Asymmetric, epoxidation

Asymmetric Epoxidation.—[V(0)(0R)20gBu ] is reported to be the active catalyst in the asymmetric epoxidation of /ra j-oct-2-ene by t-butyl hydroperoxide in the presence of menthol, ROH, and [Y(OXacac)2]. t-Butyl hydroperoxide also effects asymmetric epoxidation of alkenes and allyl alcohols in the presence of (56) and bis[(+)-3-trifluoroacetylcamphoratol]oxovanadium, respectively, Other studies in this area are summarized in Table 4. 

Asymmetric Epoxidation. Asymmetric epoxidation of nonfunctionalized alkenes manifests a great synthetic challenge. The most successful method of asymmetric epoxidation, developed by Katsuki and Sharpless,332 employs a Ti(IV) alkoxide [usually Ti(OisoPr)4], an optically active dialkyl tartrate, and tert-BuOOH. This procedure, however, was designed to convert allylic alcohols to epoxy alcohols, and the hydroxyl group plays a decisive role in attaining high degree of enantiofa-cial selectivity.333,334 Without such function, the asymmetric epoxidation of simple olefins has been only moderately successful 335 

Chiral metalloporphyrins317,341-343 and salen [/V,/V -bis(salicylideneamino) ethane]344-347 complexes constitute the most enantioselective nonenzymatic olefin epoxidation catalysts, yielding epoxides with 50-80% enantiomeric excess. 

Enzymatic epoxidation has proven to be the best method to achieve high enantio-selectivity348-350 [Eqs. (9.81) and (9.82)351 352]. 

The disadvantage of this method is that only terminal alkenes give epoxides with high enantiomeric excess. For example, in microsomal aerobic epoxidation pro-pene, trans-2-butene and 2-methyl-2-butene are transformed to the corresponding epoxides with 40%, 14% and 0% ee, respectively.350 Chloroperoxidase, however, was shown to be very effective in the epoxidation of cis alkenes.353 

A one-step, metal-catalyzed direct hydroxyepoxidation [ene reaction under irradiation in the presence of triplet oxygen (see Section 9.2.2) and a transition-metal catalyst] to produce epoxy alcohols with high diastereoselectivities is a useful synthetic procedure.354 

Asymmetric epoxidation ranks as one of the most reliable and selective methods for the formation of single enantiomer products. In particular, the asymmetric epoxidation of allylic alcohols with tert-butyl hydroperoxide (t-BuOOH), 

The epoxidation reaction is normally best carried out with only 5-10 mol% of the titanium catalyst in the presence of activated molecular sieves. These conditions avoid the traditional use of stoichiometric catalyst and provide a mild and convenient method (although often at the expense of a slight reduction in enantioselectivity and rate of reaction). Numerous examples of highly enantioselective epoxidations of allylic alcohols by this procedure have been reported. For example, the allylic alcohol 44 was converted selectively into the epoxides 45 and 46 (5.56). 

A wide selection of substituted allylic alcohols are amenable to asymmetric epoxidation under these conditions. Allylic alcohols with E-geometry or unhindered Z-allylic alcohols are excellent substrates (5.57). However, branched Z-allylic alcohols, particularly those branched at C-4, exhibit decreased reactivity and 

The titanium-catalysed reaction is highly chemoselective for epoxidation of allylic alcohols. Thus, the dienol 47 gave only the epoxide 48 (5.58). The reaction is also tolerant of many different functional groups, including esters, enones, acetals, epoxides, etc. 

The kinetic resolution reaction can be used for the asymmetric synthesis of chiral secondary allylic alcohols or their corresponding epoxides. The yield of either is, of course, limited to 50%, starting from the racemic allylic alcohol, but the methodology has found widespread use in organic synthesis. For example, epoxidation of the racemic allylic alcohol 54 gave the epoxide 55, used to prepare the anticoccidial antibiotic diolmycin A1 (5.63).  

Asymmetric Epoxidation.—Remarkably high optical yields ( 95%) are obtained in the asymmetric epoxidation of alkenes by Bu OgH in the presence of (+)- or (-)-diethyl tartrate and Ti(OPr )4. Very poor chemical yields are, however, realized if the epoxy alcohol produced is water soluble.  

