Chiral protons

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... 

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). 

Scheme 2.61 Enantioselective allene synthesis with chiral protonating agents.

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. 

This is an equilibrium reaction, and it raises a couple of points. First, there are two a-positions in the ketone, so what about the COCH3-derived enolate anion The answer is that it is formed, but since the CH3 group is not chiral, proton removal and reprotonation have no consequence. Racemization only occurs where we have a chiral a-carbon carrying a hydrogen substituent. Second, the enolate anion resonance structure with charge on carbon is not planar, but roughly tetrahedral. If we reprotonate this, it must occur from just one side. Yes, but both enantiomeric forms of the carbanion will be produced, so we shall still get the racemic mixture. 

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... 

Chiral a-sulfinyl alcohol (S,i s)-ll was also shown to be a promising chiral proton donor in catalytic protonation of 2-methyl tetralone enolate by Asen-sio s group [19]. 

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. 

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... 

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. 

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