Allylic alcohols titanium epoxidation

Sharpless asymmetric epoxidation of allylic alcohols, asymmetric epoxidation of conjugated ketones, asymmetric sulfoxidations catalyzed, or mediated, by chiral titanium complexes, and allylic oxidations are the main classes of oxidation where asymmetric amplification effects have been discovered. The various references are listed in Table 4 with the maximum amplification index observed. 

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]. 

The SAE is arguably one of the most important reactions discovered in the last 30 years. The SAE converts the double bond of allyl alcohols into epoxides with high enantioselective purity using a titanium tetraisopropoxide catalyst, Ti(0-iPr)4, chiral additive, either L-(+)-diethyl tartrate [(+)-DET, 7.45] or D-(—)-diethyl tartrate [(—)-DET, 7.46], and tert-butyl peroxide (t-BuOOH, TBHP (f-butylhydroperoxide)) as the source of the oxidant in stoichiometric amounts (see section 1.5, references 28-30 of Chapter 1). 

Keywords Epoxidation, Epoxy alcohol, Allylic alcohol. Titanium-mediated epoxidation. Titanium tartrate complex. Kinetic resolution. Ligand acceleration... 

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... 

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 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 number of reaction variables or parameters have been examined. Catalyst solutions should not be prepared and stored since the resting catalyst is not stable to long term storage. However, the catalyst solution must be aged prior to the addition of allylic alcohol or TBHP. Diethyl tartrate and diisopropyl tartrate are the ligands of choice for most allylic alcohols. TBHP and cumene hydroperoxide are the most commonly used terminal oxidant and are both extremely effective. Methylene chloride is the solvent of choice and Ti(i-OPr)4 is the titanium precatalyst of choice. Titanium (IV) t-butoxide is recommended for those reactions in which the product epoxide is particularly sensitive to ring opening from alkoxide nucleophiles. ... 

Titanium-IV compounds with their Lewis acid activity may catalyze an interfering rearrangement of the starting allylic alcohol or the epoxy alcohol formed. In order to avoid such side-reactions, the epoxidation is usually carried out at room temperature or below. 

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 enantioselective epoxidation method developed by Sharpless and co-workers is an important asymmetric transformation known today. This method involves the epoxidation of allylic alcohols with fcrt-butyl hydroperoxide and titanium (sopropoxide in the presence of optically active pure tartarate esters, see Eqn. (25). 

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 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 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. 

A combination of DAT and a metal alkoxide other than titanium alkoxide serves as a poor catalyst for the epoxidation of allylic alcohols. However, the combination of DAT and silica-supported tantalum alkoxides (2a) and (2b) prepared from Ta(=CHCMe3)(CH2Cme3)3 and silica(5oo) shows high enantioselectivity in the epoxidation of E-allylic alcohols, though chemical yields are not very great (Scheme 4).3... 

The use of alkylhydroperoxides as epoxidizing agents for allylic alcohols under catalytic conditions was soon expanded into enantioselective epoxidation with use of the more mild titanium alkoxides in the presence of chiral tartaric esters116. As concerns the epoxidation of functionalized dienes, these now so-called Sharpless conditions [Ti(OPr )4, dialkyl tartrate, TBHP] have been utilized to enantioselectively epoxidize 1,4-pentadiene-... 

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. 

Following the success with the titanium-mediated asymmetric epoxidation reactions of allylic alcohols, work was intensified to seek a similar general method that does not rely on allylic alcohols for substrate recognition. A particularly interesting challenge was the development of catalysts for enantioselective oxidation of unfunctionalized olefins. These alkenes cannot form conformationally restricted chelate complexes, and consequently the differentiation of the enan-tiotropic sides of the substrate is considerably more difficult. 

As a further example of a hydroxyl-assisted epoxidation, geraniol and nerol bearing two isolated C=C double bonds were regioselectively epoxidized with TS-1 at the 2-position (near the OH group), as reported by Kumar et al. (795). On the basis of these results, Kumar et al. (195) proposed that the transition state of the epoxidation of allylic alcohols involves coordination of the alcoholic functional group to the Ti active site and that the double bond interacts with one of the peroxidic oxygen atoms, not with the titanium site (Scheme 9). 

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... 

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. 

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