Resolution carboxylic acid derivatives

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

Finally, high-resolution XH NMR techniques employing fast MAS have been used to study the structure and dynamics of a hexabenzocoronene carboxylic acid derivative [25] shown below. 

A particularly attractive starting material is the homochi-ral carboxylic acid derivative, obtained by conventional resolution. Esterification and then simple amine addition and oxidative decomplexation produces a precursor of (—)-gabacuUne (Scheme 33). 

Chromatographic Resolutions. 1-(1-Naphthyl)ethylamine serves as a chiral derivatization agent useful in preparing diastereomeric amides from racemic acids for chromatographic resolution. For example, various terpenoid acids, after conversion to the diastereomeric amides using (R)-(+)-NEA, were analyzed by HPLC to define the enantiomeric composition (eq 4). Application of the procedure has been used to analyze the enantiomeric purity of several carboxylic acid derivatives. ... 

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. 

This phase can be used in the preparative and analytical stereochemical resolution of a wide variety of compounds, including acetate derivatives of alcohols and diols benzylic alcohol derivatives pora-substituted d-phenyl-d-valerolactones 3,4-dihydro-2H-pyran-2-carboxylic acid derivatives phenylvinylsulfoxide fra s-stilbene oxide (46). 

Carboxylic acid derivatives that have a-substituents can exist as chiral compounds. The resolution of the enantiomers of such compounds is a useful process, leading to the preparation of a-amino acids, a-hydroxy adds and other a-substituted carboxylic acids and their derivatives in enantiomerically enriched form. In addition, the racemization of such compounds can be achieved by a deprotonation/reprotonation sequence, as shown in Fig. 9-13. 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

In addition to in situ racemization of a-substituted carboxylic acid derivatives by deprotonation/reprotonation, a procedure involving halide exchange has been developed135, 361. Whilst the a-halo esters undergo racemization at a reasonable rate, the corresponding carboxylates are almost inert to racemization under the reaction conditions. Using immobilized phosphonium halide and CLEC (cross-linked enzyme crystals), a dynamic resolution procedure has been developed for the hydrolysis of a-bromo and a-chloro esters (Fig. 9-17). The enantiomeric excess in each case was similar to that achieved for simple kinetic resolution reactions using the same enzyme/substrate combinations. 

The hydrolysis of carboxylic acid derivatives using a DKR-based approach is not hmited to cyclic carhonyl compounds as exemplified in Scheme 5.6. For example, when an acyclic racemic thioester (possessing an electron-withdrawing arylsulfanyl group at the a-position) is subjected to enzymatic resolution, hydrolysis occurs smoothly to give the chiral carboxylic acid in high enantiomeric excess... 

CHAiUNCt Spectroscopic data for two carboxylic acid derivatives are given in NMR-A and NMR-B. Identify these compounds, which may contain C, H, O, N, Cl, and Br but no other elements, (a) H NMR spectrum A (one signal has been amplified to reveal all peaks in the multiplet). IR 1728 cm. High-resolution mass spectrum m/z for the molecular ion is 116.0837. 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

This was first experimentally verified for the [2.2]metacyclophane-4-carboxylic acid (55) which had to be prepared by an elaborate 7-step synthesis 771 in order to avoid an electrophilic substitution which might have led to a transanular ring closure (as had been observed in so many cases of [2.2]metacyclophanes)12). The resolution of 55 was accomplished via salt formation with (-t-)-l-phenylethylamine and gave the levorotatory acid ([a]D —9° in CHC13) which then was transformed into several optically active derivatives. The enantiomeric purity of 55 (and therefore of all compounds correlated with it) was confirmed by nmr spectroscopy of the diastereo-meric esters with (—)-l-phenylethanol77) as well as by HPLC of its diasteromeric naphthylamides 55). 

The chirality of methano[10]anulene-2-carboxylic acid (96) was derived from results of a kinetic resolution as outlined for cyclophanes in Section 2.9.3. The reaction of the anhydride of 96 with (—)-l-phenylethylamine as well as the kinetic resolution of 102 (unambiguously correlated with 96 via the acetyl derivative 99) with (+)-2-phenylbutanoic anhydride (Horeau s method) — affording an excess of (+)-carbinol 102 — led to the assignment of the descriptor (S) to (+ )-96 and all its derivatives U7). 

Chemical Properties. Hydrogenation of menthols yields / -menthane oxidation with chromic acid or catalytic dehydrogenation yields menthones. Dehydration under mild conditions yields 3-/ -menthene as the main product. Reaction with carboxylic acids or their derivatives yields menthyl esters, which are used mainly as aroma substances and in pharmaceutical preparations and formulations. The esterification of menthols with benzoic acid is used on an industrial scale in the resolution of racemic menthol. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

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