Prolinamide, addition with

L-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to -nitrostyrenes, giving syn-de s up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. 

Inverse (cis) diastereoselectivity was obtained in the intramolecular Michael addition with the cysteine-derived prolinamide analog, 63 (Scheme 2.55) [45]. 

A range of prolinamides, some bearing one or more additional amino groups, have been developed as catalysts in water 107 o-hydroxyaromatic substituents likewise give high selectivity in this solvent (and in neat ketone solution) for direct aldols of aralde-hydes with ketones.108... 

The same method, using Co(acac)2 and the chiral diamines has also been applied to several other stabilized carbanions and enones with up to 100% yield, however, the asymmetric inductions did not exceed 40% ee59. Similarly, a catalyst derived from Ni(acac), and (+ )-(S)-2-(anili-nomethyl)pyrrolidine, (—)-(5)-prolinamide or (—)-(S)-prolinol catalyzes the conjugate addition of nitromethane to benzalacetone, chalcone and 2-cyclohexenone with up to 59% ee62,67. 

Prolinamides featuring additional chiral elements and functional groups may find special utilities, for example to deal with more complicated substrates. There is a report of aldol reaction between a-methylthio acetone and aldehydes which relies on 7b.For promoting reactions of ethyl glyoxylate, the dipeptide 10 has been employed. 

Organocatalysed asymmetric Michael addition has been extensively studied because of the interest in the adducts as valuable intermediates in organic synthesis. The use of a carbonyl compound as donor and prolinamides as catalysts supposes the formation of the corresponding enamine which adds to the a,p-unsaturated compound activated by formation of hydrogen bonds with the carboxamide substituent. In general, the major diastereoisomer has syn configuration because the enamine attacks from its re-face to the re-face of the double bond (Scheme 6.2). 

However, more active and selective eatalysts are adamantyl-L-prolinamide 36, and camphor-lO-sulfonamide-based prolinamides 37, which contain additional stereocentres. Prolinamides derived from bile acids such as epiandrosterone 38, or cholic acid 39 ° exert good enantiocontrol, probably because the cholestanic structure that forms a functionalised chiral cavity with the appended prolinamide groups that were able to exert a good stereocontrol on the orientation of the substrate. 

Prolinamide derivative 40 and (5 )-l,10-bi-2-naphthol was found to be the most effeetive eombination for the addition of aldehydes to nitro-olefins affording the addition products with excellent yields and stereoselection (ee and de up to 99%). 

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. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

Four new benzamido-functionalized prolinamides act as organocatalysts for aldols of aldehydes and cyclic ketones in water, with de/ee up to 96/98%, suggesting that while lateral amide functionality facilitates selectivity in water, introduction of additional chirality into prolines is not essential. ... 

In the area of the asymmetric organocatalytic Strecker reaction, a novel A,A -dioxide catalyst derived from BINOL and prolinamide was successfully applied at only 2 mol% of catalyst loading as an organocatalyst to the Strecker reaction of ketoimines with a fairly wide substrate scope, providing excellent enantioselectivities of up to 99% ee. In addition, a chiral thiourea catalyst was... 

One of the simplest stractures is prolinamide 37 (Figure 24.13), which catalyzed the direct aldol reaction of acetone with 4-nitrobenzaldehyde in water in 50% ee. In the absence of water no reaction took place [59]. Further experiments were carried out using proline-thioamide 38 (Figure 24.13). Brine was found to be a suitable reaction medium for the aldol reaction of several cyclic ketones with electron-deficient aldehydes catalyzed by 38 (5mol%) and in the presence of CI2CHCOOH as additive [60]. 

Catalyst 46 (Figure 24.16) was used in 1 1 DMF/water mixture [66] or in water in the presence of 20mol% ofbenzoic or stearic acid as additive [67]. Prolinamide 47 was used in water in the presence of TFA as additive (Figure 24.16). The latter catalyst was also widely employed with Zn(OTf)2 as additive (5mol%) under aqueous conditions to give aldols in excellent ee values [68]. 

A C2-symmetric pyrrolidine-based tetraamine promotes additions of ketones to nitroolefins and chalkones with respective yields of <99% and <91% and relative ee values of <91% and <93%. Excellent enantioselectivities have been reported for conjugate addition of ketones to nitroalkenes catalysed by chiral pyrrolidine sulfamides incorporation of an additional chiral centre in the side-chain is of negligible advantage. Additions of ketones to nitroolefins have also been promoted by a chiral amino-naphthalene-derived prolinamide. " ... 

Another proUne-based catalyst was also tested in solvent-free aldol reactions under baU-miUing conditions, for example, derivatives of l,T-binaphthyl-2,2 -diamine or proUne-based dipeptides. Nijera [62] and coworkers used a combination of (SJ-binam-bis-L-prolinamide and benzoic acid to catalyze a direct aldol reaction under solvent-free conditions using conventional magnetic stirring. In addition, comparative studies with ball milling (400 rpm) were carried out for the reaction of cyclohexanone and 4-nitrobenzaldehyde but no improvement was observed. After 1.5 h quantitative conversion and similar diastereoselectivity and enantioselectivity were obtained using these methods [62]. Moreover, a study... 

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