Acetaldehyde aldol addition

Mixed aldol condensations can be effective only if we limit the number of reaction pos sibilities It would not be useful for example to treat a solution of acetaldehyde and propanal with base A mixture of four aldol addition products forms under these condi tions Two of the products are those of self addition... 

The -butyraldehyde may be obtained from acetaldehyde [75-07-0] by aldol addition followed by hydrogenation, or from propylene by the 0x0 process. This latter process is predominantly favored (Eig. 7). 

Pentaerythritol is produced by reaction of formaldehyde [50-00-0] and acetaldehyde [75-07-0] in the presence of a basic catalyst, generally an alkah or alkaline-earth hydroxide. Reaction proceeds by aldol addition to the carbon adjacent to the hydroxyl on the acetaldehyde. The pentaerythrose [3818-32-4] so produced is converted to pentaerythritol by a crossed Cannizzaro reaction using formaldehyde. All reaction steps are reversible except the last, which allows completion of the reaction and high yield industrial production. 

The name aldol was introduced by Wurt2 in 1872 to describe the product resulting from this acid-cataly2ed reaction of acetaldehyde. The addition will occur with base catalysis as well. 

In E. coli GTP cyclohydrolase catalyzes the conversion of GTP (33) into 7,8-dihydroneoptetin triphosphate (34) via a three-step sequence. Hydrolysis of the triphosphate group of (34) is achieved by a nonspecific pyrophosphatase to afford dihydroneopterin (35) (65). The free alcohol (36) is obtained by the removal of residual phosphate by an unknown phosphomonoesterase. The dihydroneoptetin undergoes a retro-aldol reaction with the elimination of a hydroxy acetaldehyde moiety. Addition of a pyrophosphate group affords hydroxymethyl-7,8-dihydroptetin pyrophosphate (37). Dihydropteroate synthase catalyzes the condensation of hydroxymethyl-7,8-dihydropteroate pyrophosphate with PABA to furnish 7,8-dihydropteroate (38). Finally, L-glutamic acid is condensed with 7,8-dihydropteroate in the presence of dihydrofolate synthetase. 

Manufacture. Cinnamaldehyde is routinely produced by the base-cataly2ed aldol addition of ben2aldehyde /7(9(9-with acetaldehyde [75-07-0], a procedure which was first estabUshed in the nineteenth century (31). Formation of the (H)-isomer is favored by the transition-state geometry associated with the elimination of water from the intermediate. The commercial process is carried out in the presence of a dilute sodium hydroxide solution (ca 0.5—2.0%) with at least two equivalents of ben2aldehyde and slow addition of the acetaldehyde over the reaction period (32). 

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

D. A. Evans, P. H. Carter, E M. Carreira, J. A. Pmnet, A. B. Charette, M. Lautens Asymmetric Synthesis of Bryosta-tin 2 , Angew. Chem, Int. Ed. Engl. 1998,37,2354-2359. For methodological studies on asymmetric Cu-catalyzed aldol addition, see D. A. Evans, J. Murry, M. C. Koz-lowski C2-Symmetric Cu(II) Complexes as Chiral Lewis Adds. Catalytic Enantiosdective Aldol Additions of Silylketene Acetals to (Benzyloxy)acetaldehyde , J. Am Chem. Soc 1996,118,5814-5815. 

Another promising route was reported in patent and open hterature by both DSM and Diversa [13, 14]. This route employs a 2-deoxy-D-ribose 5-phosphate aldolase (DERA) that catalyzes a tandem aldol addition in which two equivalents of acetaldehyde (AA) are added in sequence to chloroacetaldehyde (CIAA) to produce a lactol derivative that is similar to the 3,5-dihydoxy side chain of synthetic statins (Figure 6.2e). Diversa screened environmental libraries for novel wild-type DERAs and identified an enzyme that was both tolerant to increased substrate concentrations and more active than DERA from E. coli in the target reaction [13]. 

Stereochemically controlled synthesis of this subunit, which contains five stereogenic centers, is important to an efficient bleomycin synthesis. (2S,3S,4i )-4-(/er/-Butoxycarbonyl-amino)-3-hydroxy-2-methylpentanoic acid (15) was obtained via a stereoselective syn aldol addition of a boron Z-enolate with (27 )-2-(tert-butoxycarbonylamino)propanal (Scheme 4). Similarly, the L-threonine subunit 18 was prepared by diastereoselective syn aldol addition of an N- acy I ox azo I i di n one stannous Z-enolate with acetaldehyde. The bithiazole unit 19 was prepared using a direct DCC-promoted condensation of 3-(methylsulfanyl)propylamine. Convergent access to tetrapeptide S was obtained by coupling of acid 15 and deprotected 18 to give dipeptide 20, followed by further coupling with the bithiazole 19 to ultimately give tetrapeptide S (21). 

A wide range of natural and unnatural monosaccharides has been generated by exploiting the catalytic capacity of aldolases which perform reactions equivalent to nonenzymatic aldol additions [54]. More than 20 aldolases have been identified so far and can be divided into three main groups, accepting either dihydroxyace-tone phosphate (DHAP), acetaldehyde, or pyruvic acid, and phosphoenolpyruvate as nucleophilic methylene component. A common feature is their high stereocontrol in the formation of the new C-C bond. As presented in Scheme 10 all four possible vicinal diols are accessible by selection of the appropriate DHAP-aldo-lase [2, 55], all of which show a distinct preference for the two stereocenters and a broad substrate tolerance for the aldehyde component. 

