Experiment #3: Asymmetric Synthesis – Use of a Chiral Manganese Catalyst for the Enantioselective Epoxidation of Alkenes† INTRODUCTION Chemists have discovered and developed many elegant and synthetically useful transformations of carbon-carbon double bonds. One important class of reactions involves the oxidation of olefins (or alkenes) to epoxides, which serve as synthetic intermediates towards a wide variety of oxygen-bearing functionalities.1 For example, epoxides react with strong nucleophiles (e.g. RS- , RSi-) under basic conditions and even weak nucleophiles (e.g., H2O) will react under acidic conditions with opening of the epoxide ring. Hydrolysis in dilute mineral acid is a widely used method for the preparation of (trans)-1,2-diols from alkenes. Reactions with carbon nucleophiles such as Grignard reagents and organocuprates lead to ring opening and carbon-carbon bond formation. † This laboratory experiment is modified with permission from the California Institute of Technology Chemistry 5b Laboratory Manual (2002).2 Reductions using aluminum-hydride reagents afford alcohols. In addition, epoxides undergo Lewis acid-catalyzed rearrangements to carbonyls, and base catalyzed rearrangements to allylic alcohols. Traditionally, olefin epoxidations have been accomplished using a variety of peroxy-acids. Since the early 1980's, however, a number of effective transition metal-based catalyst systems have been developed that have significantly extended the scope of these reactions by allowing enantioselective oxygen transfer to form asymmetric epoxides. The most prevalent of these systems has been the oxidation of prochiral allylic alcohols (which uses tert-butyl hydroperoxide in the presence of titanium tetra(isopropoxide) and either (+)- or (-)-diethyl tartrate) to give asymmetric epoxides in high enantioselectivities and yields. This method was developed by K. Barry Sharpless and co-workers (now at Scripps Research Institute) and is commonly referred to as the “Sharpless asymmetric epoxidation”. The high enantioselectivity of this reaction is attributed to pre-coordination of the alcohol functional group to the titanium center, which serves to orient the face of the incoming double bond (see graphic on the next page). As such, this reaction is only effective for allylic alcohols, i.e., functionalized alkenes.3 In 1990, Eric N. Jacobsen and co-workers (now at Harvard University) published the first of several important papers on the enantioselective epoxidation of unfunctionalized olefins catalyzed by chiral manganese complexes.2 The general reaction is that shown below: Jacobsen's Catalyst[O]OR4R2R3R1R1R2R3R4OR1R3R2R4or In Jacobsen’s systems, the stereoselectivity relies solely on nonbonded interactions, thus lifting the requirement for a pre-coordinating pendant group (such as the alcohols above). In fact, alkyl- and aryl-substituted olefins react with Jacobsen’s systems to give the highest enantioselectivity yet realized for nonenzymatic catalysts. This Chem 346 laboratory experiment involves the synthesis of and experimentation with the most successful catalyst among the many manganese catalysts that Jacobsen and co-workers investigated. The catalyst, now commonly known as Jacobsen’s Catalyst has the following structure (shown on next page):4 NNOOMnHHCl For this extremely useful compound, Eric Jacobsen was awarded the 1994 Fluka Prize for Reagent of the Year. The Fluka Prize is awarded annually for a new compound that has been shown to be “a reagent of prime importance, useful in organic chemistry, biochemistry, or analytical chemistry.” Jacobsen’s Catalyst can be prepared in three steps according to reactions shown in Scheme I.5 One of the highly attractive aspects of Jacobsen’s Catalyst is that it can be synthesized easily from readily available, low cost starting materials. The first step is a chiral resolution of (R,R)-1,2-diaminocyclohexane from a mixture of cis and trans isomers of the diamine. This is accomplished by using L-(+)-Tartaric acid to form diastereomeric salts of the diamine. The relatively low aqueous solubility of the salt of the R,R diamine allows it to be crystallized in high enantiomeric purity. In the second step, the tartrate salt of (R,R)-1,2-diaminocyclohexane is reacted with two molar equivalents of 3,5-di-tert-butylsalicylaldehyde to form the diimine (Schiff base). Finally, reaction of the diimine, 2, with manganese (II) acetate in the presence of lithium chloride and atmospheric oxygen forms [(R,R)-N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-hexanediaminato(2-)] manganese (III) chloride. You will work in pairs and each student pair will investigate the epoxidation of one of the following alkenes using the Jacobsen’s Catalyst they prepared. The enantiomeric selectivity of the epoxidation reaction will be determined by gas chromatography (GC) analysis of the resulting epoxide using a chiral GC column. Each group will share the results of their analysis with the other groups. Styrene1,2-Dihydronaphthalene Molecular models are extremely useful in the study of reactions of this type. Physical models allow the researcher to visualize various approaches and specific orientations that the alkene can adopt relative to the catalyst as the epoxidation takes place. Each pair of students will build a molecular model of the catalyst and the alkenes being investigated. You should use the models to make predictions regarding enantioselectivity with your substrate and to rationalize your observed results. Note: A good time to build the models is during the one-hour reflux period of the ligand synthesis. Include this analysis in your lab report! EXPERIMENTAL General. The following catalyst preparation and epoxidation procedures are general and may be scaled to the amount of starting compounds available. All solvents may be used without further purification. All reactions should be carried out in a fume hood, if possible.6 A. Catalyst Preparation Resolution of a chiral diamine –