Tryptophan reaction with formaldehyde

Reaction of aldehydes with the indole NH group of tryptophan in proteins has been reported in tetanus toxin (251) and tobacco mosaic virus (26). In the latter instance, the Folin s phenol reagent color value decreased as the reaction with formaldehyde proceeded, and increased with removal of the aldehyde by dialysis in dilute acid. Indole, pure tryptophan, and glycyl tryptophan behaved in a similar manner, but not t3unsine nor glycyltyrosine. Benzaldehyde, acetaldehyde, propionalde-hyde, and butyraldehyde were also used in this work with similar effect. Reversal of formaldehyde inactivation of tobacco mosuc virus could not be confirmed (356). It was also claipaed that the drop in phenol color could not be correlated with a decrease in virus infectivity. 

The reactions of tryptophan and of tryptamine derivatives with formaldehyde require special comment. Whereas tryptamine and its 5- and 7-methoxy and i id-A-methyl and -ethyl derivatives react... 

Pictet-Spengler cyclization of L-tryptophan with formaldehyde afforded the monochiral carboxylic acids 20a,b, whereas cyclization with acetaldehyde yielded the diastereomeric carboxylic acids 21a,b (23). Acids 20a,b with a hydrogen at C-1 are enantiomers, but acids 21a,b are diaste-reomers the cis isomer 21a was the major reaction product when the cyclization of L-tryptophan with acetaldehyde was carried out in the presence of sulfuric acid. Direct removal of the carboxy group in these acids is difficult, but it can be accomplished in several steps dehydration of the amides prepared from the acids with phosphorus oxychloride affords nitriles, and the nitrile group can be removed by reduction with sodium borohydride in pyridine-ethanol (31). 

Following up this idea they synthesized )8-carboline and 1-methyl-/3-carboline by reaction of tryptophan with formaldehyde and acetaldehyde, respectively, under oxidizing conditions. The steps of this biogeneticaUy patterned synthesis have been repeatedly studied and are fuUy discussed in Sections III, A, l,aand III,E,2,a,i. The formation of l,2,3,4-tetrahydro-)8-carbolines as the initial step in the biogenesis of jS-carboline alkaloids, by reaction of tryptophan or trypta-mine or the corresponding hydroxylated derivatives with aldehydes or a-keto acids, derivable from a-amino acids, is a widely held concept. Two lines of circumstantial evidence favor this hypothesis. First, a number of simple l,2,3,4-tetrahydro-)8-carboline derivatives have been found to occur naturaUy. l-Methyl-l,2,3,4-tetrahydro-]8-carbo-line (461 = B = H eleagnine) has been isolated from Elaeagnus... 

Poindexter and Carpenter (2972) reported the isolation and identification of 9//-pyrido[3,4-/>]indole (norharman) and l-methyl-9//-pyrido[3,4-/>]indole (barman) from CSC. They reported that the yield of the total barmans in hurley and flue-cured MSSs was between 15 and 20 xg/gram of tobacco smoked, values which were 40 to 50 times that of the barmans in the unsmoked tobacco. Since the weight of tobacco in cigarettes sold at that time approximated 1 gram, the yield of these two compounds was about 15-20 Xg/cig. Poindexter and Carpenter concluded from experiments with radiolabeled tryptophan that the barmans (found to be radiolabeled in the smoke) were generated pyrogenetically from a reaction between aldehydes (formaldehyde for norharman, acetaldehyde for barman) and the tryptophan in tobacco. 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

Reaction of the aldehyde, Na-methylvellosimine (168), with 37% aqueous formaldehyde (25 equiv.) and 2 N KOH (10 equiv.) in methanol at room temperature for 10 h afforded optimum yields of the desired diol 211. The two prochiral hydroxymethyl functions in 211 were differentiated by the DDQ-mediated oxidative cyclization of the hydroxyl group at the 3-axial position of C-17 with the benzylic position at C-6. This gave the desired cyclic ether 212. Oxidation of the hydroxymethyl functionality was achieved with (PhSe0)20 to provide the aldehyde, which was further oxidized with KOH/R/MeOH to the methyl ester 210. Consequently, the total synthesis of (-l-)-dehydrovoachalotine (210) was achieved in 28% overall yield from D-(- -)-tryptophan. 

The thermal Yonemitsu-type reaction of ethyl 2-nitroace-tate with variably substituted indoles and formaldehyde in toluene led to the formation of various tryptophan precursors in moderate to high yields [134]. Molecular sieves supported the Knoevenagel condensation step. A closely related catalyst-free version was published by Jerdme et al. in 2009 [43]. P-Ketoesters represent the CH-acidic component that undergoes a Yonemitsu-type reaction at slightly elevated temperatures to provide the desired products in moderate yields within 6-20 h. 

Besides the alkaloids that are restricted to phylogenetically related taxa, there are a number that are so widely and randomly distributed in the plant kingdom that it is impossible to use them for taxonomic purposes. It is notable that alkaloids of quite simple structure are the most randomly distributed. Some methylated derivatives of tyrosine and tryptophan, as well as condensation products of their compounds with simple aldehydes like formaldehyde and acetaldehyde, are encountered in small units distributed all over the plant families. Since the reactions are very simple and relatively inexpensive in energy requirements, it is not surprising that their products are so widespread. Some of these compounds are either very weak poisons or not toxic at all. 

The process of toxin inactivation by formaldehyde treatment is pooriy understood. However, it does involve the formation of a Schiff s base, either with lysine or arginine residues in the protein, foiiowed by cross-linking to residues such as tyrosine, lysine and tryptophan. The quality control for this reaction is bioassay of the resultant toxoid using an animal model but there is the possibility of using mass spectrometry to follow the modification (Fig. 27.21). ... 

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