Preparation of epoxides

13 Assign a name for each of the following compounds. Be sure to assign the configuration of each chirality center and indicate the configuration(s) at the beginning of the name. 

Epothilones are a class of novel compounds first isolated from the bacterium Sorangium cellulosum in Southern Africa. 

The discovery of the antitumor behavior of these naturally occurring epoxides led to a search for related compounds that might exhibit enhanced potency and selectivity. In October 2007, the FDA approved one such derivative, called ixabepilone, for treatment of advanced breast cancer. Ixabepilone is an analog of epothilone B, in which the ester linkage is replaced with an amide linkage, highlighted in red. 

Ixabepilone is currently being marketed by Bristol-Myers Squibb under the trade name Ixempra. Several other analogs of the epothilones are currently undergoing clinical trials for treatment of many different forms of cancer. The next decade is likely to witness several epothilone analogs emerge as new anticancer agents. 

Recall from Section 9.9 that alkenes can be converted into epoxides upon treatment with peroxy acids (see Mechanism 9.6). 

Base-promoted ring closure of vicinal halohydrins 

Epoxidation of alkenes with peroxy acids was discussed in Section 6.11 and is represented by the general equation 

An important preparative methodology which has developed rapidly over the last few years is the (salenjMn mediated epoxidation of alkenes (the Jacobsen-Katsuki epoxidation). While the practical utility of this protocol is indisputable, the mechanistic imderpinnings have been the matter of some debate. Adding to this ongoing dialectic is a result from a recently published DFT study, which suggests the salen ligand itself is involved in the transition state of the 

Metal mediated epoxidahon is remarkably diverse, with many types of ligand systems being represented. For example, a cytochrome P450 BM-3 mutant (139-3) has been developed using directed evolution, which exhibits high activity towards epoxidation of several non-natural substrates. Thus, exposure of styrene 4 to BM-3 variant 139-3 in phosphate buffer containing methanol and NADPH resulted in the quantitative conversion to styrene oxide 5. For terminal aliphatic alkenes, however, allyhc hydroxylation is the predominant process 04T525 . 

Highly efficient small molecular P450 mimics have also been developed. The sterically stabilized metalloporphyrin [Mn(TDCPP)Cl] 6 catalyzes the mild and highly diastereoselective epoxidation of protected cyclohexenol derivative 7 using hydrogen peroxide as the terminal oxidant. The preference for trara-epoxides is rationalized on the basis of non-bonded 

Metal-catalyzed epoxidations can also work quite efficiently even with very simple ligand systems. For example, 1-octene 13 is converted to its corresponding epoxide in practically quantitative yield within 5 min upon exposure to peracetic acid in the presence of the Mn(II)-bipyridyl complex at 0.1 mol% catalyst loading 04OL3119 . 

Metal-catalyzed epoxidations are becoming important on the industrial scale, since the ability to use molecular oxygen as the terminal oxidant offers considerable operational and environmental benefits. The crucial feedstock propylene oxide 16 can be produced using molecular oxygen and a catalytic system of palladium(II) acetate and a peroxo-heteropoly compound in methanol 04CC582 . A discussion of some quantum chemical calculations with regard to the industrially relevant peroxometal epoxidation catalysts has recently appeared in the literature 04SCR645 . 

Another method for generating an epoxidation catalyst on a solid support is to simply absorb or non-covalendy attach the catalyst to the solid support 06MI493 . Epoxidation of olefin 6 with mCPBA and catalyst 8 provides 7 in quantitative yields and with 89% ee. The immobilization of 8 on silica gel improves the enantioselectivity of the reaction providing 7 with 95% ee. Recycling experiments with silica-8 show a decrease in both yield and the enantiomeric excess for each cycle (45% ee after 4 cycles). This is attributed to a leaching of the catalyst from the silica gel. Two other solid supports, a Mg-Al-Cl-LDH resin (LDH) and a quaternary ammonium resin (Q-resin) were also examined. It was expected that ionic attraction between 8 and the LDH or Q-resin would allow the catalyst to remain immobilized through multiple cycles better than with silica gel. Both of these resins showed improved catalytic properties upon reuse of the catalyst (92-95% ee after 4 cycles). 

