Ti/tartrate-catalyzed asymmetric epoxidation

Success in the use of Ti tartrate catalyzed asymmetric epoxidation depends on the presence of the hydroxyl group of the allylic alcohol. The hydroxyl group enhances the rate of the reaction, thereby providing selective epoxidation of the allylic olefin in the presence of other olefins it also is essential for the achievement of asymmetric induction. The role played by the hydroxyl group in this reaction is described in a later section of this chapter. The need for a hydroxyl group necessarily limits the scope of this asymmetric epoxidation to a fraction of all olefins. Fortunately, allylic alcohols are easily introduced into synthetic intermediates and are very versatile in organic synthesis. The Ti tartrate catalyzed asymmetric epoxidation of allylic alcohols has been applied extensively as documented in the literature and in this review. The development of methods aimed at catalytic asymmetric epoxidation of unfunctionalized olefins is described in Chapter 6B, whereas the catalytic asymmetric dihydroxylation of olefins, which provides an alternate method for olefin functionalization, is described in Chapter 6D. 

A.2. FUNDAMENTAL ELEMENTS OF Ti-TARTRATE CATALYZED ASYMMETRIC EPOXIDATION... 

A.3. REACTION VARIABLES FOR Ti-TARTRATE CATALYZED ASYMMETRIC EPOXIDATION 235... 

The hallmark of Ti-tartrate catalyzed asymmetric epoxidation is the high degree of enantiofacial selectivity seen for a wide range of allylic alcohols. It is natural to inquire into what the mechanism of this reaction might be and what structural features of the catalyst produce these desirable results. These questions have been studied extensively, and the results have been the subject of considerable discussion [6,135,136]. For the purpose of this chapter, we review the aspects of the mechanistic-structural studies that may be helpful in devising synthetic applications of this reaction. 

A.3. REACTION VARIABLES FOR Ti-TARTRATE CATALYZED ASYMMETRIC EPOXIDATION 235 TABLE 6A.1. Compatibility of Functional Groups with the Asymmetric Epoxidation Reaction... 

This section presents a summary of the currently preferred conditions for performing Ti-catalyzed asymmetric epoxidations and is derived primarily from the detailed account of Gao et al. [4]. We wish to draw the reader s attention to several aspects of the terminology used here and throughout this chapter. The terms Ti-tartrate complex and Ti-tartrate catalyst are used interchangeably. The term stoichiometric reaction refers to the use of the Ti-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 Ti-tartrate complex in a catalytic ratio (usually 5-10 mol %) relative to the substrate,... 

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 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 nonconventional tartrate esters (1) to (3) have been used to probe tite mechanism of the asymmetric epoxidation process. These chain-linked bis(tartrate) molecides when complexed with 2 equiv. of Ti(OBu )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. Although on occasion a ligand has been found that has the capability to induce high enantioselectivity into selected substrates (see Section 3.2.T.3), none has exhibited the broad scope of effectiveness seen with the tartrate esters. 

Chiral Ligand for Asymmetric Catalysis. Dimethyl l-tartrate is a demonstrated chiral ligand for the Ti -catalyzed asymmetric epoxidation of allylic alcohols (Sharpless epoxidation), and the Zn -mediated asymmetric cyclo-propanation of allylic alcohols (Simmons-Smith reaction), see lodomethylzinc Iodide Enantioselectivities in these reactions... 

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 [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... 

Sharpless asymmetric epoxidation Ti-alkoxide-catalyzed epoxidation of prochiral and chiral allylic alcohols in the presence of a chiral tartrate ester and an alkyl hydroperoxide. 408... 

The Sharpless epoxidation proceeds by a completely different mechanism from these reactions. This asymmetric O-transfer reaction uses catalytic amounts of Ti(0-t-Pr)4 and (+)- or ( )-diethyl tartrate to catalyze the epoxidation of allylic alcohols by f-BuOOH. The enantioselectivities are usually very good. 

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]. 

Epoxidations and dihydroxylations catalyzed by soluble PEG-bound catalysts are well-established reactions and this chemistry has been discussed in recent reviews [5,83,84]. In a recent report [85], tartrate esters 44 prepared with a PEG750 or PEG2000 shown to be effective in the asymmetric epoxidation of (E)-hex-2-en-l-ol using Ti(0(CH(CH3)2))4 and (CH3)3COOH in CH2CI2 at -20 °C. Yields of 85% were obtained with e.e. values of the epoxide of 93% - a... 

The ability of zeolites to adsorb and retain small molecules such as water forms the basis of their use in the noncatalytic synthesis of fine chemicals (Van Bekkum and Kouwenhoven, 1988, 1989). One of the best recent examples is the use of NaA zeolite in the Sharpless asymmetrical epoxidation of ally lie alcohols (see Chapter 10) (Gao et al., 1987 Antonioletti et al 1992). In this Ti(IV)-catalyzed epoxidation by t-butyl hydroperoxide in the presence of diethyl tartrate (reaction 6.4), it has been demonstrated that the inclusion of zeolites (3 A or 4 A) leads to high conversion (>95%) and high enantioselectivity (90-95% ee). The effect of the zeolite is quite dramatic. It is believed that the role of the zeolite is to protect the titanium isopropoxide catalyst from water, perhaps generated during the reaction. 

The Sharpless epoxidation serves as the predominant approach for the asymmetric epoxidation of allylic alcohols, which is catalyzed with L-(+)/D-(-)-diethyl tartrate and titanium tetraisopropoxide (Ti(O-f-Pr) ) using TBHP as the oxidant [9, 19]. Primary allylic alcohols are t5qjical substrates for Sharpless epoxidation, and the same system could be used to kinetically resolve racemic secondary allylic alcohols as well [116,117]. 

---