Dihydroxyacetone amination

These observations are explained by the mechanism shown in the figure. NaBH4 inactivates Class I aldolases by transfer of a hydride ion (H ) to the imine carbon atom of the enzyme-substrate adduct. The resulting secondary amine is stable to hydrolysis, and the active-site lysine is thus permanently modified and inactivated. NaBH4 inactivates Class I aldolases in the presence of either dihydroxyacetone-P or fructose-1,6-bisP, but inhibition doesn t occur in the presence of glyceraldehyde-3-P. 

Preparation of the key tropine is achieved by any one of several variations on the method first developed by Robinson, which involves reaction of a primary amine with dihydroxyacetone and glyoxal. Reduction of the carbonyl group in the product (86) followed by acylation affords the aminoester (88). Transesterification with ester aldehyde 89... 

Several other non-nitrogenous products have been identified as products of the Maillard reaction. These include butanol, butanone, butane-dione, and pentane-2,3-dione as well as dihydroxyacetone, glycer-aldehyde, and D-erythrose. Obviously, the same products are present after mild acidic or basic degradation of carbohydrates. Thus, the necessity of an amine or amino acid in the mechanism of their formation is uncertain. 

Dihydroxyacetone forms dimeric ketosylamines when it reacts with primary amines at low temperatures. However, the reaction of dihydroxyacetone with amino acids apparently generates pyruvaldehyde (23) as an intermediate for several products, including allomaltol (5-hydroxy-2-methyl-4-pyranone). In contrast to other amino acids, glycine reacts with dihydroxyacetone to yield a preponderance of butanedione. 

Enzymes are very sophisticated systems that apply sound chemical principles. The side-chains of various amino acids are used to supply the necessary bases and acids to help catalyse the reaction (see Section 13.4). Thus, the enzyme aldolase binds the dihydroxyacetone phosphate substrate by reacting the ketone group with an amine, part of a lysine amino acid residue. This forms an imine that becomes protonated under normal physiological conditions. 

Aldolases such as fructose-1,6-bisphosphate aldolase (FBP-aldolase), a crucial enzyme in glycolysis, catalyze the formation of carbon-carbon bonds, a critical process for the synthesis of complex biological molecules. FBP-aldolase catalyzes the reversible condensation of dihydroxyacetone phosphate (DHAP) and glyceralde-hyde-3-phosphate (G3P) to form fructose-1,6-bisphosphate. There are two classes of aldolases the first, such as the mammalian FBP-aldolase, uses an active-site lysine to form a Schiff base, whereas the second class features an active-site zinc ion to perform the same reaction. Acetoacetate decarboxylase, an example of the second class, catalyzes the decarboxylation of /3-keto acids. A lysine residue is required for good activity of the enzyme the -amine of lysine activates the substrate carbonyl group by forming a Schiff base. 

Fig. 10.1 Cellular formation and metabolism of methylglyoxal (MG). AGEs advanced glycoxida-tion endproducts DHAP dihydroxyacetone phosphate G3P glyceraldehyde 3-phosphate F-6P fructose 6-phosphate F-1,6P2 fmctose 1,6-bisphosphate Gly-I II glyoxalase I II SSAO semicarbazide-sensitive amine oxidase AMO amine oxidase.

Intermolecular Nucleophilic Substitution with Heteroatom Nucleophiles. A patent issued in 1965 claims substitution for fluoride on fluorobenzene-Cr(CO)3 in dimethyl sulfoxide (DMSO) by a long list of nucleophiles including alkoxides (from simple alcohols, cholesterol, ethylene glycol, pinacol, and dihydroxyacetone), carboxylates, amines, and carbanions (from triphenyhnethane, indene, cyclohexanone, acetone, cyclopentadiene, phenylacetylene, acetic acid, and propiolic acid). In the reaction of methoxide with halobenzene-Cr(CO)3, the fluorobenzene complex is ca. 2000 times more reactive than the chlorobenzene complex. The difference is taken as evidence for a rate-limiting attack on the arene ligand followed by fast loss of halide the concentration of the cyclohexadienyl anion complex does not build up. In the reaction of fluorobenzene-Cr(CO)3 with amine nucleophiles, the coordinated aniline product appears rapidly at 25 °C, and a carefiil mechanistic study suggests that the loss of halide is now rate limiting. 

