Sharpless asymmetric epoxidation natural products synthesis

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. ... 

Sharpless "asymmetric epoxidation" has been used in the enantioselective synthesis of several natural products, including the kinetic resolution of allylic alcohols [11] and the creation of ... 

Sharpless asymmetric epoxidation ° is an enantioselective epoxidation of an allylic alcohol with ferf-butyl hydroperoxide (f-BuOOH), titanium tetraisopropoxide [Ti(0-fPr)4] and (-b)- or (—)-diethyl tartrate [(-b)- or (—)-DET] to produce optically active epoxide from achiral allylic alcohol. The reaction is diastereoselective for a-substituted allylic alcohols. Formation of chiral epoxides is an important step in the synthesis of natural products because epoxides can be easily converted into diols and ethers. 

The enantioselective total synthesis of the annonacenous acetogenin (+)-parviflorin was accomplished by T.R. Hoye and co-workers." The b/s-tetrahydrofuran backbone of the natural product was constructed using a sequential double Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation. The bis allylic alcohol was epoxidized using L-(+)-DET to give the essentially enantiopure bis epoxide in 87% yield. 

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... 

Since the first report by Katsuki and Sharpless in 1980 [21], the asymmetric epoxidation of allylic alcohols has been widely applied to the synthesis of various compounds [22]. Among several asymmetric epoxidations developed, the Sharpless asymmetric epoxidation (AE) is undoubtedly the most popular and versatile method, which has greatly contributed to the progress of natural product synthesis. 

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 asymmetric epoxidation of functionalized alkenes still attracts considerable attention. Synthetic chemists continue to be in search of new and improved routes to epoxides, since they provide versatile intermediates for natural product synthesis. The topic of preparative techniques for chiral epoxides is seldom broached without the mention of the Sharpless epoxidation. Indeed, the impact of this protocol cannot be overestimated, as new applications continue to be reported. For example, linear poly(tartrate ester) ligands have been used this past year to generate a solid-supported Sharpless-type catalyst <97CC123>. 

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 Sharpless asymmetric epoxidation procedure has become invaluable in the synthesis of complex natural products although the precise organometallic nature of this reaction is not yet known. Of particular merit, the research groups of Sharpless and Masamune have elegantly illustrated the utility of the procedure by the synthesis of saccharides and polyhydroxylated natural products. 

Synthesis of (+)-lactacystin Lactacystin 7 is one of the most important biologically active pyrrolidinone-based natural products found in nature. It was isolated from the culture broth of a Streptomyces in 1991, and since that time, it has generated an enormous interest as a consequence of its highly selective and irreversible inhibition of the 20S pro-teasome. Its synthesis was first reported by Corey and Reichard, and an alternative more recent approach is based on the preparation of an oxazoline 8 that is produced via formation of a 2-ethynyl-allyl epoxide 10 via Sharpless asymmetric epoxidation of the allyl alcohol 9 (Scheme 34.3). The reaction was carried out in the presence of catalytic amounts of calcium hydride and silica gel (whose role is not described in the paper) at —40°C to — 18°C obtaining the desired product 10 in 89% yield and >95% ee determined by integration of the F resonances of the corresponding Mosher ester derivative. 

Amphidinolide V 38 is a 14-membered macrocycbc structure belonging to the same family of marine natural products that presents an epoxide functional group and seven C=C double bonds. To epoxidize one double bond selectively and leave unaffected the others, a Sharpless asymmetric epoxidation of an allyl alcohol 39 residue was introduced in the synthesis of the intermediate molecule 40 (Scheme 34.11). In detail, the reaction was performed with Ti(IV) and (+)-l-DET as chiral ligand under classic experimental conditions leading to the formation of the epoxide 41 in 77% yield (ee not reported). 

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

Hoye applied a bidirectional acid-mediated epoxide-opening sequence to the total synthesis of the annonaceous aceto-genin parviflorin (136 Scheme 4.27) [61]. This reaction employed a Sharpless asymmetric dihydroxylation (ADH) reaction of 137, in which the epoxides were introduced by a double Sharpless epoxidation to yield a diol intermediate that was immediately treated with CEjCO H to yield 138 in 85% yield. No competition from 6-cxo-pathways was reported, showing the kinetic preference for tetrahydrofuran formation over tetrahydropyran formation. The natural product was accessed through a multistep route from 138 that inverted the configurations of the two alcohol centers. 

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