Silyl enol ethers protonation, enantioselective

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""... 

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...

Cycloheptanones attained better enantioselectivity values than their six-membered analogs and the use of alkyl-substituted silyl enol ethers resulted in only moderate enantioselectivities. Indeed, replacement of P=0 by P=S or P=Se in the phospho-ramide catalyst led to improved results in terms of reactivity as well as enantioselectivity. The catalyst loading could be decreased to 0.05 mol% without a deleterious effect on the enantioselectivity (one example). Optimization experiments revealed the critical influence of the achiral proton source on the reactivity and enantioselectivity. This observation suggests a two-step mechanism for the protonation reaction (Scheme 71). 

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... 

BINOL-Me, and stoichiometric amounts of 2,6-dimethylphenol as an achiral proton source, protonation of the ketene bisftrime-thylsilyl)acetal derived from 2-phenylpropanoic acid proceeds at —80°C to give the (5)-carboxylic acid with 94% ee. (/ )-BINOL-Me is far superior to (/ )-BINOL as a chiral proton source during the catalytic protonation, and 2,6-dimethylphenol is the most effective achiral proton source. In addition, it is very important that the molar quantity of SnCU should be less than that of (/ )-BINOL-Me to achieve a high enantioselectivity. For the reaction of 2-phenylcyclohexanone, however, the use of tin tetrachloride in molar quantities lower than BINOL-Me remarkably lowers the reactivity of the chiral LBA (eq 3). Excess SnCLt per chiral proton source, in contrast, promotes this protonation. In the protonation of silyl enol ethers less reactive than ketene bis(trialkylsilyl) acetals, chelation between excess tin tetrachloride and 2,6-dimethylphenol prevents the deactivation of the chiral LBA. 

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]. 

In contrast, moderate enantioselectivity is observed in the protonation of l-(tri-methylstannyl)methyl-2-phenylcyclohexene as a (Z)-allyltrimethyltin, and the absolute stereochemical selectivity is analogous to that in the protonation of the silyl enol ether derived from 2-phenylcyclohexanone (Sch. 6). 

The ( )/ (Z) substrate-dependent absolute stereochemistry and the steric influence of 5n-substituents on the enantioselectivity observed in these reactions suggest that the mechanism is essentially different from that of silyl enol ethers. Although the detailed stereochemical course has not been ascertained, it is possible that the protonation occurs via a two-chlorine-bridged intermediate between allyltrimethyltin and LBA. Keck et al. have reported that transmetalation between allyltributyltin and free... 

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). 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

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

Shortly after, the same group published a study where readily available carboxylic acids, diacids, and N-protected amino acids were screened as proton sources [6]. The same substrates were used in the presence of citric acid instead of HF. This catalytic system displayed somewhat lower selectivity. For example, by using similar experimental conditions in the presence of citric acid at —10 °C, the enantioseiective protonation of silyl enol ether 5c afforded the corresponding ketone 7c in excellent yield but lower enantioselectivity (up to 75% ee, Scheme 7.4, to be compared with entry 3, Table 7.1). However, upon further optimization, this process seems appealing in terms of simplicity, practicability, environmental concerns, and cost therefore, adjustable for industrial use. 

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]. 

Nakai and a coworker achieved a conceptually different protonation of silyl enol ethers using a chiral cationic palladium complex 40 developed by Shibasaki and his colleagues [61] as a chiral catalyst and water as an achiral proton source [62]. This reaction was hypothesized to progress via a chiral palladium enolate which was diastereoselectively protonated by water to provide the optically active ketone and the chiral Pd catalyst regenerated. A small amount of diisopropylamine was indispensable to accomplish a high level of asymmetric induction and the best enantioselectivity (79% ee) was observed for trimethylsilyl enol ether of 2-methyl-l-tetralone 52 (Scheme 11). 

Proton transfer. Protonation of prostereogenic enolates with the y-hydroxyselenoxides, such as 1, sometimes gives excellent ee. The SnCl complex of a methyl ether of chiral BINOL can be used in catalytic amounts to protonate silyl enol ethers, affording ketones in high optical yields. A catalytic enantioselective deprotonation to form a bromoalkene is achieved by KH in the presence of A-methylephedrine. 

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 ... 

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

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. 

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

In 2008, we reported the use of chiral IV-trifyl thiophosphoimide to catalyze enantioselective protmiation of silyl enol ethers with various achiral proton sources (Fig. 13) [56]. It was found that neither the achiral acids nor stoichiometric amount of chiral catalyst alone can protonate the silyl enol ether substrate under such reaction conditions. We believe the combined BBA catalyst, which is an oxonium cation with chiral thiophosphoimide counteranion, is the reactive species for this protonation reaction. On the other hand, since the extremely bulky chiral counter anion cannot accomplish the desilylation step, presence of achiral proton source for catalyst regeneration turns out to be essential. 

---