Pyruvic aldehyde, hydroxy

To demonstrate the versatility of this process and to provide a relevant model study for the synthesis of 1, we investigated an extension to medium-sized heterocycles. Thus, the diastereomeric silyl ethers 8a-b were selected to test this application by generation of the corresponding 9-membered oxacyclic dienes (Scheme 3). The preparation of 8a-b began with the reduction of pyruvic aldehyde dimethoxy acetal with NaBH4 in MeOH/THF to afford hydroxy acetal 2 (84%). Alkylation of the sodium salt of 2 with propargylic bromide afforded 3 (85%). Conversion of 3 to 5 was achieved by alkyne iodination followed by a c/s-reduction of... 

Step 6 is the final step in the cellulose-to-lactic acid cascade, involving the isomerization of the 2-keto-hemi-acetal (here pyruvic aldehyde hydrate) into a 2-hydroxy-carboxyhc acid. This reaction is known to proceed in basic media following a Cannizzaro reaction with 1,2-hydride shift [111], Under mild conditions, Lewis acids are able to catalyze this vital step, which can also be seen as an Meerwein-Ponndorf-Verley reduction reaction mechanism. The 1,2-hydride shift has been demonstrated with deuterium labeled solvents [110, 112], Attack of the solvent molecule (water or alcohol) on pymvic aldehyde (step 5) and the hydride shift (step 6) might occur in a concerted mechanism, but the presence of the hemiacetal in ethanol has been demonstrated for pyruvic aldehyde with chromatography by Li et al. [113] andfor4-methoxyethylglyoxal with in situ CNMRby Dusselier et al. (see Sect. 7) [114]. 

Fructose, a /3-hydroxy ketone, is then cleaved into two three-carbon molecules—one ketone and one aldehyde—by a reverse aldol reaction. Still further carbonyl-group reactions then occur until pyruvate results. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

The second example was the pyruvate decarboxylase catalyzed formation of (ll )-l-hydroxy-l-phenyl-2-propanone (PAC) with benzaldehyde as substrate (Fig. 5 a) [64]. This second reaction shows one potential limitation of this method. Some compounds are too volatile for direct measurement by MALDl mass spectrometry or they do not ionize directly due to their nonpolar character. In this case, these compounds have to be derivatized prior to their measurement in order to reduce their volatihty and to introduce ionizable functions. This is, however, often very easy using well estabhshed quantitative reactions, e.g., formation of oximes from aldehydes and sugars (Fig. 5b). 

In addition, Cushman and co-workers121 reported the synthesis of a 1-hydroxyethylene dipeptide with a Pro moiety at the C-terminus using the reaction between an a-amino aldehyde and a lithium cyclopentanone enolate. Matternich and Liidi 22 described the synthesis of a y-(aminoalkyl)-a-hydroxy-y-lactone starting from the addition of an a-amino aldehyde to a pyruvate enolate. 

Biomimetic Synthesis of Solerone. We applied pyruvate decarboxylase [EC 4.1.1.1] (PDC) as key enzyme for the biomimetic synthesis elucidating the formation of solerone 1 figure 1). The thiamine diphosphate depending enzyme from Saccharomyces cerevisiae is responsible for the decarboxylation of pyruvate in the course of alcoholic fermentation. After loss of carbon dioxide from 2-oxoacids the resulting aldehyde is released. Alternatively, the cofactor-bound decarboxylation product can react with a further aldehyde. By the latter acyloin condensation a new carbon-carbon bond will be formed, thus opening a biosynthetic way to a-hydroxy carbonyl compounds 11J2). 

