Chiral proton sources

Mikami and Yoshida extended the scope of this method considerably by using propargyl phosphates and chiral proton sources [94], The propargylic phosphates thereby have been found to be advantageous owing to their high reactivity towards palladium and the extremely low nudeophilicity of the phosphate group [95]. In some cases, it was even possible to obtain allenes from primary substrates, e.g. ester 194 (Scheme 2.60) [96]. A notable application of this transformation is the synthesis of the allenic isocarbacydin derivative 197 from its precursor 196 [97]. 

By employing chiral proton sources for the protonation of the intermediate samarium species 184/185, highly enantioenriched allenes were accessible in some cases [98]. Thus, in the reaction of propargylic phosphate 198, (R,Rj- 1,2-diphenyl-1,2-ethandiol (200) and (R)-pantolactone (201) were found to give the highest selec-tivities, affording allene 199 with up to 95% ee (Scheme 2.61). 

The allenyl carboxylate 35 was obtained in an enantiomerically enriched form by the palladium-catalyzed reduction of the racemic phosphate 34 using a chiral proton source [53]. The two enantiomers of the (allenyl)samarium(III) intermediate are in rapid equilibrium and thus dynamic kinetic resolution was achieved for the asymmetric preparation of (i )-35 (Scheme 3.18). 

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... 

A new chiral proton source (111), based on an asymmetric 2-oxazoline ring, has been found to be capable of effecting asymmetric protonation of simple prochiral metal enolates (112) to give corresponding ketones (113) which need not bear polar groups. 

Repeated deprotonation of 278 removed due to a high H/D kinetic isotope effect the 1-proton, forming the dideuterio compound 279 with low diastereoselectivity . It is quite likely that a dynamic thermodynamic resolution is the origin. Intermediate 277 is configurationally labile, enabling an equilibration of the diastereomeric ion pairs 277 and epi-211. Similar studies were undertaken with 1-phenyl-l-pyrid-2-ylethane (280) and l-(4-chlorophenyl)-l-(pyrid-2-yl)-3-(dimethylamino)propane (281) (50% eef. An improvement of the achieved enantiomeric excesses resulted when external chiral proton sources, such as 282 or 283, were applied (84% ee for 280 with 283 and 75% ee for 281). 

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. 

Commercially available amino acid derivatives have been tested as chiral proton sources for protonation of lithium enolates catalytic A -L-aspartyl-L-phenylalanine methyl ester gave an ee of 88%.292... 

Asymmetric protonation of lithium enolates has been examined using commercially available amino acid derivatives as chiral proton sources.139 Among the amino acid... 

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-... 

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 Chen group also demonstrated a successful conjugate addition/ asymmetric protonation of a-prochiral imide 4 using thiophenol in the presence of 10 mol% 3 (Scheme 6.1) [43]. It was hypothesized that the ammonium group of the catalyst serves as a chiral proton source for the catalyst-stabilized enone intermediate formed after initial 1,4-addition of the thiol (Fig. 6.4). 

Keywords Protonation, Metal enolates, Chiral proton sources, Achiral proton sources... 

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... 

Later, the same group showed that a racemic open chain benzyl p-ketoester was also converted to the corresponding optically active ketone according to a similar procedure using cinchona alkaloids 21 or 22 as a chiral proton source [23],... 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

Finally, in 2006, Xu and Lin reported an asymmetric reduction of 2-acyl-arylcarboxylates using Sml2 and a catalytic amount of a chiral proton source.19 For example, reduction of 17 gave chelated anion 18 that was protonated by enantiomerically pure oxazolidinone 19. A stoichiometric, achiral proton source, 2,2,6,6-tetramethylpiperidine, then regenerated the chiral proton source. Lactone 20 was obtained in excellent yield and high enantiomeric excess (Scheme 4.11).19... 

Double stereodifferentiation was effective in the protonation of the lithium enolate of (—)-menthone using chiral imides derived from Kemp s triacid. This protonating agent gathers both the chelation with the chiral oxazoline and a cumbersome protonating imide site. Moreover, a catalytic version was set up using 0.1 equivalent of the chiral imide in the presence of a non-chiral proton source (Scheme 73)357,358. 

Using these selenoxides as a chiral proton source (CPS), the enantioselec-tive protonation of the enolates of 2-benzylcyclohexane 86 a,b was found to be quite effective (Scheme 10). 

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. 

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. 

Since the first report by Duhamel, most of the enantioseiective protonations were involving metal enolates and, therefore, the use of stoichiometric amounts of the chiral proton sources although catalytic versions are now emerging [7]. This subsection has summarized the three noticeable examples describing the... 

The research group of Muzart and Henin studied extensively the palladium-catalyzed EDP of allyl- or benzyl-carboxylated compounds. Mainly two types of substrates, prochiral enol carbonates A and racemic (3-keto esters B, were used to afford enols C as transient species [25]. In the presence of a chiral proton source, asymmetric protonation/tautomerization of enols led to enantioenriched ketones D... 

Scheme 7.21). A survey of different chiral proton sources showed that it was necessary to use a P-amino alcohol rather than an alcohol, an amine, or an acid as chiral inductor. 

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-... 

The aforementioned catalytic process was further apphed to diastereoselec-tive protonation of a chiral enolate of (-)-menthone (Scheme 6) [52]. When the lithium enolate 49 was quenched with BHT at -78 °C, an 86 14 mixture of transproduct 50 and cfs-product 51 was obtained. Reaction of the enolate 49 with (S)-imide 31 (0.1 equiv), which was derived from (S)-l-cyclohexylethylamine, followed by slow addition of BHT (1 equiv) at the same reaction temperature furnished a higher frans-selectivity (50 51=95 5). The enantiomer of (S,S)-imide 30 showed a similar level of frans-selectivity, while ds-isomer 51 was produced as a major product (50 51=31 69) in reaction with (S,S)-imide 30. This is an example of diastereoselective protonation in which a new stereogenic center is formed under the influence of a chiral proton source rather than of the asymmetric carbon of the enolate 49. 

A C2-symmetric homochiral diol 13 (DHPEX) is a chiral proton source developed by Takeuchi et al., for samarium enolates which are readily prepared by Sml2-mediated allylation of ketenes [25,26]. In the stoichiometric reaction using DHPEX 13, they found that -45 C was the best reaction temperature for the enantioface discrimination, e.g., when methyl (1-methyl-l-phenylethyl)ketene 55 was used as a substrate, the product exhibited 95% ee [27]. The catalytic reaction was carried out using trityl alcohol as an achiral proton source which was added to a mixture of in situ generated samarium enolate 56 and DHPEX 13 (0.15 equiv) slowly so as not to exceed the ratio of the achiral proton source to DHPEX 13 of more than 0.7. The highest ee (93% ee) of product 57 was gained when the achiral proton source was added over a period of 26 h (Scheme 8) [27]. 

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... 

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