Tartrate esters epoxidation

The epoxidation of allylic alcohols can also be effected by /-butyl hydroperoxide and titanium tetraisopropoxide. When enantiomerically pure tartrate ligands are included, the reaction is highly enantioselective. This reaction is called the Sharpless asymmetric epoxidation.55 Either the (+) or (—) tartrate ester can be used, so either enantiomer of the desired product can be obtained. 

Sharpless epoxidation involves treating an allylic alcohol with titanium(IV) tetraisopropoxide [Ti(0-/Pr)4], tert-butyl hydroperoxide [t-BuOOH], and a specific enantiomer of a tartrate ester. 

The Sharpless epoxidation is a popular laboratory process that is both enantioselective and catalytic in nature. Not only does it employ inexpensive reagents and involve various important substrates (allylic alcohols) and products (epoxides) in organic synthesis, but it also demonstrates unusually wide applicability because of its insensitivity to many aspects of substrate structure. Selection of the proper chirality in the starting tartrate esters and proper geometry of the allylic alcohols allows one to establish both the chirality and relative configuration of the product (Fig. 4-1). 

In 1980 a useful level of asymmetric induction in the epoxidation of some alkenes was reported by Katsuki and Sharpless121. The combination of titanium (IV) alkoxide, an enantiomerically pure tartrate ester and tert-butyl hydroperoxide was used to epoxidize a wide variety of allylic alcohols in good yield and enantiomeric excess (usually >90%). This reaction is now one of the most widely applied reactions in asymmetric synthesis131. 

In 1980, Katsuki and Sharpless[1] reported that, with the combination of a titanium(IV) alkoxide, an enantiomerically pure tartrate ester [for example (+)-diethyl tartrate ((+)-DET) or (+) di-iso-propyltartrate ((+)-DIPT)] and tert-butyl hydroperoxide, they were able to carry out the epoxidation of a variety of allylic alcohols in good yield and with a good enantiomeric excess (Figure 5.1). 

Table 5.1 Catalytic asymmetric epoxidation of allylic alcohols using a combination of titanium wopropoxide. enantiomerically pure tartrate ester ((+)-DET or (+)-DIPT) and rerr-butyl hydroperoxide (yield and enantiomeric excess, according to the relevant publication). ...

If optimal conditions are desired for a specific asymmetric epoxidation.variation of the tartrate ester is likely to be a useful exercise. 

One of the first attempts to extend polymer-assisted epoxidations to asymmetric variants were disclosed by Sherrington et al. The group employed chiral poly(tartrate ester) hgands in Sharpless epoxidations utilizing Ti(OiPr)4 and tBuOOH. However, yields and degree of stereoselection were only moderate [76]. In contrast to most concepts, Pu and coworkers applied chiral polymers, namely polymeric binaphthyl zinc to effect the asymmetric epoxidation of a,/9-unsaturated ketones in the presence of terPbutyl hydroperoxide (Scheme 4.11). 

The use of tartrate esters was an obvious place to start, especially since both enantiomers are readily available commercially and had already found widespread application in asymmetric synthesis (Figure 11) (e.g.. Sharpless asymmetric epoxidation).23.24 Reagents 36-38 are easily prepared and are reasonably enantioselective in reactions with achiral, unhindered aliphatic aldehydes (82-86% ee) typical results are given in Figure 12.3c,h Aromatic and a,p-unsaturated aldehydes, unfortunately, give lower levels of enantioselection (55-70% e.e.). It is also interesting to note that all other C2 symmetric diols that we have examined (2,3-butanediol, 2,4-pentanediol, 1,2-diisopropylethanediol, hydrobenzoin, and mannitol diacetonide, among others) are relatively ineffective in comparison to the tartrate esters (see Table ll).25... 

We began these studies with the intention of applying this tandem asymmetric epoxidation/asymmetric allylboration sequence towards the synthesis of D-olivose derivative 63 (refer to Figure 18). As the foregoing discussion indicates, our research has moved somewhat away from this goal and we have not yet had the opportunity to undertake this synthesis. This, as well as the synthesis of the olivomycin CDE trisaccharide, remain as problems for future exploration. Because it is the enantioselectivity of the tartrate ester allylboronates that has limited the success of the mismatched double asymmetric reactions discussed here, as well as in several other cases published from our laboratorythe focus of our work on chiral allyiboronate chemistry has shifted away from synthetic applications and towards the development of a more highly enantioselective chiral auxiliary. One such auxiliary has been developed, as described below. 

