Racemic 2-hydroxyaldehydes

The high stereoselectivity of the transketolase reaction also enables the resolution of racemic a-hydroxyaldehydes23,26. Treatment of racemic 2-hydroxyaldehydes and hydroxypyruvic acid with transketolase, gave the corresponding L-2-hydroxyaldehydes that are not substrates for the enzyme and, therefore, remained unreacted. The corresponding D-enantiomers were consumed and gave the condensation products. 

The Zn +-dependent aldolases facilitate effective kinetic resolution of racemic 2-hydroxyaldehydes (rac-50) as substrates by an overwhelming preference (d.e. >95) for the L-configured enantiomers l-50 this enables control... 

In addition, antipodes of racemic 2-hydroxyaldehydes 50 tvith a (2R)-hydroxyl group are discriminated tvith complete enantioselectivity this enables efficient kinetic resolution (Figure 5.53) [260, 261]. Vicinal diols of (3S,4R) configuration are thereby generated tvith high stereocontrol. This... 

Figure 10.26 Short enzymatic synthesis of L-fucose and hydrophobic analogs, and of L-rhamnose, by aldolization-ketol isomerization, including kinetic resolution of racemic hydroxyaldehyde precursors.

Racemic pantolactone is prepared easily by reacting isobutyraldehyde (15) with formaldehyde ia the presence of a base to yield the iatermediate hydroxyaldehyde (16). Hydrogen cyanide addition affords the hydroxy cyanohydria (17). Acid-cataly2ed hydrolysis and cyclization of the cyanohydria (17) gives (R,3)-pantolactone (18) ia 90% yield (18). 

The (racemic) tmns disulfoxide of 1,3-dithiolane 59 is readily deprotonated at C2 by lithium hexamethyldisilazide, and the resulting anion reacts with aldehydes at -78°C with moderate to excellent diastereoselectivity to give mainly the products 60, although subsequent cleavage of these to give the a-hydroxyaldehydes was not described (97JOC1139). 

Figure 10.17 Kinetic enantiopreference of class II DHAP aldolases useful for racemic resolution of a-hydroxyaldehydes.

Enzymatic reduction of carbonyl compounds and enzymatic enantioselective transformation of racemic or meso alcohols (25,43.) are two methodologies that have proven to be beneficial in the preparation of optically active hydroxyl compounds, key chiral building blocks used in carbohydrate and natural product syntheses (44-45. Our interest in this area is to develop enzymatic routes to optically active glycerol and furan derivatives, and hydroxyaldehydes. 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

The rabbit FruA discriminates the enantiomers of its natural substrate with a 20 1 preference for D-GA3P (12) over its L-antipode [202], Assistance from anionic binding was revealed by a study on a homologous series of carboxylated 2-hydroxyaldehydes which showed optimum enantioselectivity when the distance of the charged group equaled that of 12 (Scheme 15, Fig. 11) [299], The resolution of racemic substrates is not, however, generally useful since the kinetic enantioselectivity for nonionic aldehydes is rather low [202], 3-Azido substituents (69) can lead to an up to 9-fold preference of enantiomers in kinetically controlled experiments [300] while hydroxyl (70 preference for the... 

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]. 

Interestingly, transketolase recognizes chirality in the aldehydic acceptor moiety to a greater extent than the aldolases. Thus, when (stereochemically stable) racemic a-hydroxyaldehydes are employed as acceptors, an efficient kinetic resolutiOTi of the a-center is achieved (Scheme 2.202). Only the (a/ )-enantiomer is transformed into the corresponding keto-triol leaving the (o5)-counterpart behind [1510]. In a related manner, when ( )-3-azido-2-hydroxypropionaldehyde was chosen as... 

Aldol Reaction (Section 19.2) The aldol reaction involves nucleophilic addition of the enolate anion of one aldehyde or ketone to the carbonyl group of another aldehyde or ketone. The product of an aldol reaction is a j8-hydroxyaldehyde or a /3-hydroxyketone. An aldol reaction can be base catalyzed or acid catalyzed. If base is regenerated at the end of the reaction, it is base catalyzed, and if acid is regenerated, it is acid catalyzed. In both reactions, one or two new chiral centers are often created, leading to racemic products unless a starting aldehyde, ketone, or catalyst is chiral and present as a single enantiomer. 

Transketolase has been used for the key steps in chemoenzymatic syntheses of (+)-exo-brevicomin 111 from racemic 2-hydroxybutyraldehyde [236], and of the azasugars l,4-dideoxy-l,4-imino-D-arabinitol [196] or N-hydroxypyrrolidine 124 [265] from 3-azido (95) and 3-O-benzyl (122) derivatives, respectively, of glyceraldehyde (Figure 5.55). Such syntheses were all conducted with intrinsic racemate resolution of 2-hydroxyaldehydes and profited from utilization of 119. Further preparative applications include the synthesis of valuable ketose sugars, particularly fructose analogs [258]. Transketolase has also been used for in-situ generation of erythrose 4-phosphate from fructose 6-phosphate in a multi-enzymatic synthesis of DAHP (26 Figure 5.17) [131]. 

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