Enolates asymmetric protonation

Finally, a method to generate enantioenriched a-fluoro carboxylic acids using N-heterocyclic carbene catalysts was reported by Rovis (Scheme 13.12) [28]. Starting from achiral a-fluoroenals, initial attack of the carbene to the aldehyde and subsequent tautomerization generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by water produced enantiopure a-fluoro carboxylic acids. Thus, in contrast to the other methods... 

An alternative method for the formation of enantioenriched a-chloroesters, using A-heterocyclic carbene catalysts, was reported by Reynolds and Rovis (Scheme 13.14) [34]. In a similar mechanism to that presented in Scheme 13.12, initial attack of the carbene to the aldehyde and loss of HCl generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by a phenol produced enantiopure a-chloroesters. In contrast to the approach to chiral a-chloroesters presented in Scheme 13.13, a variety of aryl esters can be incorporated into the product by using different aryl alcohols (ArOH). Additionally, a carbon-chlorine bond is not formed in this reaction. Rather the introduction of a stereocenter in the chlorinated products is achieved via asymmetric protonation. This method was elaborated to use water as the proton/alcohol source to produce chiral a-chloro carboxylic acids (i.e., as in Scheme 13.12) [28]. Moreover, the use of D2O generated chiral a-chloro-a-deutero carboxylic acids. 

The low-temperature method is effective not only in the kinetic resolution of alcohols but also in the enantioface-selective asymmetric protonation of enol acetate of 2-methylcyclohexanone (15) giving (f )-2-methylcyclohexanone (16). The reaction in H2O at 30°C gave 28% ee (98% conv.), which was improved up to 77% ee (82% conv.) by the reaction using hpase PS-C 11 in /-Pt20 and ethanol at 0°C. Acceleration of the reaction with lipase PS-C 11 made this reaction possible because this reaction required a long reaction time. The temperature effect is shown in Fig. 14. The regular temperature effect was not observed. The protons may be supplied from H2O, methanol, or ethanol, whose bulkiness is important. 

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. 

Catalytic asymmetric protonation of a prochiral amide enolate by a chiral diamine (10mol%) has been achieved through careful optimization of the proton-shuttle conditions which must apply. ... 

For a short review on asymmetric protonation of enol derivatives, see Yanagisawa, A. Ishihara, K. Yamamoto, H. Synlett 1997, 411 20. 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

Reviews have featured asymmetric protonations of enol derivatives133 and of enolates and enols.134 Highly enantiofacial protonation of prochiral lithium enolates has been achieved using chiral /J-hydroxy sulfoxides.135... 

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

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 methods for the asymmetric protonation of metal enolates have appeared however, the catalytic mechanisms are fundamentally the same as that described in Scheme 2 of the 1st edition. 

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... 

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... 

Actually, most asymmetric protonations concern lithium enolates, although increased e.e. values have been reported when swapping from Li to Mg or Zn enolates. It would therefore be far beyond the scope of this section to list the numerous examples already described in the literature. Furthermore, an excellent review was published at the end of... 

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

Kim and coworkers have evaluated the performance of a set of /S-hydroxyethers in the asymmetric protonation of the lithium enolate of 2-methyltetralone374. Their best results were obtained with a salt-free enolate (generated by adding methyllithium in ether to the corresponding silylenol ether in methylene chloride), and using a dichlorobenzylic alcohol as CPA, at any temperature between —25 and —98 °C (Scheme 80). 

SCHEME 80. Deracemization of methyltetralone by asymmetric protonation of the lithium enolate generated by cleavage of the corresponding enolether374... 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Nonalkylated 3,4-dehydroprolines 914 were obtained in 76-81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the A -BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88-90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at —30°C). The diastereoselectivity of the reaction was detected by HPLC. 

The lithium amide of (,S S)-(1) has been used to convert racemic a-substituted ketones into optically active ketones via sequential deprotonation/asymmetric protonation of rigid prochiral enolates. Enantiomeric enrichment may occur during the protonation step as a result of the tight coordination between the enolate and the lithium amide in the form of diastereomeric complexes (eq 7). ... 

