Ketones organocatalytic addition

Probably the most important organocatalytic addition to a,P-unsaturated ketones is the synthesis of the Wieland-Miescher ketone. This bicyclic diketone is obtained by a Robinson aimulation consisting of a first Michael addition to vinyl methyl ketone followed by an intramolecular aldol reaction. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Triethoxysilyl acetylene (51) allows a new organocatalytic approach toward the introduction of the alkyne moiety via a nucleophilic addition to aromatic aldehydes, ketones, and aldimines, with EtOK as catalyst (10 mol%). Although a catalytic asymmetric version has not yet been developed, the application of a chiral auxiliary, in the case of imines 53 (Scheme 7.9), led to an impressively high dia-stereoselectivity (20 1) [54], unparalleled by other acetylenic organometallics. 

The asymmetric organocatalytic transformation of a ketone into an alcohol may be realized with the combination achiral silanexhiral phase-transfer catalyst, such a quaternary ammonium salt. The final alcohol is then recovered by an additional hydrolytic step. The asymmetric reduction of aryl alkyl ketones with silanes has been reported (ee-values up to 70%), the catalysts utilized being ammonium fluorides prepared from the quinine/quinidine series (e.g., 18 in Scheme 11.6) [19]. (For experimental details see Chapter 14.21.1). The more appropriated silanes were (Me3SiO)3SiH or (MeO)3SiH (some examples are... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

In 2013 Chen et al. reported the direct organocatalytic Michael addition of cyclic ketones to l,l-bis(phenylsulfonyl)ethylene using the camphor-derived pyrrolidine 25." The desired Michael adducts were obtained in high chemical yields and very good stereoselectivities (Scheme 11.21). 

In 2013 Cozzi et al. prepared the 2-(diethylferrocenyl) pyrrolidine (S)-36 starting from ferrocenyl ethyl ketone (Scheme 11.37) and proved its effectiveness in different organocatalytic transformations, namely the Michael addition of aliphatic aldehydes to aromatic nitroalkenes (Scheme 11.38A) and the SNl-asymmetric a-allgflation of carhonyl compounds (Scheme 11.38B). ... 

Although organocatalytic intramolecular conjugate additions have been reported (see Sect 1.3.1.3), the Michael acceptor is almost always either a ketone or an aldehyde, since the coimnon mode of activation for these systems is through iminium ion... 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

The first organocatalytic conjugate addition of ketones to trani-P-nitrostyrene was independently reported by Barbas [107], and List [108] using L-proline as catalyst with good yields but very low enantioselectivities (0-23% ee). A subsequent study by Enders et al. showed a profound solvent effect in the reaction since in MeOH the enantioselectivity could be increased to 76% for the major syn diastereoisomer in the reaction between 3-pentanone and tran -P-nitrostyrene employing a 20 mol% of... 

The different solvents, additives, and cosolvents present in the reaction media can assist in the stabilization of the transition state and favor one facial preference for the approaching of the substrates as depicted in proposed transition state D [52b] (Fig. 2.10) for the 32-catalyzed Michael addition of ketones to nitrostyrene. In this case, a cooperative hydrogen-bond solvent participation (represented by H O) takes place resembling the oxyanion hole commonly found in enzymes for stabilizing transition states. It seems then very clear that intra- and intermolecular hydrogenbonding interactions play a key role in the organocatalytic cycle. 

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

Scheme 2.82 Organocatalytic asymmetric conjugate addition of a-substituted P-ketoesters to a,p-unsaturated ketones catalyzed by 127...

A bifunctional iminiumyhydrogen-bonding catalysis has been very recently employed for the first enantioselective organocatalytic conjugate addition of a phosphorous nucleophile (diarylphosphane oxides) to a,ji-unsaturated ketones [370]. The process, which allows efficient additions to cyclic and linear enones as well as the generation of quaternary stereocenters, is catalyzed by quinine-derived thiourea... 

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