Development of novel chiral N-heterocyclic carbenes and synthetic studies towards the total synthesis of gephyronic acid
Chow, Yeong Shenq
Date of Issue2016
School of Physical and Mathematical Sciences
A-Heterocyclic carbenes (NHC) are valuable ligands in catalysis. Their powerful a-donating and weak x-accepting properties allow stronger binding to the metal than phosphines and generate a class of air-stable electron-rich complexes that are highly active in several catalytic chemical reactions where harsh conditions are usually required. In addition, these NHC ligands are also effective as organocatalysts and catalyze numerous interesting organic transformations such as the Umpulong benzoin condensation and Stetter reaction. However, successful applications of the NHCs, either as chiral ligands or chiral organocatalysts, in asymmetric catalysis are still limited. This could be due to the small pool of chiral NHCs. The emphasis of this thesis is placed on the development of novel chiral NHCs to increase the library of chiral NHCs, investigation on the application of NHCs in catalysis and manifestation of its applicability on the enantioselective synthesis of natural products. In the introductory chapter, a general discussion of the classes and synthetic methodologies of NHCs is provided, followed by a highlight of various chiral NHCs that have been reported and their applications as chiral ligands or chiral nucleophilic catalysts in asymmetric catalysis. The alluring need for the development of novel chiral NHCs leads us to design and investigate the synthesis of two novel classes of chiral NHCs, as reported in Chapter 2. We have designed a new class of Nheterocyclic carbenes that possesses a novel A-heterocycle backbone containing the chiral l,T-binahthyl scaffold. In the course of preparing the novel chiral carbenes, we have successfully synthesized a new class of chiral vicinal diamines, which could be potentially applied as chiral ligands or chiral organic catalysts in asymmetric catalysis. We have also designed a novel bidentate chiral hydroxyalkyl-imidazopyridin- 3-ylidene for which we have successfully synthesized the NHC precursor imidazopyridinium salt 92a albeit in low yield. The investigation on the applications of NHCs in catalysis is reported in Chapter 3. We have investigated the applications of the seven-membered chiral amidinium salt 99.BF4 as a chiral ligand and an organocatalyst in asymmetric catalysis. Synthetic studies towards the synthesis of silver(I)-99 complex, which could potentially be a good reagent to transfer the carbene ligands to other transition metals, is also discussed. Works on the NHC-catalyzed formation of acyl-imidazole from aldehydes with a suitable oxidant, with the aim that this NHC-catalyzed reaction could potentially leads to the one-pot synthesis of ketones from aldehydes, is also reported in this chapter. The synthetic studies towards the total synthesis of gephyronic acid is discussed in Chapter 4. Two retrosynthesis, retrosynthesis (A) and (B), are proposed for the synthesis of gephyronic acid. Retrosynthesis (A), which includes the NHCcopper catalyzed asymmetric 7S-b0rati0n of oy3-unsaturated ester or the complementary NHC-copper catalyzed silyl conjugate addition as one of the key steps, provides a platform for us to investigate the potential applications of the chiral NHCs that we have designed and discussed in Chapter 2. Retrosynthesis (B), which is based on classical methodologies, was designed to allow a relatively more secure pathway for the identification of the absolute stereochemistry of C8 of gephyronic acid, which remains undetermined.