Epoxidation, Sharpless

The asymmetric epoxidation of an allylic alcohol 1 to yield a 2,3-epoxy alcohol 2 with high enantiomeric excess, has been developed by Sharpless and Katsuki. This enantioselective reaction is carried out in the presence of tetraisopropoxyti-tanium and an enantiomerically pure dialkyl tartrate—e.g. (-1-)- or (-)-diethyl tartrate (DET)—using tcrt-butyl hydroperoxide as the oxidizing agent. 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary  

A model for the catalytically active species in the Sharpless epoxidation reaction is formulated as a dimer 3, where two titanium centers are linked by two chiral tartrate bridges. At each titanium center two isopropoxide groups of the original tetraisopropoxytitanium-(IV) have been replaced by the chiral tartrate ligand  

The oxygen atom O-1 adds to the carbon-carbon double bond, while the oxygen 0-2 forms a covalent bond to the titanium center. As a result complex 5 is 

The reaction is limited to allylic alcohols other types of alkenes do not or not efficiently enough bind to the titanium. The catalytically active chiral species can be regenerated by reaction with excess allylic alcohol and oxidant however the titanium reagent is often employed in equimolar amount. 

Asymmetric oxidations have followed the usual development pathway in which face selectivity was observed through the use of chiral auxiliaries and templates. The breakthrough came with the Sharpless asymmetric epoxidation method, which, although stoichiometric, allowed for a wide range of substrates and the stereochemistry of the product to be controlled in a predictable manner [1]. The need for a catalytic reaction was very apparent, but this was developed and now the Sharpless epoxidation is a viable process al scale, although subject to the usual economic problems of a cost-effective route to the substrate (see later) [2]. The Sharpless epoxidation has now been joined by other methods and a wide range of products are now available. The pow er of these oxidations is augmented by the synthetic utility of the resultant epoxides or diols that can be used for further transformations, especially those that use a substitution reaction (see Chapter 7) [1]. 

Although the original Sharpless epoxidation method was stoichiometric, the development of a catalytic method has allowed the reaction to be amenable to scale up. The addition of molecular sieves for the removal of trace amounts of water is important in the catalytic procedure [2,9-11]. 

An improved work-up procedure increases the yield for allyl alcohols containing a small number of carbon atoms [15-17], Futhermore, less reactive substrates provide the epoxide readily [18], 

The reaction time has been reduced dramatically by the addition of calcium hydride, silica gel, or montmorillonite catalysts [18,27-29]. 

The power of the Sharpless epoxidation method is augmented by the versatility of the resultant 2,3-epoxy alcohols [1] and the development of the catalytic variation [2]. 

For example, when CH3CH2OH (ethanol) is ingested, it is oxidized in the liver first to CH3CHO (acetaldehyde), and then to CH3COO (acetate anion, the conjugate base of acetic acid). Acetate is the starting material for the synthesis of fatty acids and cholesterol. Both oxidations are catalyzed by the enzyme alcohol dehydrogenase. 

If more ethanol is ingested than can be metabolized in a given time, the concentration of acetaldehyde builds up. This toxic compound is responsible for the feelings associated with a hangover. 

Antabuse, a drug given to alcoholics to prevent them from consuming alcoholic beverages, acts by interfering with the normal oxidation of ethanol. Antabuse inhibits the oxidation of acetaldehyde to the acetate anion. Because the first step in ethanol metabolism occurs but the second does not, the concentration of acetaldehyde rises, causing an individual to become violently ill. 

Like ethanol, methanol is oxidized by the same enzyme to give an aldehyde and an acid formaldehyde and formic acid. These oxidation products are extremely toxic because they cannot be used by the body. As a result, the pH of the blood decreases, and blindness and death can follow. 

Because alcohol dehydrogenase has a higher affinity for ethanol than methanol, methanol poisoning is treated by giving ethanol to the afflicted individual. With both methanol and ethanol in the patient s system, alcohol dehydrogenase reacts more readily with ethanol, allowing the methanol to be excreted unchanged without the formation of methanol s toxic oxidation products. 

Problem 12.27 What carbonyl compound is fomied when each alcohol is treated with HCr04 -Amberlyst A-26 resin  

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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 Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

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. 

By employing Sharpless epoxidation as a key step, a multistep chemical synthesis of (E)-pantolactone has also been reported (55). 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

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. 

The Sharpless epoxidation is one of the most important of the newer organic reactions. Although limited to allylic alcohols, it has found wide application in natural product synthesis. 

Sesquiterpenoid. 203, 1071 Sex hormone, 1082-1083 Sharpless, K. Barry. 734 Sharpless epoxidation, 735 Shell (electron), 5 capacity of, 5 Shielding (NMR). 442 Si prochirality, 315-316 Sialic acid. 997 Side chain (amino acid), 1020 Sigma (cr) bond, 11 symmetry of, 11 Sigmatropic rearrangement, 1191-1195... 

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

Finally, the necessity arose for the synthesis of pentulose 21, labeled with, 3C on the central carbons, C-2 and C-3, for an independent biosynthetic study, which is reported in Section III.5.27 The doubly labeled ester 34 (Scheme 14) is readily available by a Wittig- Homer condensation of benzyloxyacetaldehyde with commercially available triethylphosphono-(l,2-l3C2)acetate. Chirality was introduced by the reduction of ester 34 to the allylic alcohol, which produced the chiral epoxide 35 by the Sharpless epoxidation procedure. This was converted into the tetrose 36, and thence, into the protected pentulose 37 by the usual sequence of Grignard reaction and oxidation. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

The stereochemistry of the first step was ascertained by an X-ray analysis [8] of an isolated oxazaphospholidine 3 (R = Ph). The overall sequence from oxi-rane to aziridine takes place with an excellent retention of chiral integrity. As the stereochemistry of the oxirane esters is determined by the chiral inductor during the Sharpless epoxidation, both enantiomers of aziridine esters can be readily obtained by choosing the desired antipodal tartrate inductor during the epoxidation reaction. It is relevant to note that the required starting allylic alcohols are conveniently prepared by chain elongation of propargyl alcohol as a C3 synthon followed by an appropriate reduction of the triple bond, e. g., with lithium aluminum hydride [6b]. 

Fig. 12.4. Successive models of the transition state for Sharpless epoxidation. (a) the hexacoordinate Ti core with uncoordinated alkene (b) Ti with methylhydroperoxide, allyl alcohol, and ethanediol as ligands (c) monomeric catalytic center incorporating t-butylhydroperoxide as oxidant (d) monomeric catalytic center with formyl groups added (e) dimeric transition state with chiral tartrate model (E = CH = O). Reproduced from J. Am. Chem. Soc., 117, 11327 (1995), by permission of the American Chemical Society. 

Visual models, additional information and exercises on Sharpless Epoxidation can be found in the Digital Resource available at Sprmger.com/carey-sundberg. 

Fig. 12.6. Conformational factors affecting syn and anti diastereoselectivity in Sharpless epoxidation. If substituent R4 > H, A1,3 strain favors the syn product. If R4 = H, the preferred transition structure leads to anti product. Reproduced from/. Org. Chem., 67, 1427 (2002), by permission of the American Chemical Society.

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

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