Prolinamides enantioselective reactions

Scheme 6.6 Different enantioselective reactions catalysed by prolinamides.

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Almagi D, Alonso DA, Nijera C. Prolinamides versus prolinethioamides as recyclable catalysts in the enantioselective solvent-free inter- and intramolecular aldol reactions. Adv Synth Catal 2008 350 2467-72. 

Owing to the increased acidity of an NH group of thioamide relative to the parent amide, proline-thioamide 25a behaves as an excellent catalyst. It has been demonstrated that the reaction occurs in a biphasic medium. Najera" and Li independently synthesised thioamides 25b and 25c,d for enantioselective direct aldol reactions. These ligands were found to be better alternatives to L-prolinamides and provided excellent levels of enantio-seiectivity as compared to their parent ligands. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Sugar-hased prolinamide 16m has also been employed as catalyst for the asymmetric Michael addition of cyclohexanones to p-nitroslyrenes. During optimisation of the reaction conditions, the authors found that the polarity of the solvent does not modify the yield or stereoselectivity, but the best ee was obtained under neat conditions at -20 °C. Ammonium ionic liquids 41a,b are also efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitro-olefins giving the adducts with excellent yields and enantioselectivities and modest to high diastereoselectivities. 

A Toluensulfonyl-L-prolinamide 15b was used as catalyst in the enan-tioselective Michael addition of carbonyl compounds to (B)-nitrostyrene in ionic liquids under different reaction conditions. The best yields (up to 98%) and enantioselectivity (70% ee) were obtained in a basic ionic liquid [bmim]BF4 at room temperature. 

The simplest L-Prolinamide 1 is an effective catalyst for a-phenyl-selenylation reactions of aldehydes with Al-(phenylseleno)-phthalimide, although no mention of the enantioselectivity of the process has been reported (eqn. (3) in Scheme 6.4). 

To extend the operation period of prolinamide-derived IL-supported catalysts, bis-amides 58a-e were synthesised from (25, 4R)-4-hydro yproline and various diamines. C2-Symmetric compounds 58c-e bearing p-phenyle-nediamine, l,2-diaminocyclohexane or 1,2-diphenyl ethylenedia-mine ° structural units exhibited excellent catalytic performance in asymmetric cross-aldol reactions between ketones 8 and aldehydes 9 in the aqueous medium and could be recycled 15 times without any decrease of activity or loss of enantiocontrol. Furthermore, bis-amide 58e efficiently catalysed aldol reactions of acetone with a-ketoesters 62 to afford a-hydrojqr-y-ketoesters 63 in a nearly quantitative yield, yet with moderate enantioselectivity (Scheme 10.14). 

Hydroxy ketones can be synthesized via the pyrrolidine sulfonamide- and prolinamide-catalyzed direct aldol reaction of methyl-aryl ketones with aromatic aldehydes [51]. Modest enantioselectivities were obtained for all donors and acceptors studied. Yields are strongly affected by the nature of the substrates (Chart 3.2). These ketones react also with acetals and hemiacetals of ttichloro- or trifluoroacetaldehyde in the presence of prohne-derived tetrazol to provide the desired aldols [28c, 52]. 

General reviews include the direct aldol/" aldoi and related processes,the Zimmerman-Traxler TS model used to explain the stereochemistry of the aldoi condensation,catalysis of direct asymmetric aldols by prolinamides versus prolinef/zioamides, " " the catalytic asymmetric aldoi reaction in aqueous media (considering both organometallic and organocatalytic approaches), " the use of BINAP oxide in enantioselective direct aldols,and the use of metal enolates as synthons. " ... 

A simple trifunctional L-prolinamide (48) based on 8-aminoquinoline catalyses enantioselective aldols of aromatic and aliphatic aldehydes with acetone. L-Proline-anilide (49) is a simple and cheap organocatalyst of direct aldols, giving y e Aldelee up to 99/98/99% in large-scale reactions, and is readily recoverable and reusable. Proline anthranilamide-based pseudopeptides act as bifunctional catalysts for direct aldols, giving good yields and detee up to 99/96%. ... 

A combination of ytterbium (or zinc) triflate and chiral C2-symmetric prolinamide ligand leads to high enantioselectivities in direct aldol reactions under aqueous conditions (Scheme 27). The presence of 5 mol% of the catalyst affords an asymmetric intermolecular aldol reaction between umnodified ketones and aldehydes to give antiproducts with excellent enantioselectivities up to 99% ee. 

In the last year, an impressive number of highly efficient enantioselective aldolisations have been catalysed by variously substituted prolinamides. As an example, Chimni et ctl. have demonstrated that very simple protonated (5)-prolinamide derivatives efficiently catalysed aldol reactions of ketones with aromatic aldehydes in water. The best results concerning a range of cyclohexanones are collected in Scheme 2.11. When applied to aliphatic ketones, the protocol provided the aldol adducts in good yields, albeit with lower diastereo-and enantioselectivities (<63% de and <48% ee, respectively). 

In 2009, Fu et al. developed highly 4-phenoxy-substituted prolinamide phenols, which could promote the asymmetric aldolisation of cyclohexanone with a range of aldehydes with a high degree of diastereo- and enantioselectivity in a large amount of water (Scheme 2.12). The best enantioselectivities of up to 97% ee were obtained with the most steric hindered catalyst that bore a tert-butyl group on the phenol moiety. The scope of the reaction could be extended to aliphatic ketones with enantioselectivities of up to 94% ee, albeit with low to moderate diastereoselectivities of up to 50% de. 

When the aldolisation of cyclohexanone with aldehydes was performed in the presence of 4-hydroxy-prolinamide alcohols as the organocatalysts, the aldol adduct was obtained in comparable high yields and excellent enantioselectivities of up to 99% ee. Interestingly, the extension of this methodology to acetone provided by reaction with various benzaldehydes the corresponding aldol adducts in still excellent enantioselectivities in a range of 97-99% ee, as shown in Scheme 2.13. 

Ma et al. have found that the presence of molecular sieves increased the diastereo- and enantioselectivity in the aldolisation of cycKc ketones with various aromatic aldehydes using binaphthyl-based axially chiral prolinamides as the organocatalysts. The beneficial influence of the molecular sieves could be due to their water-trapping properties, preventing water-mediated background reactions. The best results are collected in Scheme 2.15. 

However, in contrast to the relatively well-developed cyanation of aldimines, limited reports were related to the cyanation of ketoimines. In this context, Feng et al. have designed a novel Ai, A -dioxide catalyst derived from BINOL and prolinamide in order to be applied as organocatalyst for the asymmetric Strecker reaction of ketoimines with fairly wide substrate scope and excellent enantioselectivities of up to 99% ee (Scheme 3.34)." A low catalyst loading of 2 mol % combined with mild reaction conditions and an operational simplicity made this strategy facile to be used for the synthesis of pharmaceutically important chiral disubstituted a-amino nitriles. 

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