HIGHLY ENANTIOSELECTIVE TRANSITION METAL-CATALYZED HYDROGENATION EACTIONS: AN EFFICIENT TOOL FOR THE SYNTHESIS OF PHARMACEUTICALS AND OTHER BIOACTIVE MOLECULES

Open Access
Author:
SUN, XIANFENG
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
March 06, 2008
Committee Members:
  • Xumu Zhang, Committee Chair
  • Harry R Allcock, Committee Chair
  • Lasse Jensen, Committee Member
  • Raymond Edward Schaak, Committee Member
  • Zi Kui Liu, Committee Member
Keywords:
  • asymmetric hydrogenation
  • chiral ligand
Abstract:
Catalytic asymmetric synthesis is a significant component in modern organic chemistry. Transition metal enantioselective catalysis is certainly among the most challenging and widely investigated areas in organometallic chemistry. The design and synthesis of efficient chiral phosphorus ligands and the exploration of their applications in transition metal-catalyzed asymmetric hydrogenations are the main focus of this dissertation. By introducing a bridge with variable length to link the chiral atropisomeric biaryl groups, a novel class of conformationally rigid Cn-TunePhos (n = 1-6) ligands was designed and synthesized in three different routes. The additional non-chiral linkage not only minimizes the conformational rotation but also defines the dihedral angle and the bite angle with improved precision. This family of TunePhos ligands has proven highly efficient in a variety of asymmetric hydrogenations. Ru/Cn-TunePhos catalyzed asymmetric hydrogenation of allyl phthalimides provided an efficient method for the synthesis of ¦Â-methyl chiral amines. A series of C3-TunePhos derivatives with different steric and electronic properties was prepared by atropdiastereoselective Ullmann coupling reaction of the biaryl diethyl phosphonate. The procedure is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess > 99%. Enantiomerically pure Ru complexes containing these ligands have been prepared and applied to the catalytic enantioselective hydrogenation of ¦Â-keto esters. An excellent level of enantioselection (up to 99.5% ee) has been attained. A pair of bisphosphine ligands containing double hybrid chiral axials in a six-carbon bridging unit were designed and synthesized. The presence of chiral binaphthyl auxiliary together with another chiral biphenyl phosphine moiety offers the opportunity to prepare diastereomeric ligands. The matching and mismatching effects caused by interactions between the two stereochemical elements within each ligand displayed dramatic difference in asymmetric hydrogenation of ¦Á-keto esters. An efficient Rh-bisphospholane catalyzed highly enantioselective synthesis of 3-arylbutanoic acids was explored with several remarkable features: 1) Up to 99% ee values and 5,000 turnover numbers can be achieved; 2) cooperation of highly rigid electron-donating P-chiral bisphospholane DuanPhos ligand with optimal solvent and additive is the key to efficient transformations; 3) the simplicity of obtaining substrates and highly enantioselective hydrogenation under mild conditions make this approach more attractive and practical.