Vinyl epoxides are highly useful synthetic intermediates. The epoxidation of dienes using Mn-salen type catalysts typically occurs at the civ-olefin. Epoxidations of dienes with sugar-derived dioxiranes have previously been reported to react at the trans-olefin of a diene. A new oxazolidinone-sugar dioxirane, 9, has been shown to epoxidize the civ-olefin of a diene 06AG(I)4475 . A variety of substitution on the diene is tolerated in the epoxidation, including aryl, alkyl and even an additional olefin. All of these substitutions provided moderate yields of the mono-epoxide with good enantioselectivity. 

An exploration of structural modifications on the activity of prolinol catalysts has been published 06T12264 . More electron-rich aromatic rings on the prolinol scaffold improve the activity in the epoxidation of a, 3-enones. The reaction of 10 with an enone and f-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. 

Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides 06JA2105 . Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones 06JA5475 . An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

Z-stilbene 5 mol% FeCI3-6H20, H202,15 mol% 5-chloro-1-methylimidazole 24% 

The asymmetric epoxidation of homoallylic alcohols has continued to be a problematic area. A potential solution has recently been published 07JA286 07T6075 . The use of bis-hydroxamic acid 1 as a chiral ligand for a vanadium catalyst has provided both excellent yields and enantioselectivity. This method works well with both cis- and trans-alkenes. 

A number of new oxaziridinium epoxidation reagents have been reported. A new axially chiral epoxidation catalyst 4 has been reported 070BC501 . These catalysts, as are others, are converted to an oxaziridinium with Oxone, which then epoxidizes the olefin. This study examined several chiral groups on the nitrogen as well as both atropisomers. The (S,F)-isomer 4 provided the (1R,2R) epoxide with moderate enantioselectivity and 82% conversion. The (.V,A/)-isomcr of 4 provided the (lS,2S)-epoxide in slightly lower enantiomeric excess (76%) and lower conversion as well. 

Chiral dioxiranes continue to be examined for the synthesis of enantioenriched epoxides. An interesting report details the use of a dioxirane derived from oxazolidinone 7 for the 

A very specific yet interesting epoxidation method for bicyclic a,(3-unsaturated sulfones has been reported 07SL1948 . Reaction of bicyclic sulfone 10 with A-methylmorpholine N-oxide (NMO) provides the epoxide product in generally good yields. Other amine oxides such as trimethylamine A-oxide work in this reaction, however non-strained sulfones do not react even with heating. 

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The following section describes the preparation of epoxides by the base promoted ring closure of vicinal halohydrms Because vicinal halohydrms are customarily prepared from alkenes (Section 6 17) both methods—epoxidation using peroxy acids and ring closure of halohydrms—are based on alkenes as the starting materials for preparing epoxides... 

Reaction of perfluoroaLkenes and hypochlorites has been shown to be a general synthesis of perfluoroepoxides (32) (eq. 7). This appears to be the method of choice for the preparation of epoxides from internal fluoroalkenes (38). Excellent yields of HFPO from hexafluoropropylene and sodium hypochlorite using phase-transfer conditions are claimed (34). 

Butyl hypochlorite has been used for the preparation of epoxides (269). 

In a pioneering article, Farrall et al. [61] reported the preparation of fuUy regenerable sulfonium salts anchored to an insoluble polymer and their use in the preparation of epoxides by reaction of their ylides with carbonyl compounds. Their results clearly indicate that... 

High-valent ruthenium oxides (e. g., Ru04) are powerful oxidants and react readily with olefins, mostly resulting in cleavage of the double bond [132]. If reactions are performed with very short reaction times (0.5 min.) at 0 °C it is possible to control the reactivity better and thereby to obtain ds-diols. On the other hand, the use of less reactive, low-valent ruthenium complexes in combination with various terminal oxidants for the preparation of epoxides from simple olefins has been described [133]. In the more successful earlier cases, ruthenium porphyrins were used as catalysts, especially in combination with N-oxides as terminal oxidants [134, 135, 136]. Two examples are shown in Scheme 6.20, terminal olefins being oxidized in the presence of catalytic amounts of Ru-porphyrins 25 and 26 with the sterically hindered 2,6-dichloropyridine N-oxide (2,6-DCPNO) as oxidant. The use... 

