Catalytic Asymmetric Aminohydroxylation Of Prochiral Olefins

The chiral β -amino alcohol and vicinal diol moieties appear in numerous chiral drugs, such as Taxol, Propranolol, Metoprolol, Salbutamol and Amino acids etc.. The asymmetric aminohydroxy-lation (AA) and dihydroxylation (AD) discovered by Sharpless and his coworkers have rapidly become invaluable synthetic tools in organic chemistry. The great value is given in the possibility of introducing a chiral vicinal diol and β -amino alcohol moieties from readily available prochiral olefms in a single step. Expectively, Sharpless shared the Nobel Chemistry Prize in 2001.Although the reactions have had widespread applications in organic synthesis, there have been few large-scale industrial productions of chiral β -amino alcohol and vicinal diol. In many cases, problems arise that appear to be related to some combination of the following issues: 1) A A reaction still lacks the extensive substrate scope. 2) Chemo-, regio- and enantioselectivities in AA reaction cause by-products, which make the separation of the "target" molecule troublesome. 3) The chiral catalyst complex in AD and AA reactions are formed in situ by chiral ligand and osmium tetraoxide. Not only are chiral ligands and osmium tetraoxide quite expensive, but Osmium tetraoxide is also highly toxic.Recently, scientists devoted themselves to optimizing reaction condition, developing novel highly effective and cheap chiral ligand and catalysis system, recovering and reusing chiral catalysts (transition metal complex) to promote the large-scale preparation of chiral compounds.In this project, researches were carried out as follows:Firstly, a dimeric cinchona alkaloid derivative ligand, (QN)2AQN, was synthesized for the first time. And the other ligand (DHQD)2PYDZ was synthesized in a modified method. Then, three chiral ligands (QN)2PHAL, (QN)2AQN and (DHQD)2PYDZ were applied to the AA reactions of a series of prochiral olefins to study the effect of the ligands on the chemo-, regie- and enantioselectivities in A A reaction. The substrate scope was expanded in the A A reaction of five methyl cinnamates with excellent enantioselectivities by using (QN)2PHAL as chiral ligand.Secondly, the effect of solvent system on chemical yield and enantio- selectivities in AA reaction of styrene was investigated.Thirdly, design and synthesis of a soluble polymer-bound ligand: QN-AQN-OPEG-OMe for the asymmetric dihydroxylation of a series of olefins. Furthermore, the reaction activities and the recovery of chiral ligand were studied.Fourthly, the soluble polymer-bound ligandQN-AQN-OPEG-OMe was applied to the asymmetric synthsis of chiral intermadiate of the widely prescribed drug metoprolol (Betaloc) with satisfactory results for the first time.This dissertation consists of six parts:Part I : Asymmetric aminohydroxylation of terminal aromaticolefins and f-cinnamic ester catalyzed by(QN)2PHAL-OsO4 complexa. Synthesis of (QN)2PHALA mixture of quinine, 1,4-dichlorophthalazine, KOH and K2CO3 in dry toluene were refluxed, with azeotropic removal of water for 14h, to afford (QN)2PHAL in 72% yield by chromatography (eluent, Me2CO: EtOAc:Et3N = 450:50:30) .b. A A reactionEffective experimental conditions for 1 mmol olefins in the AA reactions employed 3.1 equiv. benzyl jV-chlorocarbamate (the oxidant and nitrogen source), 4mol% K2OsO2(OH)4 and 5mol% (QN)2PHAL and nPrOH/H2O(1:1), excellent enantioselectivity as well as specific regio and chemoselectivity were observed. 85-99%ee and 48-76% isolated chemical yields of the products were achieved.The AA raction of styrene in the solvent system (nPrOH/H2O 1.7:1) could increase the chemical yield from 48% to 57% and the optical purity of the products from 85% to 93%ee.Part II: Asymmetric aminohydroxylation of E-methyl cinnamates catalyzed by (QN)2PHAL-OsO4 complexChemo-, regio- and enantioselectivities of five methyl cinnamates in AA reactions were studied. In the similar experimental condition, five methyl cinnamates reacted smoothly to give the B -amino alcohol i...