Other studies of oxidation reactions are summarized in Table 4. 

232 Treatise on Dinitrogen Fixation. Sections I and II. Inorganic and Physical Chemistry and Biochemistry ed. R. W. F. Hardy, F. Bottomley, and R. C. Burns, J. Wiley, New York. 1979. 

The Pd +Cu )-catalysed reduction of nitric oxide by carbon monoxide (i.e., C0 + 2N0 C02+N20), which takes place in hydrochloric acid is believed to involve a Cu -Pd -NO species. The catalytic reduction of nitric oxide with ammonia by aqueous [Cu(NH3)4] + has been compared with those in which a Y-type zeolite was employed as a support.  

Metalated chiral salen ligands were first introduced during the 1990s by Jacobsen and Katsuki as highly enantioselective catalysts for the asymmetric 

The polymer-supported chiral salen complex 146 was also prepared by the condensahon reachon between (lS,2S)-l,2-cyclohexanediamine 144 and 

Together with hydrogenation and isomerization, epoxidation completes the trio of commercially significant applications of enantioselective homogeneously catalyzed reactions. Stereospecific olefin epoxidation is distinctive in that it creates two chiral centers simultaneously. 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 tert.-butyl hydroperoxide and titanimn isopropoxide in the presence of optically active pure tartrate esters (Eq. 3-14). 

This synthesis of a chiral epoxide as an intermediate to (+)-disparlure, the pheromone for the gypsy moth, was commercialized in 1981. The resulting epoxyalcohol (see Eq. 3-14) is formed in 80% yield and 90-95% enantiomeric purity before recrystallization. It was found that the use of molecular sieves greatly improves this process by removing minute amounts of water present in the reaction medium. Water was found to deactivate the catalyst. Further conversion to (4-)-disparlure requires three subsequent conventional reaction steps via an intermediate aldehyde. 

The introduction of this asymmetric epoxidation route on the multi-kilogram scale reduced the price of disparlure by an order of magnitude. The very high activity of the substance used for insect control suggests that a production capacity of only a few kg/a is required to satisly demand. 

A more recent alternative approach, developed by Jacobsen and co-workers, concerns the catalytic asymmetric epoxidation of unfunctionalized olefins using cheap NaOCl as oxidant in the presence of Mn complexes of chiral Schiff bases as catalysts, the so-called salene (Fig. 3-4). Values of 97% e.e. have been achieved using cis-disubstituted or trisubstituted alkenes. Equation 3-15 describes the Jacobsen epoxidation of olefins schematically. 

Salen ligands can be obtained from sahcylaldehyde and diamines. In principle, the Jacobsen route provides greater flexibility than Sharpless epoxidation procedure. Potential problems to full-scale commercialization include the availability of the olefins and the Schiflfbase (salen) ligands on a large scale, and the activity and stabUity of the catalyst. 

Epoxides are interesting starting materials for further derivatisation. In most instances the reaction will lead to the formation of mixtures of enantiomers (that is when the alkenes are prochiral, or when the faces are enantiotopic). Four important reactions should be mentioned in this context  

Entry Ligand Molar ratio 4 Ti Ligand Yield ee (%) Ref. 

Tartaric acid derivatives were also grafted onto the surface of silica and in the mesopores of silica MCM-41. ° The enantiomeric excesses obtained were comparable to those measured in the homogeneous Sharpless epoxidation, but a lower conversion was observed, probably due to slower diffusion of the substrate and the product in and out of the inorganic material. The recycling ability of the supported ligand was not indicated. 

Rather than resorting to heterogeneous supported ligands, Choudaiy et al. used heterogeneous titanium-pillared montmorillonite instead of titanium tetraisopropoxide. Additional molecular sieves was not required and excellent enantioselectivities and yields were obtained (86% yield and 94% enantiomeric excess for 5). The titanium catalyst can be simply removed by filtration, however, no recycling experiment was reported. 

The search for atom-economical epoxidation of olefins led to the recent discovery of efficient titanium catalysis using aqueous hydrogen peroxide as the oxidant.From the viewpoint of green chemistry, aqueous hydrogen peroxide is the oxidant of choice, since it is inexpensive, with a high active hydrogen content (47%) and the only byproduct is water. 