Two potent glycosidase inhibitors, (—)-l-deoxymannonojirimycin (—)-7 and (+)-l-deoxynojiri-mycin (+)-8, are readily obtained in three steps utilizing RAMA as a catalyst in the key C-C bond forming step [22,30]. From racemic 3-azido-2-hydroxypropanal and dihydroxyacetone monophosphate (DHAP), diastereomeric 6-azidoketones are formed. Following the acid phosphatase-catalyzed removal of phosphate and subsequent reductive amination (Scheme 13.15), the products are isolated in a 4 1 ratio favoring the manno derivative. A similar result is obtained with... 

Valiolamine (89), an aminocyclitol produced by Streptomyces hygroscopicus var. limoneus, is a potent inhibitor of pig intestinal maltase and sucrase, with IC50 values of 2.2 and 0.049 pM, respectively [107]. Numerous iV-substituted valiolamine derivatives were synthesized to enhance its a-glucosidase inhibitory activity in vitro and the very simple derivative voglibose (90), which is obtained by reductive amination of valiolamine with dihydroxyacetone, was selected as the potential oral antidiabetic agent [108]. Its IC50 values toward maltase and sucrase were 0.015 and 0.0046 pM, respectively. Voglibose (the brand name Basen) has been commercially available for the treatment of type 2 diabetes in Japan since 1994. 

Again in the first step of the reaction between 1,3-dihydroxyacetone monophosphate (5.41) and glyceraldehyde-3-phosphate catalysed by aldolase to form fructose-1,6-diphosphate or the reverse reaction, a ketimine (5.42) is formed between the substrate and the e-amino group of a Lys residue in the enzyme. The formation of this intermediate (5.42) can be demonstrated similarly by trapping it as a secondary amine using NaBH4 to reduce the ketimine. The glyceraldehyde-3-... 

Reaction of dihydroxyacetone with ammonia and hydrogen is a good illustration of the different reactivities of hydroxyl and carbonyl groups during amination over metal catalysts. When the reaction is performed at a relatively mild temperature (< 100 °C, 100 bar) in liquid ammonia, Raney Ni affords 2-amino-1,3-propanediol in 99 % yield [28]. Under these conditions activation of hydroxyl groups is negligible. Similarly, the carbonyl group of an aldose or ketose reacts with ammo-... 

Patents have been issued on the oxidation of glycerol and derivatives. A 54 % yield of sodium glycerate was claimed for oxidation of glycerol over Pd/C at pH 8-13 [94]. Amination of glyceric acid with NH3 solution yielded 38% serine [95]. This amino acid was also obtained by oxidation of serinol [96], prepared by reductive amination of dihydroxyacetone [97]. 

In 2008, Barbas et al. reported the first primary amine-containing amino acid-catalysed indirect a n -Mannich reactions of dihydroxyacetone and acyclic protected dihydroxyacetone derivatives with a variety of imines derived from both aliphatic and aromatic aldehydes.In spite of moderate diastereoselec-tivities, good to high yields and enantioselectivities were obtained by using an L-threonine derivative as the organocatalyst in A -methylpyrrolidinone as the solvent and 5-methyl-l-7/-tetrazole as an additive, as shown in Scheme 3.14. 

The reaction of dihydroxyacetone phosphate (DHAP) with racemic or (R)-3-azido-2-hydroxypropanol under the influence of rhamnulose-1-phosphate aldolase or fuculose-1-phosphate aldolase afforded azidoketose intermediates which were converted by way of palladium-mediated reductive amination into a number of novel compounds including 1,6-dideoxy-D-galactojirimycin (24), 1,6-dideoxy-L-altojirimycin (25), 1-deoxy-D-talojirimycin (26), 1-deoxy-L-mannojirimycin (27) and 1-deoxy-L-rhamnojirimycin (28). ... 

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