Epoxidation Titanium isopropoxide

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. 

The original epoxidation with titanium-tartrate is homogeneous, but it can be carried out heterogeneously without diminishing enantioselectivity by using titanium-pillared montmorillonite catalyst (Ti-PILC) prepared from titanium isopropoxide, (+)-DAT, and Na+-montmorillonite.38 Due to the limited spacing of Ti-PILC, the epoxidation becomes slower as the allylic alcohol gets bulkier. 

Since its discovery in 1980,7 the Sharpless expoxidation of allylic alcohols has become a benchmark classic method in asymmetric synthesis. A wide variety of primary allylic alcohols have been epoxidized with over 90% optical yield and 70-90% chemical yield using TBHP (r-BuOOH) as the oxygen donor and titanium isopropoxide-diethyl tartrate (DET, the most frequently used dialkyl tartrate) as the catalyst. One factor that simplifies the standard epoxidation reaction is that the active chiral catalyst is generated in situ, which means that the pre-preparation of the active catalyst is not required. 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

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 chiral precatalyst is a titanium species. It is generated by the in situ treatment of titanium isopropoxide with diethyl or diisopropyl tartarate. The relative amounts of Ti(OPr )4 and the tartarate ester have a major influence on the rate of epoxidation and enentioselectivity. This is because the reaction between Ti(OPr )4 and the tartarate ester leads to the formation of many complexes with different Ti tartarate ratios. All these complexes have different catalytic activities and enantioselectivities. At the optimum Ti tartarate ratio (1 1.2) complex 9.35 is the predominant species in solution. This gives the catalytic system of highest activity and enantioselectivity. The general phenomenon of rate enhancement due to coordination by a specific ligand, with a specific metal-to-ligand stoichiometry, is called ligand-accelerated catalysis. 

Chiral epoxides are important intermediates in organic synthesis. A benchmark classic in the area of asymmetric catalytic oxidation is the Sharpless epoxidation of allylic alcohols in which a complex of titanium and tartrate salt is the active catalyst [273]. Its success is due to its ease of execution and the ready availability of reagents. A wide variety of primary allylic alcohols are epoxidized in >90% optical yield and 70-90% chemical yield using tert-butyl hydroperoxide as the oxygen donor and titanium-isopropoxide-diethyltartrate (DET) as the catalyst (Fig. 4.97). In order for this reaction to be catalytic, the exclusion of water is absolutely essential. This is achieved by adding 3 A or 4 A molecular sieves. The catalytic cycle is identical to that for titanium epoxidations discussed above (see Fig. 4.20) and the actual catalytic species is believed to be a 2 2 titanium(IV) tartrate dimer (see Fig. 4.98). The key step is the preferential transfer of oxygen from a coordinated alkylperoxo moiety to one enantioface of a coordinated allylic alcohol. For further information the reader is referred to the many reviews that have been written on this reaction [274, 275]. 

Aymmetric ring-opening reactions of other meso epoxides using catalysts derived from trimethylsilyl azide with titanium isopropoxide are described (3). 

Ti(OPr )4/Bu OOH/tartrate ester (Sharpless oxidation) (titanium isopropoxide/t-butyl hydroperoxide dialkyl tartrate) Dichloromethane -20 enantioselective epoxidation of allylic alcohols... 

With chiral ligands, the transition-metal catalyst-hydroperoxide complex yields optically active oxiranes. " One of the most significant advances in the formation of chiral epoxides from allyl alcohols has recently been reported by the Sharpless group. Using (-l-)-tartaric acid, ferf-butylhydroperoxide, and titanium isopropoxide, they were able to obtain chiral epoxides in very high enantiomeric excess. The enantiomeric epoxide can be obtained by employing (—)-tartaric acid (Eq. 33a). 

The lithiation of ethyl allyl sulfide followed by transmetallation with titanium isopropoxide engenders an allyltitanium reagent formulated as (26 Scheme 8). This and related reagents add to aldehydes or ketones to afford hydroxy sulfides, which are converted to epoxides as shown. The power of this method for the stereoselective generation of even trisubstituted epoxides is evident from Scheme 8 and equation (18). Reagent (26a), prepared as shown in Scheme 8a, undergoes addition to ketone (26b) to afford product exclusively resulting from chelation-controlled diastereofacial addition (as a mixture of epimers at the position shown). ... 

In general, the reaction accomplishes the efficient asymmetric synthesis of hydroxymethyl epoxides from allylic alcohols (Scheme 8.4). Operationally, the catalyst is prepared by dissolving titanium isopropoxide, diethyl or diisopropyl tartrate (DET or DIPT, respectively), and molecular sieves in CH2CI2 at -20 °C, followed by addition of the allylic alcohol or t-BuOOH. After a brief weiiting period (presumably to allow the ligand equilibration to occur on titanium), the final component of the reaction is added. 

