Prolines amino acids-derived chiral

However, it was not until the beginning of 1994 that a rapid (<1.5 h) total resolution of two pairs of racemic amino acid derivatives with a CPC device was published [124]. The chiral selector was A-dodecanoyl-L-proline-3,5-dimethylanilide (1) and the system of solvents used was constituted by a mixture of heptane/ethyl acetate/methanol/water (3 1 3 1). Although the amounts of sample resolved were small (2 ml of a 10 inM solution of the amino acid derivatives), this separation demonstrated the feasibility and the potential of the technique for chiral separations. Thus, a number of publications appeared subsequently. Firstly, the same chiral selector was utilized for the resolution of 1 g of ( )-A-(3,5-dinitrobenzoyl)leucine with a modified system of solvents, where the substitution of water by an acidified solution... 

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. 

Several different types of chiral additives have been used including (IR)-(-)-ammonium-IO-camphorsulfonic acid, cyclodextrins. proteins, and various amino acid derivatives such as //-benzoxycarbonyl-glycyl-L-proline as well as macrocyclic antibiotics. 

Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of ,/i-unsalurated aldehydes. Protected a,a-diphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81-95% conversion with up to 96 4 dr and 98% ee.204... 

The chiral pool has provided the backbone of many products. Carbohydrates [17] and amino acids are often used because of the high degree of functionality and the ready availability of these compounds from natural sources. Enalapril maleate contains the dipeptide L-alanyl-L-proline (Figure 16.1a) [18]. Aztreonam is derived from L-threonine (Figure 16.1b) [19].The chiral ester 2 was prepared from an amino acid derivative 1 (Figure 16.1c) [20]. In this transformation the original chiral center from L-cysteine was destroyed, similar to self-immolative processes [21]. 

Aldol reaction with L-proline as catalyst has been extended to a-ketols thereby generating anti-diols. Transition state 48 is consistent with the results of aldol condensation catalyzed by Et2Zn-Ph,PS in the presence of a bisprolinol. a-Amino acid derived imi-dazolidinones serve as chiral auxiliaries in the same manner as the corresponding oxa-zolidinones. In employing 4-f-butylthiazolidin-2-thione, the presence of one or two equiv of a base leads to syn products of opposite enantiomeric series. 

In the above examples, L-a-amino acids induce the natural 13P-chirality. Amines or amino acid derivatives (esters, amides) are much less effective, and a tertiary amino acid, hygrinic acid, was ineffective. For trione 13a, secondary amino acids (e.g., proline) are best for 13b and 13c [R > H, see also the Danishevsky (Scheme 8) and Tsuji (Scheme 10) syntheses below], a primary amino acid (e.g., L-phenylalanine) is preferred. The mechanism of the reaction has not yet been clarified. ... 

For reactive aldehydes, proline-derived 7V-sulfonylcarboxamides were investigated as catalysts by Ley and co-workers [45], Berkessel et al. [46], and Kokotos and co-workers [47]. Not only did amino acid derivatives promote the aldol reaction, but also chiral diamines in the presence of an acid were also found to be effective [48]. The yield and enantioselectivity were the same as for the proline-catalyzed reactions. In combination with polyoxometalate acid, a diamine could be used in 0.33 mol%, but for less reactive aldehydes the yields are still low [49]. 

Reactions of chiral A, -iodanes, amino acid-derived benziodazole oxides 58 [76], (5)-proline based reagents 59 [77], and iodylarenes 60 bearing ester motives [78] with non-symmetric sulfides to give asymmetric sulfoxide formation further recognized the importance of such transformations. 

An interesting application (Scheme 15) was the diastereoselective synthesis of [1,4]benzodiazepines and pyrrolo[l,4]benzodiazepines (41). The photolysis of chiral, a-amino-acid-derived substrates proceeded with high diastereoselectivity and the fra s-diastereoisomers were formed exclusively. Additionally, for two substrates derived from proline and a proline analogue, remarkably high memory of chirality effects were determined with ee values of 86% and >98%, respectively. 

ESI MS is a technique more often used in the studies of chiral amino acids. All chiral amino acids commonly occurring in proteins were determined using A-tert-butoxycarbonyl derivatives of proline, phenylalanine, and 0-benzylserine [29] as chiral selectors. Formation of dimers, trimers, and tetramers was studied using collision-induced dissociations (CIDs) method. The observed dissociation efficiency was strongly dependent on the chirality of the amino acids and the type of chiral selectors. 

A -carbobenzyloxy)-amino acid derivatives (A(-CBZ), for example, N-CQZ-isoleucyl-L-proline (ZIP), (V-CBZ-alanyl-L-proline (ZAP), and (V-CBZ-proline (ZP). Different /3-blockers have been enantioseparated so far (propranolol, pindolol, timolol, atenolol, alprenolol, and metoprolol) using CSA as a chiral counter-ion. There is only one example in the available literature for the use of methanol/0.262 M /3-CD (35 65, v/w) for the chiral separation of labetalol and the obtained separation factor was 1.07. 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

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. 

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

The synthesis in Scheme 13.30 was also done in such a way as to give enantiomer-ically pure longifolene. A starting material, whose chirality is derived from the amino acid L-proline, was enantioselectively converted to the product of Step A in Scheme 13.30. 

---