Asymmetric Epoxidation and Kinetic Resolution

In epoxidation reactions, allyl alcohol can act as a prochiral alkene. Enantiomerically, pure glycidol isomer, the epoxide of allyl alcohol, may be used to make (S)-propranolol, a drug for heart disease and hypertension. The basic mechanism of epoxidation reaction, the transfer of an oxygen atom from t-butyl hydroperoxide to the alkene functionality, is as discussed earlier (see reaction 8.5.2.3). 

The precatalyst, however, is a chiral rather than a Mo complex. It is generated by the in situ treatment of titanium isopropoxide with optically pure diethyl or diisopropyl tartrate. As L-tartaric acid is a natural product, the optically pure ligand is easily made. As shown by reaction 8.5.3.1, at the optimum Ti tartarate ratio (1 1.2), complex 8.32 is the predominant species in solution. This gives the catalytic system of highest activity and enantioselectivity. 

Electrophilic attack by the distal, i.e., non-carbon-bonded oxygen atom, produces 8.34. In 8.34, the epoxide oxygen donates a lone pair to titanium. On reaction with isopropanol, as shown by the outer cycle, 8.34 releases the epoxide and f-butanol and regenerates 8.32. Alternatively, as shown by the inner cycle it can also react with allyl alcohol and f-butyl hydroperoxide. This reaction also regenerates 8.33 

The chiral environment around the Ti atom ensures that the allyl alcohol is oriented in such a way that the oxygen atom transfer takes place only on one particular enantioface. The discrimination between the two possible enantiofaces is stereoelectronic rather than pure steric in nature. 

Kinetic, spectroscopic, and computational data are consistent with this mechanism. It must be noted that coordination by allyl alcohol to the titanium center is essential for the preferential positioning of only one of the two possible enantiofaces. With alkenes that do not have any such functional groups, and consequently cannot coordinate, the titanium tartarate system gives poor enantioselectivities. 

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A number of tartrate-like ligands have been studied as potential chiral auxiliaries in the asymmetric epoxidation and kinetic resolution processes [6,20b], Although on occasion a ligand has been found that has the capability to induce high enantioselectivity into selected substrates (see Section, 6A.7.3.) none has exhibited the broad scope of effectiveness seen with the tartrate esters. 

Catalysts may need to be aged for optimal activity. This was noted with the Ti(Oi-Pr)4/(+)-diethyl tartrate catalyst used for asymmetric epoxidation and kinetic resolution [27]. Both addition sequence and aging are essential for proper preparation of the catalyst. Experimentation is necessary to determine if catalytic activity benefits from aging. 

In a series of papers, the application of titanium alkoxide catalysts to the synthesis of sugars has been described. Asymmetric epoxidation and kinetic resolution of (48) afforded (+)-(49) (27% >95%e.e.) and (—)-(48) (33% 72%e.e.). The ring-opening reactions of the chiral epoxides that are produced, for example, from cis- and from trans- 50) provide new routes to saccharides. The reagents also find use in the synthesis of pheromones e.g., (+)-disparlure and (+)-2,6-dimethylhepta-l,5-dien-3-ol acetate via the epoxide (52), which was obtained from the dienol (51) by using D-(—)-... 

Applications of asymmetric epoxidation and kinetic resolution procedures The importance of the Sharpless AE and KR procedures is best measured by the speed with which they have become a part of the synthetic chemist s bag of tricks . Although a measure of their utility can be gleaned from examples given in sections... 

DET, the (5)-enantiomer reacted faster than the (/ )-enantiomer to give (/ )-alcohol 62a with high enantiomeric purity [24]. Addition of catalytic amounts of CaH2 and silica gel to the reaction system enhances the epoxidation rate [25]. Furthermore, the asymmetric epoxidation and kinetic resolution with a catalytic amount of Ti(Oi-Pr)4 and a chiral tartrate can be achieved in the presence of MS 4A, without impairing the enantioselectivity [26],... 

Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless KB. Catalytic asymmetric epoxidation and kinetic resolution modified procedures including in situ derivatization. 7. Am. Chem. Soc. 1987 109(19) 5765-5780. 

J. C. Lorenz, M. Frohn, X. M. Zhou, J. R. Zhang, Y. Tang, C. Burke, Y. Shi, Transition state studies on the dioxirane-mediated asymmetric epoxidation via kinetic resolution and desymmetrization, /. Org. Chem. 70 (2005) 2904. 

Highly active oligomeric (salen)Co complexes such as (198) were designed for asymmetric hydrolysis of meso-epoxides and kinetic resolution of terminal epoxides, based on cooperative bimetallic mechanism postulated for epoxide ring-opening reactions (Scheme 16.59) [83, 84]. 

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Based on the landmark studies of Jacobsen and coworkers, who employed chiral (salen)CoX complexes for the asymmetric ring opening and kinetic resolution of aliphatic epoxides [18-20], Lu and coworkers synthesized highly isotactic copolymer from rac-propylene oxide and carbon dioxide (Scheme 5) [21]. 

The [3-hydroxy amines are a class of compounds falling within the generic definition of Eq. 6A.6. When the alcohol is secondary, the possibility for kinetic resolution exists if the Ti-tartrate complex is capable of catalyzing the enantioselective oxidation of the amine to an amine oxide (or other oxidation product). The use of the standard asymmetric epoxidation complex (i.e., T2(tartrate)2) to achieve such an enantioselective oxidation was unsuccessful. However, modification of the complex so that the stoichiometry lies between Ti2 (tartrate) j and Ti2(tartrate)1 5 leads to very successful kinetic resolutions of [3-hydroxyamines. A representative example is shown in Eq. 6A.11 [141b,c]. The oxidation and kinetic resolution of more than 20 secondary [3-hydroxyamines [141,145a] provides an indication of the scope of the reaction and of some... 

The allylic alcohol binds to the remaining axial coordination site where stereochemical and stereoelec-tronic effects dictate the conformation shown in Figure 5. The structural model of catalyst, oxidant and substrate shown in Figure 5 illustrates a detailed version of the formalized rule presented in Figure 1. Ideally, all the observed stereochemistry of epoxy alcohol and kinetic resolution products can be rationalized according to the conq>atibility of their binding with the stereochemistry and stereoelectronic requirements imposed by this site. A transition state model for the asymmetric epoxidation complex has been calculated by a frontier orbital preach and is consistent with the formulation portrayed in Figure... 

The original report32 of the titanium-catalyzed asymmetric epoxidation of allylic alcohols in 1980 has been followed by hundreds of applications, the majority of which use the initially reported conditions. In the decade since the introduction of this reaction numerous improvements have been made41. The most complete discussion of the preparative aspects of both the asymmetric epoxidation and the kinetic resolution was presented by the Sharpless group42. This paper details the effects of reagent stoichiometry and concentration, substrate concentration, aging of the catalyst and variation of oxidant, solvent and tartrate as well as workup procedures. What is particularly noteworthy in this presentation is that significant amounts of unpublished work are drawn upon to develop recommendations for successful reaction. 

Before the dihydroxylation reaction burst onto the asymmetric scene, asymmetric epoxidation and associated kinetic resolutions were possibly the most popular methods of producing single enantiomers simply because they worked so well. The epoxidation could, for example, be used reliably in undergraduate laboratories. 

We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the chapter. Interestingly, Sharpless other famous asymmetric method - dihydroxylation - has not found widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic, too wilful. In other words, it is not sensitive to the chirality of the substrate and charges ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution with dihydroxylation,19 but they are more rare. However, the dihydroxylation is even more useful and much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric dihydroxylation is in the Double Methods section. 

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