Chiral carboxylic acid derivatives

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

Analogous to the KRED reductions they can be performed as whole-cell biotransformations [48, 49] (baker s yeast, for example, contains a number of EREDs) or with isolated enzymes [50-52]. In the latter case the nicotinamide cofactor can 

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An a-chiral carboxylic acid derivative is again invoked. An additive is introduced in the first step to ensure that there will be no racemization during formation of the amide. 

The determination of the enantiometric purity of optically active carboxylic acids and amino acids is important not only for an evaluation of their asymmetric syntheses, but optical resolution of racemic modifications of chiral carboxylic acid derivatives and chiral amino acids is also industrially important. A separation on both an analytical and a preparative scale of the racemically modfied and commercially available carboxylic acids 21a-24a and amino acids 25a-27a was attempted by utilizing (4/ ,5S)-MPOT (5). The condensations between 5 and the carboxylic and amino acids 21a-27a were carried out as usual to afford the corresponding 3-acyl-(4/ ,5S)-MPOT derivatives 21b-27b. Their analytical separation was readily achieved by HPLC. H-NMR techniques can also be useful for the analysis of the diastereoisomeric ratio of amides 21b-27b. 

With regard to asymmetric synthesis, the possibility that a stereogenic center outside the sigmatropic framework can direct the stereochemical outcome of the electrocyclic process has been intensively exploited recentlyOne method for asymmetric induction has been realized with X representing a chiral carboxylic acid derivative. From the various chiral auxiliaries studied, the C2 symmetrical amide (32) seems to be the most effective, giving via its zirconium enolate) essentially 100% diastereoselectivity and erythro selection, thus permitting ready access to optically active a-hydroxycarboxylic acids (equation 40). 

In the following example we consider stereoselective a-alkylation of selected chiral carboxylic acid derivatives. 

Because oxidation is often preferably avoided in industrial practice, a potential alternative method of obtaining chiral carboxylic acid derivatives is the relatively under-investigated asymmetric palladium-catalyzed hydroxy-carbonylation and alkoxycarbonylations. Whereas this... 

The literature presents a large number of examples concerning the use of known oxazolidinones as chiral auxiliaries in many kinds of reactions. Rare is the use of A-amino derivatives of oxazolidinones, which were used to synthesise new A-acylhydrazones 207. Radical addition reactions occurred with high diastereoselectivity <00JA8329>. The use of glycolate oxazolidinones 210 proved to be efficient for the enantioselective preparation of a-alkoxy carboxylic acid derivatives . Photochemical reaction of vinyl... 

Acylsultam Systems. Oppolzer et al.53 developed a general route to enantiomerically pure crystalline a,a-disubstituted carboxylic acid derivatives by asymmetric alkylation of A -acylsul tarns. Acylsultam 50 can be readily prepared from the inexpensive chiral auxiliary sultam 53.5 4... 

The methyl and benzyl esters of proline were also used as chiral auxiliaries in respective acrylamides, but the isoxazoline cycloadducts were obtained with only poor to modest stereoselectivity (189,190). The related indoline-2-carboxylic acid derivative 33, however, showed excellent ability to direct nitrile oxide attack, favoring one rotamer (Scheme 6.37), and thereby leading to 3-phenylisoxazoline-5-carboxamide... 

The problem in the above example is to perform an enantiocontrolled electrophilic substitution in the a-position of a carboxylic acid derivative 1. To this end, chiral auxiliary 2, readily available in both (R) and (5) form from phenylalanine, is attached to the acid chloride 1 by amide formation. The amide 3 is converted into the (T )-enolatc 4, with the chelate ring forming... 

The logical consequence of using chiral acids as CDAs for amines, as outlined in Figure 6, is that (.R)- and (S)-l-(aryl)ethylamines (Table 1, entries 39 to 43) almost ideally fulfill the requirements of CDAs for separating chiral acids due to the difference in bulkiness of the substituents on the stereogenic centers. Amino acid derivatives such as L-leucinamide also serve well as CDAs. Both types have been highly appreciated as can be seen from the number of applications listed in Table 2. The condensation reactions between the chiral carboxylic acids and amines (CDAs) can be performed in several ways. However, the mildest but quantitative ones will be most appropriate in order to minimize the potential risks of racemization of any stereogenic center. Otherwise, erroneous analytical data or optically impure diaslereomers could be obtained in the course of the preparative separation. 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

The Gabriel-Cromwell reaction of amines with chiral c/., 3-unsaturated a-bromo carbonyl compounds was exploited for the synthesis of aziridine-2-carboxylic acid derivatives. 79 This procedure was optimized for a solid support synthesis in which the peptide resin was acylated with 2,3-dibromopropanoic acid active ester in the presence of 3 equivalents of NMM to produce directly on resin the a-bromoacrylamide for the addition of amines to produce the aziridine ring. 80 ... 

A practicable strategy to provide access to chiral pyrazolidine-3-carboxylic acid (16) makes use of asymmetric dipolar cycloaddition of diazoalkanes to u,p-unsaturated carboxylic acid derivatives. For this purpose a chiral auxiliary of the alkene component is used, e.g. Op-polzer s1166 1671 (lf )-2,10-camphorsultam.t164l As shown in Scheme 7, by reaction of (tri-methylsilyl)diazomethane (41) with /V-( aery I oy I )cam p h ors u 11 am (42), the AL(4,5-dihy-dropyrazoline-5-carbonyl)camphorsultam (43) is obtained. Reduction of 44 with sodium cyanoborohydride leads to A-(pyrazolidine-3-carbonyl)camphorsultam (45) as the 35-dia-stereoisomer (ee 9 1) in 65 to 80% yields.[164] The camphorsultam 45 is then converted into the methyl ester 46 by reaction with magnesium methylate without racemizationj1641... 

The enantiomerically pure (5)-4-(benzyloxycarbonyl)-l-(ferf-butoxycarbonyl)piperazine-2-carboxylic acid derivative 54 is also prepared by a multistep cyclization of chiral (5)-3-[(benzyloxycarbonyl)(prop-2-enyl)amino]-2-[(fert-butoxycarbonyl)amino]propanoic acid (53) as shown in Scheme ll/241 ... 

Various chiral auxiliaries have been linked to insoluble supports and used to prepare enantiomerically enriched carboxylic acid derivatives (Entries 2 and 3, Table 13.8). Although the recovery of support-bound chiral auxiliaries is certainly easier than in solution reactions, there have been reports of variable results regarding the stereoselectivity of C-alkylations on insoluble supports [131], It seems that the optimi-... 

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