Asymmetric epoxidation enol ethers

The first asymmetric Mn(salen)-catalyzed epoxidation of silyl enol ethers was carried out by Reddy and Thornton in 1992. Results from the epoxidation of various silyl enol ethers gave the corresponding keto-alcohols in up to 62% ee Subsequently, Adam and Katsuki " independently optimized the protocol for these substrates yielding products in excellent enantioselectivity. 

The oxidation of enol ethers and their derivatives is a useful method for the synthesis of a-hydroxy-ketones or their derivatives, which are versatile building blocks for organic synthesis. Since enol ethers and esters are types of olefin, some asymmetric epoxidation and dihydroxylation reactions have been applied to their oxidation. 

Following their success with chiral ketone-mediated asymmetric epoxidation of unfunctionalized olefins, Zhu et al.113 further extended this chemistry to prochiral enol silyl ethers or prochiral enol esters. As the resultant compounds can easily be converted to the corresponding a-hydroxyl ketones, this method may also be regarded as a kind of a-hydroxylation method for carbonyl substrates. Thus, as shown in Scheme 4-58, the asymmetric epoxidation of enol silyl... 

For example, 1-donor-substituted cyclopropancmethanols may be efficiently produced by cyclopropanation of suitably substituted enol ethers, by reaction of 1-donor-substituted 1-lithio-cyclopropanes with carbonyl compounds, or by addition of carbon nucleophiles to 1-donor-substituted cyclopropanecarbaldehydes. Oxaspiropentanes, important precursors of cyclobutanones, may as easily be obtained by epoxidation of methylenecyclopropanes, or by reaction of carbonyl compounds with diphenylsulfonium cyclopropanide and l-bromo-1-lithiocyclopropanes, respectively. Moreover, as the stereochemistry of most rearrangements may be efficiently controlled, asymmetric syntheses begin to appear. 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

It should finally be pointed out that the mild reaction conditions typically employed in dioxirane-mediated oxidations enable the asymmetric epoxidation of enol ethers and enol esters. With the silyl ethers, work-up provides enantiomeri-cally enriched a-hydroxy ketones. As summarized in Table 10.1, quite significant enantiomeric excesses were achieved by use of catalyst 10 at loadings ranging from 30 [30] to 300 mol% [31]. Enol esters afford the intact acyloxyepoxides enantiomeric purities are, again, quite remarkable. 

Cavallo et al. from (+)-dihydrocarvone and evaluated in the asymmetric epoxida-tion of several silyl enol ethers [32]. Enantiomeric excess up to 74% was achieved in the epoxidation of the TBDMS trans-enol ether of desoxybenzoin with the fluoro ketone 19d (30 mol% of the ketone catalysts). In earlier work Solladie-Cavallo et al. had shown that the fluoro ketones 19a and 19e can be used to epoxidize trans-stilbene with up to 90% ee (30 mol% ketone catalyst) [33], Asymmetric epoxidation of trans-methyl 4-para-methoxycinnamate using ketone 19e as catalyst is discussed in Section 10.2. 

Asymmetric epoxidation of silyl enol ethers mediated by a derivative of 3 (possessing a 3-nitro-phenyl group instead of a pentafluorophenyl group) gave a-hydroxy ketones with up to 62% ee. These reactions were shown to proceed through unstable a-siloxy epoxides5. 

Recently, Armstrong and Tsuchiya have prepared the chiral tetrahydropyranone 56 and examined its use in asymmetric epoxidation reactions. Phenylcyclohexene oxide was formed in excellent yield and high ee however, low enantioselectivity was observed with a trimethylsilyl enol ether (Scheme 21) <2006T257>. 

Hydroxy-ketones have also been obtained very conveniently by epoxidation or dihydroxylation of silyl enol ethers (derived from ketones with either kinetic or thermodynamic control), for example with mCPBA or osmium tetroxide and N-methylmorpholine-A-oxide. Asymmetric dihydroxylation, for example with AD-mix-a or -(3 (see Section 5.3), can provide highly enantioenriched products (6.56). ... 

Enol ethers are interesting substrates for epoxidations since a-hydroxy ketones or the corresponding acetals are isolated, depending on the choice of solvent. Kat-suki has used enol ethers as substrates, including the cyclic enol ether (4.67), which affords the hydroxy acetal product (4.68). ° Adam has used silyl enol ethers and silyl ketene acetals as substrates. A typical example is provided by the asymmetric oxidation of silyl enol ether (4.69), generating the oi-hydroxy ketone (4.70) after a suitable work up. ... 

Chiral nonracemic a-hydoxylated ketones are commonly accessed by asymmetric epoxidation or dihydroxylation of enol ethers and this methodology is discussed in the relevant sections of this book. Another general method for the enantioselective a-oxygenation of ketones and aldehydes is by reaction of an electrophilic source of oxygen with chiral nonracemic enamines or enolates or in the presence of Lewis acids. 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

After experimentation it was found that Baeyer-Villiger oxidation could be suppressed and the amount of catalyst could be reduced to 20 mol% if the reaction was carried out between pH 10 and 11 (Scheme 1.13) [33,34], Yields were increased (65-95%) and the catalytic system resulted in slightly higher ees (91-97% ee). The synthetic utility of this system has been widely explored with the successful asymmetric epoxidation of various hydroxyalkenes (90-94% ee) [35], enol ethers and enol esters (80-91% ee) [36], enynes (90-97% ee) [37], vinylsilanes (84-94% ee) [38], cis-aUcenes (84-97% ee)[39, 40], terminal alkenes (30-94% ee) [41], and mono-epoxidation of conjugated dienes (90-97% ee) [42],... 

A large proportion of Davis s work has been involved in the elucidation of the transition state employed in the transfer of the oxygen from the oxaziridine to the olefin substrate. Davis favoured the planar transition state and was at the time supported by theoretical calculations however, more recent calculations favour the spiro transition state [6]. Davis has also described the asymmetric oxidation of enolate anions by chiral oxaziridines, which led to a-hydroxyketones with enanti-oselectivities of up to 95% ee [56, 57], Silyl enol ethers have also been reported to give epoxides when treated with oxaziridines, but the instability of these compounds is too great to allow isolation [37,58,59], To date, only Davis has reported successful isolation of a-silyloxy epoxides [60],... 

In 2000, Solladie-Cavallo synthesized fluorinated ketones 408 from (+)-dihydrocarvone and investigated them in the asymmetric epoxidation of different fran -stilbenes and silyl enol ethers (Fig. 7.20) [285-287]. Later she reported rigid fran -decalones 409 which gave up to 70% ee (409a) and 20% ee (409b) in the epoxidation of ran -P-methylstyrene (Fig. 7.20) [288]. 

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

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