Enolate compounds asymmetric protonation

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. 

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... 

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

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 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... 

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... 

Catalytic enantioselective protonation of prochiral ketone enolates is a beneficial route to optically active carbonyl compounds possessing a tertiary asymmetric carbon at the a-position. In the asymmetric protonation of trimethylsilyl enolates with methanol, BINAP-AgF has been found to act as a chiral catalyst [90,91], which is also known to catalyze asymmetric allylation of aldehydes with allylic trimethoxysilanes [42] as well as asymmetric aldol reaction with trimethoxysilyl enolates [54]. This protonation can be most effectively performed using 6 mol% ofBINAP and 10 mol% of... 

The carbonyl group in a ketone or aldehyde is an extremely versatile vehicle for the introduction of functionality. Reaction can occur at the carbonyl carbon atom using the carbonyl group as an electrophile or through enolate formation upon removal of an acidic proton at the adjacent carbon atom. Although the carbonyl group is an integral part of the nucleophile, a carbonyl compound can also be considered as an enophile when involved in an asymmetric carbonyl-ene reaction or dienophile in an asymmetric hetero Diels-Alder reaction. These two types of reaction are discussed in the next three chapters. 

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. 

For catalytic asymmetric aldol-type reactions, the transformation of the methylene compounds to a silyl enolate or a silyl ketene acetal was at one time necessary. Recently, the aldol reaction of aldehydes with non-modified ketones was realized by use of the lanthanum-Li3-trisf(/ )-bi-naphthoxidej catalyst 22 [18]. According to the proposed catalytic cycle, after abstraction of an a-proton from the ketone, the reaction between the lithium-enolate complex and the aldehyde... 

Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an a.symmetric Michael addition of thiols to a,fS- xn-saturated carbonyl compounds followed by an asymmetric enolate protonation [20]. 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

The normal Birch reduction is most interesting when applied to aromatic ethers 209 or acids 213. The addition of two electrons may make a dianion in which the charges keep away from the ether 210 but conjugate with the acid 214. Protonation of 210 gives the enol ether 211 and hence the non-conjugated enone 212. The dianion 214 has a proton which transfers to the less stable anion leaving the enolate 215 that can be alkylated to give 216. None of these compounds is chiral and there appears to be little scope for asymmetric induction. 

One set of reactions deserves special mention the conversion of a chiral carbonyl derivative to an achiral enolate that is then protonated enantioselectively. This is clearly a synthetic method that achieves enantiopurity from a racemate but it is clear (because the intermediate is typically isolated) that the separation is achieved not by a separation of enantiomers but rather by their destruction and recreation. The enantioselective step of interest is more akin to a regular synthetic asymmetric step on a prochiral species, and it is for this reason that such techniques in general have not been covered in this book in detail, for fear of mission creep into asymmetric catalysis proper. Nonetheless, the achievements of enantioselective protonations in particular have been striking [138, 139], given the extent to which the pfC s ofaU the compounds involved must be understood for the processes to be effective. An early example serves to illustrate the potential [140]. Amide 23 (Scheme 7.5) was converted to its lithium enolate that could be enantioselectively protonated with chiral acid 24 furthermore, the process could be catalytic in 24 when an achiral acid 25 was added slowly during the reaction. The overall process was only effective when the pKa of the chiral acid was finely tuned. 

The bis-cinchona alkaloids have been shown to be efficient and enantioselective catalysts for a wide range of asymmetric reactions. A (DHQ)2AQN (AQN 9,10-anthraquinone-l,4-diyl) compound (49) is reported to catalyze the protonation of enol trifluoroacetates in the presence of hydrogen carbonate and with formation of the products in good yield and enantioselectivity (Scheme 6.58) [122]. 

Lectka et al. reported on a practical methodology for the catalytic, asymmetric synthesis of (3-lactams 203. Compound 203 results from the reaction of ketenes (or derived zwitterionic enolates) 201 and imines 202 via C—N alkylative cyclization using benzoylquinine as a chiral catalyst and a proton sponge as the stoichiometric base with moder-ate-to-good yield and excellent diastereoselectivity and enantioselectivity (Scheme 40.41). " ... 

---