Explorations on Transition Metal-Catalyzed Enantioselective Cyclization Reactions and Applications of Thiourea Ligands

This dissertation, "Explorations on Transition Metal-catalyzed Enantioselective Cyclization Reactions and Applications of Thiourea Ligands" by Min, Yang, 楊敏, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled EXPLORATIONS ON TRANSITION METAL- CATALYZED ENANTIOSELECTIVE CYCLIZATION REACTIONS AND APPLICATIONS OF THIOUREA LIGANDS submitted by Yang Min for the Degree of Doctor of Philosophy at The University of Hong Kong in November 2005 Transition metal-catalyzed carbon-carbon bond formation and carbon- heteroatom bond formation are powerful tools in synthetic chemistry, and have been widely applied in the construction of cyclic compounds. The aim of this project is to develop enantioselective cyclization reactions by the application of transition metals and chiral ligands. A chiral Lewis acid-promoted highly enantioselective intramolecular carbonyl ene cyclization reaction of unsaturated α-keto esters has been developed (Scheme 1). In the presence of chiral Lewis acids such as [Sc((R, R)-Ph- pybox)](OTf) and [Cu((S, S)-Ph-box)](OTf), unsaturated α-keto esters (1.1c-f) 3 2 underwent carbonyl ene reactions smoothly under mild conditions to give cis-1- hydroxyl-2-vinyl esters (1.2c-f) with two new chiral centers, including a quaternary one, in good yields (> 81%), excellent cis stereoselectivities (diastereomeric ratio up to 50:1), and good to excellent enantiomer excesses (up to 99%). This easy entry to the highly functionalized chiral cyclic products under mild conditions will definitely make this catalytic enantioselective method a useful tool for the construction of the chiral skeletons of many medicinal agents and bioactive molecules. A new palladium-catalyzed enantioselective oxidative tandem cyclization method has been developed. In the presence of a catalytic amount of Pd(tfa) /(-)- sparteine with cheap and environmentally benign molecular oxygen as the terminal oxidant, a series of polycyclic indoline derivatives 2.2 with up to two stereocenters (2.2fb) are readily prepared in a single step in good yields and moderate to good enantiomer excesses (up to 91%; Scheme 2). These represent the first examples of enantioselective oxidative tandem cyclization reactions under aerobic conditions. A class of sterically bulky cyclic thiourea ligands (L1-11, Figure 1) have been synthesized. Ligand L1, with bulky t-butyl groups on the aryl moiety, was found to be effective in the palladium-catalyzed oxidation of alcohols under aerobic conditions, in which L1 exhibited good stability to oxidizing agents and efficiently prevented palladium from undergoing aggregation (Scheme 3). This new catalyst system has been applied to a wide variety of substrates such as benzylic alcohols, aliphatic secondary alcohols and allylic alcohols, producing the desired carbonyl compounds in moderate to excellent yields. However, the attempts to apply the chiral thiourea ligands (L7-11) to the palladium-catalyzed oxidative kinetic resolution of secondary alcohols did not give satisfactory results. Scheme 1 Chiral Lewis acid OEt OEt OH 81 87% yield n CH Cl, rt H 2 2 dr > 50:1 75 91% ee _ _ 1.1c 1.2c d d n = 1, 2 Chiral Lewis Acid: or Sc(OTf), Cu(OTf), 2 NN N N Ph Ph Ph Ph Cu(OTf) (20 mol%) 5R 5R 1R OR 1S OR OR L* (22 mol%), CH Cl, rt 2 2 OH 2R 2S OH L* = NN major 1.3e/f 1.1e R = CH 1.2e/f Ph Ph R = Bn 1.1f 91 94% yie