By prolinamides

Scheme 6.4 a-Functionalisation of carbonyl compounds promoted by prolinamides. 

Scheme 6.6 Different enantioselective reactions catalysed by prolinamides.

Scheme 11.11 Asymmetric Michael addition between w-butanal or 3-methyl-butanal and (i )-p-nitro-styerene catalysed by prolinamides 13.

Scheme 4.23 Cross aldol reaction catalyzed by prolinamide 74...

SCHEME 3.7. The direct aldol reaction of benzaldehyde (2b) with acetone catalyzed by prolinamides. 

Diethylformylphosphonate hydrate reacts as an acceptor with cyclopentanone (78), giving desired aldol 79 in excellent yield and stereoselectivity. Surprisingly, this reaction can be catalyzed by prolinamide even though it proved to be ineffective for the aldol [61]. 

SCHEME 11.7. A -Nitrosoaldol reaction of a-branched aldehydes promoted by prolinamide 10. 

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. " ... 

Encapsulated rhodium complexes were prepared from Rh-exchanged NaY zeolite by complexation with (S)-prolinamide or M-tert-butyl-(S)-prolinamide [73,74]. Although these catalysts showed higher specific activity than their homogeneous counterparts in non-enantioselective hydrogenations, the hydrogenation of prochiral substrates, such as methyl (Z)-acetamidocinnamate [73] or ( )-2-methyl-2-pentenoic acid [74], led to low... 

Besides sesquiterpene lactones, an alkaloid analyzed as CgH14N203 (45), was isolated from the leaves of Arnica montana L. (80). Distinction between the two possible structures 45 (amide-urethane) and 46 (ester + urea) was accomplished by a selective synthesis from prolinamide. 

NBD-amino acids (serine, threonine, valanie, phenylalanine, and histidine) were separated by using a 20 mM ammonium acetate buffer (pH 9.0) containing 10 mM copper acetate, 20 mM L-prolinamide, and 1 mM SDS. The elution order was the L-enantiomer followed by the D-form except in NBD-histidine. Weng et al. [32] described chiral separation of tryptophan on a poly(methyl methacrylate) microfluidic chip coated with bovine serum albumin (32 mm... 

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... 

The leaves of Arnica montana L. contain a new alkaloid, N-ethoxycarbonyl-L-prolinamide (1). Its structure has been established by mass, i.r., and n.m.r. spectral analysis, and confirmed by synthesis from L-proline by conversion into the amide followed by reaction with ethyl chloroformate. The synthesis also settles the absolute configuration of the new alkaloid.3... 

Most small peptides derived from protein sources contain a variety of polar and non-polar amino acids and as such are more difficult to handle. Nevertheless appreciation of the problems and considered chemical manipulation have allowed their MS elucidation [177-184] although a practical limit of about six amino acids in the peptide is reached before degradative procedures become advisable. An important step before sequencing a peptide by mass spectrometry is whenever possible to obtain the amino acid content by hydrolysis and conventional column chromatographic analysis. This assists in the selection of any chemical pretreatment and with the spectral interpretation. A variety of small peptides has been identified by a combination of methods and include 5 - 0X0 - L - prolyl - L - histadyl - L - prolinamide (2-pyrollidone-5-carboxylyl-... 

Sekine has reported the synthesis and anticancer activity of Phosmidosine (18) and its demethylated parent (19). The Phosmidosines were obtained by reaction of an appropriately protected 8-oxoadenosine 5 -0-phosphoramidite and N-protected prolinamide in the presence of 5-(3,5-dinitrophenyl)-l//-tetrazole, followed by in situ oxidation with t-BuOOH to form the iV-acyl phosphoramidate linkage. These syntheses required extensive work with regard to the choice of protecting groups on the adenine moiety, as this was crucial for successful P-N bond formation. ... 

Calcitonin (ihyrocalcilonin) is a 32-amino-acid polypeptide hormone secreted by parafollicular cells of the thyroid glands in response lo hypocalcemia. The entire 32-residue peplide appears to be required for activity, bccau.se smaller fragments are totally inactive. Common structural features of calcitonin isolated fntm different species are a COOH-lerminal prolinamide. a disulfide bond between residues I... 

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. 

Fteproduced from GuiSena G, del Carmen Hita M. Nijera C, Vidzquez SF Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (SJ-binam-L-prolinamide. Tetrahedron Asymm 2007 18 2300-4. Copyright (2007). with permission from Elsevier. 

Guillena G, del Carmen Hita M, Nijera C, Viozquez SF. A highly efficient solvent-free asymmetric direct aldol reaction organocatalyzed by recoverable (5)-Binam-L-Prolinamides. ESI-MS evidence of the enamine-iminium formation. 1 Org Chem 2008 73 5933-43. 

The most widely accepted hypothesis to explain the regio- and stereo outcome of the prolinamide-catalysed aldol reactions supposes the formation of the most stable enamine (generally E-anti) by reaction of the donor carbonyl compound with the pyrrolidine nucleus, and simultaneous activation of the acceptor by hydrogen-bond formation with the carboxamide substituent. Then, the major product is formed by preferential attack of the enamine re-face to the re-face of the carbonyl, as summarised in the ternary complex A (Scheme 6.1). 

Catalyst 10 was introduced for reactions in aqueous systems in the presence of surfactant Brdnsted acids, and 13 promotes the aldol reaction in the presence of a base, whereas prolinamide 4, prepared by click stra-tegy, has been used for the first aldol reaction of thiazolecarbaldehyde with methyl-isopropyl ketone on water with excellent results. Phthalimido-prolinamide 12 is also effective in promoting aldol reactions in neat conditions. 

The search for improving the efficiency of prolinamides as organocataiysts led to immobilisation of the active molecules into a solid support being considered." Two different strategies have been applied for the immobilisation the postmodification of a polymeric support, and the bottom-up synthesis by copolymerisation of several monomers, one of them containing the prolinamide moiety (Figure 6.2). 

In the first approach, prolinamides have been supported on micelleforming species, dendrimers (32a-c), polystyrene (26, 31a-d), poly-vinylidene chloride, phenolic polymers, ionic liquids, silica (28, 29), other inorganic supports (30), ° and polymer-modified small peptides. Supported prolinamide catalysts have also been prepared by acrylic and styrene (27) copolymerisation. 

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). 

---