Silyl enantioselective protonation

Enantioselective protonation of silyl enol ethers using a SnCl4-BINOL system has been developed (Scheme 83). 45 This Lewis-acid-assisted chiral Bronsted acid (LBA) is a highly effective chiral proton donor. In further studies, combined use of a catalytic amount of SnCl4, a BINOL derivative, and a stoichiometric amount of an achiral proton source is found to be effective for the reaction.346 347... 

BINOL derivative SnCl4 complexes are useful not only as artificial cyclases but also as enantioselective protonation reagents for silyl enol ethers. " However, their exact structures have not been determined. SnCl4-free BINOL derivatives are... 

Monoalkyl ethers of (R,R) 1,2-bis[3,5-bis(trifluoromethyl)phenyl]ethanediol, 24, have been examined for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals in the presence of SnCU (Scheme 12.21) [25]. The corresponding ketones and carboxylic acids have been isolated in quantitative yield. High enantioselectivities have been observed for the protonation of trimethylsilyl enol ethers derived from aromatic ketones and ketene bis(trimethylsilyl)acetals derived from 2-arylalkanoic acids. 

Scheme 70 Enantioselective protonation of silyl enol ethers...

The fir st examples of the highly enantioselective protonation of silyl enol ethers, such as (32), have been reported (68-94% ee), using a complex of SnCLt and the monomethyl ether of BINOL (i )-(33). hr this catalytic cycle, the active catalyst is reprotonated by a bulky phenol (Scheme 10).43... 

Yamamoto et al. reported full research details on catalytic enantioselective protonation under acidic conditions in which prochiral trialkylsilyl enol ethers and ketene bis(trialkyl)silyl acetals were protonated by a catalytic amount of Lewis acid assisted Bronsted acid (LBA15 or 16) and a stoichiometric amount of 2,6-dimethylphenol as an achiral proton source [20]. 

A one-pot procedure from the racemic silyl enol ether to (5)-2-phenylcyclohexanone has been realized by combination of the isomerization and subsequent enantioselective protonation cat-... 

Enantioselective protonation of prochiral silyl enol ethers is a very simple and attractive means of preparing optically active carbonyl compounds [135]. It is, however, difficult to achieve high enantioselectivity by use of simple chiral Brpnsted acids because of conformational flexibility in the neighborhood of the proton. It is expected that coordination of a Lewis acid to a Brpnsted acid would restrict the direction of the proton and increase its acidity. In 1994, the author and Yamamoto et al. found that the Lewis acid assisted chiral r0nsted acid (LBA) is a highly effective chiral proton donor for enantioselective protonation [136]. 

To demonstrate the synthetic usability of the isomerization, a one-pot procedure from the racemic silyl enol ether to the (5)-2-phenylcyclohexanone was developed by combining the isomerization with subsequent enantioselective protonation catalyzed by (i )-BINOL-Me in the presence of 2,6-dimethylphenol, tin tetrachloride, and MeaSiCl (Eq. 96). We also succeeded in the enantiomer-selective isomerization of racemic silyl enol ethers. For example, during isomerization of the same racemic silyl enol ether with 5 mol % (i )-BINOL-Me-SnCl4 at -78 °C for 2 min, the (f )-silyl enol ether was recovered in 42 % yield with 97 % ee. This absolute stereopreference is consistent with that in the above enantioselective protonation (Eq. 97). 

Recently, Levacher and coworkers developed the first organocatalytic enantioselective protonation of silyl enol ethers S using readily available cinchona alkaloids [5]. 

Catalytic enantioselective protonations of metal enolates already published can be roughly classified into two methods carried out under basic conditions and acidic conditions. The process under basic conditions is, for example, the protonation of reactive metal enolates such as lithium enolates with a catalytic amount of chiral acid and an excess of achiral acid. The process under acidic conditions employs silyl enol ethers or ketene silyl acetals as substrates. Under the influence... 

Silyl enol ethers, known as chemically stable and easy handled enolates, can be protonated by a strong Bronsted acid. Our group demonstrated that a Lewis acid-assisted Bronsted acid (LBA 17), generated from optically pure binaphthol and tin tetrachloride, was a chiral proton source of choice for asymmetric protonation of silyl enol ethers possessing an aromatic group at the a-position [33, 34]. Binaphthol itself is not a strong Bronsted acid, however, LBA 17 can proto-nate less reactive silyl enol ethers since the acidity of the phenolic protons of 17 is enhanced by complexation with tin tetrachloride. The catalytic asymmetric protonation of silyl enol ethers was accomplished for the first time by LBA 18. Treatment of ketene bis(trimethylsilyl)acetal 60 with 0.08 equiv of LBA 18 and a stoichiometric amount of 2,6-dimethylphenol as an achiral proton source afforded (S)-2-phenylpropanoic acid (61) with 94% ee (Scheme 10) [35]. LBA 19 derived from binaphthol monoisopropyl ether has been successfully applied to the enantioselective protonation of meso 1,2-enediol bis(trimethylsilyl) ethers under stoichiometric conditions [36]. 

