Acceptors aldehyde formation

The overall mechanistic picture is, however, more complex than the cycle shown in Scheme 1.1, as shown by the elegant work by Armstrong, Blackmond and co-workers.They demonstrated that the presence of water in trace amounts is necessary, mainly to inhibit the off-cycle formation of oxazolidi-nones 2 that originate from iminium ions 1 formed by a side reaction of proline with the acceptor aldehyde. Formation of 2 has the consequence of reducing the available amount of proline. Thus, though water has a negative effect on the formation of the enamine, too, its presence ensures an increase in the extant catalyst loading and, consequently, yields increase as well. 

The structure of the complex of (S)-tryptophan-derived oxazaborolidine 4 and methacrolein has been investigated in detail by use of H, B and NMR [6b. The proximity of the coordinated aldehyde and indole subunit in the complex is suggested by the appearance of a bright orange color at 210 K, caused by formation of a charge-transfer complex between the 7t-donor indole ring and the acceptor aldehyde. The intermediate is thought to be as shown in Fig. 1.2, in which the s-cis conformer is the reactive one. 

The benzoin reaction typically consists of the homocoupling of two aldehydes, which results in the formation of inherently dimeric compounds, therefore limiting the synthetic utility. The aoss-benzoin reaction has the potential to produce four products, two homocoupled adducts and two cross-benzoin products. Several strategies have been employed to develop a selective cross-benzoin reaction, including the use of donor-acceptor aldehydes, acyl silanes, acyl imines, as well as intramolecular reactions. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

A particularly successful synthesis of Epothilone A is based on two DERA-cata-lyzed steps. In these two of the seven stereocentres of Epothilone A were established. When a racemic aldehyde was released in situ from its acetal, DERA converted only the R-enantiomer into the stable cyclic hemiacetal. This is a combined kinetic resolution and carbon-carbon bond formation yielding a building block with two chiral centers. Since the alcohol function was oxidized, the optical information obtained from the kinetic resolution was lost. Thus, for the overall yield it would have been better if DERA had displayed no stereoselectivity towards the acceptor (Scheme 5.32). In the DERA-catalyzed synthesis of another part of Epothilone A DERA is again highly stereoselective. Fortunately its preference is for the S-enan-tiomer of the acceptor aldehyde, the enantiomer that has to be submitted to the carbon-carbon bond formation in order to obtain the desired building block, again a stable hemiacetal (Scheme 5.32). Indeed, both DERA-catalyzed reactions yield open chain products that form stable cyclic hemiacetals. This ensures that the equilibria of these aldol reactions are shifted towards the desired products. Further synthetic manipulations converted these intermediates into Epothilone A [55]. 

Aldehydes also arise as normal by-products of yeast fermentation. Acetaldehyde is the ultimate electron acceptor in the conversion of glucose to ethanol. In this pathway, aldehyde dehydrogenase (ADH) reduces acetaldehyde to ethanol with the corresponding oxidation of NADH. Acetaldehyde levels are therefore dependent on the fermentation conditions, e.g., temperature, O2 levels, pH, SOj levels, and yeast nutrient availability (13, 14). Yeast strain can also affect aldehyde formation and excretion (15-17). For example, film yeasts used in sherry production are selected for their ability to produce very high acetaldehyde levels (18). 

The transketolase enzyme of Racker el obtained in crystalline form from baker s yeast, catalyzes the cleavage of ribulose-5-phosphate, with the formation of D-glyceraldehyde-3-phosphate upon the addition of an acceptor aldehyde, such as ribose-5-phosphate or glycolaldehyde. The reaction of hydroxypyruvate with D-glyceraldehyde-3-phosphate as acceptor aldehyde leads to the decarboxylation of the hydroxypyruvate with the formation of ribulose-5-phosphate. The transketolase enzyme was demonstrated to have a requirement for thiamine pyrophosphate. ... 

From a stereochemical point of view, the approach of the aldol acceptor to the enzyme-nucleophile complex is stereospecific, following an overall retention mechanism. On the other hand, the facial differentiation of the acceptor aldehyde carbonyl is usually high but, in some instances, depends on the substrate structure, and the stereochemical outcome does not always follow that of the natural acceptor. Although enzymatic aldol addition is a reversible reaction, for most applications, the C—C bond formation is favored for thermodynamic reasons because the primary aldol adducts can often form more stable cyclic ketal... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

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. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Typically, lyases are quite specific for the nucleophilic donor component owing to mechanistic requirements. Usually, approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospedfically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzymes, in general irrespective of the constitution or configuration of the substrate, which renders the enzymes highly predictable. On the other hand, most of the lyases allow a reasonably broad variation of the electrophilic acceptor component that is usually an aldehyde. This feature... 

Sulfate reducers can use a wide range of terminal electron acceptors, and sulfate can be replaced by nitrate as a respiratory substrate. Molybdenum-containing enzymes have been discovered in SRB (also see later discussion) and, in particular, D. desulfuricans, grown in the presence of nitrate, generates a complex enzymatic system containing the following molybdenum enzymes (a) aldehyde oxidoreduc-tase (AOR), which reduces adehydes to carboxylic acids (b) formate dehydrogenase (FDH), which oxidizes formate to CO2 and (c) nitrate reductase (the first isolated from a SRB), which completes the enzy-... 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

D-erythro-Pentulose 5-phosphate (XLIV) has been formed by the action of transketolase on hydroxypyruvate (XLII) and D-glycerose 3-phosphate, the hydroxypyruvate being decarboxylated196 to active glycolaldehyde which then reacts with the triose phosphate by an acyloin reaction.28 The active glycolaldehyde is also formed from L-glycero-tetrulose, d-altro-heptulose 7-phosphate, D-fructose 6-phosphate, and D-i/ireo-pentulose 5-phosphate and it reacts with various aldehydes (acceptors) to give ketoses.198, 200 Thus, substitution of L-gfh/cero-tetrulose for hydroxypyruvate in the above experiment also resulted in formation of D-en/i/iro-pentulose... 

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