Trisubstituted alkene epoxidation

A number of chiral ketones have been developed that are capable of enantiose-lective epoxidation via dioxirane intermediates.104 Scheme 12.13 shows the structures of some chiral ketones that have been used as catalysts for enantioselective epoxidation. The BINAP-derived ketone shown in Entry 1, as well as its halogenated derivatives, have shown good enantioselectivity toward di- and trisubstituted alkenes. 

Epoxidation using manganese salen complexes is very easy to carry out it occurs under aqueous conditions and commercial house bleach can be used as the oxidant. The results are similar to those reported in the literature Table 6.1 gives other examples of alkenes which can be epoxidized using the same procedure. This method gives good results, especially for disubstituted Z-alkenes but trisubstituted alkenes can be epoxidized as well. 

Among many other methods for epoxidation of disubstituted E-alkenes, chiral dioxiranes generated in situ from potassium peroxomonosulfate and chiral ketones have appeared to be one of the most efficient. Recently, Wang et /. 2J reported a highly enantioselective epoxidation for disubstituted E-alkenes and trisubstituted alkenes using a d- or L-fructose derived ketone as catalyst and oxone as oxidant (Figure 6.3). 

Shi s method gives good results for disubstituted /f-alkenes compared to the Jacobsen epoxidation previously described, which is more specific for disubstituted Z-alkenes. Concerning the epoxidation of trisubstituted alkenes, the epoxidation of 1-phenyl-1-cyclohexene could not be validated because of... 

Table 6.2 Epoxidation of disubstituted />alkenes and trisubstituted alkenes by ketone derived from D-fructose[2].

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

Binaphthol- and biphenyl-derived ketones (9 and 10) were reported by Song and coworkers in 1997 to epoxidize unfunctionalized alkenes in up to 59% ee (Fig. 3, Table 1, entries 9, 10) [37, 38]. Ketones 9 and 10 were intended to have a rigid conformation and a stereogenic center close to the reacting carbonyl group. The reactivity of ketones 9 and 10 is lower than that of 8, presumably due to the weaker electron-withdrawing ability of the ether compared to the ester. In the same year, Adam and coworkers reported ketones 11 and 12 to be epoxidation catalysts for several trans- and trisubstituted alkenes (Table 1, entries 11,12). Up to 81% ee was obtained for phenylstilbene oxide (Table 1, entry 25) [39]. 

The breakthrough came already in 1996, one year after Curd s prediction, when Yang and coworkers reported the C2-symmetric binaphthalene-derived ketone catalyst 6, with which ee values of up to 87% were achieved. A few months later, Shi and coworkers reported the fructose-derived ketone 7, which is to date still one of the best and most widely employed chiral ketone catalysts for the asymmetric epoxidation of nonactivated alkenes. Routinely, epoxide products with ee values of over 90% may be obtained for trans- and trisubstituted alkenes. Later on, a catalytic version of this oxygen-transfer reaction was developed by increasing the pH value of the buffer. The shortcoming of such fructose-based dioxirane precursors is that they are prone to undergo oxidative decomposition, which curtails their catalytic activity. 

CATALYTIC ENANTIOSELECTIVE EPOXIDATION OF TRANS-DISUBSTITUTED AND TRISUBSTITUTED ALKENES WITH ARABINOSE-DERIVED ULOSE... 

We recently reported our results on the asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes, using Oxone as oxidant, catalyzed by readily available arabinose-derived 4-uloses containing tunable steric blockers that control the enantioselectivity of the epoxidation.Ulose (3), containing a 2, 3 -diisobutyl acetal unit, was the most efficient catalyst and displayed good enantioselectivity. 

The preparation is easy to reproduce and since d- and L-arabinose are commercially available in large quantities, both enantiomers of ulose (3) are readily accessible. The enantioselectivity of the asymmetric epoxidation using ulose (3) towards frawi-disubstituted and trisubstituted alkenes is shown in Table 6.4. 

Preparation of nonracemic epoxides has been extensively studied in recent years since these compounds represent useful building blocks in stereoselective synthesis, and the epoxide functionality constitutes the essential framework of various namrally occurring and biologically active compounds. The enantiomericaUy enriched a-fluorotropinone was anchored onto amorphous KG-60 silica (Figure 6.6) this supported chiral catalyst (KG-60-FT ) promoted the stereoselective epoxidation of several trans- and trisubstituted alkenes with ees up to 80% and was perfectly reusable with the same performance for at least three catalytic cycles. 

The preparation of the silica supported a-fluorotropinone is easy to reproduce as a commercially available solid support was employed the asymmetric epoxidation has been applied to trans- and trisubstituted alkenes affording the corresponding... 

The epoxidation procedure developed by Yian Shi of Colorado State University has become one of the workhorses of enantioselective synthesis. That work has been based around trans and trisubstituted alkenes. Professor Shi has now developed (Tetrahedron Lett. 2004,45, 8115) an efficient protocol for the enantioselective epoxidation of aryl-substituted cis alkenes such as 6. 

The trisubstituted alkene of 10 was more readily oxidized than was the congested tetrasubstituted alkene, so the more reactive alkene was temporarily epoxidized. After ozonolysis, the epoxide was reduced off using the Sharpless protocol. It is a tribute to the specificity of this reagent that the easily-reduced a-acetoxy ketone is not affected. Selective silylation of the more accessible ketone followed by melhylenation, hydrolysis and addition of methyl lithium to the outside face of the previously protected carbonyl then delivered 1. 

The formation of peracids as the effective oxidizing species has often been proposed for oxidations with sodium percarbonate in the presence of organic acids or acid anhydrides30-32. It was observed that at room temperature and in dichloromethane as solvent, the addition of acetic anhydride induced the epoxidation by sodium perborate of mono-, di- and trisubstituted alkenes, including a,/i-unsaturated ketones in a slightly exothermic reaction33 (equation 6). 

The rigid, chiral salen complexes of Mn(III) shown below catalyze the asymmetric epox-idation of alkenes when treated with commercial bleach (NaOCl). This synthesis of enan-tio-enriched epoxides is particularly powerful since the method is applicable to unfunctionalized olefins. In general, (Z)-l,2-disubstituted alkenes afford higher enantioselectiv-ities than do the ( )-isomers or trisubstituted alkenes. The reaction mechanism is com-plex and proceeds via the formation of a Mn(III,IV) dinuclear species. ... 

The phorphorus betaine method is recommended for inversion of the stereochemistry of acyclic di- and trisubstituted alkenes. Highly hindered epoxides react very slowly with LDP and alkenes are not obtained in good yield. Keto groups interfere with the sequence owing to enolate formation unless 2 eq. of reagent is used. Epoxy esters cannot be deoxygenated in practical yield. 

Even if the only difference between the two alkenes is the number of substituents, that can be enough for some reactions. If the substituents are simple alkyl or aryl groups, then the more highly substituted alkene will be the more nucleophilic. This is enough to allow the epoxidation of the trisubstituted alkene in citronellene2 28 while leaving the monosubstituted alkene intact and provide a source of the optically active acid 31 for Nicolaou s synthesis of rapamycin.3... 

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