Titanium tartrate complex

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Figure 6.2 Enantiofacial differentiation in AE, depending on the configuration of the diethyl tartrate ligand in the titanium complex 2.

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 4 A Molecular Sieves System. The initial procedure for the Sharpless reaction required a stoichiometric amount of the tartrate Ti complex promoter. In the presence of 4 A molecular sieves, the asymmetric reaction can be achieved with a catalytic amount of titanium tetraisopropoxide and DET (Table 4-2).15 This can be explained by the fact that the molecular sieves may remove the co-existing water in the reaction system and thus avoid catalyst deactivation. Similar results may be observed in kinetic resolution (Table 4-3).15... 

Enantioselective allyltitanation of aldehydes with a chiral tartrate-derived titanium complex [44]... 

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. 

Uemura et al. [49] found that (R)-1,1 -binaphthol could replace (7 ,7 )-diethyl tartrate in the water-modified catalyst, giving good results (up to 73% ee) in the oxidation of methyl p-tolyl sulfoxide with f-BuOOH (at -20°C in toluene). The chemical yield was close to 90% with the use of a catalytic amount (10 mol %) of the titanium complex (Ti(0-i-Pr)4/(/ )-binaphthol/H20 = 1 2 20). They studied the effect of added water and found that high enantioselectivity was obtained when using 0.5-3.0 equivalents of water with respect to the sulfide. In the absence of water, enantioselectivity was very low. The beneficial effect of water is clearly established here, but the amount of water needed is much higher than that in the case of the catalyst with diethyl tartrate. They assumed that a mononuclear titanium complex with two binaphthol ligands was involved, in which water affects the structure of the titanium complex and its rate of formation. 

This reaction has now been applied to a very great number of substituted allylic alcohols, and the mechanistic and stereoisomeric features of the reaction are becoming clearer.11 In broad outline, it would appear that the initial step is an alkoxy-exchange reaction between two alkoxy residues in the titanium complex and the two hydroxyl groups in the tartrate ester, thus ... 

The known allylic alcohol 9 derived from protected dimethyl tartrate is exposed to Sharpless asymmetric epoxidation conditions with (-)-diethyl D-tartrate. The reaction yields exclusively the anti epoxide 10 in 77 % yield. In contrast to the above mentioned epoxidation of the ribose derived allylic alcohol, in this case epoxidation of 9 with MCPBA at 0 °C resulted in a 65 35 mixture of syn/anti diastereomers. The Sharpless epoxidation of primary and secondary allylic alcohols discovered in 1980 is a powerful reagent-controlled reaction.12 The use of titanium(IV) tetraisopropoxide as catalyst, tert-butylhydro-peroxide as oxidant, and an enantiopure dialkyl tartrate as chiral auxiliary accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. If the reaction is kept absolutely dry, catalytic amounts of the dialkyl tartrate(titanium)(IV) complex are sufficient. 

A number of stereospecific non-enzyme catalysts have been developed that convert achiral substrates into chiral products. These catalysts are usually either complex organic (Figure 10.8(a)) or organometallic compounds (Figure 10.8(b)). The organometallic catalysts are usually optically active complexes whose structures usually contain one or more chiral ligands. An exception is the Sharpless-Katsuki epoxidation, which uses a mixture of an achiral titanium complex and an enantiomer of diethyl tartrate (Figure 10.8(c)). 

In order to prevent competing homoallylic asymmetric epoxidation (AE, which, it will be recalled, preferentially delivers the opposite enantiomer to that of the allylic alcohol AE), the primary alcohol in 12 was selectively blocked as a thexyldimethylsilyl ether. Conventional Sharpless AE7 with the oxidant derived from (—)-diethyl tartrate, titanium tetraisopropoxide, and f-butyl hydroperoxide next furnished the anticipated a, [3-epoxy alcohol 13 with excellent stereocontrol (for a more detailed discussion of the Sharpless AE see section 8.4). Selective O-desilylation was then effected with HF-triethylamine complex. The resulting diol was protected as a base-stable O-isopropylidene acetal using 2-methoxypropene and a catalytic quantity of p-toluenesulfonic acid in dimethylformamide (DMF). Note how this blocking protocol was fully compatible with the acid-labile epoxide. 

Oxidation in the presence of chiral titanium tartrate (modified Sharpless method). Inspired by the Sharpless asymmetric epoxidation48 of allylic alcohols with hydroperoxides in the presence of chiral titanium complex [diethyl tartrate (DET) and Ti(0-i-Pr)4], Kagan and co-workers46 and Modena and co-workers47 developed almost at the same time two variations of this reaction leading to o.p. sulfoxides with high enantiomeric purity. 

Titanium complexes (Sharpless Ti tartrate asymmetric epoxidation catalyst)... 

The first two reactions (Scheme 2) were stoichiometric with respect to the chiral titanium complex (using (J ,l )-diethyl tartrate), but they are included in the scope of asymmetric catalysis as the titanium complexes are not consumed. 

Catalytic asymmetric cyanation using 20 mol % of the complex of Ti(Oz-Pr)4 with diisoporpyl tartrate (10 Fig. 1) was reported by Oguni [42,43]. The mixture of Ti(Oi-Pr)4 and 10 (Fig. l)did not exhibit high enantioselectivity. Moreover, the selectivity and the reactivity were still low when the formed isopropyl alcho-hol was removed under reduced pressure using the freeze-dry method. High reactivity and an enantioselectivity of up to 90% were observed when the isopropyl alcohol was again added to the freeze-dried titanium complex. 

Among the reactions catalyzed by titanium complexes, the asymmetric epoxidation of allylic alcohols developed by Sharpless and coworkers [752, 807-810] has found numerous synthetic applications. Epoxidation of allylic alcohols 3.16 by ferf-BuOOH under anhydrous conditions takes place with an excellent enantioselectivity (ee > 95%) when promoted by titanium complexes generated in situ from Ti(0/ -Pr)4 and a slight excess of diethyl or diisopropyl (R,R)- or (iS, 5)-tartrates 2.69. The chiral complex formed in this way can be used in stoichiometric or in catalytic amounts. For catalytic use, molecular sieves must be added. Because both (RJ )- and (5,5)-tartrates are available, it is posable to obtain either enantiomeric epoxide from a single allylic alcohol. Cumene hydroperoxide (PhCMe20OH) can also be used in place of ferf-BuOOH. This method has been applied to industrial synthesis of enantiomeric glycidols [811, 812]. 

The Sharpless epoxidation of allyl alcohols 3.16 by /erf-butyl hydroperoxide under catalysis with chiral titanium complexes is a very popular method that has frequently been used in industry [811, 812, 853], This epoxidation was initially developed with stoichiometric amounts of tartrate catalysts. Today, it is usually performed in the presence of catalytic amounts of Ti(0/ -Pr)4 and diethyl or diisopropyl tartrate (2R,3R)- or (25,35)-2.69 (R = Et or r-Pr). The reactions are conducted at or near room temperature in the presence of molecular sieves. Several... 

---