Enantioselective chiral proton

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... 

Scheme 2.61 Enantioselective allene synthesis with chiral protonating agents.

The enantioselective synthesis of an allenic ester using chiral proton sources was performed by dynamic kinetic protonation of racemic allenylsamarium(III) species 237 and 238, which were derived from propargylic phosphate 236 by the metalation (Scheme 4.61) [97]. Protonation with (R,R)-(+)-hydrobcnzoin and R-(-)-pantolactone provided an allenic ester 239 with high enantiomeric purity. The selective protonation with (R,R)-(+)-hydrobenzoin giving R-(-)-allcnic ester 239 is in agreement with the... 

Enantioselective protonation of ketone metal enolates constitutes an important method for the preparation of optically active ketones. Fuji and coworkers have shown interest in the magnesium countercation in the enantioselective protonation of such enolates. Pertinent results are obtained with protonation of Mg(II) enolates of 2-alkyltetralones and carbamates derived from l,l -binaphtalene-2,2 -diol as chiral proton sources, as indicated in equation 82 and Table 11. 

The Muzart group reported an organocatalytic protonation reaction based on an in situ-formation of the required enolate by photochemical tautomerization of the chiral ammonium enolate 26 as an initial step [21]. The ammonium ion in 26 functions as the chiral proton source. Subsequent esterification affords the desired car-boxylate 20 in up to 65% yield and enantioselectivity in the range 40-85% ee. An example is shown in Scheme 9.8. The best results were obtained by use of the secondary, N-isopropyl-substituted aminobornanol for formation of the chiral ammo-... 

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2)25 In this method, the achiral alcohol plays two roles it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol. 

The chemistry of asymmetric protonation of enols or enolates has further developed since the original review in Comprehensive Asymmetric Catalysis [1], Numbers of literature reports of new chiral proton sources have emerged and several reviews [2-6] cover the topics up to early 2001. This chapter concentrates on new examples of catalytic enantioselective protonation of prochiral metal enolates (Scheme 1). Compounds 1-41 [7-45] shown in Fig. 1 are the chiral proton sources or chiral catalysts reported since 1998 which have been employed for the asymmetric protonation of metal enolates. Some of these have been successfully utilized in the catalytic version. 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

Both chiral amines42 and chiral protonating agents43 have been used for the enantioselective deracemisation of a-substituted aldehydes and ketones via the derived enamine. However, the enantiomeric excesses achieved were usually not very high and there have been no new developments reported in this area41. 

Ninomiya and Naito established an enantioselective variant of their enamide photocyclization based on chiral proton donors. The enamide photocyclization... 

The third type of cyclization examined in the presence of chiral lactam hosts is the [6 7r]-cyclization of enamide 28a, the protonation step of which has been already enantioselectively directed with up to 38% ee by chiral proton donors, as described in Sec. Ill [46]. When the cyclization of enamide 28a was... 

Chiral Reagent The diamino phenyl borane (6) derived from (15,25)-l,2-diaminocyclohexane has been used as a chiral proton source for the enantioselective protonation of prochiral cyclic lithium enolates, with ee s up to 93% (eq 9). (15,25)-1,2-Dia-minocyclohexane proved to be highly superior to 1,2-diphenyl ethylenediamine or bis-naphthylamine. 

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. 

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]. 

Several methodologies have been developed to generate the prostereogenic intermediate necessary to achieve enantioselective protonation but all have in common a stable or transient species, enol or enolate, which is being protonated by a chiral proton source. In specific cases, it is difficult to determine the real structure of the intermediate obtained, enolate or enol or both, because of the lack of its characterization and precise mechanistic investigations. 

Next to Muzart s work, Baiker and coworkers reinvestigated the reaction parameters of the palladium-catalyzed EDP of cyclic [i-kcto esters in the presence of various chiral proton sources including cinchona alkaloids [31]. When working with benzyl ester 55a as model compounds, they demonstrated the crucial effect of the solvent on the enantioselectivity of the reaction. In the palladium-catalyzed debenzylation of 55a carried out at room temperature with hydrogen, the highest conversions but the lowest enantioselectivities were achieved in protic polar solvents... 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

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]. 

Various methods using a stoichiometric amount of chiral proton sources or chiral ligands are available for enantioselective protonation of metal enolates e.g., protonation of metal enolates preformed by deprotonation of the corresponding ketones or by allylation of ketenes [6,7,8,9,10,11,13,17,18,19,21,22,25,26, 29,30,31,32,37,40,41,42,43,49,50,53,54,55,56,57,59,60,63], the Birch reduction of a, 3-unsaturated acids in the presence of a sugar-derived alcohol 2... 

By reduction of benzil with samarium in the presence of quinidine as chiral proton source up to 82 % (f )-benzoin is obtained with 69 % ee. If, however, the intermediate samarium-endi-olate, which has not been protonated, is oxidized to benzil by oxygen, only 61 % (-R)-benzoin is isolated, but with much higher enantioselectivity (91 % ee)l48a. 

Such a catalytic cycle is most important both from a theoretical and practical point of view (see also 10-Li -> 10 and 12-Li -> 12). It implies that reaction of 4-Li with (5,5)-5 (probably by chelation between the imide and oxazoline moiety of 5) must be > 10 times faster than with one of the achiral proton sources present. Protonation of enolate 6-Li with the rather simple chiral proton source (S,5)-7 provides (5)-6 with the highest enantioselectivity achieved so far186. 

An ingenious method has been developed to transform ketene 2 into the industrially important (S)-a-cyclogeranium acid thioester 3 with high enantioselectivity even by a catalytic process (stoichiometric 97% ee, 85% yield)17la. By slow addition of 1 equivalent of an aryl thiol ArSH to a mixture of ketene 2 and 5 mol% of the chiral base (—)-4-Li, thioester (S)-3 is formed. (-)-4-Li and ArSH react to form (-)-4, probably complexed to ArSLi which adds to 2. An intermediate of the assumed structure 5 is formed which breaks down by chiral proton transfer into (S)-3 and the starting base ( —)-4-Li. 

Use of a chiral proton source, a chiral base or base/chiral ligand complex circumvents the problem of incorporation and removal of a chiral auxiliary. Simpkins and coworkers opened the possibility of enantioselective protonation as a method for the asymmetric syntheses of 1-substituted tetrahydroisoquinolines [77]. Using the chiral amine 98 as a proton source, deracemization of 97 proceeded in up to 93 7 er, alleviating the requirement for a chiral auxiliary (Scheme 28). 

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