Mechanism of epoxidations

In the previous sections, epoxidation was accompanied by a net oxidation of the substrate. We would like to conclude our discussion of various mechanisms of epoxide formation by presenting one example in which the substrate does not undergo a change in redox state. 

The structure of the reagent, the mechanism of epoxide opening, deoxygenations, dimerizations and intermolecular additions will be discussed first before covering the preparatively much more important cyclization reactions [36]. 

Before entering the discussion of the synthetic results, a brief description of the structure of Cp2TiCl and the mechanism of epoxide opening is given. These results serve as a guide for choosing a suitable catalyst for a given application. 

The mechanism of epoxide formation (Scheme 7) has not been established but the intermediacy of nickel enolates and ensuing aldol type reactions are suspected28 (cf. Zn-mediated formation of furans from a-bromoketones29). A limitation on the synthesis is that R cannot be aryl for these cases, the products are 2,4-diarylfurans (see Section IV,B,1).30... 

The catalyst is preliminarily oxidized to the state of the highest valence (vanadium to V5+ molybdenum to Mo6+). Only the complex of hydroperoxide with the metal in its highest valence state is catalytically active. Alcohol formed upon epoxidation is complexed with the catalyst. As a result, competitive inhibition appears, and the effective reaction rate constant, i.e., v/[olefin][ROOH], decreases in the course of the process due to the accumulation of alcohol. Water, which acts by the same mechanism, is still more efficient inhibitor. Several hypothetical variants were proposed for the detailed mechanism of epoxidation. 

Figure 4.4 Mechanism of epoxidation using diethylzinc and methylpseudoephedrine.

Figure 5.2 Mechanism of epoxidation using titanium(TV) chiral complex.

Figure 6.2 Mechanism of epoxidation using a manganese(III) complex.

Figure 6.4 Mechanism of epoxidation by a chiral ketone catalyst.

FIGURE 6.10 Mechanism of epoxide hydrolase-catalyzed hydrolytic opening of an epoxide. 

The Mechanism of Epoxide Opening through Electron Transfer ... 

Scheme 2 Mechanism of epoxide opening through direct ET...

Fig-1 Structural features of 10 necessary for establishing competing mechanisms of epoxide opening... 

A critical input in unraveling the catalytic mechanism of epoxide hydrolases has come from the identification of essential residues by a variety of techniques such as analysis of amino acid sequence relationships with other hydrolases, functional studies of site-directed mutated enzymes, and X-ray protein crystallography (e.g., [48][53][68 - 74]). As schematized in Fig. 10.6, the reaction mechanism of microsomal EH and cytosolic EH involves a catalytic triad consisting of a nucleophile, a general base, and a charge relay acid, in close analogy to many other hydrolases (see Chapt. 3). 

R. N. Armstrong, C. S. Cassidy, New Structural and Chemical Insight into the Catalytic Mechanism of Epoxide Hydrolases , Drug Metab. Rev. 2000, 32, 327 - 338. 

The mechanism of epoxidation has been studied in detail both with P450 enzymes [68] and synthetic metal porphyrins [69], The problem finding a conclusive answer on how the enzymatic reaction proceeds is due to the fact that intermediates have not been detected but inferred by investigating the stereochemistry of product formation. By and large it is safe to say that the reaction depends on the steric hindrance imposed by the olefin s substitutents, the electron donating character of the olefin, and the electron demand of the oxo-iron(IV) porphyrin used. In particular the last aspect makes it difficult to draw conclusions from reactions with model compounds, since these metal porphyrins behave quite differently from native P450 due to the distinct electronic nature of both the metal and the porphyrin. 

All these data are consistent with the cyclic peroxymetalation mechanism of epoxidation shown in equation (26). 

However, most of the debate in this area has been over the mechanism of epoxidation by cytochrome P450 (c-P450) and its analogs. C-P450 is a monooxygenase whose active center is an iron(III) porphyrin136 its catalytic cycle is shown in Scheme 53137. 

In a seminal contribution [42a], Que and coworkers revealed insight into the reaction mechanisms of epoxidation and dihydroxylation using the pentadentate TPA and bpmen ligands. Some of those compounds had earlier shown remarkable... 

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