This method has proven to be an extremely useful means of synthesizing enantiomerically enriched compounds. Various improvements in the methods for carrying out the Sharpless oxidation have been developed.48 The reaction can be done with catalytic amounts of titanium isopropoxide and the tartrate ester.49 This procedure uses molecular sieves to sequester water, which has a deleterious effect on both the rate and enantioselectivity of the reaction. Scheme 12.9 gives some examples of enantioselective epoxidation of allylic alcohols. 

The oxygen that is transferred to the allylic alcohol to form epoxide is derived from tert-butyl hydroperoxide. The enantioselectivity of the reaction results from a titanium complex among the reagents that includes the enantiomerically pure tartrate ester as one of the ligands. The choice whether to use (+) or (-) tartrate ester for stereochemical control depends on which enantiomer of epoxide is desired. 

A polymer-supported Sharpless epoxidation catalyst was prepared using linear poly(tartrate ester) catalyst ligands 43.65 This catalyst system was used in the reaction of tranA-hex-2-en- l-ol with titanium tc/ra-isopropoxide and tert-butyl hydroperoxide to afford the desired epoxide in high chemical yield and moderate enantiomeric excess. 

Catalytic asymmetric epoxidation.1 Addition of heat-activated, powdered 3-5 A molecular sieves to the asymmetric epoxidation of allylic alcohols increases the rate and, more importantly, permits use of catalytic amounts of titanium reagent and the tartrate ester. However, it is still important to use at least a 10% excess of the tartrate ester over Ti(0-i-Pr)4 a 20% excess is usually advisable. In general, 5% of Ti(0-i-Pr)4 and 7.5% of the tartrate ester is used for the catalytic epoxidation. 

The enantioselectivity principles portrayed in Figure 6A.1 have been followed without exception in all epoxidations of prochiral allylic alcohols reported to date, and one may use these principles to assign absolute configurations to the epoxy alcohols prepared by the method. On the other hand, epoxidation of allylic alcohols with chiral substituents at C-l, C-2, and/or C-3 does not always follow these principles, and assignment of absolute configuration to the products must be made with care. Even in the latter cases, reliable assignments usually can be made if the outcome (diastereomeric ratio) of epoxidation with both the (+) and (-)-tartrate ester ligands is compared. 

The second stoichiometry consideration is the ratio of catalyst to substrate. As noted in the preceding section, virtually all asymmetric epoxidations can be performed with a catalytic amount of Ti-tartrate complex if molecular sieves are added to the reaction milieu. A study of catalyst/substrate ratios in the epoxidation of cinnamyl alcohol revealed a significant loss in enantioselectivity (Table 6A.2) below the level of 5 mol % catalyst. At this catalyst level, the reaction rate also decreases, with the consequence that incomplete epoxidation of the substrate may occur. Presendy, the recommended catalyst stoichiometry is from 5% Ti and 6% tartrate ester to 10% Ti and 12% tartrate ester [4],... 

Optically active tartrate esters are the source of chirality for the asymmetric epoxidation process. With a few subtle exceptions, the esters used conventionally—dimethyl (DMT), diethyl (DET), and diisopropyl tartrate (DIPT)—are equally effective at inducing asymmetry during the crucial epoxidation event. The minor exceptions that have been noted include (a) a slight improvement... 

The nonconventional tartrate esters 1-3 have been used to probe the mechanism of the asymmetric epoxidation process [20a]. These chain-linked bistartrates when complexed with 2 equiv. of Ti(0-f-Bu)4 catalyze asymmetric epoxidation with good enantiofacial selectivity. 

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. 

Polymer-linked tartrate esters have been prepared and used for asymmetric epoxidation in efforts to simplify reaction workup procedures and to allow recycling of the chiral tartrate [21]. The tartrates were linked through an ester bond to either a hydroxymethyl or a hydroxyethyl group on the polymer backbone to form 4 and 5, respectively. 