The final example (Scheme 5.73) illustrates the efficient preparation of epoxide 212 from 2-iodo-l,6-anhydro-D-glucose 67 (see Scheme 5.5) [221,222]. This Cerny epoxide [109] is a useful and versatile precursor to a range of 2-substituted glucose derivatives 213, which can be elaborated further to suitable glycosyl donors. 

Preparation of epoxides (oxirans) on the commercial scale as resin or polymer components is widely practised. Careful control of conditions is necessary to avoid hazards, and the several factors involved are reviewed. 

There are two sources of epoxidized triglycerides, the first is the isolation of naturally epoxidized oUs, and the other is the preparation of epoxidized triglycerides via oxidation of the more readily available unsaturated seed oils. 

Examples of the use of dimethylsulfoniurn methylide and dimethylsulfoxonium methylide in the preparation of epoxides are listed in Scheme 2.19. Entries 1-4 illustrate epoxide formation with simple aldehydes and ketones. 

Recently, Hashimoto and Kanda reported a simple and efficient epoxidation using Oxone in a biphasic system of ethyl acetate and water. This reaction is suitable for large-scale preparation of epoxides and does not require any PTC or pH control (equation 45). 

Makosza and co-workers have reported the preparation of epoxides from a-halo carbanions and ketones, according to the Darzens reaction, under PT conditions, using TEBA72,73 or dibenzo-18-crown-6.74 The ratio of isomers depends on the reaction conditions.75,76 Asymmetric induction has been reported in the Darzens reaction using chiral catalysts.77,78 The use of several chloro carbanions as well as K2C03 and Na2C03 in the solid state has also been studied. 

Methods for the preparation of epoxides will undoubtedly occupy tlxo minds of chemists for many years, as improvement of existing techniques and development of new approaches are sought in this important field of heterocyclic chemistry. 

Stephenson has developed a convenient procedure for preparing J-chloro-3-phenoxy-2-propanols from epichlorohydrin nnd phenols, which is economical of reagents and minimizes the formation of undesirable side-products (Eq. 600). He has also greatly extended the applicability of hydrogen chloride transfer for the preparation of epoxides. ... 

Both reagents transfer a methylene group in efficient and selective pathways. So it is not surprising that sulfur ylides have been widely used as synthetic tools for the preparation of epoxides. The reactions can make use of sulfonium salts under phase transfer catalytic conditions, and the cheap and easily accessible trimethyl sulfonium methyl sulfate and triethylsulfonium ethyl sulfate were found to show a high reactivity under such conditions [450]. 

Beside the preparation of epoxides and the formation of OH group186 19°, dioxiranes can also be used to oxidize other functional groups191-196. 

A 1,2-diol arising from a trans-hydroxylation process is formed from an alkene by way of an intermediate epoxide which is subjected to a ring-opening reaction and hydrolysis. The epoxides may be isolated when the alkene is reacted with perbenzoic add or m-chloroperbenzoic acid (Section 4.2.56, p. 457) in a solvent such as chloroform or dichloromethane the preparation of epoxides by this method and by other important procedures are discussed and illustrated... 

Epoxidation. Oxone decomposes in the presence of a ketone (such as acetone) to form a species, possibly a dioxirane (a), which can epoxidize alkenes in high yield in reactions generally conducted in CH2C12-H20 with a phase-transfer catalyst. An added ketone is not necessary for efficient epoxidation of an unsaturated ketone. The method is particularly useful for preparation of epoxides that are unstable to heat or acids and bases.3 The acetone-Oxone system is comparable to m-chloroperbenzoic acid in the stereoselectivity of epoxidation of allylic alcohols. It is also similar to the peracid in preferential attack of the double bond in geraniol (dienol) that is further removed from the hydroxyl group.4... 

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

An interesting method for the preparation of epoxides using radical methodology has been reported [95AJC233]. Addition of cyclohexyl iodide 1 under reductive or non reductive conditions to ethyl t-butylperoxymethylpropenoate 2 at refluxing temperatures furnished the epoxide 4 in moderate yield. The reaction proceeds through an intramolecular homolytic displacement. 

Finally, Sato and co-workers have added a twist to the known preparation of epoxides from the action of sulfur ylides on carbonyl compounds. In this version, the requisite sulfur ylides are formed by desilylation of [(trimethylsilyl)methyI]sulfonium salts (e.g., 45) in DMSO. This avoids the strongly basic conditions typically encountered in the preparation of sulfur ylides [95SYN649],... 

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