Enol silyl ether substrates

Enantiotopos discrimination, 93, 128, 142, 234, 235, 331 Ene reactions asymmetric, 223 binaphthol, 222 chiral metal complexes, 222 intramolecular, 226 methyl glyoxylate, 290 Enol silyl ether substrates, 128, 228, 230 Enol substrates, 28 Enolates ... 

Fe(OTf)2-catalyzed aziridination of enol silyl ethers with PhlNTs followed by ring opening led to a-N-tosylamido ketones in good yields (Scheme 27) [81]. With silyl ketene ketal (R = OMe) as substrate, the N-tosyl-protected amino acid ester was obtained in 50% yield. In contrast, the copper (I) salt CuClOq was found not effective for this substrate [82]. 

Another useful method for the asymmetric oxidation of enol derivatives is osmium-mediated dihydroxylation using cinchona alkaloid as the chiral auxiliary. The oxidation of enol ethers and enol silyl ethers proceeds with enantioselectivity as high as that of the corresponding dihydroxylation of olefins (vide infra) (Scheme 30).139 It is noteworthy that the oxidation of E- and Z-enol ethers gives the same product, and the E/Z ratio of the substrates does not strongly affect the... 

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... 

Since enol silyl ethers are readily accessible by a number of methods in a regioselective manner and since the trialkylsilyl moiety as a potential cationic leaving group facilitates the termination of a cyclization sequence, unsaturated 1-trialkylsilyloxy-1-alkenes represent very promising substrates for radical-cation cyclization reactions. Several methods have been reported on the synthesis of 1,4-diketones by intermolecular oxidative coupling of enol silyl ethers with Cu(II) [76, 77], Ce(IV) [78], Pb(IV) [79], Ag(I) [80] V(V) [81] or iodosoben-zene/BFa-etherate [82] as oxidants without further oxidation of the products. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

In 1977, Murai and co-workers described the catalytic addition of hydrosilane and carbon monoxide to an internal olefin to give enol silyl ethers in which one molecule of CO is incorporated.103-105 During the time period covered by this review, the transition metal-catalyzed reaction of HSiR3/ CO has been reported for many substrates. The catalytic system provides a facile route to a number of materials that are valuable in organic synthesis. The hydrosilane/CO system is very interesting, as different products can be obtained depending on substrate, catalyst, and reaction conditions employed. 

Co2(CO)8-catalyzed reactions of benzylic acetates with trimethylsilane and CO proceed under mild reaction conditions to give trimethylsilylethers of /3-phenethylalcohol in 43-76% yield. The highest yields are observed for benzyl acetates with electron-donating substituents.111 Secondary alkyl acetates are also good substrates in the reaction system, yielding enol silyl ethers.112 In addition, the cobalt complex is an effective catalyst for siloxymethylation of five-membered cyclic ortho esters, as shown in Eq. (41).113... 

Considerable use has also been made of allyl carbonates as substrates for the allylation of Pd enolates.9 The reaction of Pd° complexes with allyl enol carbonates119,120 proceeds by initial oxidative addition into the allylic C—O bond of the carbonate followed by decarboxylation, yielding an allylpalladium enolate, which subsequently produces Pd° and the allylated ketone (equation 22). In like fashion, except now in an intermolecular sense, allyl carbonates have been found to allylate enol silyl ethers (equation 23),121 enol acetates (with MeOSnBu3 as cocatalyst) (equation 24),122 ketene silyl acetals (equation 25)123 and anions a to nitro, cyano, sulfonyl and keto groups.115,124 In these cases, the alkoxy moiety liberated from the carbonate on decarboxylation serves as the key reagent in generating the Pd enolate. 

On the other hand, methylaluminum bis(4-bromo-2,6-di-fert-butylphenoxide) can effect the a-alkylation of enol silyl ethers of a variety of ketones, esters and some aldehydes108. Use of the (Z-Bu)Me2Si group is recommended in the ketene silyl acetal substrates. Use of a less bulky Me3Si or Et3Si group leads to a mixture of monoalkylation products and rearranged a-silyl esters. 

Bis(pentafluorophenyl) tin dibromide effects the Mukaiyama aldol reaction of ketene silyl acetal with ketones, but promotes no reaction with acetals under the same conditions. On the other hand, reaction of silyl enol ether derived from acetophenone leads to the opposite outcome, giving acetal aldolate exclusively. This protocol can be applied to a bifunctional substrate (Equation (105)). Keto acetal is exposed to a mixture of different types of enol silyl ethers, in which each nucleophile reacts chemoselectively to give a sole product.271... 