The transketolase (TK EC 2.2.1.1) catalyzes the reversible transfer of a hydroxy-acetyl fragment from a ketose to an aldehyde [42]. A notable feature for applications in asymmetric synthesis is that it only accepts the o-enantiomer of 2-hydroxyaldehydes with effective kinetic resolution [117, 118] and adds the nucleophile stereospecifically to the re-face of the acceptor. In effect, this allows to control the stereochemistry of two adjacent stereogenic centers in the generation of (3S,4R)-configurated ketoses by starting from racemic aldehydes thus this provides products stereochemically equivalent to those obtained by FruA catalysis. The natural donor component can be replaced by hydroxy-pyruvate from which the reactive intermediate is formed by a spontaneous decarboxylation, which for preparative purposes renders the overall addition to aldehydic substrates essentially irreversible [42]. 

The amino group of hydrazides react with aldehydes and ketones. For example, 2-hydrazinocarbonylpyrazine refluxed with acetone-ethanol gave 2-isopropylidene-hydrazinocarbonylpyrazine (51) [which was reduced in methanol over palladium-charcoal to 2-(2 -isopropylhydrazinocarbonyI)pyrazine] (1366,1428,1429). Other references to similar reactions include the following reactions 2-hydrazinocarbonylpyrazine with p-acetamidobenzaldehyde (138) 4-hydroxy-, 4-hydroxy-3-methoxy-and 2-carboxy-3,4-dimethoxybenzaldehydes (1319) furfural (1201) and pyruvic acid (1201) 2-amino-3-hydrazinocarbonylpyrazine with acetone and benzaldehyde (1214) and 2-hydrazinocarbonyl-5,6-dimethyl-3-methylaminopyrazine with acetone (428). 

As early as 1930 it was proposed fhat fhe production of 2-hydroxy ketones (here (P)-PAC) is a side reaction of pyruvate decarboxylase (PDC) [18, 19]. Later, it was shown unequivocally that fhiamine diphosphate (ThDP)-dependent PDC catalyzes both the decarboxylation of pyruvate and fhe carboligation of the intermediate activated aldehyde to benzaldehyde (Scheme 4.2 A). 

The action of transketolase generates vicinal diols having the same stereochemistry as the products of RAMA-catalyzed condensation. The enzyme, however, has two signiHcant advantages over RAMA the reaction docs not require DHAP, and the products arc not phosphorylated. The ketose functionality can be replaced by hydroxy pyruvate, which provides a hydroxyketo equivalent after decarboxylation. No other hydroxy acid has yet been found that is accepted by transketolase. Although the enzyme is absolute in its requirement for the R configuration of the hydroxy functionality at C2 of the aldehyde, there seem to be no other stereochemical requirements. Transketolase accepts a range of aldoses as substrates, and should be a useful enzyme for carbohydrate synthesis (Table 1) (37). 

Enzymes which degrade a-keto acids to COg and aldehydes contain thiamine pyrophosphate (D 10.4.5) as coenzyme. The keto acid is added in a reversible reaction to carbon atom 2 of the thiazole ring of thiamine pyrophosphate giving an oc-hydroxy acid derivative. This compound is decarboxylated and split to an aldehyde and thiamine pyrophosphate. Figure 25 shows this sequence of reactions for the enzyme pyruvate decarboxylase which splits pyruvate to acetaldehyde and COg. 

In the oxidative decarboxylation of pyruvate and oxoglutarate, as shown in Figure 3, TPP functions as a carrier of active aldehyde to form the intermediates, hydroxyethyl-TPP and a-hydroxy-P-carboxypropyl-TPP, which are finally transferred to coenzyme A (CoA) to form acetyl-CoA and succinyl-CoA, respectively. 

The acceptor aldehyde can be glycolaldehyde, 3-p-glyceraldehyde, 5-p-ribose, or 5-p-desoxyribose. There are really two quite separate processes which are catalyzed by Racker s yeast enzyme first, a non-oxidative decarboxylation of hydroxypyruvic acid to active glycolaldehyde and CO2 second, a transketolation of active glycolaldehyde from the enzyme to the acceptor aldehyde. One must conceive of the enzyme as the bearer of a keto group (ECO) which reacts with hydroxy-pyruvate to form an acyloin, with CO2 being liberated in the process ... 

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