Titanium isopropoxide. Sharpless

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. 

This method has proven to be an extremely useful means of synthesizing enantiomeri-cally enriched compounds. Various improvements in the methods for carrying out the Sharpless oxidation have been developed.56 The reaction can be done with catalytic amounts of titanium isopropoxide and the tartrate ligand.57 This procedure uses molecular sieves to sequester water, which has a deleterious effect on both the rate and enantioselectivity of the reaction. 

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... 

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]. 

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). 

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. 

The first such process is a variant of the oxacyclo-propanation reaction discussed in Section 12-10, as applied specifically to 2-propenyl (allylic) alcohols. However, instead of a peroxycarboxylic acid, the reagent is ferf-butyl hydroperoxide in the presence of titanium (TV) isopropoxide ( Sharpless epoxidation ), the function of the chiral auxiliary being assumed by tartaric acid diethyl ester (Real Life 5-3). The naturally occurring (-l-)-[2/ ,3/ ]-diethyl tartrate and its nonnatural (—)-(25,35) mirror image are both commercial products. One delivers oxygen to one face of the double bond, the other to the opposite face, as shown below, giving either enantiomer of the oxacyclopropane product with high enantiomer excess (Section 5-2). 

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... 

An important breakthrough in asymmetric epoxidation has been the Katsuki-Sharpless invention [1], The reaction uses a chiral Ti(IV) catalyst, t-butylhydroperoxide as the oxidant and it works only for allylic alcohols as the substrate. In the first report titanium is applied in a stoichiometric amount. The chirality is introduced in the catalyst by reacting titanium tetra-isopropoxide... 

Sharpless Asymmetric Epoxidation This is a method of converting allylic alcohols to chiral epoxy alcohols with very high enantioselectivity (i.e., with preference for one enantiomer rather than formation of racemic mixture). It involves treating the allylic alcohol with tert-butyl hydroperoxide, titanium(IV) tetra isopropoxide [Ti(0—/Pr)4] and a specific stereoisomer of tartaric ester. For example,... 

A polymer-supported Sharpless epoxidation catalyst was prepared using linear poly(tartrate ester) catalyst ligands 43.65 This catalyst system was used in the reaction of tranA-hex-2-en- l-ol with titanium tc/ra-isopropoxide and tert-butyl hydroperoxide to afford the desired epoxide in high chemical yield and moderate enantiomeric excess. 

Titanium-pillared montmorillonite may be used as a heterogeneous catalyst for the Sharpless asymmetric epoxidation of allylic alcohols (Scheme 20) (46). The enantiomeric purities of the epoxy products are comparable with those achieved using homogeneous Ti isopropoxide with molecular sieves as water scavengers (Chapter 4). Since basal spacing of the recovered catalyst after the reaction is unaltered, the catalyst can be recycled. 

High diastereoselectivity is found in the epoxidation of fluoroallylic alcohols with titanium(IV) isopropoxide and fert-butyl hydroperoxide337. The anomalous Sharpless asymmetric epoxidation has been used in the synthesis of L-erythro- and D-threo-sphingosines338. 

Three synthetic approaches were used to provide armodafinil during the process development by Cephalon/Novasep.34 Since the racemic modafinil is commercially available, the resolution via preferential crystallization of modafinic acid 6 was employed for phase I clinical trials and was subsequently replaced by large-scale chiral chromatography. Meanwhile, an economical enantioselective synthetic route was developed by using asymmetric oxidation catalyzed by a titanium (IV) isopropoxide and diethyl tartrate with cumene hydroperoxide (the Sharpless/Kagan system).363... 

Epoxy alcohols. A few years ago Mihelich1 was granted a patent for preparation of epoxy alcohols by photooxygenation of alkenes in the presence of titanium or vanadium catalysts. Adam et al.2 have investigated this reaction in detail and find that Ti(IV) isopropoxide is the catalyst of choice for epoxidation of di-, tri-, and tetrasubstituted alkenes, acyclic and cyclic, to provide epoxy alcohols. When applied to allylic alcohols, the reaction can be diastereo- and enantioselective. The reaction actually proceeds in two steps an ene reaction to provide an allylic hydroperoxide followed by intramolecular transfer of oxygen catalyzed by Ti(0-i-Pr)4. The latter step is a form of Sharpless epoxidation and can be highly stereoselective. 

The Sharpless epoxidation uses ferf-butyl hydroperoxide, titanium(IV) isopropoxide, and a dialkyl tartrate ester as the reagents. The following epoxidation of geraniol is typical. 

Before leaving the area of oxene chemistry, there is one further system worthy of mention the manganese Schiff-base complexes. The Schiff-base complexes were prepared in response to the Katsuki-Sharpless system for stereospecific epoxidation (Figure 2.19).57 The Katsuki-Sharpless system consists of titanium(IV) isopropoxide and ( + )- or (—)-diethyl tartrate with... 

Tertiary alkylamines can be converted into the corresponding N-oxides with hydrogen peroxide or with peroxy acids. r-Butyl hydroperoxide has also been used in the presence of a catalyst such as VO(acac)2. Sharpless and coworkers have carried out the oxidative kinetic resolution of several -hy-droxy tertiary amines such as (41) with r-butyl hydroperoxide, titanium(IV) isopropoxide and ( l )-diiso-propyl tartrate, the titanium(IV) tartrate ratio being alx)ut 2 1. After 60% conversion, one enantiomer was selectively oxidized, and Ae other enantiomer could be recovered in good optical purity (Scheme 23). 

The Sharpless reagent consists of three components rcrr-butyl hydroperoxide, (CHgjgCOOH a titanium catalyst—usually titanium(IV) isopropoxide, Ti[OCH(CH3)2l4 and diethyl tartrate (DET). There are two different chiral diethyl tartrate isomers, labeled as (+)-DET or (-)-DET to indicate the direction in which they rotate polarized light. 

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