Proline and derivatives

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Aldol reaction. Aldol reaction catalyzed by proline and derivatives has been reviewed. A ball-mill operation on cycloalkanones, ArCHO with (5)-proline leads to predominantly anri-aldol products. The aldol reaction between 4-tetrahydrothiapyrone with the racemic 3-aldehyde based on the same heterocycle shows excellent enantiotopic group-selectivity and thence manifesting dynamic kinetic resolution. ... 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

L-proline and derivatives function as effective catalysts in the a-fimctionahsation of aldehydes with a range of heteroatomic species (see Section 5.3) and Vignola and List have attempted to apply this methodology to the asymmetric a-alkylation. While the intermolecular reaction has proved unsuccessful, high ees in the cycli-sation of aldehydes such as (12.53) have been achieved using (S)-a-methylproline (12.52). 

FIGURE 4.1 Anatomy of an amino acid. Except for proline and its derivatives, all of the amino acids commonly found in proteins possess this type of structure. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Note It is possible to differentiate amino acids by color on the basis of the markedly different shades produced [2, 3]. Proline and hydroxyproline, that only react weakly with ninhydrin, also yield pink-red colored derivatives [2]. Ergot alkaloids and LSD are detected by spraying with 10% hydrochloric add and then heating to 110°C for 20 min after they have been treated with the reagent [9]. Ergot alkaloids and LSD yield red to purple zones when treated in this manner other alkaloids, e.g. reserpine, emetine, quinine, strychnine, pilocarpine, atropine, scopolamine, cocaine and opium alkaloids, do not give a reaction [9]. 

Palladium-catalysed asymmetrie allylations of various carbonyl compounds have been studied by Hiroi et al. using various types of chiral sulfonamides derived from a-amino acids. In particular, the chiral bidentate phosphinyl sulfonamide derived from (5)-proline and depicted in Scheme 1.63 was employed in the presence of palladium to eatalyse the allylation of methyl aminoacetate diphenyl ketimine with allyl aeetate, leading to the eorresponding (7 )-product with a moderate enantioseleetivity of 62% ee. This ligand was also applied to the allylation of a series of other nueleophiles, as shown in Seheme 1.63, providing the eorresponding allylated produets in moderate enantioseleetivities. 

Gruttadauria, M., Giacalone, F. and Noto, R. (2008) Supported proline and proline-derivatives as recyclable organocatalysts. Chemical Society Reviews, 37 (8), 1666-1688. 

The process is not limited to acyclic amino acids, as cyclic compounds such as proline and pipecolic acid derivatives can also be employed, though in these cases more complex heterobicyclic substances are formed. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Compound 331 was prepared using the free amino acid derived by coupling the product between proline and a substituted tryptophan. It was employed for studies on the biosynthesis of the anthelmintic agent paraherquamide <2001T5303>. Compound 332 was obtained by TFA-mediated reaction from the corresponding NH-/-Bu dipeptide... 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

Amino acids derivatized with 9-fluorenylmethyl chloroformate (90) were separated by CE and determined by LIF with a pulsed laser LOD 0.5 nM (SNR 2)322. A sensitive technique for amino acids is capillary zone electrophoresis (CZE) combined with LIF of their fluorescein isothiocyanate (133) derivatives. Not all amino acids give good resolution. LOD for proline and arginine were 0.3 and 0.5 nM, respectively323. 

Zhao, X., Hoesl, C. E., Hoefher, G. C., Wanner, K. T. Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidme-2-acetic acid. Eur. J. Med. Chem. 2005, 40, 231-247. 

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