Carbene-catalyzed enantioselective access to bioactive dihydropyridazinones and atroposelective access to binaphthyl ligands

• Main Author: Mondal Bivas
• Other Authors: Robin Yonggui Chi
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Science::Chemistry
• Online Access: https://hdl.handle.net/10356/156030
• Institution: Nanyang Technological University

Development of new methodology for quick access to important molecular motifs is a growing field of research in synthetic organic chemistry. In this aspect, N-heterocyclic carbene (NHC) has witnessed a significant achievement, specifically in asymmetric synthesis, in last two decades. Special attention has been given to efficient asymmetric access to bioactive molecules and other valuable scaffolds with potential applications. In this thesis, we have introduced two interesting NHC-catalyzed methodology development for access to biologically active dihydropyridazinone scaffolds and bicyclic vinyl esters, a precursor to binaphthyl-based ligands. In chapter 1, different activation modes enabled by NHC have been discussed briefly. This includes three main domains of NHC-catalysis, (a) chemistry of umpoled acyl-anion, (b) catalysis involving homoenolate intermediate, and (c) acyl-azolium chemistry. In chapter 2, we have discussed a new (3+3)-cycloaddition reaction between rarely explored umpoled 1,3-dinucleophiles from arylidene hydrazones and α,β-unsaturated acylazolium to access biologically important 6-aryl dihydropyridazinone scaffolds in excellent outcome (up to 89% yield and 98.5:1.5 e.r.). Further, we have discussed the conversion of the products from our catalytic cycle to clinically approved drugs (Levosimendan, Pimobendan) and bioactive molecules (DNMDP, Meribendan). In chapter 3, we have demonstrated an unprecedented carbene-catalyzed dynamic kinetic resolution (DKR) on bicyclic ketone/enol to access atropo-enriched enolic ester in excellent yield (up to 95%) and moderate optical purity (up to 91.5:8.5 e.r.). Worthy to note this is the first example of NHC-catalyzed DKR process to access axially chiral compounds. We also have discussed that many ligands have the similar scaffolds with the product from our catalytic cycle. In the end, we have shown the importance of our methodology by formal synthesis of a ligand from our catalytic product with high efficiency.