Aldehydes, penicillamine

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

Kovacs-Hadady and Kiss [27] studied the chromatographic characteristics of thia-zolidinecarboxylic acid derivatives, formed by reaction of (i>) and (L)-penicillamine with various substituted benzaldehydes and heterocyclic aldehydes in order to evaluate the aldehydes as derivatizing agents for separation of the penicillamine enantiomers. The TLC method of Martens et al. [28] was used. Transformation to thiazolidine carboxylic acids with benzaldehyde and substituted benzaldehydes was not complete, so formaldehyde is still the preferred reagent for separation of the enantiomers. 

New NMR information on the state of coordinated 2-formylglycinate in [Co(en)2(formgly)], showing it to be in hydrate plus enol form rather than in aldehyde form, has led to a new theory for the mechanism of the reaction of coordinated formylglycinate with penicillamine (402). 

Reaction between D-Cys and an oxazoline aldehyde, prepared from l-Phe gave the bicyclic compound 83 [92H(34)903], A derivative of the same system was obtained from penicillamine with a functionalized AA (88CC1128). 

D-penidllamine can promote the elimination of copper (e.g., in Wilson s disease) and of lead ions. It can be given orally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal regimen (p. 320). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. 

The increasingly accepted hypothesis that acetaldehyde may be the causative agent in initiating the multitude of acute pharmacological and chronic pathophysiological effects of alcohol prompted Nagasawa et al. to seek methods to reduce its blood levels. One possibility would be the administration of (S)-penicillamine (4), a compound related to cysteine. The condensation of this amino acid with acetaldehyde produced 2,5,5-trimethylthiazolidine-4-carboxylic acid 242). The chirality of this compound was deducted by NMR analysis to be 72% 2S, 4S and 28% 2R, 4S. Thus, this result is consistent with the configuration found previously for the thiazolidines formed from (R)-cysteine and aldehydes 241 ... 

Cross-linking can be inhibited by agents that can react with the aldehyde groups of allysyl and hydroxyllysine residues. Penicillamine reacts with the aldehyde groups, forming a thiazolidine complex and rendering the aldehyde groups unavailable for cross-link formation. 

The enzyme from mammalian liver mitochondria or the hemolysate residue of bird erythrocyte is inhibited by reagents that react with the pyridoxal moiety such as cysteine, CoASH, and L-penicillamine. These probably react with the aldehyde group of the coenzyme to form a thiazolidine ring HCN can form a cyanohydrin [Gibson et al., 45, 36]. Aminomalonate is also a good inhibitor (Ki = 2x 10" M). 

Both components in Procaine-penicilUn can be determined using nitrous acid.< > When the samples are hydrolysed, both hydrolysis products, penillo-aldehyde and penicillamine, most likely undergo nitrosation. If hydrolysis is not carried out, Procaine forms a diazotate, the wave of which is measured. 

Heterocyclic compounds. Thiazolidine-4-carboxylic acid and 5,6-dimethylthiazolidine-4-car-boxylic acid are formed by formaldehyde condensation from cysteine and penicillamine, respectively. The derivatization of penicillamine has been published (195). Table 14 and Fig. 15 present a summary of these results. The chromatographic characteristics of the thiazolidine carboxylic acids formed by the reaction of D,L-peniciIlamine with various substituted benzaldehydes and heterocyclic aldehydes have also been studied (177). 3-Carboxy-morpholine was separated by Gunther et al. (102). 

In penicillin G, for example, the penicillamine is c clized into a thiazo-lidine ring by reaction of the aldehyde group (formyl radical) with the thiol and NH groups. 

Chromatographic separation of d- and L-penicillamine was carried out after derivatization with substituted benzaldehydes and heterocyclic aldehydes [26]. 

Sample preparation 0.1 mmol of penicillamine was dissolved in 0.1 ml of water, then 0.5 ml of aldehyde solution of 0.1 mmol/1 concentration in methanol was added. After sealing, the mixture was kept at 60-65°C for 8 h. 

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