Prolinamide derivatives

The AgOTf-catalyzed, PhSeBr-induced ring closure of the prolinamide-derived cinnamoylamide 92 proceeded via A-addition to the olefin, which afforded the fra r-substituted pyrrolo[l,2- ][l,4]diazepin-l,5(277)-dione 93 in 73%... 

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

These include prolinamides derived from anilines 2a-c,h, 2-hydroxyanilines 2d-f, o-diaminobenzene derivatives 2g, amino-naphthalene ferrocenylamines 11, anthranilic acid-based pro-... 

Especially interesting are prolinamides derived from [1R,2R]-diaminocyclohexane 17a-f, ° (lJ ,2J )-l,2-diphenylethanediamine 18a-f, ... 

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%). 

Various i-prolinamides, derived from chiral p-amino alcohols, are active hifunctional catalysts for nitro-Michael additions of ketones to p-nitrostyr-enes. In particular, catalyst 25e exhibits the highest catalytic performance working in polar aprotic solvents. 

In spite of the plethora of prolinamide-derived catalysts developed until now, some problems, such as the high catalyst loading or long reaction times, remain unresolved. The search for catalysts that improve the reactivity of both the donor or acceptor will continue to be an area of development in the future. 

In 2008, Gruttadauria and coworkers synthesised prolinamide derivatives 54a and 54b, in which prolinamide units were anchored to a polystyrene support via thiol-ene coupling reactions. In the presence of these heterogeneous catalysts, cyclic ketones or acetone 8 reacted with atyl aldehydes 9 to afford corresponding chiral aldols 10 (Scheme 10.l). The best yields of 10 and stereoselectivity of the reactions (dr antilsyn) 96 4-98 2 and 89-99% ee) were attained in a 1 2 (v/v) water/chloroform solvent system, in which water pushed reagents to the concentrated organic phase where asymmetric reactions occurred, meanwhile chloroform ensured swelling of the polymer chain. However, the activity of catalysts 54a and 54b became... 

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). 

Fig. 4.3 Prolinamides derived for chiral compounds beeiring one or more stereogenic centers...

Fig. 4.4 Prolinamides derived for chiral compounds bearing a stereogenic axis...

Also, the use of prolinamide derivatives bearing a stereogenic axis such as in the spiro compound 57 (Fig. 4.4) has been further explored in the reaction of acetone (26.5 equiv.) with several aliphatic and aromatic aldehydes at -25°C. Although its high activity permitted to reduce the amount of catalyst to only 1 mol%, the results were in general modest (50-87% yield, 19-76% ee) [116]. More complicated chiral calix[4]-arene based prolinamide 58 (10 mol%) required the use of acetic acid (20 mol%) as co-catalyst to give the aldol products derived from cyclohexanone (7.3 equiv.) and several aromatic aldehydes, with moderated yields and selectivities (35-93% yield, 66-88% de, 50-79% ee) [117],... 

Other prolinamides derived from chiral diamines have been synthesized and employed as catalyst in the intermolecular aldol reaction. Thus, diamide 59a (20 mol%. Fig. 4.5) containing only one unit of proUne has been used in the aldol reaction of cyclohexanone (19.2 equiv.) with different aromatic aldehydes. The use of 20 mol% of acetic acid is required to enhance the catalytic activity [118a, b]. It seems that both NH group of diamide stabilized the transition state, activating the electrophile. Changing the R group in catalyst 59, would influence the acidity of the... 

Aldols derived from less reactive aldehydes can be more efficiently obtained with prolinamides derived from p-amino alcohols, for example 14. The terminal hydroxyl group was included to activate the electrophile [35]. Moreover, the presence of an electron-withdrawing substituent at the a-carbon of the amine moiety influences amide acidity [35a]. Prolinamides 15 and 16 possessing a tertiary hydroxyl group in... 

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). 

Prolinamide derivatives were found to be highly compatible with IL media. Asymmetric aldol reactions catalyzed by proline amide 18 [42], bis-amide 19 [43], or suUbnylated amide 20 [44] could be efficiently carried out in molten salts [bmim]... 

BF4] or [bmim][PF6] (Scheme 22.8). Bis-amide 19-catalyzed aldol reactions performed in [bmimllBFJ required a much lower excess of donor ketone 21 (3 equiv. instead of 30 equiv. in proline-catalyzed reactions) and allowed a synthesis of chiral compounds 22 bearing heterocyclic, prenyl, or metallocene units [43], The improved catalytic performance of prolinamide derivatives in ionic liquids might be due to a stabihzation of the iminium intermediate formed from the ketone and the catalyst or because of the enhanced nucleophilicity of the enamine [42]. Notably, IL dilution with water (1 1 by volume) accelerated the enamine/iminium ion hydrolysis and raised reaction rates and product yields, with the enantioselec-tivity being retained or even becoming somewhat higher than under water-free conditions [45], Furthermore, the catalyst/lL/water system could be easily recycled five times without aldol yield, dr, and ee losses. 

Several substituted prolinamides, derived from chiral enantiopure aziridines, of general formula 42 (Figure 24.13), were used in aldol reactions. Optimization of the reaction conditions with cyclic ketones showed that no product was formed when the reaction was carried out in organic solvents such as CHCI3 and DMF. 

---