Enantioselective protonation. Cleavage of enol silyl ethers and ketene bis(tri-alkylsilyl) acetals by the complex leads to chiral ketones and esters. 

The enantioselective protonation of silyl enol ethers, such as (12.39), by a catalyst has been achieved using 2 mol% of the proton source (12.40). The acidity of (12.40) is enhanced by coordination to a Lewis acid. The silyloxy group is activated by fluoride ion and up to 99% ee in the asymmetric protonation of a-aryl substituted cyclic silyl enol ethers such as (12.39) has been obtained using a Lewis acidic BINAP. / F complex.In a similar vein, silyl enol ethers of tetralones and indanones undergo asymmetric protonation with moderate to good ee using catalytic quantities of hydrogen fluoride salts of cinchona alkaloids in the presence of acyl fluorides and ethanol, which act as a stoichiometric source of HE 28... 

General procedure for the enantioselective protonation of silyl enol ether ... 

Silyl enol ethers of P-amido substituted cyclohexanone give [2+2] cyclisadons to form N-heterocycles, fluoroalkyl amides convert cyclohexanones to the enol ether, C N02)4 witii benzocyclohexanone gives a-nitroketones, and with diazoesters give optically active siloxycyclopropanes. Pb(OAc)4 gives acetoxy derivatives, deracemisation by enantioselective protonation demonstrated, methyl vinyl ketones added to give a,e-diones, and... 

Notably, optimization studies exposed the critical influence of phenol on the reactivity and enantioselectivity within this manifold, suggesting a two-step pathway as illustrated in Figure 9. Initially, enantioselective protonation takes place from the chiral Brdnsted acid 57 or oxonium ion pair 60, generated by rapid proton transfer between 57 and phenol, to silyl enol ether 61 to form chiral ion pair 62. This is followed by desilylation with phenol to form the corresponding ketone 63, silylated phenol, and catalyst 57 for further turnover. 

Scheme 12 Catalytic enantioselective protonation of enol silyl ethers...

LBA catalyst prepared from tin(IV) chloride and chiral BINOL can be used as stoichiometric reagent for enantioselective protonation of silyl enol ethers [54]. 

Stoichiometric use of BINOL, activated by tin(IV) chloride, for the highly enantioselective protonation of silyl enol ethers and silyl ketene acetals was reported by Yamamoto and coworkers. A remarkable progress came from the use of BINOL monomethyl ether 481 in catalytic amounts, while 2,6-dimethylphenol serves as the stoichiometric proton source. Again, activation by tin(IV) chloride was required to convert silicon enolates 482 and 484 into ketone 483 and carboxylic acid 485, respectively, with high enantiomeric excess. This is one of the very few enantioselective protonations that is not restricted to cyclic enolates, as illustrated by the application of the protocol to sUyl ketene acetal 484. Racemization of the products does not occur to a significant extent (Scheme 5.121) [239]. 

Silicon Enolates Silyl enol ethers are well known as stable and easily handled enolates. Several research groups took advantage of this higher stability to develop new and innovative enantioselective protonation protocols (Scheme 31.16). ° However, despite the impressive advances made in the development of enantioselective silyl enol ether protonation the last 20 years, then-use as a synthetically useful tool remains sporadic. Indeed, to the best of our knowledge, there has only been a sole report that was applied to the enantioselective silyl enol ether protonation as a key step for natural product synthesis.i° ° i""... 

Ishihara K, Kaneeda M, Yamamoto H. Lewis acid assisted chiral Brpnsted acid for enantioselective protonation of silyl enol ethers and ketene bis(trialkylsilyl)acetals. J. Am. Chem. Soc. 1994 116 11179-11180. 

Yanagisawa A, Touge T, Arai T. Enantioselective protonation of silyl enolates catalyzed by a binap-AgF complex. Angew. Chem. Lnt. Ed. 2005 44 1546-1548. 

Poisson T, Oudeyer S, Dalla V, Marsais F, Levacher V. Straightforward organocatalytic enantioselective protonation of silyl enolates by means of cinchona alkaloids and carboxylic acids. Synlett 2008 2447-2450. 

Poisson T, Gembus V, Dalla V, Oudeyer S, Levacher V. Organocatalyzed enantioselective protonation of silyl enol ethers scope, limitations, and application to the preparation of enantioenriched homoisoflavones. J. Org. Chem. 2010 75 7704-7716. 

This chapter covers organocatalytic processes where the enantio-determining step involves a proton transfer. Most of the organocatalytic processes outlined herein share a key step in common, i.e. the enantioselective protonation of an enolate or enol intermediate species obtained in situ from various precursors. The main organocatalytic approaches reported in the literature may be classified according to the nature of these precursors (Scheme 3.1). Special emphasis will be giveu to decarboxylation of malonates, addition of protic nucleophiles (NuH) to keteues or to a,P-unsaturated carbonyl compounds. We will also focus on tautomerisation of enols formed in situ via photodeconjugation of a,P-unsaturated esters and on the protonation of silyl enolates. Finally, a last section will be devoted to other miscellaneous substrates. 

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