Sharpless asymmetric epoxidation titanium catalysts

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. ... 

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. 

The known allylic alcohol 9 derived from protected dimethyl tartrate is exposed to Sharpless asymmetric epoxidation conditions with (-)-diethyl D-tartrate. The reaction yields exclusively the anti epoxide 10 in 77 % yield. In contrast to the above mentioned epoxidation of the ribose derived allylic alcohol, in this case epoxidation of 9 with MCPBA at 0 °C resulted in a 65 35 mixture of syn/anti diastereomers. The Sharpless epoxidation of primary and secondary allylic alcohols discovered in 1980 is a powerful reagent-controlled reaction.12 The use of titanium(IV) tetraisopropoxide as catalyst, tert-butylhydro-peroxide as oxidant, and an enantiopure dialkyl tartrate as chiral auxiliary accomplishes the epoxidation of allylic alcohols with excellent stereoselectivity. If the reaction is kept absolutely dry, catalytic amounts of the dialkyl tartrate(titanium)(IV) complex are sufficient. 

Whereas these solid catalysts tolerate water to some extent, or even use aqueous H2O2 as the oxidant, the use of homogeneous Ti catalysts in epoxi-dation reactions often demands strictly anhydrous conditions. The homogeneous catalysts are often titanium alkoxides, possibly in combination with chiral modifiers, as in the Sharpless asymmetric epoxidation of allylic alcohols (15). There has recently been an increase in interest in supporting this enantioselective Ti catalyst. 

Sharpless reagent (Section 12.15) The reagent used in the Sharpless asymmetric epoxidation. The Sharpless reagent consists of ferr-butyl hydroperoxide, a titanium catalyst, and one enantiomer of diethyl tartrate. 

Two examples of such processes are shown in Scheme 1.6. One is the titanium TADDOLate-catalyzed addition of diethylzinc to myrtenal (see Section 4.3, [52] the other is the Sharpless asymmetric epoxidation (see Section 8.2.2, [58,63]). In both cases, the diastereoselectivity for the reaction of the substrate with an achiral reagent is low (65-70% ds), while the catalysts have enantioselectivities of >95% with achiral substrates. In these cases of double asymmetric induction, the catalyst completely overwhelms the facial bias of the chiral substrate. 

Katsuki-Sharpless asymmetric epoxidation. Since its introduction in 1980 [10], the Katsuki-Sharpless asymmetric epoxidation (AE) reaction of allylic alcohols has been one of the most popular methods in asymmetric synthesis ([11-14]). In this work, the metal-catalyzed epoxidation of allylic alcohols described in the previous section was rendered asymmetric by switching from vanadium catalysts to titanium ones and by the addition of various tartrate esters as chiral ligands. Although subject to some technical improvements (most notably the addition of molecular sieves, which allowed the use of catalytic amounts of the titanium-tartrate complex), this recipe has persisted to this writing. 

Epoxidations. Grafting tantalum onto silica to form a useful catalyst for the Sharpless asymmetric epoxidation of allyl alcohols is contrary to the ineffective titanium species on a similar support. Vanadium-complexed chiral hydroxamic... 

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 Sharpless asymmetric epoxidation of allylic alcohols (one of the reactions that helped K. Barry Sharpless earn his part of the 2001 Nobel Prize) offers a good example of an enantioselective technique that can be used to create either enantiomer of an epoxide product. This reaction uses a diester of tartaric acid, such as diethyl tartrate (DET) or diisopropyl tartrate (DIPT), as the source of chirality. The dialkyl tartrate coordinates with the titanium tetraisopropoxide [Ti(Oi-Pr)4] catalyst and t-butyl hydroperoxide (r-BuOOH) to make a chiral oxidizing agent. Since both enantiomers of tartaric acid are commercially available, and each enantiomer will direct the reaction to a different prochiral face of the alkene, both enantiomers of an epoxide can be synthesized. 

Sharpless Asymmetric Epoxidation (Section 11.8D) Oxidation of the carbon-carbon double bond of a 1° allylic alcohol by tert-butyl hydroperoxide in the presence of a chiral catalyst consisting of either (+)- or (-)-diethyl tartrate and titanium tetraisopropoxide gives an enantiomerically pure epoxide. The enantiomer formed depends on which enantiomer of diethyl tartrate is used in the catalyst. 

Asymmetric Epoxidation Reactions. While Ti(0-i-Pr)4 clearly has the capacity to bring about the nucleophilic ring-cleavage of 2,3-epoxy alcohols (see above), it remains the preferred species for the preparation of the titanium tartrate complex central to the Sharpless asymmetric epoxidation process (see, for example, eq 7). Since f-butoxide-mediated ring-opening of 2-substituted 2,3-epoxy alcohols (a subclass of epoxy alcohols particularly sensitive to nucleophilic ring-cleavage) is much slower than by isopropoxide, the use of Ti(0-f-Bu)4 is sometimes recommended in place of Ti(0-i-Pr)4. However, with the reduced amount of catalyst that is now needed for all asymmetric epoxidations, this precaution appears unnecessary in most instances. 

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... 

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. 

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... 

There has recently been much work in this area using Ru-based catalysts, particularly with porphyrin-based catalysts, following the work by Sharpless et al. on asynunetric epoxidation of allylic alcohols by a titanium-based tartrate system. There are reviews on asymmetric epoxidations catalysed by chiral Ru porphyrins [5, 18]. 

Review M. G. Finn and K. B. Sharpless, On the Mechanism of Asymmetric Epoxidation with Titanium-Tartrate Catalysts, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 5, Chap. 8, Academic Press, New York, 1985 R. A. Johnson and K. B. Sharpless, Addition Reactions with Formation of Car-... 

B. E. Rossiter (1985). Synthetic aspects and application of asymmetric epoxidation , in Asymmetric Synthesis. Ed. J. Morrison. Orlando Academic Press, p. 194 M. G. Finn and K. B. Sharpless On the mechanism of asymmetric epoxidation with titanium-tartrate catalysts . Ibid., p. 247. 

APTMS-modified MCM-41 surface. In a last step, titanium tetra-wo-propoxide reacted with the chiral organic-inorganic hybrid material, to give the heterogeneous variant of the asymmetric epoxidation catalyst of allylic alcohols, proposed by Katsuki and Sharpless.312... 

Hie first of Sharpless s reactions is an oxidation of alkenes by asymmetric epoxidation. You met vanadium as a transition-metal catalyst for epoxidation with r-butyl hydroperoxide in Chapter 33, and this new reaction makes use of titanium, as titanium tetraisopropoxide, Ti(OiPr)4, to do the same thing. Sharpless surmised that, by adding a chiral ligand to the titanium catalyst, he might be able to make the reaction asymmetric. The ligand that works best is diethyl tartrate, and the reaction shown below is just one of many that demonstrate that this is a remarkably good reaction. 

The mechanism of the asymmetric epoxidation of allylic alcohols with the Sharpless-Katsuki catalyst is assumed to be very similar to the one described for the Halcon-ARCO process in Section 2.5. The key point is that the chiral tartrate creates an asymmetric environment about the titanium center (Figure 18). When the allylic alcohol and the t-butyl hydroperoxide bind through displacement of alkoxy groups from the metal, they are disposed in such a way as to direct oxygen transfer to a specific face of the C=C double bond. This point is crucial to maximize enantioselectivity. 

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