A 2 1 mixture of silver carboxy late and iodine is well known to be a good oxidant in the transformation of enol silyl ethers into the corresponding a-acyloxy carbonyl compounds (139). Five- and six-membered ring enol silyl ethers serve as the best substrates, with larger ring systems forming a-iodo carbonyl compounds as byproducts. 

The intramolecular aldol reaction in the presence of a titanium Lewis acid is a viable means of preparation of cyclic compounds. The cyclization is most conveniently performed between an enol silyl ether and an acetal, because the former is a reactive enol derivative and is readily prepared by silylation of the corresponding ketone in the presence of the acetal moiety in the same molecule. Equation (12) exemplifies a substrate undergoing intramolecular ring closure mediated by TiCU [74]. The conversion of sugar derivatives to carbocycles (called the Perrier reaction [75,76]) has been reported to occur in the presence of a Lewis acid. This process involves the aldol reaction between the enol ether and acetal moieties in the same molecule promoted by a titanium salt, as illustrated in Eq. (13) [77]. The similar reaction of a different type of substrate was also reported [78]. 

If the reaction between enol silyl ethers and a,/ -unsaturated ketones is attempted in the presence of a titanium Lewis acid, the mode of the reaction switches to 1,4-addition with reference to the unsaturated ketone [109-113]. The reaction of an enol silyl ether is shown in Eq. (30) [114]. Ketene silyl acetals react with a,j8-unsaturated ketones in similar 1,4-fashion, as exemplified in Eq. (31) [115]. Acrylic esters, which often tend to polymerize, are also acceptable substrates for a, -unsaturated carbonyl compounds [111]. A difluoroenol silyl ether participated in this cationic reaction (Eq. 32) [116], and an olefinic acetal can be used in place of the parent a-methylene ketone [111] to give the 1,5-diketone in good yield (Eq. 33) [117]. More results from titanium-catalyzed 1,4-addition of enol silyl ethers and silyl ketene acetals to a,f -unsaturated carbonyl compounds are summarized in Table 4. 

The neighboring group participation was invoked for the preferential capture of a ketonic function of keto aldehyde substrates by enol silyl ethers in TMSOTf-cat-alyzed reactions [42], TMSOTf initially coordinates with the aldehyde, and the ketonic oxygen attacks intramolecularly the activated aldehydic carbonyl, thus resulting in the domino-type activation of ketonic functions (Scheme 2-15). 

A wide range of nucleophilic substrates of different reactivity were trifluoromethylated with these reagents. The substrates include carbanions, activated aromatics, heteroaromatics, enol silyl ethers, enamines, phosphines, thiolate ions and iodide anions. " (Scheme 3.8) The least reactive substrates, such as triphenylphosphine, aniline and phenols, require the use of the most reactive dinitro derivative. Most of the reactions can be conveniently performed with the unsubstituted 5-trifluoromethyl dibenzothiophenium salt (35). The least reactive sulfonium salts are the acyclic sulfonium compounds which reacted only with the sodium thiolates.55,59... 

Diaryliodonium salts react more or less easily with carbonyl compounds to afford the C-arylated derivatives. Depending upon the nature of the substrate, different experimental conditions have been used. These reactions are generally performed in alcoholic solvents (r-BuOH, r-AmOH.) or in DMF, at temperatures ranging from low (- 78°C) to reflux of the solvent. Arylation of simple ketones has been obtained either by reaction of the ketone enolates with an appropriate diaryliodonium salt, i or by reaction of the ketone enol silyl ether with diaryliodonium fluoride. Phenylation of the potassium enolate of acetone (13) with diphenyliodonium bromide (14) afforded a modest yield of the monophenylation product, but the stimulation with solvated electrons led to overreaction due to the subsequent reaction of the iodobenzene, a good SrnI arylating agent under these conditions. 9... 

In previous work using Pd catalysts, cycloisomerizations involving substrates bearing siloxy groups at the allylic position generated 1,3-dienes preferentially (Equation 1.49, path a), in contrast to their normal behavior [47]. In the Ru-catalyzed version, the normal 1,4-diene is obtained (Equation 1.49, path b), which generates a very useful enol silyl ether with excellent chemo-, regio-, and diastereoselectivity [48]. 

