Sharpless epoxidation examples

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

In order to obtain good yields, it is important to use dry solvent and reagents. The commercially available t-butyl hydroperoxide contains about 30% water for stabilization. For the use in a Sharpless epoxidation reaction the water has to be removed first. The effect of water present in the reaction mixture has for example been investigated by Sharpless et al. for the epoxidation of (E)-a-phenylcinnamyl alcohol, the addition of one equivalent of water led to a decrease in enantioselectivity from 99% e.e. to 48% e.e. 

Epoxide-derived radicals are generated under very mild reaction conditions and are therefore valuable for intermolecular C-C bond-forming reactions [27,29]. The resulting products, 5-hydroxyketones, 5-hydroxyesters or 5-lactones constitute important synthetic intermediates. The first examples were reported by Nugent and RajanBabu who used a variety of epoxides, such as cyclohexene oxide and a Sharpless epoxide (Scheme 7). 

Roy and his group have synthesized a number of THF derivatives from suitable ethers of Sharpless epoxides [86,87]. The example shown... 

Natural compounds are also applied as chiral ligands in enantioselective homogeneous metallo-catalysts. A classical example is the Sharpless epoxidation of primary allylic alcohols with tert-butyl hydroperoxide [37]. Here the diethyl ester of natural (R,R)-(+)-tartaric acid (a by-product of wine manufacture) is used as bi-dentate ligand of the Ti(iv) center. The enantiomeric excess is >90%. The addition of zeolite KA or NaA is essential [38], bringing about adsorption of traces of water and - by cation exchange - some ionization of the hydroperoxide. 

Ferrocene is best deprotonated by f-BuLi/f-BuOK in THF at 0 since BuLi alone will not lithiate ferrocene in the absence of TMEDA and leads to multiple lithiation in the presence of TMEDA. In the example in Scheme 134, a sulphur electrophile and a Kagan-Sharpless epoxidation lead to the enantiomerically pure sulphinyl ferrocene 278. The sulphinyl group directs stereoselective ortholithiation (see Section I.B.2), allowing the formation of products such as 279. Nucleophilic attack at sulphur is avoided by using triisopropylphenyllithium for this lithiation. 

Even in the case of the Sharpless epoxidation reaction, where the stereochemical course has been confirmed in many examples, exceptions have been reported. As an illustration On enantioselective epoxidation in the presence of L-( + )-DIPT, meso-1,5-hcxadiene-3,4-diol (24a) gave epoxide 25 (formed in an unexpected mode) as the main product136 227 whereas, ( )-ben-zyl ether 24b, obtained from 24a by monobenzylation, on kinetic resolution in the presence of l.( + )-dipt yielded monoepoxide (+)-26, which belongs to the enantiomeric series (see also pp 420, 449 and 470) 37. 

Fig. 3.7. Definition of the enantiomeric excess ee using the Sharpless epoxidation of allylic alcohol as an example. The chiral auxiliary is tartaric acid diethyl ester (diethyl tartrate, DET).

Thus, in cw-vic-dihydroxylations of alkenes with 0s04 tertiary amines, like pyridine, have ligand acceleration effects (this term was introduced in Section 3.4.6, using the Sharpless epoxidation as an example). 

The quality of enantioselective reactions is numerically expressed as the so-called enantiomeric excess (ee). It is equal to the yield of the major enantiomer minus the yield of the minor enantiomer in the product whose total yield is normalized to 100%. For example, in the Sharpless epoxidation of allyl alcohol (see Figure 3.7). S - and R-glycidol are formed in a ratio of 19 1. For a total glycidol yield standardized to 100%, the S-glycidol fraction (95% yield) thus exceeds the /f-glycidol fraction (5% yield) by 90%. Consequently, S-glycidol is produced with an ee of 90%. 

Several approaches to the enantioselective oxidation of sulfides have been reported,61 including enzymatic approaches,62 use of optically pure oxidants,63 and several modifications of the Sharpless epoxidation procedure.63,64 The success of these procedures is somewhat substrate dependent for example, dialkyl sulfides and more complex substrates can give unpredictable results. 1,3-Dithiane itself is oxidized with only ca. 20% ee optically pure DiTOX has, however, been obtained by resolution.65... 

Metals that are capable of 2e redox changes, typically main group elements and 4d and 5d transition metals, can give heterolysis of a peroxide to form a diamagnetic oxidant that may avoid the radical pathways seen in the case of equation (14-15). O atom transfer to the substrate is possible in this way. Sharpless epoxidation provides an excellent example. In this case rBuOOH is the primary oxidant, Ti(i-OPr)4 is the catalyst precursor and a tartrate ester is the ligand that induces a high ee in the epoxy alcohol formed from an allylic alcohol. This reaction has been successfiiUy developed on an industrial scale. 

Modern reactions While there is no shortage of new chemical reactions to present in an organic chemistry test, I have chosen to concentrate on new methods that introduce a particular three-dimensional arrangement in a molecule, so-called asymmetric or enanti-oselective reactions. Examples include Sharpless epoxidation (Chapter 12), CBS reduction (Chapter 20), and enantioselective synthesis of amino acids (Chapter 28). 

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