Prolines amines

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

A test for secondary amines (e.g. proline) is the Chloranil test (1 drop of a 2% acetaldehyde solution in DMF, followed by one drop of a 2% solution of p-chloranil in DMF, leave for 5 mins). A positive test gives blue stained beads. 

Proline is the only amino acid in Table 27.1 that is a secondary amine, and its presence in a peptide chain introduces an amide nitrogen that has no hydrogen available for hydrogen bonding. This disrupts the network of hydrogen bonds and divides the peptide into two separate regions of a helix. The presence of proline is often associated with a bend in the peptide chain. 

This group was developed for the protection of amino acids. It is formed from 4-ethoxy-l,l,l-trifluoro-3-buten-2-one in aqueous sodium hydroxide (70-94% yield). Primary amino acids form the Z-enamines, whereas secondary amines such as proline form the -enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane at rt. ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

The feasibility of this approach was demonstrated with a model library of 36 compounds prepared from a combination of three Boc protected L-amino acids (valine 23, phenylalanine 24, and proline 25) and 12 aromatic amines (3,4,5-trimethoxyaniline (26), 3,5-dimethylaniline (27), 3-benyloxyaniline (28), 5-aminoindane (29), 4-tert-butylamline (30), 4-biphenylamine (31), 1-3-benyloxyani-line (28), 5-aminoindane (29), 4-tert-butylaniline (30), 4-biphenylamine (31), 1-aminonaphthalene (32), 4-tritylaniline (33), 2-aminoanthracene (34),... 

Phosphinous amides, based on proline and tetrahydroisoquinoline carboxylic acid, bearing a second donor center (50, Ar=Ph R =H, CH3,Tr, Ph R =H, CH3,Tr, Ph and 51, R =H,Tr R =H,Tr) (Scheme 40) have been developed for use in allylic alkylation and amination of substituted propenyl acetates, yielding the corresponding products in 87-98% (5-94% ee) and 29-97% (14-93% ee) respectively [55, 167]. With bidentate ligands of type 38 where R=(S)-PhMeCH, and with the bis(aminophosphanes) 52 (R=Ph) similar allylic alkylations have been also tested [168,169]. 

Evidence exists that the relative solubility of amines and inhibitors in heterogeneous oil-water systems could be decisive in formation of nitrosamines and blocking these reactions, Nitrosopyrrolidine formation in bacon predominates in the adipose tissue despite the fact that its precursor, proline, predominates in the lean tissue (5,6,7). Mottram and Patterson (8) partly attribute this phenomenon to the fact that the adipose tissue furnishes a medium in which nitrosation is favored, Massey, et al, (9) found that the presence of decane in a model heterogeneous system caused a 20-fold increase in rate of nitrosamine formation from lipophilic dihexylamine, but had no effect on nitrosation of hydrophilic pyrrolidine. Ascorbic acid in the presence of decane enhanced the synthesis of nitrosamines from lipophilic amines, but had no effect on nitrosation of pyrrolidine. The oil-soluble inhibitor ascorbyl palmitate had little influence on the formation of nitrosamines in the presence or absence of decane. 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

A drawback to conventional amino analysis by chromatography is the need for pre- or post-column derivatization to improve sensitivity. Ninhy-drin, the reagent originally applied for detection, has been increasingly displaced by other reagents such as phenylisothiocyanate,71 9-fluorenylethyl chloroformate,72 and o-phthaldialdehyde (OPA). OPA allows fluorimetric detection, which offers the potential for greater sensitivity.73 A limitation of OPA is that it doesn t derivatize secondary amines, so an additional reaction must be added for proline detection. And, as noted for amine analysis in section A5.4.2, such derivatization adds to the analysis time and may yield unstable products. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

THF) containing 10% (v/v) of trifluoroacetic acid (TFA). After microwave irradiation for 25 s at 60 °C, the mixture was concentrated to dryness, 5 equivalents each of N,N-diisopropylethy]amine (DIEA) and (S)-proline acid chloride in bdmimPF6/ THF were added, and the resulting mixture was stirred at room temperature for 3 min. Finally, after in situ deprotection with 20% piperidine (v/v) in bdmimPF6/ THF at 60 °C for 1 min in the microwave reactor, the target compounds were obtained as mixtures of diastereomers. 

Recently, a novel method for the synthesis of a library of substituted prolines with microwave technology [95] has been described. In the first step, 1 equivalent of an amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with subsequent irradiation at 180 °C for 2 min. In the second step, 0.85 equivalents of the maleimide are added and the resulting solution is heated at 180 °C for an additional 5 min. This methodology allowed the production of a solution-phase library of 800 compounds with a crude purity between 65 and 82% (Scheme 9.45). The compounds were purified by solid-supported reagent scavenging to afford the final products with a purity between 90 and 98% and in 79-85 % yield [96]. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Bromocriptine is rapidly and completely metabolised in animals and man. The major components of the urinary metabolites have been identified as 2-bromo-lysergic acid and 2-bro-mo-isolysergic acid. Apart from the hydrolytic cleavage of the amine bond and the isomerization at position 8 of the lysergic acid moiety, a third principal biotransformation pathway consists in the oxidative attack of the molecule at the proline fragment of the peptide part, predominantly at position 8, giving rise to the formation of a number of hydroxylated and further oxidized derivatives of bromocriptine, and in addition of conjugated derivatives thereof. 

For example, a proline-based chiral ligand was attached to a vinyl-substituted monomer (Fig. 42.15) by reacting vinylbenzoyl chloride with the amine functionality of the ligand [106]. As mentioned previously, the apolar Merrifield resin as a support is not swollen in polar solvents. Hence, in order to match the polarity of the resin with that of the typically used substrates in enantioselective hydrogenation, the functionalized monomer was copolymerized with polar units of methacrylic acid 2-hydroxyethyl ester. 

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