Titanium tartrate asymmetric epoxidation

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. 

The essence of titanium-catalyzed asymmetric epoxidation is illustrated in Figure 1. As shown there, the four essential components of the reaction are the allylic alcdiol substrate, a titanium(IV) alkoxide, a chiral tartrate ester and an aUcyl hydroperoxide. The asynunetric complex formed from these reagents de-... 

This section presents a summary of the currently preferred conditions fw perfrmning titanium-catalyzed asymmetric epoxidations and is derived primarily from the detailed account of Gao et al We wish to draw the reader s attention to several aspects of the terminology used here and throughout this chapter. The terms titanium tartrate complex and titanium tartrate catalyst are used interchangeably. The term stoichiometric reaction refers to the use of the titanium tartrate complex in a stoichiometric ratio (100 mol %) relative to the substrate (allylic alcohol). The term catalytic reaction (or quantity) refers to the use of the titanium tartrate complex in a catalytic ratio (usually S-10 mol %) relative to the substrate. 

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 What is particularly noteworthy in this presentation is that significant amounts of unpublished work are drawn upon to develop recommendations for successful reaction. 

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

Tartaric acid is the least expensive chiral starting material with twofold symmetry available from natural sources. The Sharpless Ti tartrate asymmetric epoxidation catalyst consists of titanium(IV) tetraisopropoxide (Ti(OiPr)4) in combination with a chiral tartrate diester to induce asymmetry in the reaction of allylic alcohols. It is used with an alkyl hydroperoxide such as TBHP in the presence of 3A or 4A molecular sieves (to remove water) for the epoxidation of allylic alcohols [75]. It was the first effective asymmetric epoxidation catalyst reported. 

The original report on the titanium-catalysed asymmetric epoxidation of allylic alcohols (Sharpless system) prescribed stoichiometric amounts of the titanium tartrate catalyst in the general procedure and many applications of this asymmetric epoxidation have been carried out using stoichiometric or near-stoichiometric amounts of the catalyst. Sharpless has reported the first general procedure for the asymmetric epoxidation of allylic alcohols using catalytic ( <10 %) amounts of titanium(IV) isopropoxide and diethyl tartrate. 

Titanium-catalyzed asymmetric epoxidation of allylic alcohols employing titanium alkoxide, an optically active tartrate ester and an alkyl hydroperoxide. A high degree of enantiomeric purity is attainable having predictable absolute stereochemistry ... 

One of the most useful organic reactions discovered in the last several decades is the titanium-catalyzed asymmetric epoxidation of primary aUyUc alcohols developed by Professor Barry Sharpless, then at Stanford University. The reagent consists of tert-butyl hydroperoxide, titanium tetraisopropoxide [Ti(0-iPr)J, and diethyl tartrate. Recall from Section 3.4B that tartaric add has two chiral centers and exists as three stereoisomers a pair of enantiomers and a meso compound. The form of tartaric add used in the Sharpless epoxidation is either pure (+)-diethyl tartrate or its enantiomer, (-)-diethyl tartrate. The fert-butyl hydroperoxide is the oxidizing agent and must be present in molar... 

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... 

Transition metal-catalyzed epoxidations, by peracids or peroxides, are complex and diverse in their reaction mechanisms (Section 5.05.4.2.2) (77MI50300). However, most advantageous conversions are possible using metal complexes. The use of t-butyl hydroperoxide with titanium tetraisopropoxide in the presence of tartrates gave asymmetric epoxides of 90-95% optical purity (80JA5974). 

The Sharpless-Katsuki asymmetric epoxidation reaction (most commonly referred by the discovering scientists as the AE reaction) is an efficient and highly selective method for the preparation of a wide variety of chiral epoxy alcohols. The AE reaction is comprised of four key components the substrate allylic alcohol, the titanium isopropoxide precatalyst, the chiral ligand diethyl tartrate, and the terminal oxidant tert-butyl hydroperoxide. The reaction protocol is straightforward and does not require any special handling techniques. The only requirement is that the reacting olefin contains an allylic alcohol. 

In light of the previous discussions, it would be instructive to compare the behavior of enantiomerically pure allylic alcohol 12 in epoxidation reactions without and with the asymmetric titanium-tartrate catalyst (see Scheme 2). When 12 is exposed to the combined action of titanium tetraisopropoxide and tert-butyl hydroperoxide in the absence of the enantiomerically pure tartrate ligand, a 2.3 1 mixture of a- and /(-epoxy alcohol diastereoisomers is produced in favor of a-13. This ratio reflects the inherent diasteieo-facial preference of 12 (substrate-control) for a-attack. In a different experiment, it was found that SAE of achiral allylic alcohol 15 with the (+)-diethyl tartrate [(+)-DET] ligand produces a 99 1 mixture of /(- and a-epoxy alcohol enantiomers in favor of / -16 (98% ee). 

