Titanium isopropoxide diethyl tartrate

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. 

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. 

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... 

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... 

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... 

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... 

These reports were followed in 1980 by the discovery that, in the presence of titanium(IV) isopropoxide and ( + )- or (-)-diethyl tartrate, epoxidation of allylic alcohols by alkyl hydroperoxides was highly enantioselective32. Since both enantiomers of the tartrates are readily available, both enantiomers of epoxides were accessible. In the several hundred examples reported to date33 use of (-)-dialkyl tartrates yields epoxides arising from approach of the oxidant from the top side of the plane shown in Figure 2, whereas the (+)-dialkyl tartrates promote delivery of the oxygen from the bottom33. 

Hydrogen peroxide or t-butyl hydroperoxide may be used in the presence of a catalyst such as sodium tungstate(VI) or vanadyl acetylaceto-nate [ MeC0CH=C(0 )Me 2V0] for the epoxidation of allylic alcohols. The stereochemistry of the hydroxyl group has a profound effect on the stereochemistry of epoxidation. A system which has been applied to allylic alcohols, to make optically active epoxides, utilizes titanium(rV) isopropoxide, t-butyl hydroperoxide and either of the enantiomeric forms of diethyl tartrate. This system forms chiral epoxides of predictable stereochemistry. When the reactivity of epoxides is combined with the... 

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. 

Diethyl D-tartrate (12.04 g, 58.4 mmol) was dissolved in CH2CI2 (109 mL) and the water content of the resulting clear solution determined by Karl Fischer titration. This solution was transferred to a thoroughly dried reaction vessel containing the sulfide (10.85 g, 29.2 mmol) under an inert atmosphere and stirred to give a pale yellow solution. Titanium isopropoxide (8.96 mL, 29.2 mmol) was added, followed by distilled water (0.50 mL, 27.8 mmol, 0.95 equivalents, to bring the total amount of water to 1.00 equivalents). The reaction mixture was cooled to -15 °C and cumeme... 

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. 

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. 

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. 

Allylic alcohols are converted to epoxides by oxidation with tert-hutyl hydroperoxide in the presence of certain transition metals. The most significant aspect of this reaction— called the Sharpless epoxidation— is its high enantioselectivity when carried out using a combination of tert-hutyl hydroperoxide, titanium(IV) isopropoxide, and diethyl tartrate. 

The value of this reaction was recognized with the award of the 2001 Nobel Prize in Chemistry to its creator K. Barry Sharpless. Sharpless epoxidation of allylic alcohols can be carried out with catalytic amounts of titanium(IV) isopropoxide and, because both enantiomers of diethyl tartrate are readily available, can be applied to the synthesis of either enantiomer of a desired epoxy alcohol. 

Scheme 8.20. A representation of the overall stereopecific conversion of allylic alcohol to oxirane as a function of the absolute stereochemistry of the diethyl tartrate used to form a complex with titanium(IV) isopropoxide.

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). 

The precatalyst, however, is a chiral rather than a Mo complex. It is generated by the in situ treatment of titanium isopropoxide with optically pure diethyl or diisopropyl tartrate. As L-tartaric acid is a natural product, the optically pure ligand is easily made. As shown by reaction 8.5.3.1, at the optimum Ti tartarate ratio (1 1.2), complex 8.32 is the predominant species in solution. This gives the catalytic system of highest activity and enantioselectivity. 

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