Asymmetric epoxidation mechanism

Transition metal-catalyzed epoxidations, by peracids or peroxides, are complex and diverse in their reaction mechanisms (Section 5.05.4.2.2) (77MI50300). However, most advantageous conversions are possible using metal complexes. The use of t-butyl hydroperoxide with titanium tetraisopropoxide in the presence of tartrates gave asymmetric epoxides of 90-95% optical purity (80JA5974). 

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. ... 

By studying the NMR spectra of the products, Jensen and co-workers were able to establish that the alkylation of (the presumed) [Co (DMG)2py] in methanol by cyclohexene oxide and by various substituted cyclohexyl bromides and tosylates occurred primarily with inversion of configuration at carbon i.e., by an 8 2 mechanism. A small amount of a second isomer, which must have been formed by another minor pathway, was observed in one case (95). Both the alkylation of [Co (DMG)2py] by asymmetric epoxides 129, 142) and the reduction of epoxides to alcohols by cobalt cyanide complexes 105, 103) show preferential formation of one isomer. In addition, the ratio of ketone to alcohol obtained in the reaction of epoxides with [Co(CN)5H] increases with pH and this has been ascribed to differing reactions with the hydride (reduction to alcohol) and Co(I) (isomerization to ketone) 103) (see also Section VII,C). 

The protocol developed by Jacobsen and Katsuki for the salen-Mn catalyzed asymmetric epoxidation of unfunctionalized alkenes continues to dominate the field. The mechanism of the oxygen transfer has not yet been fully elucidated, although recent molecular orbital calculations based on density functional theory suggest a radical intermediate (2), whose stability and lifetime dictate the degree of cis/trans isomerization during the epoxidation <00AG(E)589>. 

The mechanism behind the polyamino acid-catalysed asymmetric epoxidation is particularly difficult to understand. The active catalyst exists as a paste or a gel following treatment with the organic solvent. Thus, studies on the helix/)8-sheet structure of the amorphous solid, the form of the polyamino acid in the absence of solvent, are probably not meaningful in this context. 

SCHEME 55. Proposed reaction mechanism for the zinc-mediated asymmetric epoxidation of a, 6-enones... 

In 1980, Katsuki and Sharpless described the first really efficient asymmetric epoxidation of allylic alcohols with very high enantioselectivities (ee 90-95%), employing a combination of Ti(OPr-/)4-diethyl tartrate (DET) as chiral catalyst and TBHP as oxidant Stoichiometric conditions were originally described for this system, however the addition of molecular sieves (which trap water traces) to the reaction allows the epoxidation to proceed under catalytic conditions. The stereochemical course of the reaction may be predicted by the empirical rule shown in equations 40 and 41. With (—)-DET, the oxidant approaches the allylic alcohol from the top side of the plane, whereas the bottom side is open for the (-l-)-DET based reagent, giving rise to the opposite optically active epoxide. Various aspects of this reaction including the mechanism, theoretical investigations and synthetic applications of the epoxy alcohol products have been reviewed and details may be found in the specific literature . 

Review M. G. Finn and K. B. Sharpless, On the Mechanism of Asymmetric Epoxidation with Titanium-Tartrate Catalysts, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 5, Chap. 8, Academic Press, New York, 1985 R. A. Johnson and K. B. Sharpless, Addition Reactions with Formation of Car-... 

The nonconventional tartrate esters 1-3 have been used to probe the mechanism of the asymmetric epoxidation process [20a]. These chain-linked bistartrates when complexed with 2 equiv. of Ti(0-f-Bu)4 catalyze asymmetric epoxidation with good enantiofacial selectivity. 

The hallmark of Ti-tartrate catalyzed asymmetric epoxidation is the high degree of enantiofacial selectivity seen for a wide range of allylic alcohols. It is natural to inquire into what the mechanism of this reaction might be and what structural features of the catalyst produce these desirable results. These questions have been studied extensively, and the results have been the subject of considerable discussion [6,135,136]. For the purpose of this chapter, we review the aspects of the mechanistic-structural studies that may be helpful in devising synthetic applications of this reaction. 

An alternate mechanism invoking an ion-pair transition-state assembly has been proposed to account for the enantioselectivity of the asymmetric epoxidation process [137]. In this proposal, two additional alcohol species are required in the transition-state complex. This... 

Studies of bis-tartrate esters and other tartrate ligands for titanium-mediated asymmetric epoxidation have provided evidence against the sole intermediacy of monomeric titanium-tartrate species in the parent system329,330. Other tartrate ligands have been studied in attempts to gain a better understanding of the mechanism of the Sharpless epoxidation330. 

B. E. Rossiter (1985). Synthetic aspects and application of asymmetric epoxidation , in Asymmetric Synthesis. Ed. J. Morrison. Orlando Academic Press, p. 194 M. G. Finn and K. B. Sharpless On the mechanism of asymmetric epoxidation with titanium-tartrate catalysts . Ibid., p. 247. 

Stoichiometric sulfur ylide epoxidation was first reported by A.W. Johnson [23] in 1958, and subsequently the method of Corey and Chaykovsky has found widespread use [24-26]. The first enantioselective epoxidations using stoichiometric amounts of ylide were reported in 1968 [27, 28]. In another early example, Hiyama et al. used a chiral phase-transfer catalyst (20 mol%) and stoichiometric amounts of Corey s ylide to effect asymmetric epoxidation of benzaldehyde in moderate to good enantiomeric excess (ee) of 67 to 89% [29]. Here, we will focus on epoxidations using catalytic amounts of ylide [30-32]. A general mechanism for sulfur ylide epoxidation is shown in Scheme 10.2, whereby an attack by the ylide on a carbonyl group yields a betaine intermediate which collapses to yield... 

Another method is to use poly-L-amino acids as catalysts in alkaline media (Julia-Colanna epoxidation) for the asymmetric epoxidation of chalcones and other electron-poor olefins with H202 [287]. SmithKline Beecham workers used this method (see Fig. 4.105) as a key step in the synthesis of a leukotriene antagonist, although it required 20 equivalents of H202 and 12 equivalents of NaOH, based on substrate [288]. The mechanism probably involves the asym-... 

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