Achiral proton sources

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... 

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). 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

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

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... 

In contrast, Koga and coworkers found that enantioselective protonation of lithium enolates of 2-substituted-l-tetralones occurred with a catalytic amount of chiral tetraamine 30 in the presence of water as an achiral proton source [34]. This protonation system is noteworthy, since high enantioselectivities are observed notwithstanding the existence of a large excess of water. 

Yamamoto et al. reported full research details on catalytic enantioselective protonation under acidic conditions in which prochiral trialkylsilyl enol ethers and ketene bis(trialkyl)silyl acetals were protonated by a catalytic amount of Lewis acid assisted Bronsted acid (LBA15 or 16) and a stoichiometric amount of 2,6-dimethylphenol as an achiral proton source [20]. 

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... 

The authors have succeeded in the enantioselective protonation using a stoichiometric amount of an achiral proton source and a catalytic amount of (R)-BINOL-Me in place of (R)-BINOL (eq 2). In the presence of 8 mol % of SnCU, 10 mol % of (/ )-... 

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. 

To identify the stereochemical course of the protonation of the vinyl carbon, cis and trans silyl enol ethers derived from menthone were isomerized by use of a deuter-ated achiral proton source. Surprisingly, only the identical syn isomer was obtained from both the silyl enol ethers. Thus reaction of the cis isomer occurs via an anti Se mechanism whereas reaction of the trans isomer occurs via a syn Se mechanism. Interestingly, this cis silyl enol ether was isomerized more rapidly than the trans isomer. In the cis silyl enol ether, deuterium was located at a psewdo-axial position in the isomerized product. Therefore, the anti-S pathway can be explained by the product developing control via the product-like transition state assembly. The syn-S pathway for the trans silyl enol ether can be explained by substrate control via the favored intermediate. The relative contributions of the two pathways depend on the relationship between the free energies of their transition state assemblies (Sch. 8). 

The irradiation of a,P-unsaturated esters (122 see Scheme 30) derived from diacetone glucose in the presence of an achiral proton source, such as alcohol, amine, or aminoalcohol, gave the p,y-unsaturated product (123) in moderate to high yield, with good de (for iV,iV-dimethylaminoethanol additive, de a 98%)... 

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. 

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]. 

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). 

For the selection of suitable chiral and achiral proton sources, the following factors should be considered ... 

In some cases an anionic carbon center retains its stereogenicity due to a pyramidal structure and therefore protonation with an achiral proton source will preserve optical activity. A typical example is given by hydrogen/deuterium exchange reactions in 0.1 M sodium methoxide in methanol-J with the following optically active substrates19. 

Even water as the achiral proton source can yield an optically active ketone from a racemic one, provided that the deprotonation is performed with an optically active amine149. 

Moroever, a variety of achiral proton sources produce (R)-4 with 60-81 % ee in the presence of as little as 0.01 equivalents of (5,5)-5. With 0.1 equivalents of (5,.S>5 this catalytic enantiose-lective prolunation reaches the same level of selectivity as with 1 equivalent of (S,S)-51 8t. ... 

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. 

If dilithium ephedrinc is used as the base, enantioselectivities obtained with achiral proton sources are similar to those obtained with chiral sources (table below). Compared with lithium hexamethyldisilazane, lower ee s are observed with dilithium ephedrine due to mismatching, although no corresponding improvements occur which could be expected for the matching effects13 9b. 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

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. 

The catalytic cycle, as proposed by the authors, is also displayed in Scheme 5.120. The reaction of Uthium enolate 478 with the chiral proton source 476 leads to nonracemic ketone 479 and the lithium salt 480. An irreversible proton transfer then occurs from the achiral proton source ArOH to the lithiated imide. Thus, the chiral proton source 476 is regenerated under release of lithium phenolate, and the catalytic cycle closes. 

It is important to note that a stoichiometric use of the achiral proton source is crucial to obtain high enantioselectivity for this catalytic system to scavenge a cationic silicon species. The authors proposed two plausible transition states for each BBA form (Scheme 1.35). As in the case of TADDOL, BBA formation should lead to high enantioselectivity by virtue of their well-organized chiral cavities. 

Ishihara and Yamamoto designed a Bronsted acid assisted chiral Bronsted acid catalyst (40), bearing a bis (trifly l)methyl group (Figure 2.31) [152]. The enantios-elective Mannich-type reaction of ketene silyl acetals with aldimines catalyzed by (40) in the presence of stoichiometric achiral proton source gave (S)-P-amino esters in high yields with good enantiomeric excesses. 

The aim to develop a straightforward access to enan-tioenrichied a-damascone led Fehr and Galindo to the elaboration of a second catalytic process. This second approach involved a fast protonation step of the known chiral aggregate by an external achiral proton source, without background protonation of the uncomplexed Li-enolate of a-damascone, Li-20 or Li-24 (Scheme 31.10). 

This approach is based on the kinetic of the protonation step indeed, the chiral enol-enolate hybrid should react faster than the uncomplexed enolate as well as faster than the achiral enolate complex, resulting from the complexa-tion of the achiral proton source with the Li enolate. To address these difficulties, Fehr and co-workers described an elegant and efficient catalytic enantioselective protonation using 20 mol% of (—)-//-E and 0.85 equiv of phenyl-2-propanone 23. This process affords the corresponding saturated (S)-a-damascone (5)-24) with 94% yield and excellent enantioselectivity (94% ee). It should be noted that this catalytic process might also be used for the enantioselective protonation of the key thioester (50-20, which could be obtained with 98% ee using 50 mol% of ( )-//-E. 

Protonation of the chiral enolate by an achiral proton source... 

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