiral transition metal catalysed conditions. These macrocyclic chiral diols can be extended to the corresponding diphosphines and can be applied to various asymmetric transformations like enantioselective intramolecular hydroarylations. Next, the construction of macrocyclic C-N and N-N axially chiral pyridone-based cyclophanes is proposed under catalytic chiral rhodium complex using suitable diazo precursors. They can be transformed into corresponding chiral phosphine ligands and utilised for asymmetric arylations. Planar chiral cyclophanes are important skeletons due to their applications in natural products, host-guest chemistry, catalysis and drug development. We propose a synthetic plan for a sulfur-containing planar chiral macrocycle using an aryl thioether tethered with an ansa chain and diazo functionality under suitable chiral conditions. Finally, a cyclic peptide-based macrocyclic natural product, biarylitide, is proposed using the key step as the site-selective insertion of metal carbene.