Since the seminal work of Lucette Duhamel [3] in 1976 describing what is the first direct asymmetric protonation of an enolate (in fact its enamine analogue), it is only in 1992 that Takeuchi et al. successfully used a cinchona alkaloid for the enantioselective protonation of a particular samarium enediolate under mild conditions [4], Samarium diodide reduced benzil 1 into the corresponding enediolate 2, which was then enantioselectively protonated by quinidine 3 at room temperature, affording (R)-benzoin 4 in 91% ee (Scheme 7.3). The presence of molecular oxygen was necessary to obtain high selectivities. However, the procedure was not catalytic as 3 equiv of quinidine 3 were needed. Moreover, only one substrate was described showing the limits of this procedure. 

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... 

Asymmetric protonation of the enolates or silyl enol ethers derived from l,3-dioxolan-4-ones... 

Asymmetric protonation of enols or enolates is an efficient route as is asymmetric alkylation of enolates to prepare carbonyl compounds which possess a tertiary asymmetric carbon at the a-position (Scheme 1). Numerous successful methods have been developed and applied to organic synthesis. Several reviews of asymmetric protonation have been pubHshed [1,2,3,4,5] and the most recent... 

Asymmetric protonation of a metal enolate basically proceeds catalytically if a coexisting achiral acid A-H reacts with the deprotonated chiral acid A -M faster than with the metal enolate, a concept first described by Fehr et al. [44]. A hypothesis for the catalytic cycle is illustrated in Scheme 2. Reaction of the metal enolate with the chiral acid A -H produces (R)- or (S)-ketone and the deprotonated chiral acid A -M. The chiral acid A -H is then reproduced by proton transfer from the achiral acid A-H to A -M. Higher reactivity of A -M toward A-H than that of the metal enolate makes the catalytic cycle possible. When the achiral acid A-H protonates the enolate rapidly at low temperature, selective deprotonation of one enantiomer of the resulting ketone by the metallated chiral acid A -M is seen as an alternative possible mechanism. 

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. 

Muzart and coworkers have succeeded in a catalytic asymmetric protonation of enol compounds generated by palladium-induced cleavage of 3-ketoesters or enol carbonates under nearly neutral conditions [47,48]. Among the various optically active amino alcohols tested, (-i-)-e do-2-hydroxy-endo-3-aminoborn-ane (25) was effective as a chiral catalyst for the enantioselective reaction. Treatment of the P-ketoester of 2-methyl-1-indanone 58 with a catalytic amount of the amino alcohol 25 (0.3 equiv) and 5% Pd on charcoal (0.025 equiv) under bubbling of hydrogen at 21 °C gave the (P)-enriched product 59 with 60% ee... 

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]. 

A chiral (3, (3, (3 -trifluoro-2 -propanol (14) was used for asymmetric protonation of lithium enolate (15) (Scheme 4.8) [43]. The determining factor for the product chirality in this reaction was found to be the chirality of carbinol carbon, but another chirality of the sulfinyl sulfur also affects the enantiomeric excess of the product. Thus, a binary chelation of the chiral fluorinated alcohol to the lithium was suggested. 

Asymmetric protonations of prochiral ketenes, metal enolates or enamines are performed with chiral alcohols, amines or amine salts [552], Recently, good enantiomeric excesses ( 80%) have been obtained in ketene protonations with the following a-hydroxyesters methyl (R)- or ([Pg.88]

Asymmetric protonations of prochiral enolates or enaroines by enantiopure carboxylic acids typically occur with low enantioselectivity, but there are some exceptions. P. Duhamel, L. Duhamel and coworkers accomplished the " deracemi-zation of Schiff bases of a-aminoesters [552], The best selectivities (ee 70%) are obtained when the substrates are deprotonated by Li (ify-A -ethylphene-thylamide, and then reprotonated at -70°C by (fy )-diacyltartaric add 2.2 (R = fert-BuCO) [154] (Figure 4.4). In another successful application, asymmetric protonation of the potassium enolale of racemic benzoin 4.7 by (RJR) 2.2 (R = terf-BuCO) gjves the (S)-enantiomer with a good enantiomeric excess [552] (Figure 4.4). 

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