THE DEVELOPMENT AND APPLICATIONS OF ELECTRON-RICH PHOSPHORUS-CONTAINING LIGANDS IN ASYMMETRIC HYDROGENATION

Open Access
Author:
Shang, Gao
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
March 10, 2008
Committee Members:
  • Xumu Zhang, Committee Chair
  • Steven M Weinreb, Committee Chair
  • Harry R Allcock, Committee Member
  • Beth A Williams, Committee Member
  • Yanming Wang, Committee Member
Keywords:
  • Asymmetric hydrogenation
  • Catalysis
  • chiral phosphorus-containing ligands
Abstract:
Catalytic asymmetric transformations are important synthetic approaches for the preparation of enantiomerically enriched products. Among numerous methodologies developed in the past few decades, transition metal-catalyzed asymmetric hydrogenation has been demonstrated as one of the most efficient methods. In this particular area, two directions of research can be found. One is the exploration of unsaturated prochiral molecules that can serve as hydrogenation substrates and produce important chiral product using current available catalysts. On the other hand, the continuous development of novel chiral ligands, usually phosphorus containing ligands, also plays a key role in improving the efficiency of this methodology. It is interesting to note that an important discovery in one direction can frequently promote the studies in the other. These two directions are also the main focuses of this dissertation. From chapter 2 to chapter 4, three kinds of challenging substrates were studied in transition metal-catalyzed hydrogenation reaction and important chiral products were obtained in good yields and selectivities. In chapter 2, A highly enantioselective synthesis of arylglycine derivatives through Rh-bisphosphine catalyzed asymmetric hydrogenation is presented. The stable N-PMP protected α-aryl imino esters were synthesized from the corresponding α-ketoesters in high yields. Using a rhodium catalyst with an electron rich and rigid Rh-TangPhos, high ee values have been achieved in the hydrogenation of N-PMP protected α-aryl imino esters. An efficient Pd-bisphosphine catalyzed hydrogenation of unfunctionalized N-tosylimines is presented in chapter 3. N-tosylimines could be synthesized from corresponding ketones exclusively in E configuration and readily served as substrates for asymmetric hydrogenation. Excellent enantioselectivities (up to 99% ee) and conversions (up to >99%) could be achieved when Pd(OCOCF3)2 complexed with an electron-rich rigid chiral bisphosphine, TangPhos, was employed. A variety of aromatic, aliphatic and cyclic chiral amines can be prepared from this methodology. In chapter 4, two β-receptor agonists (-)-denopamine and (-)-arbutamine were prepared in good yields and enantioselectivities via asymmetric hydrogenation of unprotected amino ketones for the first time using Rh catalysts bearing electron-rich phosphine ligands. A series of -primary and secondary amino ketones were synthesized and hydrogenated to produce various 1,2-amino alcohols in good yields and enantioselectivies. This Rh-electron rich phosphine catalyzed asymmetric hyderogenation represents one of the most promising and convenient approaches to the asymmetric synthesis of chiral amino alcohols. Despite the high diversity of chiral phosphorus ligands and their great achievement on various transformations, most of them are extremely air sensitive. The tedious synthesis and handling procedures limit them from being widely used in industrial applications. Progress in the development of new generation of air stable secondary phosphine oxide (SPO) ligands is presented in chapter 5. A series of highly active and air stable SPO ligands were prepared and the preliminary results in transition metal-catalyzed asymmetric hydrogenation were reported.