Asymmetric Epoxidation of Allylic Alcohols and Mechanisms

In epoxidation reactions allyl alcohol can act as a prochiral alkene. Enantio-merically pure glycidol isomers (see Table 1.1) may be used to make S-propanolol 9.61, a drug for heart disease and hypertension. The mechanistic details of the epoxidation reaction with V5+ and Mo6+ complexes as catalysts were discussed in Section 8.6. The basic mechanism of epoxidation reaction, the transfer of an oxygen atom from f-butyl hydroperoxide to the alkene functionality, remains the same. 

The chiral precatalyst is a titanium species. It is generated by the in situ treatment of titanium isopropoxide with diethyl or diisopropyl tartarate. The relative amounts of Ti(OPr )4 and the tartarate ester have a major influence on the rate of epoxidation and enentioselectivity. This is because the reaction between Ti(OPr )4 and the tartarate ester leads to the formation of many complexes with different Ti tartarate ratios. All these complexes have different catalytic activities and enantioselectivities. At the optimum Ti tartarate ratio (1 1.2) complex 9.35 is the predominant species in solution. This gives the catalytic system of highest activity and enantioselectivity. The general phenomenon of rate enhancement due to coordination by a specific ligand, with a specific metal-to-ligand stoichiometry, is called ligand-accelerated catalysis. 

Before discussing the structural evidence for the precatalyst 9.35, we quickly go through the proposed mechanism of epoxidation. The precatalyst 9.35 reacts with one mole each of allyl alcohol and f-butyl hydroperoxide to give 9.36, where two alkoxide ligands on the same Ti atom are substituted according to reaction 9.4. 

The proposed catalytic cycle and the structure of 9.36 are shown in Fig. 9.7. Nucleophilic S v2-typc attack by the olefin to the distal oxygen atom produces the epoxy alkoxide. The chiral environment around the Ti atom ensures that the allyl alcohol is oriented in such a way that O atom transfer takes place only on one particular enantioface. The discrimination between the two possible faces is stereoelectronic rather than steric in nature. The epoxy alkoxide is then replaced by allyl alcohol to give the epoxy alcohol and 9.37. The latter can react with more f-butyl hydroperoxide to regenerate 9.36. 

The evidence for the proposed mechanism comes from kinetic, spectroscopic (multinuclear NMR), X-ray structure, and theoretical calculations. The kinetic rate law under optimum catalytic conditions is very complex. Under pseudo-first-order conditions, where the concentrations of both 9.35 and the hydroperoxide are much greater than that of allyl alcohol, the rate expression 9.5 is obeyed. In this expression the inhibitor alcohol is an inert alcohol such as isopropanol or f-butanol that is deliberately added to slow down the reaction for convenient rate measurements. The inert alcohol acts as an inhibitor, since it competes with both hydroperoxide and allyl alcohol for coordination to the Ti center. Note that expression 9.5 is consistent with the formation of an intermediate like 9.36, before the rate-determining oxygen atom transfer step. 

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