Sharpless epoxidation mechanism

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 CaH2/Si02 System. Almost by chance, Zhou and colleagues found that the reaction time in Sharpless epoxidation could be reduced dramatically by adding a catalytic amount of calcium hydride and silica gel to the reaction system, although the mechanism is not yet clarified (Table 4 1).12... 

The formation of methylperoxy intermediates—i.e., the product of a formal insertion of O2 into the metal-methyl bond—was substantiated by the observation of epoxidation of allylic alkoxides (Scheme 6), in analogy to the proposed mechanism for the Sharpless epoxidation utilizing tert-butylhydroperoxide (TBHP). A similar oxygen atom transfer from a coordinated alkylperoxide to olefin was also postulated for the epoxidation of olefins with TBHP catalyzed by Cp Mo(0)2Cl [31]. The use of organomolybdenum oxides in olefin epoxidafion cafalysis (albeit not with O2) has recently been reviewed [32]. 

In cases where only enantiomers are formed, the absolute configuration needs to be determined. This situation occurs when the reaction does not involve the permanent attachment of a group containing a chiral unit to the substrate (e.g., use of a chiral reagent52 or a chiral catalyst53) and only one chiral unit is created or in cases where more than one chiral unit is formed, the mechanism of the reaction ensures that only one pair of enantiomers can result (cf. the Sharpless epoxidation, p 403). 

Sachtler proposes a "dual site" mechanism where the hydrogen is dissociated on the Ni surface and then migrates to the substrate which is coordinated to the adsorbed nickel-tartrate complex. In this context it is of interest that the well known Sharpless epoxidation probably takes place on a dimeric tartrate complex of Ti. Sachtler suggests that both the anion and the cation have a function which varies according to the conditions used. It is not clear whether the spillover mechanism is also proposed for the reaction in solution [55]. 

A variant of the Sharpless epoxidation methodology, introduced by Kagan, does provide a useful chemical method.4 208 209 The method is susceptible to the reaction conditions as shown by nonlinear effects,210 and the mechanism is not clear.211,212... 

A considerable amount of work was required to optimize the leaving group and avoid racem-ization through a Payne rearrangement mechanism.12 Of course, the Sharpless epoxidation of allyl alcohols is well-known to access these 3-functionalized epoxides. 

Mechanism The mechanism of the Sharpless epoxidation is quite complicated. Either enantiomer of diethyl tartrate (7.45 or 7.46) maybe used and these affect the chirality of the epoxide formed. The enantiomer 7.45 induces epoxide formation on the bottom face and... 

The Sharpless epoxidation proceeds by a completely different mechanism from these reactions. This asymmetric O-transfer reaction uses catalytic amounts of Ti(0-t-Pr)4 and (+)- or ( )-diethyl tartrate to catalyze the epoxidation of allylic alcohols by f-BuOOH. The enantioselectivities are usually very good. 

Key Words Ethylene oxide, Propylene oxide. Epoxybutene, Market, Isoamylene oxide. Cyclohexene oxide. Styrene oxide, Norbornene oxide. Epichlorohydrin, Epoxy resins, Carbamazepine, Terpenes, Limonene, a-Pinene, Fatty acid epoxides, Allyl epoxides, Sharpless epoxidation. Turnover frequency, Space time yield. Hydrogen peroxide, Polyoxometallates, Phase-transfer reagents, Methyltrioxorhenium (MTO), Fluorinated acetone, Alkylmetaborate esters. Alumina, Iminium salts, Porphyrins, Jacobsen-Katsuki oxidation, Salen, Peroxoacetic acid, P450 BM-3, Escherichia coli, lodosylbenzene, Oxometallacycle, DFT, Lewis acid mechanism, Metalladioxolane, Mimoun complex, Sheldon complex, Michaelis-Menten, Schiff bases. Redox mechanism. Oxygen-rebound mechanism, Spiro structure. 2008 Elsevier B.V. 

We believe that the mechanism for the Sharpless epoxidation can be generalized, and that the heterogeneously catalyzed propylene epoxidation step in the SMPO process proceeds in a similar fashion, as depicted in the simplified mechanism shown in Fig. 13.6. 

Interactive mechanism for the Sharpless epoxidation of allylic alcohols... 

The ring opening of epoxides by inorganic azides is the initial step of a general synthetic route to aziridines. Because enantiopure epoxides are readily available by Sharpless epoxidation and other methods, their ring opening by azide ions provides one of the best approaches to the synthesis of enantiopure aziridines. The stereochemistry of the aziridines can be reliably predicted on the basis of the mechanisms of the steps involved. 

The types of reactions that can be catalyzed by transition metal complexes are now very numerous and are very widely used in synthesis. We have already met a number of them—osmium in catalysis of dihydroxylation reactions, titanium in Sharpless epoxidation, various metals in hydrogenation reactions of alkenes, and the Ziegler-Natta process for polymerization. In this section, we will just highlight a few types that have been popular—an oxidation, some hydrogenations, and some coupling reactions. Although outline reaction mechanisms will be given, this is for interest only—they are beyond the scope of this text, and many are more complicated than is shown here. 

Chromylchloride, Cr02Cl2, the main subject of the publication which led to the original discussion about the mechanism [12], shows a very different reactivity compared to the other transition metal oxides discussed above. Even in the absence of peroxides, it yields epoxides rather than diols in a complex mixture of products, which also contains cis-chlorohydrine and vicinal dichlorides. Many different mechanisms have been proposed to explain the great variety of products observed, but none of the proposed intermediates could be identified. Stairs et al. have proposed a direct interaction of the alkene with one oxygen atom of chromylchloride [63-65], while Sharpless proposed a chromaoxetane [12] formed via a [2+2] pathway. 

With regard to epoxidation activity, the peroxo complex MoO(C>2)2-hinpt exhibits close similarity to peracids. Based on this observation, Sharpless et al. suggested [11] a concerted (direct) mechanism as an alternative to the insertion mechanism. That mechanism, which is assumed to proceed via a... 

Density functional calculations reveal that epoxidation of olefins by peroxo complexes with TM d° electronic configuration preferentially proceeds as direct attack of the nucleophilic olefin on an electrophilic peroxo oxygen center via a TS of spiro structure (Sharpless mechanism). For the insertion mechanism much higher activation barriers have been calculated. Moreover, decomposition of the five-membered metallacycle intermediate occurring in the insertion mechanism leads rather to an aldehyde than to an epoxide [63]. 

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 . 

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