Epoxidation catalysts were prepared from these polymer-linked tartrates by combination with 0.5 equiv. of Ti(0-i-Pr)4, based on the weight of tartrate ester, which had been added to the polymer. Epoxidation of geraniol with 4 or 5 gave epoxy alcohol with 49 and 65% ee, respectively. Recycling of the polymer-linked tartrate was possible, but the subsequent epoxidation suffered from significant loss in enantioselectivity [21 ]. 

Relative rate data for the kinetic resolution/epoxidation of 1-substituted allylic alcohols of varying structure are summarized in Table 6A.8. The j values at -20°C for all entries in Table 6A.8 were determined using DIPT as the chiral ligand. Additionally, for several entries (1-3, 10, 11) the dependence of rel on temperature, 0 versus -20°C, and on steric bulk of the tartrate ester (DIPT vs. DET vs. DMT) has been measured. Lower reaction temperature and larger tartrate ester groups are factors that clearly increase the magnitude of kre] and, therefore, improve the efficiency of the kinetic resolution process. Although the results summarized in Table 6A.8... 

A number of derivatives of the tartaric acid structure have been examined as substitutes for the tartrate ester in the asymmetric epoxidation catalyst. These derivatives have included a variety of tartramides, some of which are effective in catalyzing asymmetric epoxidation (although none display the broad consistency of results typical of the esters). One notable example is the dibenzyltartramide, which in a 1 1 ratio (in reality, a 2 2 complex as shown by an X-ray crystallographic structure determination [138]) with Ti(0-i-Pr)4 catalyzes the epoxidation of allylic alcohols with the same enantiofacial selectivity as does the Ti-tartrate ester complex [18], It is remarkable that, when the ratio of dibenzyltartramide to Ti is changed to 1 2, epoxidation is catalyzed with reversed enantiofacial selectivity. These results are illustrated for the epoxidation of a-phenylcinnamyl alcohol (Eq. 6A.12a). 

The essence of the asymmetric epoxidation process, including correlation of enantiofacial selectivity with tartrate ester stereochemistry, is outlined in Figure 6A. 1. No exceptions to the face-selectivity rules shown in Figure 6A.1 have been reported to date. Consequently, one can use this scheme with considerable confidence to predict and assign absolute configuration to the epoxides obtained from prochiral allylic alcohols. When allylic alcohols with chiral substituents at C-l, C-2, and/or C-3 are used in the reaction, the assignment of stereochemistry to the newly introduced epoxide group must be done with considerably more care. 

A density functional study of the transition structures of Ti-catalyzed epoxidation of allylic alcohol was performed, which mimicked the dimeric mechanism proposed by Sharpless et al.5 Importance of the bulkiness of alkyl hydroperoxide to the stereoselectivity, the conformational features of tartrate esters in the epoxidation transition structure, and the loading of allylic alcohol in the dimeric transition structure model were pointed out. 

Studies of bis-tartrate esters and other tartrate ligands for titanium-mediated asymmetric epoxidation have provided evidence against the sole intermediacy of monomeric titanium-tartrate species in the parent system329,330. Other tartrate ligands have been studied in attempts to gain a better understanding of the mechanism of the Sharpless epoxidation330. 

A tartrate-modified solid Ti catalyst has also been prepared starting from a montmorillonite clay (31). This clay can be pillared with Ti polycations prepared by acid hydrolysis of Ti(OiPr)4. In the presence of tartrate ester, an allylic alcohol such as tram-2-buten-l-ol is epoxidized in 91% yield with 95% ee. These results are superior even to those for the homogeneous catalyst. Moreover, the reaction also proceeds in the absence of the molecular... 

Finally, two other practical points are worth mentioning. The early procedures for asymmetric epoxidation called for dilute solutions of sodium hydroxide to effect tartrate ester hydrolysis. For the reasons given 1n Note 11, one should always (unless one is certain that the epo y alcohol 1s completely Insoluble in water) use Instead NaOH 1n brine. In this procedure, the excess tert-butyl hydroperoxide (TBHP) was destroyed early in the work-up (FeSC ), although this is not essential because dilute solutions of TBHP are... 

The Sharpless epoxidation uses ferf-butyl hydroperoxide, titanium(IV) isopropoxide, and a dialkyl tartrate ester as the reagents. The following epoxidation of geraniol is typical. 

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