Alternatively, an enantiomerically pure catalyst that is not an enzyme can be used to obtain an enantiomerically pure target molecule. For example, an enantiomerically pure epoxide of an allylic alcohol can be prepared by treating the alcohol with tert-butyl hydroperoxide, titanium isopropoxide, and enantiomerically pure diethyl tartrate (DET). The structure of the epoxide depends on the enantiomer of diethyl tartrate used. 

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using fert-butylhydroperoxide in the presence of a chiral titanium-tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of a-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used . Thus treatment of racemic A-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [( )-74] with fert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-/)4], calcium hydride (CaHa), silica gel and L-(+)-diisopropyl tartrate [l-(+)-DIPT] gave (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [(S)-74] in high chemical yield and enantiomeric excess . Similarly prepared were the (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)-n-propylamine and other homologues of (S)-74 using l-(+)-D1PT. When D-(—)-DIPT was used, the enantiomers were formed . ... 

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. 

Epoxidation of oleic and linoleic acid was readily achieved by treatment with the acetonitrile complex of hypofluorous acid (55). Phase-transfer-catalyzed biphasic epoxidation of unsaturated triglycerides was accomplished with ethylmethyldioxirane in 2-butanone (56). The enantioselective formation of an a,P-epoxy alcohol by reaction of methyl 13()S)-hydroperoxy-18 2(9Z,llfi) with titanium isopropoxide has been reported (57). An immobilized form of Candida antartica on acrylic resin (Novozyme 435) was used to catalyze the perhydrolysis and the interesterification of esters. Unsaturated alcohols were converted with an ester in the presence of hydrogen peroxide to esters of epoxidized alcohols (e.g., epoxystearylbutyrate) directly (58). Homoallyl ethers were obtained from olefinic fatty esters by the ethylaluminium-in-duced reactions with dimethyl acetals of formaldehyde, acetaldehyde, isobutyralde-hyde, and pivaldehyde (59). Reaction of 18 2(9Z, 12Z) with 50% BF3-methanol gave monomethoxy and dimethoxy derivatives (60). A bulky phosphite-modified rhodium catalyst was developed for the hydroformylation of methyl 18 1 (9Z)and 18 1(9 ), which furnished mixtures of formylstearate and diformylstearate (61). 

Bao and co-workers also reported enantioselective ring-opening ami-nolysis of epoxide, 93, with benzylamine, 94, catalyzed by the titanium isopropoxide-BINOL-water system (BlNOL=l,l -bi-2-naphthol-96) in toluene (reaction 7.16) [66]. Titanium isopropoxide-isopropanol, 96, system also used by Kim et al. for asymmetric methallylation of ketones (reaction 7.17) with high yield and enantioselectivity [67]. 

In 1980, Katsuki and Sharpless communicated that the epoxidation of a variety of allylic alcohols was achieved in exceptionally high enantioselectivity with a catalyst derived from titanium(IV) isopropoxide and chiral diethyl tartrate. This seminal contribution described an asymmetric catalytic system that not only provided the product epoxide in remarkable enantioselectivity, but showed the immediate generality of the reaction by examining 5 of the 8 possible substitution patterns of allylic alcohols all of which were epoxidized in >90% ee. Shortly thereafter. Sharpless and others began to illustrate the... 

A model for the catalytically active species in the Sharpless epoxidation reaction is formulated as a dimer 3, where two titanium centers are linked by two chiral tartrate bridges. At each titanium center two isopropoxide groups of the original tetraisopropoxytitanium-(IV) have been replaced by the chiral tartrate ligand ... 

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... 

These epoxide-opening conditions were originally developed by Sharpless and coworkers for the regiocontrolled opening of 2,3-epoxy alcohols [30]. It has been proposed that ligand exchange of the substrate with isopropoxide forms a covalently bound substrate-titanium complex (Chart 3.3). Nucleophilic attack on this complex at the 3-position is favored over attack at the 2-position. In the case of 49,... 

The asymmetric dihydroxylation protocol was the second massive contribution by Professor Barry Sharpless to synthetic organic chemistry. The first procedure, introduced with Katsuki, involves the catalytic asymmetric epoxida-tion of allylic alcohols. A typical example is shown in Scheme 17, wherein ( )-allylic alcohol (23) is epoxidized with tert-b utyl hyd roperox ide, in the presence of titanium tetra-isopropoxide and optically active diethyl tartrate to give the... 

Hydroxy epoxidation of dienes.2 Photosensitized oxygenation of dienes when catalyzed by titanium(IV) isopropoxide results in an epoxy alcohol, formed by an oxygen transfer from an allylic hydroperoxide. 

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