Scheme 1-9. Ca-Symmetric copper (II) complex catalyzed enantioselective aldol addition of silyl ketene acetal to benzyloxy acetaldehyde.

Recently reported synthetic studies en route to the epothilones documents a series of fascinating observations by Danishefsky of a novel aldol addition reaction (Eq. (8.10)). The epothilone strategy necessitated an unusual aldol addition reaction of 38 and (5 )-2-methyl-4-pentenal. The addition reaction gave a stereochemical outcome unexpected on the basis of the accepted models for acyclic stereocontrol in carbonyl addition reactions. Thus, the addition affords adduct 39 and 40 as a 5.5 1 diastereomeric mixture with an unexpected preference for the anti-Cram adduct. By contrast, addition to (S)-phenyl acetaldehyde affords the Cram adduct as an 11 1 mixture of diastereomers. In a series of studies, Danishefsky has noted that the positioning of unsaturation in the substrate in relation to the aldehyde C=0 appears to be critical. 

Baeyer-Drewson indigo synthesis. Formation of indigos by an aldol addition of o-nitrobenzal-dehydes to acetone, pymvic acid, or acetaldehyde. Of interest mainly as a method of protecting o-nitro-benzaldehydes. 

The possible origin of this compound can be explained by the following pathway. An aldol addition of glycine on pyruvaldehyde accompanied by decarboxylation produces the amino alcohol which, after condensation with acetaldehyde, cyclization and oxidation forms the oxazole. 

Examples of metal hydride and organometallic additions include reactions of lithium hydride and sodium hydride with acetaldehyde and its homologs [145-147], reactions of methyllithium and methylcopper with acrolein [148], and aldol additions of lithium enolates [125]. The geometry of the four-center, cyclic transition states for such additions seems to depend on the size of the metal atom (see Schemes 6.16 and 6.17). 

An economically viable alternative to the synthesis of deoxyribonuclosides has been developed as a two stage process involving 2-deoxy-D-ribose 5-phosphate aldolase (DERA) (Fig. 6.5.14) (Tischer et al. 2001). The first step was the aldol addition of G3P to acetaldehyde catalyzed by DERA. G3P was generated in situ by a reverse action of EruA on L-fructose-1,6-diphosphate and triose phosphate isomerase which transformed the DHAP released into G3P. In a second stage, the action of pentose-phosphate mutase (PPM) and purine nucleoside phosphorylase (PNP), in the presence of adenine furnished the desired product. The released phosphate was consumed by sucrose phosphorylase (SP) that converts sucrose to fructose-1-phosphate, shifting the unfavorable equilibrium position of the later reaction. 

An aldol reaction begins with addition of an enolate or enol to the carbonyl group of an aldehyde or ketone, leading to a j8-hydroxy aldehyde or ketone as the initial product. A simple example is shown below, whereby two molecules of acetaldehyde (ethanal) react to form 3-hydroxybutanal. 3 Hydroxybutanal is an aldol because it contains both an aldehyde and an alcohol functional group. Reactions of this general type are known as aldol additions. 

Evans, D.A., Kozlowski, M.C., Murry, J.A., Burgey, C.S., Campos, K.R., Connell, B.T., and Staples, R.J. (1999) C-2-symmetric copper(ll) complexes as chiral Lewis acids. Scope and mechanism of catalytic enantioselective aldol additions of enolsilanes to (benzyloxy)acetaldehyde. /. Am. Chem. Soc.. 121, 669-685. 

Recall that LDA causes irreversible enolate formation. If acetaldehyde is added dropwise to a solution of LDA, the result is a solution of enolate ions. Propionaldehyde can then be added dropwise to the mixture, resulting in a crossed aldol addition that produces one major product. This type of process is called a directed aldol addition, and its success is hmited by the rate at which enolate ions can equilibrate. In other words, it is possible for an enolate ion to function as a base (rather than a nucleophile) and deprotonate a molecule of propionaldehyde. If this process occurs too rapidly, then a mixture of products will result. 

R)-lOa) and rac-N-Cbz-2-(piperidin-4-yl)acetaldehyde ((rac)-lOb) as aldehyde acceptors (Scheme 16.4), which can be accessed from the commercially available alcohol precursors. fucA wild type as weU as FucA ", FucA , and mutants provided very low yields, and thus were not satisfactory from a preparative point of view. RhuA gave the best results using DHAP as donor (Scheme 16.4). The aldol addition of DHAP to (S)-N-Cbz-piperidin-2-carbaldehyde (S)-10a furnished the sy (3 R,4S)-configured aldol adduct, which is consistent with the results obtained with (S)-N-Cbz-proUnal derivatives [19]. On the other hand, its enantiomer (R)-10a furnished the (5R)-lla adduct as 2 3 syn(3R,4S)/anti(3R,4R) mixture. This was not observed in the case of the (R)-N-Cbz-proHnal, which exclusively provided the syn... 

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