Sharpless asymmetric epoxidation examples

Aryl and alkenyl groups undergo this anft -migration more easily than an alkyl group. This rearrangement in combination with Sharpless asymmetric epoxidation affords a stereocontrolled route to aldols and 1,3-diols (second example). 

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

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,... 

Aldol products do not have to come from an aldol condensation. In another example of catalysis by a small organic molecule, Jeffrey Bode of UC Santa Barbara reports (J- Am. Chem. Soc. 2004,126, 8126) that the thioazolium salt 7 effects the rearrangement of an epoxy aldehyde such as 6 to the aldol product 8. This is a net oxidation of the aldehyde, and reduction of the epoxide. As epoxy aldehydes such as 6 are readily available by Sharpless asymmetric epoxidation, this should be a general route to enantiomerically-aldol products. The rearrangement also works with an aziridine aldehyde such as 9, to give the ff-amino ester 10. 

This is an example of the Sharpless asymmetric epoxidation reaction of allylic alcohols 7 one of the most versatile, reliable, and synthetically... 

The reaction was also successful for substituted salicylaldehydes. When Jacobsen came to develop his asymmetric epoxidation, which, unlike the Sharpless asymmetric epoxidation, works for simple alkenes and not just for allylic alcohols, he chose salens as his catalysts, partly because they could be made so easily from salicylaldehydes. For example ... 

If we use a chiral reagent to synthesize an amino acid, however, it is possible to favor the formation of the desired enantiomer over the other, without having to resort to a resolution. For example, single enantiomers of amino acids have been prepared by using enantioselective (or asymmetric) hydrogenation reactions. The success of this approach depends on finding a chiral catalyst, in much the same way that a chiral catalyst is used for the Sharpless asymmetric epoxidation (Section 12.15). 

Allyl epoxides are produced by the acclaimed Sharpless asymmetric epoxidation reaction [75], and are important intermediates and products. For example, an allyl epoxide is a vital part of the structure of amphidinolides, a series of unique macrolides isolated from dinoflagellates (Amphidinium sp.). Amphidinolide H (AmpH) is a potent cytotoxic 26-membered macrolide with potent cytotoxicity for several carcinoma cell lines [76]. An allyl epoxide is involved in the total synthesis of prostaglandin A2 with a cuprate reagent [77]. Allyl epoxides derived from Sharpless chemistry are a practical method for construction of polypropionate structures by Lewis acid-induced rearrangement [78,79]. Other allyl epoxides such as l,2-epoxy-3-methyl-3-butanol are useful organic intermediates for the production of a-hydroxyketones, which are used for the synthesis of various natural... 

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. 

Sharpless asymmetric epoxidation of -hydroxy acrylates. A /3-hydroxy acrylate on classical epoxidation (alkaline hydrogen peroxide) gives a 1 1 mixture of syrt- and i/nf/-epoxides, but on Sharpless asymmetric epoxidation gives the. yyn-epoxidc selectively (99 1). No reaction occurs in the absence of the hydroxyl group. The asymmetric Sharplcss epoxidation also is possible with cyclic /3-hydroxy ketones (second example). 

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 Sharpless asymmetric epoxidation (sec. 3.4.D.i) exploits this chelation effect because its selectivity arises from coordination of the allylic alcohol to a titanium complex in the presence of a chiral agent. The most effective additive was a tartaric acid ester (tartrate), and its presence led to high enantioselectivity in the epoxidation.23 An example is the conversion of allylic alcohol 40 to epoxy-alcohol 41, in Miyashita s synthesis of the Cg-Ci5 segment of (-t-)-discodermolide.24 in this reaction, the tartrate, the alkenyl alcohol, and the peroxide bind to titanium and provide facial selectivity for the transfer of oxygen from the peroxide to the alkene. Binding of the allylic alcohol to the metal is important for delivery of the electrophilic oxygen and... 

The asymmetric dihydroxylation is much less fussy about the alkenes it will oxidize than Sharpless asymmetric epoxidation. Osmium tetroxide itself is a remarkable reagent, since it oxidizes more or less any sort of alkene, electron-rich or electron-poor, and the same is true of the asymmetric dihydroxylation reagent. The following example illustrates both this and a synthetic use for the diol product. 

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. 

Compounds of this general structure are extremely useful and versatile synthons because combined in one molecule are an epoxide functional group (a highly reactive electrophilic site), an alcohol functional group (a potentially nucleophilic site), and at least one chirality center that is present in high enantiomeric purity. The synthetic utility of chiral epoxy alcohol synthons produced by the Sharpless asymmetric epoxidation has been demonstrated over and over in enantioselective syntheses of many important compounds. Some examples include the synthesis... 

Many other compounds have potential as artificial sweeteners. For example, l sugars are also sweet, and they presumably would provide either zero or very few calories because our enzymes have evolved to selectively metabolize their enantiomers instead, the d sugars. Although sources of L sugars are rare in nature, all eight L-hexoses have been synthesized by S. Masamune and K. B. Sharpless using the Sharpless asymmetric epoxidation (Sections 11.13 and 22.11) and other enantioselective synthetic methods. 

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. 

In 1980, K. B. Sharpless (then at the Massachusetts Institute of Technology, presently at The Scripps Research Institute) and co-workers reported a method that has since become one of the most valuable tools for chiral synthesis. The Sharpless asymmetric epoxidation is a method for converting allylic alcohols (Section 11.1) to chiral epoxy alcohols with very high enan-tioselectivity (i.e., with preference for one enantiomer rather than formation of a racemic mixture). In recognition of this and other work in asymmetric oxidation methods (see Section 8.16A), Sharpless received half of the 2001 Nobel Prize in Chemistry (the other half was awarded to W. S. Knowles and R. Noyori see Section 7.14). The Sharpless asymmetric epoxidation involves treating the allylic alcohol with tert-butyl hydroperoxide, titanium(IV) tetraisopropoxide [Ti(0—/-POJ, and a specific stereoisomer of a tartrate ester. (The tartrate stereoisomer that is chosen depends on the specific enantiomer of the epoxide desired). The following is an example ... 

The Sharpless asymmetric epoxidations (SAEs) have been used in many cases for the synthesis of enantiopure 5,6-dihydropyrones, both in the direct mode, the conversion of a prochiral olefin into an enantioenriched epoxide, and in the kinetic resolution mode, which involves the selective epoxidation of one of the enantiomers in a racemic olefin. For example, a very recent synthesis of a natural pyrone isolated... 

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