Carbene-catalyzed dynamic kinetic resolution for asymmetric access to phthalidyl esters and benzofuranone derivatives

• Main Author: Majhi, Pankaj Kumar
• Other Authors: Robin Yonggui Chi
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Chemistry
• Online Access: https://hdl.handle.net/10356/142580
• Institution: Nanyang Technological University

In this thesis, we have demonstrated two dynamic kinetic resolution strategies enabled by N-heterocyclic carbene. Firstly, asymmetric acylation of hydroxyphthalides through N-heterocyclic carbene catalyzed dynamic kinetic resolution approach has been achieved. In addition, enantioselective modification of hydroxyphthalides containing natural products has also been achieved utilizing this DKR process. Secondly, enantioselective synthesis of 3,3'-disubstituted benzofuran-2(3H)-one derivatives bearing vicinal quaternary stereogenic centers, enabled by N-heterocyclic carbene catalyzed dynamic kinetic resolution process, has been developed. We anticipated that these methodologies can play a vital role in the synthesis of medicinally important molecules and natural products. In chapter 1, a brief introduction of dynamic kinetic resolution approach and different modes of reactions enabled by NHC catalysis have been demonstrated. N-heterocyclic carbene-catalyzed kinetic resolution and dynamic kinetic resolution have also been introduced in this chapter. In chapter 2, enantioselective acylation of hydroxyphthalides via NHC-catalyzed dynamic kinetic resolution approach has been discussed. Phthalidyl esters were achieved with high enantioselectivities and high yields (up to 99:1 e.r. and up to 96% yield). Moreover, asymmetric modification of natural products that contained hydroxyphthalide units, such as Corollosporine and Fimbricalyxlactone C, have also been demonstrated. In chapter 3, asymmetric synthesis of 3,3'-disubstituted benzofuran-2(3H)-one derivatives bearing vicinal quaternary stereogenic centers, enabled by N-heterocyclic carbene through dynamic kinetic resolution approach has been introduced. The reaction undergoes via intermolecular reversible aldol reaction followed by acylation between benzofuranyl carbonate and N-protected isatin derivatives in one pot. Chiral 3,3'-disubstituted benzofuran-2(3H)-one derivatives bearing vicinal quaternary stereogenic centers, have been achieved with excellent yields (up to 98%), excellent enantioselectivities (up to 99:1 e.r.), and excellent diastereoselctivities (up to >20:1 dr).