Dihydroxyacetone dimer

Scheme 4.4 Chemical routes to DHAP. (a) Routes from dihydroxyacetone dimer. The stable precursors are converted to DHAP by acid hydrolysis, (b) Route from 1,3-dibromoacetone. The stable precursor is converted to DHAP by treatment with NaOH.

A different, pivaloylglycol-based photolabile hnker 1.26 (83) was prepared with a complex, eight-step procedure from dihydroxyacetone dimer and aminomethyl Ten-tagel resin the linker was used to support and to further elaborate carboxylic acids. The photolytic release at 320 nm of elaborated acids compared favorably with more assessed o-nitrobenzyl linkers. 

Dihydroxyacetone dimer is readily converted to dihydroxyacetone phosphate, which participates in several metabolic pathways. 

Synthesis of DHAP. Both RAMA and Fuc-l-P aldolase require DHAP as the nucleophilic component. Although DHAP is commercially available, it is too expensive for synthetic use, and must be synthesized for preparative-scale enzymatic reactions. DHAP has been prepared via three major routes enzymatically from FDP using a combination of RAMA and triose isomerase (TIM, E.C. 5.3.1.1) (25), chemically, by phosphorylation of dihydroxyacetone dimer (26), and enzymatically by phosphorylation of dihydroxy acetone catalyzed by glycerokinase (Scheme 8) (25). 

Related to this topic, our group has also developed an interesting cascade process for the enantioselective synthesis of furofuranes in a single step by the 31a-catalyzed reaction between dihydroxyacetone dimer and a,p-unsaturated... 

Glycolaldehyde-Dihydroxyacetone Glycolaldehyde-Glyceraldehyde Glyceraldehyde Glyceraldehyde dimer Dihydroxyacetone Dihydroxyacetone dimer Glycerol... 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

An interesting sequential [3-1-2] reaction between a dihydroxyacetone dimer and oc,P-unsaturated aldehydes, which leads to the enantioselective formation of hexahydrofuro[3,4-c]furanes 150 in excellent yields and diastereo- and enantioselectivities, was also illustrated through an oxo-Michael/aldol/hemiacetahzation sequence (Scheme 1.57) [94],... 

At this time we do not have a firm nnderstanding of how CrCl2 and VCI3 catalyze the double bond isomerization and why other metal chlorides are less effective. We propose that CrCh" or VCh" anion plays a role in hydride transfer, facilitating donble bond isomerization. CnCh is less effective and both lactic acid and pyruvaldehyde are formed. FeCh" and MnCh" anions are ineffective in the transformation and only pyruvaldehyde is formed. The fact that only a small amount of 1,3-dihydroxyacetone is formed is consistent with the NMR observation that the compounds exist as hemiacetal dimers in ionic hquids and not as monomers. Otherwise 1,3-dihydroxyacetone would be expected as a major product (16). 

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. 

Scheme 8. Selective chemical phosphorylation of dimeric dihydroxyacetone...

DHAP has also been prepared by phosphorylation of dihydroxyacetone with glycerol kinase in the presence of ATP, with in situ regeneration of ATP, giving yields in excess of 80%. The use of chemical methods260 c for the preparation of DHAP generates a pure product, which results in a cleaner aldol reaction. In an improved and commonly used chemical preparation, the protected dimer of dihydroxyacetone was phosphorylated with diphenyl chlorophosphate, followed by hydrogenolysis and hydrolysis, to give clean DHAP in 61% yield (Scheme 5.8).28... 

Evidence has been accumulated that shows that transaldolase is a half the sites enzyme, in which binding of substrate to one site almost completely inactivates the other active site. As mentioned above, only 1 mole of substrate is bound to the active site, even though the enzyme is a dimer. In the presence of excess F-6-P a burst of one equivalent of G-3-P is produced followed by a slower conversion of F-6-P to G-3-P plus DHA. It appears therefore, that the blocking of one active site by adduct formation with dihydroxyacetone results in a modified second active site which is able to slowly cleave F-6-P [76], This second site behavior is identical to that found in transaldolase in which one active site has been modified by reducing the dihydroxyacetone adduct with borohydride. Photo-oxidation of one of the two histidine residues in isoenzyme III results in the loss of activity of the enzyme, as is consistent with half-sites reaction [77]. The dye l-anilino-8-naphthalene sulfonate on the other hand is bound with 2 moles of dye per mole of enzyme, indicating two binding sites for F-6-P [78]. 

The accumulated evidence, therefore, suggests that transaldolase is a dimer which is capable of binding 1 mole of dihydroxyacetone obtained from a variety of donors at one of its two active sites. This binding event converts the second active site into one which is incapable of transaldolase activity but does have an aldolase-like activity with a for F-6-P which is essentially not altered, but which has a substantially reduced rate of cleavage. Unlike the first active site this second active site allows protonation of the enamine to complete the aldol-like reaction and does not exhibit reduction with borohydride. The major reaction at the first active site is completed by binding of any of a variety of acceptor aldehydes to create a new C-3-C-4 bond. 

R. P. Bell and E. C. Baughan [J. Chem. Soc., 1937, (1947)] investigated the generalized acid-base catalysis of the depolymerization of dimeric dihydroxyacetone. In terms of the general formulation of the first-order rate constant... 

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