Intermediates, Schiff-base

METHOD 2 [89]--1M MDA or benzedrine and 1M benzaldehyde is dissolved in 95% ethanol (Everclear), stirred, the solvent removed by distillation then the oil vacuum distilled to give 95% yellow oil which is a Schiff base intermediate. 1M of this intermediate, plus 1M iodomethane, is sealed in a pipe bomb that s dumped in boiling water for 5 hours giving an orangy-red heavy oil. The oil is taken up in methanol, 1/8 its volume of dH20 is added and the solution refluxed for 30 minutes. Next, an equal volume of water is added and the whole solution boiled openly until no more odor of benzaldehyde is detected (smells like almond extract). The solution is acidified with acetic acid, washed with ether (discard ether), the MDMA or meth freebase liberated with NaOH and extracted with ether to afford a yield of 90% for meth and 65% for MDMA. That s not a bad conversion but what s with having to use benzaldehyde (a List chemical) Strike wonders if another aldehyde can substitute. 

The Schiff base intermediate (57) permits the oxidative formation of an imino intermediate which can then be converted to the 6a-methoxy derivative (Scheme 45) (76MI51100). 

Two classes of aldolase enzymes are found in nature. Animal tissues produce a Class I aldolase, characterized by the formation of a covalent Schiff base intermediate between an active-site lysine and the carbonyl group of the substrate. Class I aldolases do not require a divalent metal ion (and thus are not inhibited by EDTA) but are inhibited by sodium borohydride, NaBH4, in the presence of substrate (see A Deeper Look, page 622). Class II aldolases are produced mainly in bacteria and fungi and are not inhibited by borohydride, but do contain an active-site metal (normally zinc, Zn ) and are inhibited by EDTA. Cyanobacteria and some other simple organisms possess both classes of aldolase. 

The Chemical Evidence for the Schiff Base Intermediate in Class I Aldolases... 

Definitive identification of lysine as the modified active-site residue has come from radioisotope-labeling studies. NaBH4 reduction of the aldolase Schiff base intermediate formed from C-labeled dihydroxyacetone-P yields an enzyme covalently labeled with C. Acid hydrolysis of the inactivated enzyme liberates a novel C-labeled amino acid, N -dihydroxypropyl-L-lysine. This is the product anticipated from reduction of the Schiff base formed between a lysine residue and the C-labeled dihydroxy-acetone-P. (The phosphate group is lost during acid hydrolysis of the inactivated enzyme.) The use of C labeling in a case such as this facilitates the separation and identification of the telltale amino acid. 

The transaldolase functions primarily to make a useful glycolytic substrate from the sedoheptulose-7-phosphate produced by the first transketolase reaction. This reaction (Figure 23.35) is quite similar to the aldolase reaction of glycolysis, involving formation of a Schiff base intermediate between the sedohep-tulose-7-phosphate and an active-site lysine residue (Figure 23.36). Elimination of the erythrose-4-phosphate product leaves an enamine of dihydroxyacetone, which remains stable at the active site (without imine hydrolysis) until the other substrate comes into position. Attack of the enamine carbanion at the carbonyl carbon of glyceraldehyde-3-phosphate is followed by hydrolysis of the Schiff base (imine) to yield the product fructose-6-phosphate. 

In 1983, Yamada et al. developed an efficient method for the racemization of amino acids using a catalytic amount of an aliphatic or an aromatic aldehyde [50]. This method has been used in the D KR of amino acids. Figure 4.25 shows the mechanism of the racemization of a carboxylic acid derivative catalyzed by pyridoxal. Racemization takes place through the formation of Schiff-base intermediates. 

Figure 4.25 Racemization of amino acids through formation of Schiff-base intermediate.

Figure 3.14 Carbonyl groups can react with amine nucleophiles to form reversible Schiff base intermediates. In the presence of a suitable reductant, such as sodium cyanoborohydride, the Schiff base is stabilized to a secondary amine bond.

Thus, glycoproteins such as HRP, GO, or most antibody molecules can be activated for conjugation by brief treatment with periodate. Crosslinking with an amine-containing protein takes place under alkaline pH conditions through the formation of Schiff base intermediates. These relatively labile intermediates can be stabilized by reduction to a secondary amine linkage with sodium cyanoborohydride (Figure 20.8). 

Reaction of isatin derivatives with 2,3-diaminoquinazoline in ethanolic KOH gave indolotriazinoquinazolinones 359 and triazinoquinazolinedi-ones 360, probably through a Schiff base intermediate. Such compounds showed a significant antibacterial activity [92IJC(B)105]. 

The Klotz group has also found rate enhancements of decarboxylation reactions with PEI derivatives. Catalysis of decarboxylation of j -keto acids by small amines goes via a Schiff base intermediate. Mine s group has shown that unmodified PEI catalyzes dedeuteration effectively and that the reactions involve Schiff base intermediates 34, and references therein). Dodecyl-PEI containing free amino groups and quaternized nitrogens, dodecyl-PEI-Q-NHj, was found to be an effective catalyst for the decomposition of oxaloacetate (reaction 12) (92). At pH 4.5 the polymer is 10 times as effective as ethylamine. was found to be 3.5 x 10 " M at pH 4.5. 

