Sharpless reaction molecular sieves

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. ... 

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. 

The 4 A Molecular Sieves System. The initial procedure for the Sharpless reaction required a stoichiometric amount of the tartrate Ti complex promoter. In the presence of 4 A molecular sieves, the asymmetric reaction can be achieved with a catalytic amount of titanium tetraisopropoxide and DET (Table 4-2).15 This can be explained by the fact that the molecular sieves may remove the co-existing water in the reaction system and thus avoid catalyst deactivation. Similar results may be observed in kinetic resolution (Table 4-3).15... 

The oxidation of substituted pyridines to iV-oxides was reported by Sharpless and coworkers to proceed with yields between 78 and 99% (Scheme 154). A variety of substituents like electron donor as well as acceptor groups and alkenyl substituents are tolerated. In 1998, Sharpless and coworkers reported an alternative method for the preparation of pyridine-A-oxides in which the MTO/H2O2 catalyst could be replaced by cheaper inorganic rhenium derivatives (ReOs, Re207, HOReOs) in the presence of bis(trimethylsilyl) peroxide (equation 73). Yields of the prepared A-oxides after simple workup (filtration and bulb to bulb distillation) ranged from 70-98%. Molecular sieves slowed down the reaction while small amounts of water (0-15%) were essential for the reaction. Both electron-poor or electron-rich pyridines give high yields of their A-oxides and while para-... 

In 1980, Katsuki and Sharpless described the first really efficient asymmetric epoxidation of allylic alcohols with very high enantioselectivities (ee 90-95%), employing a combination of Ti(OPr-/)4-diethyl tartrate (DET) as chiral catalyst and TBHP as oxidant Stoichiometric conditions were originally described for this system, however the addition of molecular sieves (which trap water traces) to the reaction allows the epoxidation to proceed under catalytic conditions. The stereochemical course of the reaction may be predicted by the empirical rule shown in equations 40 and 41. With (—)-DET, the oxidant approaches the allylic alcohol from the top side of the plane, whereas the bottom side is open for the (-l-)-DET based reagent, giving rise to the opposite optically active epoxide. Various aspects of this reaction including the mechanism, theoretical investigations and synthetic applications of the epoxy alcohol products have been reviewed and details may be found in the specific literature . 

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. 

Catalytic reactions in Sharpless epoxidation were achieved in 1986 by addition of molecular sieves, which suppress the formation of nonenantioselective complexes by moisture already present in the medium or produced during the reaction [33]. Similar problems needed to be solved in the asymmetric oxidation of sulfides because a decrease in the concentration of a... 

Although the original Sharpless epoxidation method was stoichiometric, the development of a catalytic method has allowed the reaction to be amenable to scale up. The addition of molecular sieves for the removal of trace amounts of water is important in the catalytic procedure.5 21-23... 

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]. 

Tartaric acid is the least expensive chiral starting material with twofold symmetry available from natural sources. The Sharpless Ti tartrate asymmetric epoxidation catalyst consists of titanium(IV) tetraisopropoxide (Ti(OiPr)4) in combination with a chiral tartrate diester to induce asymmetry in the reaction of allylic alcohols. It is used with an alkyl hydroperoxide such as TBHP in the presence of 3A or 4A molecular sieves (to remove water) for the epoxidation of allylic alcohols [75]. It was the first effective asymmetric epoxidation catalyst reported. 

Sharpless and Katsuki described a very general method for the asymmetric epoxidation ofallylic alcohols (Scheme 9) [53]. The titanium alcoholate was initially used in stoichiometric amounts, though it was subsequently found it was possible to run the reaction catalytically in the presence of molecular sieves [54]. This method soon became a routine reaction in synthesis, because of its gener-... 