In 2005, Katsuki reported that the dimeric titanium tetradentate Schiff base complex 7, prepared from the salen 6 and titanium tetraisopropoxide 

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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... 

In all cases examined the ( )-isomers of the allylic alcohols reacted satisfactorily in the asymmetric epoxidation step, whereas the epoxidations of the (Z)-isomers were intolerably slow or nonstereoselective. The eryfhro-isomers obtained from the ( )-allylic alcohols may, however, be epimerized in 95% yield to the more stable tlireo-isomers by treatment of the acetonides with potassium carbonate (6a). The competitive -elimination is suppressed by the acetonide protecting group because it maintains orthogonality between the enolate 7i-system and the 8-alkoxy group (cf the Baldwin rules, p. 316). 

Rossiter, B. E. 1985, Synthetic Aspects and Applications of Asymmetric Epoxidation, in Morrison, J. D. 

Fig. 8. Use of Sharpless asymmetric epoxidation for the preparation of an intermediate in the synthesis of FK-506 (105), where represents the chiral...

This chemical bond between the metal and the hydroxyl group of ahyl alcohol has an important effect on stereoselectivity. Asymmetric epoxidation is weU-known. The most stereoselective catalyst is Ti(OR) which is one of the early transition metal compounds and has no 0x0 group (28). Epoxidation of isopropylvinylcarbinol [4798-45-2] (1-isopropylaHyl alcohol) using a combined chiral catalyst of Ti(OR)4 and L-(+)-diethyl tartrate and (CH2)3COOH as the oxidant, stops at 50% conversion, and the erythro threo ratio of the product is 97 3. The reason for the reaction stopping at 50% conversion is that only one enantiomer can react and the unreacted enantiomer is recovered in optically pure form (28). 

Transition metal-catalyzed epoxidations, by peracids or peroxides, are complex and diverse in their reaction mechanisms (Section 5.05.4.2.2) (77MI50300). However, most advantageous conversions are possible using metal complexes. The use of t-butyl hydroperoxide with titanium tetraisopropoxide in the presence of tartrates gave asymmetric epoxides of 90-95% optical purity (80JA5974). 

Asymmetric epoxidation of racemic unsaturated fluoro alcohols by the chiral Sharpless reagent can be exploited for kmetic resolution of enantiomers The recovered stereoisomer has 14-98% enantiomeric excess [55] (equation 50)... 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. 

Boger et al. prepared Duocarmycin SA via asymmetric epoxidation of a cyclic olefin 54." The stereochemistry set by the epoxidation step was used for subsequent C-C bond forming reactions. Epoxidation of olefin 54 was carried at -78°C to provide... 

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. 

Catalytic asymmetric epoxidation and aziridination mediated by sulfur ylides 98SL329. 

The asymmetric epoxidation of an allylic alcohol 1 to yield a 2,3-epoxy alcohol 2 with high enantiomeric excess, has been developed by Sharpless and Katsuki. This enantioselective reaction is carried out in the presence of tetraisopropoxyti-tanium and an enantiomerically pure dialkyl tartrate—e.g. (-1-)- or (-)-diethyl tartrate (DET)—using tcrt-butyl hydroperoxide as the oxidizing agent. 

Scheme 5.2-12 Mn-catalyzed asymmetric epoxidation in a [BMIM][PFg]/CH2Cl2 (v/v = 1/4)...

Figure 1. Stereofacial selectivity rule for the Sharpless asymmetric epoxidation.

Scheme 3. Asymmetric epoxidation of allylic alcohol 12 double asymmetric induction.

The essential features of the Masamune-Sharpless hexose synthesis strategy are outlined in a general way in Scheme 4. The strategy is based on the reiterative- application of a two-carbon extension cycle. One cycle comprises the following four key transformations (I) homologation of an aldehyde to an allylic alcohol (II) Sharpless asymmetric epoxidation of the allylic alcohol ... 

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-... 

Scheme 4. The Sharpless asymmetric epoxidation in the J.T. Baker Company s commercial synthesis of (7/ ,8S)-disparlure (15).

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