Examples of the double hydroxylation reaction observed for several representative substrates illustrate the scope of this reaction (Table). Path a is generally preferred by the internal olefinic isomer of the enol silyl ether of methyl alkyl ketones (entries 1-4, and 9) among which methyl sec-alkyl ketones (entries 1-3, and 9) overwhelmingly prefer the path a. Choice of the silyl group substantially affects path a vs. path b ratio path a becomes the favored pathway when the bulky tripropylsilyl group was used in place of the trimethylsilyl group (cf. entries 4 and 5). Thus steric hindrance at the site of the initial oxidation, the nature of the site of the proton removal (i.e., H in B), and the steric effect of the silyl group all contribute to the relative amounts of the two pathways. 

While only 1.0 equiv. of PMHS is needed to complete the reduction of some ketones e. g. a,a,a-trifluoroacetophenone (Ic) and methyl phenylglyoxylate (Id), excess PMHS is necessary in most cases. As shown in Table 1, inconplete conversions are mostly observed for the reduction of relatively acidic substrates i. e. y ketoesters If and Ig and /0-ketoamides Ih and li (pKa = 10-13). Therefore, a likely hypothesis is that the [Zn-diamine]/PMHS system is active not only for the reductive reaction of the carbonyl function, but also for the oxidative silylation of any enolisable group. Thus, the enol-silyl ether produced would hydrolyze back in methanol to the free enol, accounting for the consumption of extra equiv. of PMHS. Nevertheless, this hypothesis does not accotmt for the reduction of imine 3a, since no inqirovement in the conversion is noted on doubling the amount of PMHS (Scheme 3, Table 1). Other imines e. g. 3b, are readily reducible with the present Zn-diamine-methanol system. 

Cyclopropanation of enol sttyl ethers. Cyclopropanation of these substrates with the Simmons-Smith reagent has been reported by several laboratories (4, 588-589). Cyclopropanation can also be effected with diethylzinc-methylene iodide in ether or in n-pentane under controlled conditions (70-80% yields). This reagent can also be used to convert cyclic enol silyl ethers (1) to spiro ethers... 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

Hypervalent iodine reagents in combination with a source of appropriate nucleophiles are commonly used to prepare products with new C—S and C—Se bonds. Moriarty and coworkers have developed convenient procedures for the thiocyanation of organic substrates using the combination of PhICh with Pb(SCN)2 [592-594], Various enol silyl ethers 524, ketene silyl acetals 526 and 528 and p-dicarbonyl compounds 530 can be effectively thiocyanated with this combination of reagents to produce the respective thiocyanato... 

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

During a synthesis of pederol dibenzoate, a key step required formation of a regiospecific enol silyl ether in a highly oxygenated and base-sensitive substrate. The reaction was uniquely achieved by a rhodium(i)-catalysed hydrosilylation sequence (Scheme 47). ... 

The same authors have shown that independently prepared cyclohexanone enolate on treatment with borane yields trans-cyclohexane-l,2-diol in 45% yield. 2-Methylcyclohexanone, which can give two enolates under appropriate conditions, may thus be selectively converted into either a mixture of trans-diols (112) and (113) in a ratio of 42 58 or the trans-diol (114). Enol silyl ethers may also be employed as substrates for this reaction. 

Aldol Condensation with Enol Silyl Ethers. The first example of an aldol condensation between an unactivated enolate and an electrophilically activated carbonyl substrate was accomplished using enol silyl ethers and acetals or orthoesters in conjunction with a catalytic amount of Trimethykilyl Trifluoromethanesul-fonate. The reaction proceeds very readily at —78 C and affords the eo /W-aldol product with high stereoselectivity. The use of 2,2-dimethoxypropane in this reaction affords p-methoxy ketones (eq 10). 

A combination of a Pd-catalyzed arylation of a ketone followed by intramolecular cyclization of the formed enolate with an allylic silyl ether moiety in one of the substrates led to the direct formation of a 1-vinyl-lH-isochromene, as described by Wills and coworkers [164]. 

The ketone 73 was reduced chemo- and diastereoselectively and protected to provide the silyl ether 74. The ester function was then deprotonated to the corresponding ester enolate (75) that was alkylated with methyl iodide exclusively from the Re face of the enolate to afford the bicycle 76 (Scheme 11). The substrate for the retro-aldol reaction (77) was prepared by a sequence that consists of seven functional and protecting group transformations. The retro-aldol reaction converted the bicyclic yS-hydroxy ketone 77 into the 1,3-diketone 69 via the alkoxide (78) in very good yield. 

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