Sharpless reaction mechanism

The reaction mechanisms of these transition metal mediated oxidations have been the subject of several computational studies, especially in the case of osmium tetraoxide [7-10], where the controversy about the mechanism of the oxidation reaction with olefins could not be solved experimentally [11-20]. Based on the early proposal of Sharpless [12], that metallaoxetanes should be involved in alkene oxidation reactions of metal-oxo compounds like Cr02Cl2, 0s04 and Mn04" the question arose whether the reaction proceeds via a concerted [3+2] route as originally proposed by Criegee [11] or via a stepwise [2+2] process with a metallaoxetane intermediate [12] (Figure 2). 

The oxidation of olefins by chromylchloride has been known since the 19th century. Even in the absence of peroxides, this reaction yields epoxides rather than diols in a complex mixture of products, which also contains cfv-chlorohydrins and vicinal dichlorides. Many different reaction mechanisms have been proposed to explain the great variety of observed products, but none of the proposed intermediates have been identified. Stairs favors a direct interaction of the alkene with one oxygen atom of chromylchloride,139-141 while Sharpless proposed a chromaoxetane10 that forms via a [2 + 2]-pathway, a proposal which has led to intense discussions. 

The reaction mechanism of the Sharpless dihydyroxylation is given in Chapter 7, section 7.5. 

Another chemoselective ligation reaction is the [2 + 3] cycloaddition between an azide and an alkyne. This reaction has been discovered by Huisgen and was lately named click-reaction by Sharpless and Meldal [180, 181]. Whereas the Huisgen 1,3-dipolar cycloaddition leads to two isomeric triazole products at high temperature, click chemistry is performed under the catalysis of Cu(I), thus changing the reaction mechanism from a concerted to a step-wise route and resulting in the formation of the 1,4-substituted triazole as the only product, usually isolated in high yields [174, 182-186],... 

The reaction modification featuring titanium (III) as the starting point was originated somewhat later by Barry Sharpless. The mechanism is shown under (c) and is more speculative than (a) and (b). We hoped that these titanium (II) species could be made, and we are now certain that they are real and available entities. For example, titanium di-benzoxide can be isolated and shown to yield bibenzyl on thermolysis. 

The application of these theoretical methods has allowed us to explain and understand the reaction mechanism, and to determine how the different parts of the reactants (the olefin and the catalyst) are involved in the reaction. The U-shape conformation of the second generation catalyst has been confirmed by all the methods used. The three aromatic regions of the catalyst (two quinoHnes and the heterocyclic spacer) are attractively interacting with the olefin inside the binding pocket. The orientation of the olefin giving rise to the Corey and Sharpless pockets are, for most of the studied olefins, quite similar in energy therefore, to know the orientation for a particular olefin, theoretical calculations are needed. 

The two seminal contributions of Mimoun and Sharpless laboratories led to a controversy on the reaction mechanism that was lasting longer than for two decades [82] and expanded to the olefin epoxidation with other metal peroxo complexes, in particular those of rhenium. Kinetic studies of Al-Ajlouni and Espenson [83,84] on the MTO-catalyzed olefin epoxidation with H2O2 revealed the importance of both mono- and diperoxo species in the catalytic process as well as substituent effects on reaction rates, but the molecular mechanism remained uncertain. 

Fig. 20 Reaction mechanism for the two-cycle dihydroxylation of olefins with OSO4 in the presence of chiral ligands L via [3+2] addition suggested by Sharpless...

The reaction mechanism of the osmium-catalyzed dihydroxylation was intensely discussed. Boseken [31] proposed already in 1922 that the reaction proceeds via a thermally allowed concerted (3-1-2) cycloaddition reaction, while Sharpless suggested the formation of a metallaoxetane intermediate via a reversible (2-1-2) cycloaddition, followed by irreversible reductive insertion of the Os-C bond into an Os=0 bond leading to the monoglycolate ester [2] (Scheme 3). 

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. 

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. ... 

DHQD-CL or DHQ-CL) was used as the chiral auxiliary.175,176 However, the enantioselectivity observed under catalytic conditions was inferior to that observed under stoichiometric conditions. The addition of triethylammonium acetate, which increases the rate of hydrolysis of the Osvm-glycolate intermediate, improved enantioselectivity. A further improvement in enantioselectivity was brought about by the slow addition of substrates (Scheme 44).177 These results indicated that the hydrolysis of the Osvm-glycolate intermediate (57) was slow under those conditions and (57) underwent low enantioselective dihydroxylation (second cycle). Thus, Sharpless et al. proposed a mechanism of the dihydroxylation including a second cycle (Scheme 45).177 Slow addition reduces the amount of unreacted olefin in the reaction medium and suppresses the... 

This proposed catalytic mechanism (Chong and Sharpless, 1977) requires four reaction steps (3 bimolecular and 1 unimolecular), which take place on a molybdenum metal center (titanium and vanadium centers are also effective), to which various nonreactive ligands (L) and reactive ligands (e g., O-R) are bonded. Each step around the catalytic cycle is an elementary reaction and one complete cycle is called a turnover. 

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... 

Kinetic data on the influence of the reaction temperature on the enantioselectivity using chiral bases and prochiral alkenes revealed a nonlinearity of the modified Eyring plot [16]. The observed change in the linearity and the existence of an inversion point indicated that two different transition states are involved, inconsistent with a concerted [3+2] mechanism. Sharpless therefore renewed the postulate of a reversibly formed oxetane intermediate followed by irreversible rearrangement to the product. 

We first consider the Demko and Sharpless article (2001) on the synthesis of substituted tetrazoles from nitriles in water (excerpt 5D). This excerpt is particularly useful because it illustrates several types of content that authors typically discuss in synthesis papers. The authors begin by proposing two possible mechanisms for the tetrazole reaction, a two-step mechanism and a concerted mechanism. The mechanisms are presented in a scheme (Scheme 1). In the accompanying text, the authors cite evidence for both mechanisms, highlight salient features of the mechanisms, mention the results of kinetic studies, and point out that the role of zinc metal is as yet unclear. 

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 . 

The olefin oxygenations carried out with dioxygen seem to be metal-centered processes, which thus require the coordination of both substrates to the metal. Consequently, complexes containing the framework M (peroxo)(olefin) represent key intermediates able to promote the desired C-0 bond formation, which is supposed to give 3-metalla -l,2-dioxolane compounds (Scheme 6) from a 1,3-dipolar cycloinsertion. This situation is quite different from that observed in similar reactions involving middle transition metals for which the direct interaction of the olefin and the oxygen coordinated to the metal, which is the concerted oxygen transfer mechanism proposed by Sharpless, seems to be a more reasonable pathway [64] without the need for prior olefin coordination. In principle, there are two ways to produce the M (peroxo)(olefin) species, shown in Scheme 6, both based on the easy switch between the M and M oxidation states for... 

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). 

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