The emergence of the powerful Sharpless asymmetric epoxida-tion (SAE) reaction in the 1980s has stimulated major advances in both academic and industrial organic synthesis.14 Through the action of an enantiomerically pure titanium/tartrate complex, a myriad of achiral and chiral allylic alcohols can be epoxidized with exceptional stereoselectivities (see Chapter 19 for a more detailed discussion). Interest in the SAE as a tool for industrial organic synthesis grew substantially after Sharpless et al. discovered that the asymmetric epoxidation process can be conducted with catalytic amounts of the enantiomerically pure titanium/tartrate complex simply by adding molecular sieves to the epoxidation reaction mix-... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

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. 

The scope of metal-mediated asymmetric epoxidation of allylic alcohols was remarkably enhanced by a new titanium system introduced by Katsuki and Sharpless epoxidation of allylic alcohols using a titanium(IV) isopropoxide, dialkyl tartrate (DAT), and TBHP (TBHP = tert-butyl-hydroperoxide) proceeds with high enantioselectivity and good chemical yield, regardless of... 

The idea of double asymmetric induction is also applicable to asymmetric epoxidation (see Chapter 1 for double asymmetric induction). In the case of asymmetric epoxidation involving double asymmetric induction, the enantiose-lectivity depends on whether the configurations of the substrate and the chiral ligand are matched or mismatched. For example, treating 7 with titanium tet-raisopropoxide and t-butyl hydroperoxide without (+)- or ( )-diethyl tartrate yields a mixture of epoxy alcohols 8 and 9 in a ratio of 2.3 1 (Scheme 4 3). In a... 

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). ...

Catalytic asymmetric epaxidation (13, 51-53). Complete experimental details are available for this reaction, carried out in the presence of heat-activated crushed 3A or powdered 4A molecular sieves. A further improvement, both in the rate and enantioselectivity, is use of anhydrous oxidant in isoctane rather than in CH2C12. The titanium-tartrate catalyst is not stable at 25°, and should be prepared prior to use at -20°. Either the oxidant or the substrate is then added and the mixture of three components should be allowed to stand at this temperature for 20-30 min. before addition of the fourth component. This aging period is essential for high enantioselectivity. Epoxidations with 5-10 mole % of Ti(0-/-Pr)4 and 6-12% of the tartrate generally proceed in high conversion and high enantioselectivity (90-95% ee). Some increase in the amount of catalyst can increase the enantioselectivity by 1-5%, but can complicate workup and lower the yield. Increase of Ti(0-i-Pr)4 to 50-100 mole % can even lower the enantioselectivity. 

The AD has been developed into an extremely useful reaction, and Sharpless states that probably its synthetic utility surpasses that of titanium tartrate-catalysed asymmetric epoxidation [16], since the range of substrates is much larger for AD. 

Although it was also Henbest who reported as early as 1965 the first asymmetric epoxidation by using a chiral peracid, without doubt, one of the methods of enantioselective synthesis most frequently used in the past few years has been the "asymmetric epoxidation" reported in 1980 by K.B. Sharpless [3] which meets almost all the requirements for being an "ideal" reaction. That is to say, complete stereofacial selectivities are achieved under catalytic conditions and working at the multigram scale. The method, which is summarised in Fig. 10.1, involves the titanium (IV)-catalysed epoxidation of allylic alcohols in the presence of tartaric esters as chiral ligands. The reagents for this asyimnetric epoxidation of primary allylic alcohols are L-(+)- or D-(-)-diethyl (DET) or diisopropyl (DIPT) tartrate,27 titanium tetraisopropoxide and water free solutions of fert-butyl hydroperoxide. The natural and unnatural diethyl tartrates, as well as titanium tetraisopropoxide are commercially available, and the required water-free solution of tert-bnty hydroperoxide is easily prepared from the commercially available isooctane solutions. 

There has recently been much work in this area using Ru-based catalysts, particularly with porphyrin-based catalysts, following the work by Sharpless et al. on asynunetric epoxidation of allylic alcohols by a titanium-based tartrate system. There are reviews on asymmetric epoxidations catalysed by chiral Ru porphyrins [5, 18]. 

M. G. Finn, K. B, Sharpless, Epoxidation with Titanium-Tartrate Catalysts in Asymmetric Synthesis, J. D. Morrison, Ed.. Vol. 5, pp 269-271, Academic, New York 1985. 

Asymmetric epoxidation of ailylic alcohols.1 Epoxidation of allylic alcohols with r-bulyl hydroperoxide in the presence of titanium(lV) isopropoxide as the metal catalyst and either diethyl D- or diethyl L-tartrate as the chiral ligand proceeds in > 90% stereoselectivity, which is independent of the substitution pattern of the allylic alcohol but dependent on the chirality of the tartrate. Suggested standard conditions are 2 equivalents of anhydrous r-butyl hydroperoxide with 1 equivalent each of the alcohol, the tartrate, and the titanium catalyst. Lesser amounts of the last two components can be used for epoxidation of reactive allylic alcohols, but it is important to use equivalent amounts of these two components. Chemical yields are in the range of 70-85%. 

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