Transaldolase, which catalyzes reactions with d-erythrose 4-phosphate and D-fructose 6-phosphate as substrates. As in the case of fructose-1,6-bisphosphate aldolase, this enzyme uses a e-amino side-chain to form a Schiff base intermediate. In this case, however, the triose phosphate moiety is not released but is transferred to the other aldose (in this case, the aldotetrose). 

Lactobacillus delbrueckii. In 1953, Rodwell suggested that the histidine decarboxylase of Lactobacillus 30a was not dependent upon pyridoxal phosphate (11). Rodwell based his suggestion upon the fact that the organism lost its ability to decarboxylate ornithine but retained high histidine decarboxylase activity when grown in media deficient in pyridoxine. It was not until 1965 that E. E. Snell and coworkers (12) isolated the enzyme and showed that it was, indeed, free of pyridoxal phosphate. Further advances in characterization of the enzyme were made by Riley and Snell (13) and Recsei and Snell (14) who demonstrated the existence of a pyruvoyl residue and the participation of the pyruvoyl residue in histidine catalysis by forming a Schiff base intermediate in a manner similar to pyridoxal phosphate dependent enzymes. Recent studies by Hackert et al. (15) established the subunit structure of the enzyme which is similar to the subunit structure of a pyruvoyl decarboxylase of a Micrococcus species (16). 

Aldolases are part of a large group of enzymes called lyases and are present in all organisms. They usually catalyze the reversible stereo-specific aldol addition of a donor ketone to an acceptor aldehyde. Mechanistically, two classes of aldolases can be recognized [4] (i) type I aldolases form a Schiff-base intermediate between the donor substrate and a highly conserved lysine residue in the active site of the enzyme, and (ii) type II aldolases are dependent of a metal cation as cofactor, mainly Zn, which acts as a Lewis acid in the activation of the donor substrate (Scheme 4.1). 

One method for the preparation of isoxsuprine is given in Scheme 1 [5]. A mixture of l-(4-hydroxyphenyl)-l,2-propandione (1), l-methyl-2-phenoxyethylamine (2), and elemental Pt catalyst in ethanol was hydrogenated to give the Schiff base intermediate (3). This was further reduced to afford a racemic mixture of 1-(4-hydroxyphenyl)-2-(l-methyl-2-phenoxyethylamino)propanol (6), m.p. 102.5-103.5°C. Compound (6) could also be obtained using an alternate route, where 1-(4-hydroxy-phenyl)- 1 -hydroxy-2-propanone (4) is reacted with compound (2), to yield... 

Conversion of the amino group into a Schiff base intermediate offers yet another method for preparing thieno[2,3-41-pyrimidines. Sucl <2004JOC8366>. 

In collaboration with Gunter Schneider s group at the Karolinska Institute in Stockholm, the 3D structures of transaldolase and of several of its mutant derivatives have been solved. For the first time, a Schiff base intermediate of an aldolase was analyzed crystallographically. The structure of FSA was solved too, and it was found that the enzyme forms a decameric structure out of two pentamer rings. 

In enzymic decarboxylations the mechanistic pathway seems to involve Schiff base formation between an —NH2 from a lysine residue and a C=0 of the keto acid.52 Likewise, with small-molecule primary amines, catalysis of decarboxylation of /3-ketoacids53-58 has been ascribed to a Schiff base intermediate. The overall reaction for oxalacetate is... 

Enzyme-catalyzed racemization and racemization of Schiff base intermediates are also valuable techniques, but are generally restricted to amino acid racemiza-tions, which have been much more widely inveshgated than the topics discussed in this chapter [11, 12]. 

There are two classes of aldolases. Class I aldolases, found in animals and plants, use the mechanism shown in Figure 14-5. Class II enzymes, in fungi and bacteria, do not form the Schiff base intermediate. Instead, a zinc ion at the active site is coordinated with the carbonyl oxygen at C-2 the Zn2+ polarizes the carbonyl group... 

The second part of the reaction requires pyridoxal phosphate (Fig. 22-18). Indole formed in the first part is not released by the enzyme, but instead moves through a channel from the a-subunit active site to the jS-subunit active site, where it condenses with a Schiff base intermediate derived from serine and PLP. Intermediate channeling of this type may be a feature of the entire pathway from chorismate to tryptophan. Enzyme active sites catalyzing different steps (sometimes not sequential steps) of the pathway to tryptophan are found on single polypeptides in some species of fungi and bacte-... 

Treatment with sodium borohydride of the enzyme-substrate complex of aldolase A and dihydroxyacetone phosphate leads to formation of a covalent linkage between the protein and substrate. This and other evidence suggested a Schiff base intermediate (Eq. 13-36). When 14C-containing substrate was used, the borohydride reduction (Eq. 3-34) labeled a lysine side chain in the active site. The radioactive label was followed through the sequence determination and was found on Lys 229 in the chain of 363 amino acids.186/188 188b Tire enzyme is another (a / P)8-barrel protein and the side chain of Lys 229 projects into the interior of the barrel which opens at the C-terminal ends of the strands. The conjugate base form of another lysine,... 

---