Piperazine-2-carboxylic acid

Racemic piperazine-2-carboxylic acid (4-azapipecolic acid, 22) is obtained by hydrogenation of pyrazine carboxylic acid salts/236 For its enantiomeric resolution several methods have been described, e.g. fractional crystallization of its S-camphor-10-sulfonic add salt/236,237 fractional crystallization of l,4-dibenzylpiperazine-2-carboxylic add menthyl ester/238 or selective digestion of racemic piperazine-2-carboxylic add amide by leucine aminopeptidase/239 ... 

Optically pure piperazine-2-carboxylic acid (22) and related derivatives, substituted at position 5, are synthesized from piperazine-2,5-diones 50 derived from Xaa-Ser dipeptides as educts, where the substitution R1 at position 5 depends on the side group of the aminoacyl moiety (Scheme 10). After reduction of the piperazine-2,5-diones 50 to 5-alkyl-2-(hy-droxymethyl)piperazines 51 and urethane-type protection of both the imino groups, the desired A,A -bis-protected piperazine-2-carboxylic acid or related 5-alkyl derivatives 52 are obtained by selective oxidation of the hydroxymethyl group. 240 ... 

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 ... 

Scheme 11 Synthesis of (S)-4-(Benzyloxycarbonyl)-l-(re -butoxycarbonyl)piperazine-2-carboxylic Acid 2411...

Reaction of piperazine-2-carboxylic acid (22) with Z-OSu at pH 11 leads to the N4-(benzyloxycarbonyl) monoprotected derivative,12421 which is then converted with 2-(/er/-bu-toxycarbonyloxyimino)-2-phenylacetonitrile at pH 9.5 into the W-/ert-butoxycarbonyl-/V4-benzyloxycarbonyl bis-protected derivative. 242 For further steps in peptide synthesis standard protocols are applied. 

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or p-position is possible. This procedure has also been applied to the synthesis of piperazine-2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic a-hydroxy (S-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield. 

Scheme 51 Synthesis of piperazine-2-carboxylic acid peptides...

The directed sorting method will first be illustrated by the preparation of libraries of piperazine-2-carboxamide derivatives.18 The piperazine-2-carboxylic acid scaffold is a pharmacologically important19 center core... 

The piperazine-2-carboxylic acid scaffold 4 is well suited for a combinatorial approach as it is a small, constrained structure with three functional groups (one carboxylic acid and two amines) that may be conveniently substituted by solid-phase chemistry. Orthogonal protection of the two amino groups could easily be carried out on a large scale by solution-phase chemistry18 (Scheme 1). 

The second library built around the piperazine-2-carboxylic acid scaffold was designed to fill some of the diversity gaps left by the first library. 

The 4500 MicroKans containing resin bound amines 8 were placed into a 12-liter three-necked round-bottom flask fitted with an overhead stirrer. Dimethylformamide (4.5 liters) was added to swell the resin in the MicroKans. l-Alloc-4-fmoc-piperazine-2-carboxylic acid scaffold 6 (78.6 g, 180.0 mmol) was dissolved into DMF (500 ml) and added to the MicroKans. HBTU (68.3 g, 180.0 mmol) and DIEA (62.7 ml, 360.0 mmol) were then added sequentially. The reaction was stirred at RT for 6.5 h. The solution was drained and the MicroKans were washed with DMF, DCM, and Et20. The MicroKans were dried overnight with a stream of nitrogen gas. 

Benzyl-5-(1-benzyl-1 H-imidazol-4-ylmethyl)-3,6-dioxo-piperazine-2-carboxylic Acid Cyclohexylamide (109). For major diastereomer 1H NMR (500 MHz, CD3OD, ppm) 8.91 (s, 1H), 7.32-7.44, 7.23-7.32,... 

The hydrolysis of amides is not limited to the industrial synthesis of enantio-pure amino acids. Lonza has developed routes towards (S)-pipecolic acid and (R)- and (S)-piperazine-2-carboxylic acid that are based on amidases [93, 94]. 

The processes are based on whole bacterial cells. In the case of the pipecolic acid, an important building block for pharmaceutical chemistry, an S-selective amidase in Pseudomonas fluorescens cells, catalyses the reaction with high selectivity and the acid is obtained with an ee >99% (Scheme 6.27A). For the preparation of piperazine-2-carboxylic acid from the racemic amide a R- and a S-selective amidase are available. Utilising Klebsiella terrigena cells the S-enantiomer is prepared with 42% isolated yield and ee > 99%, while Burkholderia sp. cells catalyse the formation of the -enantiomer (ee=99%, Scheme 6.27 B). 

In the laboratory of A. Golebiowski, the high throughput synthesis of diketopiperazines was accomplished. These compounds can serve as 3-turn mimetics. The key step in this approach was a Petasis boronic acld-Mannich reaction between the Merrifield resin-bound piperazine-2-carboxylic acid, glyoxylic acid, and a wide range of commercially available boronic acids to provide a 1 1 mixture of the products. A specific example is shown below. 

Several papers have been devoted to analogues of 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid. One sequence, (Scheme 40), is initiated by the addition of (nitroalkyl)phosphonic diesters (410 R = Me or Et, n = 2 or 4) to A -protected -aminoacrylic ester, and leads, on the one hand, to the [Pg.172]

K-pyrazine-2-carboxylate hydrogenated with 10%-Pd-on-carbon in water at 60 and atmospheric pressure piperazine-2-carboxylic acid. Y 94%. F. e. s. E. Felder et al., Ghimia 13, 263 (1959). 

First enantioselective nitrile conversions were recently industrialized such as the preparation of (jR)-mandelic acid (Fig. 6) or are intended to be industrialized such as the synthesis of (5)-piperazine-2-carboxylic acid (Fig. 31). There are various other commercial processes in which the stereospecific conversion of nitriles is desirable. The increasing number of reports on stereoselective nitrile-converting enzymes in recent years shows that biological mechanisms hold much potential for such processes and indicates that nitrileconverting enzymes might be as useful as esterases and lipases for the synthesis of chiral building blocks. 

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