Proline amide derivatives

The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96... 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

As a part of research on the immnnosnppresant rapamycin it was found that acetylenic amides derived from diethylamine and proline gave the corresponding amide-diones with RuO /aq. Na(10 )/CCl -CH3CN [287]. 

The asymmetric halolactonization reactions of unsaturated L-proline amides, developed by Terashima and coworkers,184 has been extended to a-alkyl acrylic acid derivatives (equation 75 and Table 21).185 This allows for the synthesis of either enantiomer of an a-methyl-a-hydroxy acid using L-proline as the auxiliary. Less successful approaches to asymmetric induction with a chiral auxiliary include iodolac-... 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

All of the Amathia brominated amides are presumably biosynthesised from amino acids by similar pathways in the related bryozoans. The amathamides are amides derived formally by reaction of 2-(2,4-dlbromo-5-methoxyphenyl)ethanamlne, 68, with proline followed variously by introduction of a double bond, or methyl, methoxy or bromine substituents. The A. convoluta metabolites 70-74, and 75 from A. alternata are all also derived formally from 2-(2,4-dibromo-5-methoxy-phenyDethanamlne, 68—either by direct amide formation with tyrosine, or by having an additional aminopropyl group which is then... 

ReO(Tp)(r]2-N-X)] have been synthesized from the reaction of [ReOCl2(Tp)] with chiral bidentate ligands in which r 2-N-X = alcoholates or amidates derived from (lS,2/ )-ephedrine, (I. S, 2.S )-diphcriylcthylcricdiamine, and L-proline. These chiral-at-Re complexes have been fully characterized by NMR, IR, circular dichroism, polarimetry, and X-ray crystallography, and have been found to be stable and resistant to oxo-transfer when subjected to harsh conditions.216... 

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

The mesitylylene-bridged tris(NAH) derivative of 5-prolin-amide and the p-xylylene-bridged bis(NAH) derivative of 5-prolinol switched the steric course of reduction so as to give the enantiomeric 5-mandelate in lower e.e. 

Treatment of the benzylidene compound 144 with sodium hydroxide or sodium acetate provides the expected proline derivative 145 but without concomitant deacetylation. The use of ammonia provides the corresponding proline amide. When compound 144 is treated with sodium leucinate, the ring opens at the alternative site and deacetylation occurs, resulting in the formation of the prolyldipeptide 146 and iV-acetylleucine. If sodium glycinate or ethyl glycinate is used instead, simple deacetylation takes place to give the diketopiperazine 147. Deacetylation may also be achieved with aromatic amines in chloroform at room temperature. A... 

In a similar sequence, reaction between proline amide (125) and acetone in toluene at reflux gave dimethyl derivative (126) <85T6il>. Intramolecular cyclization of amido ester (127) gave the cyclic urea (128) (Scheme 24) <85JMC434>. 

The intermolecular aldol reaction of ketones with aldehydes has been intensively investigated since the seminal discovery of the i-proline catalysed process.Most of the modified organocatalysts, successively reported for this fundamental reaction, were amide derivatives of i-proline, able to work at lower loading in more environmentally friendly media and displaying better stereocontrol (Chapter 5). 

Prolinamides are probably the most large group of (5)-proline (1) derivatives used in the intermolecular aldol reaction, due to their easy preparation, stability of the amide linkage and the enough acidity of the NH-moiety able to activate electrophiles by hydrogen bonding. 

These data, as well as other information accumulated [6], are not in agreement with the most obvious interpretation of these phenomena, namely that partial ionization to (1, 5QH5) occurs on dissolution in apolar solvent. The NMR chemical shift behavior (i.e. effects are localized at C4/H4), lack of apparent rehybridization (a pyridinium salt has Jj3 = 180 Hz in contrast to the measured 149 Hz), and absence of cross-over all indicate that a pyridinium thiolate (1, SR) is not formed. A clue to the cause of these unusual effects is found in the observation that Dialkyl substituted amides derived from diethyl amine or proline otherwise analogous in structure to (2a) ionize immediately to pyridinium thiolates in CD3OD. No intermediate is observed. The spectra are fully consistent with pyridinium ions [6]. It is concluded that an amide proton is necessary for formation of the intermediate species. 

Other catalysts besides proline have also been investigated. A particularly large amount of data has been collected for the aldol reaction of acetone tvith p-nitrobenzaldehyde (Scheme 4.32). Simple primary a-amino acids and acyclic N-methylated a-amino acids are not catalytically active under standard reaction conditions. Of the simple cyclic amino acids studied, azeti-dine, pyrrolidine, and piperidine 2-carboxylate, proline is clearly the best catalyst, a-, a -, and, in particular, N-methylation reduce the efficiency and vhereas substitution of the 3- and 4-positions are tolerated vithout dramatic effects. Proline amide is essentially catalytically inactive under the standard reaction conditions (DMSO, room temperature, 2 h) but after three days, the aldol could be isolated in good yields, albeit vith very low enantiose-lectivity. Clearly, the carboxylic acid plays an important role in the catalysis and in determining enantioselectivity. That the enantioselectivity can be improved vas sho vn vith penicillamine derivative 168, proline derived diamine salt 169, and amide 170 [129-132]. 

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]... 

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