Among the reactions catalyzed by titanium complexes, the asymmetric epoxidation of allylic alcohols developed by Sharpless and coworkers [752, 807-810] has found numerous synthetic applications. Epoxidation of allylic alcohols 3.16 by ferf-BuOOH under anhydrous conditions takes place with an excellent enantioselectivity (ee > 95%) when promoted by titanium complexes generated in situ from Ti(0/ -Pr)4 and a slight excess of diethyl or diisopropyl (R,R)- or (iS, 5)-tartrates 2.69. The chiral complex formed in this way can be used in stoichiometric or in catalytic amounts. For catalytic use, molecular sieves must be added. Because both (RJ )- and (5,5)-tartrates are available, it is posable to obtain either enantiomeric epoxide from a single allylic alcohol. Cumene hydroperoxide (PhCMe20OH) can also be used in place of ferf-BuOOH. This method has been applied to industrial synthesis of enantiomeric glycidols [811, 812]. 

The Sharpless epoxidation of allyl alcohols 3.16 by /erf-butyl hydroperoxide under catalysis with chiral titanium complexes is a very popular method that has frequently been used in industry [811, 812, 853], This epoxidation was initially developed with stoichiometric amounts of tartrate catalysts. Today, it is usually performed in the presence of catalytic amounts of Ti(0/ -Pr)4 and diethyl or diisopropyl tartrate (2R,3R)- or (25,35)-2.69 (R = Et or r-Pr). The reactions are conducted at or near room temperature in the presence of molecular sieves. Several... 

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. 

Sharpless asymmetric epoxidation is the first example of a reaction where an achiral precursor is converted to a chiral substrate with high enantioselectivity. This discovery triggered a flurry of activity, applying the basic principles of asymmetric epoxidation to a variety of other reactions. Sharpless asymmetric epoxidation is very important in the synthesis of natural products since this reaction offers an asymmetric route to many important synthons. One example is the conversion of 224 to 225, in 95% yield (> 15 1 de), in Meyer s synthesis of disorazole Ci, where MS indicates the use of molecular sieves.321 In a second example, taken... 

The first reports from the Sharpless group described the stoichiometric use of the catalyst , however, the truly catalytic variant of the reaction was found to be more general in the presence of activated molecular sieves. The benefits of using catalytic amounts of the titanium/tartrate combination include not only reduced cost, but also an easier work-up procedure. This is particularly true for water soluble epoxide products such as glycidol. 

Stereoselectivity effects. There are several recent reports that molecular sieves can improve the stereoselectivity of various reactions such as the Sharpless epoxidation (e.g., 13,51). The beneficial effect has been attributed to water-scavenging by the sieves. Molecular sieves also show a marked effect on the diastereoselectivity of the Pd-catalyzed cyclization of cis-l,2-divinylcyclohexane with chiral acids (equation 1). In these reactions, additions of molecular sieves were found in some cases to increase the diastereo-... 

The industrial synthesis is considerably more elegant. It involves one of the few non-enzymatic, enantioselective synthetic methods, which can be widely transferred to the industrial scale the Sharpless epoxidation. Through the use of molecular sieves, K. B. Sharpless succeeded in carrying out the reaction with catalytic amounts of the enantiomericaUy pure titanium complex. Only this discovery rendered the reaction suitable for industrial dimensions. 

In 1980, Sharpless and co-workers reported on the first practical asymmetric epoxidation of allylic alcohols using titanium-tartrate complexes in combination with ferf-butyl hydroperoxide (TBHP) as an oxidant." The procedure was later improved by the addition of 3-A or 4-A molecular sieves to the reaction mixmre, and under the optimal conditions the reaction can be performed with a catalytic amount of titanium catalysts prepared from Ti(0-f-Pr)4 and L or D-diethyltartrate (DET) or diisopropyltartrate (DIPT) to provide chiral epoxides in optical purities typically greater than 90% ee (Scheme 35.1). 

The great synthetic versatility of epoxides has prompted intense efforts to identify reliable enantioselective methods for their synthesis [71]. In 1980, this challenge was met as Sharpless announced the groundbreaking discovery that titanium-tartrate complexes in combination with tert-butyl hydroperoxide readily catalyze enantioselective epoxidations of allylic alcohols [72]. This transformation has rightly earned its prominent place in the history of organic chemistry and asymmetric catalysis. In subsequent investigations it was found that the addition of molecular sieves to the reaction mixture had a beneficial effect on the process. Consequently, under optimal conditions the epoxidation reaction can be performed with only 5-10 mol % of the readily available Ti catalyst [73, 74]. A wide variety of allylic alcohols can be epox-... 

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