Piperazic acid

Some conformational studies of piperazic acids (hexahydropyridazine-3-carboxylic acids) have been reported <1998CSR437>. Piperazic acids are important compounds as they appear as subunit in many natural products (see Sections 8.01.6 and 8.01.12.2). They can be considered as rigid proline equivalents <1998JA80>. The conformation of derivatives of 3,4-dihydrophthalazine-2(l//)-carboxylic acid, a new conformationally restricted analog of phenylalanine, was also studied <1998T165>. 

HKL 2 1 N C02H H 7 L-piperazic acid (3S)-piperidazine-3-carboxylic acid (35)-[l,2]diazinane-3-carboxylic acid Piz... 

Piperazic acid (7) develops a yellow color with 4-(dimethylamino)benzaldehyde, while with ninhydrin a red color is formed. 243 Under standard conditions of acid hydrolysis piperazic acid is largely decomposed to ornithine and ammonia, but under optimized conditions (6M HC1, 3 h, 95 °C in sealed tubes) it can be recovered. 243 Piperazic acid can also be identified by IR or NMR spectroscopy. 243,244 ... 

Synthesis of Piperidazine-3-carboxylic Acid (Piperazic Acid) Peptides... 

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... 

Scheme 17 Chemical Structures of a Piperazic Acid (Piz) Residue and an a-Hydrazino Acid...

Similarly, the tosylate 278 was converted to a piperazic acid ester 279, which has been used as a precursor for the synthesis of 63 (Scheme 64) <2001CEJ41>. 

The Takai olefination [15] of 29 belongs to the lower-yielding steps in the synthesis by Nicolaou et al. (57%). Coupling with the Boc-protected piperazic acid derivative 30 gives the bis-iodovinyl compound 31, which is further elongated to 33 at the less hindered /i-NH... 

Scheme 3 Acylation of the Sterically Hindered Piperazic Acid Derivative 3 by the Amino Acid Qiloride/Silver Cyanide Methodh l...

Cyclic lipopeptides containing piperazic acid show potent toxicity against tumor cells. This class of compounds shows potent antibacterial activity against gram-positive bacteria. The following five cyclic lipopeptides are all hexadepsipeptides and are produced by Streptomyces spp. 

Cycloaddition of l,2,4-triazoline-3,5-dione or its 4-phenyl analog to penta-2,4-dienoic acid first affords the cycloadduct 33. This, upon hydrogenation to 34 and alkaline hydrolysis, gives hexahydropyridazine-3-carboxylic acid (piperazic acid) (35), 43 a constituent of the monamycine cyclohexadepsipeptides. 

Oxidation of adjacent enantiomeric piperazic acids in the cyclic peptide (88) with air or hypochlorite (89MI 601-01 > gave the corresponding peptide containing two 2,3,4,5-tetrahydropyridazine-... 

But why is acylation of piperazic acids and their precursors so difficult ... 

Whatever the "real" reasons for this peculiar behavior, interesting papers centering on the synthesis of piz/A-piz containing natural products had appeared in the chemical literature by this time (1995), notably from the laboratories of U. Schmidt,but also of C. Shin and K. Hale. All these chemists had encountered serious difficulties during the acylation of unsaturated piperazic acids and their precursors. In particular, Schmidt had discovered that only N-Cbz-valinyl chloride is sufficiently reactive to acylate a terminally protected hydrazine very similar to 88. Furthermore, Olson and Rebert had determined earlier that serinylation of piperazic acids and of its precursors by any of the common methods fails. All we could do is to confirm this conclusion even cyclic A-carboxy anhydrides (NCA s) are impotent vis-a-vis 87-88. 

To our complete surprise, variable temperature H NMR spectra of representative N-acyl piperazic acids showed no evidence of conformational motion from -89 to +120°C. This implied that the molecules in question possess an unusual degree of conformational... 

The pursuit of our synthetic objective identified new research opportunities and engendered useful methodology that has already found practical applications. For instance, the conformational properties of piperazic acids may have important ramifications in the area of peptide secondary structure, and our acylation technique has been employed by an industrial laboratory for the preparation of a drug intermediate unavailable by other methods. 

---