Aldol reactions with acetaldehyde

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Use of isocyanoacetamide 5 instead of isocyanoacetate 3 improves the enan-tioselectivity of the aldol reaction with acetaldehyde and primary alkyl aldehydes (R=Me 99% ee, trans cis=9H9, R=Et 96% ee, trans cis=95 5, R=z-Bu ... 

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

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. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

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. 

In contrast to transketolase and the DHAP-dependent aldolases, deoxyribose aldolase (DERA) catalyzes the aldol reaction with the simple aldehyde, acetaldehyde. In vivo it catalyzes the formation of 2-deoxyribose-5-phosphate, the building block of DNA, from acetaldehyde and D-glyceraldehyde-3-phosphate, but in vitro it can catalyze the aldol reaction of acetaldehyde with other non-phosphorylated aldehydes. The example shown in Scheme 6.28 involves a tandem aldol reaction... 

AW-Dimethyl-Ot-isocyanoacetamide 10 is the substrate of choice in the reaction with acetaldehyde (98.6% ee) or primary aldehydes such as propionaldehyde (96.3% ee) or isovaler-aldehyde (97.3% ee) (Scheme 8B1.5, Table 8B1.5) [19]. The oxazolinecarboxamides 11 thus prepared can be converted to P-hydroxy-a-amino acids by acidic hydrolysis. The aldol reaction... 

One obvious candidate for an electrophilic but non-enolisable compound is formaldehyde CH2=0 but it is simply too electrophilic to be well controlled. A trivial example is its reaction with acetaldehyde and hydroxide ion. The first aldol gives the expected product 43 but a second gives 44 and a third follows. Now hydroxide adds to another molecule of formaldehyde and delivers a hydride ion 45 in the Cannizzaro reaction (the other product is formate ion HCO2-) to give pentaerythritol 46, a useful compound in polymer chemistry for cross-linking but not much use to us. We need to moderate the unruly behaviour of this useful one-carbon electrophile. 

Glyoxal can be formed by oxidation of glycolaldehyde (e.g., in Scheme 2.5), but it can also be formed by autoxidation of unsaturated fats and by enzymic degradation of serine.60 2-Oxopropanal can be obtained by retroaldolisation of 1- and 3-deoxyglucosone or by hydrolysis of diacetylformoin (see Scheme 2.5). Butanedione can also be derived from diacetylformoin, but by reduction, dehydration, and hydrolysis (see Scheme 2.5). 2,3-Pentanedione can be formed from butanedione by aldol reaction with formaldehyde, dehydration, and reduction or by aldol condensation of hydroxyacetone and acetaldehyde, followed by dehydration. 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

The enzyme DERA, 2-deoxyribose-5-phosphate aldolase (EC 4.1.2.4), is unique among the aldolases in that the donor is an aldehyde. In vivo it catalyzes the reversible aldol reaction of acetaldehyde and D-glyceraldehyde 3-phosphate, forming 2-deoxyribose 5-phosphate, with an equilibrium lying in the synthetic direction (Scheme 5.41). DERA, the only well-characterized member of this type I aldolase, has been isolated from both animal tissue and microorganisms.67... 

To examine the syn/anti selectivity, Houk examined the aldol reaction of acetaldehyde and propanal with methanamine as catalyst. Reaction 6.19. The E or Z enamine can react to give syn or anti product. They located four TSs 52a-d, shown in Figure 6.22. Again, these TSs are in a half-chair conformation with internal proton transfer. The TSs involving the E isomer are lower than those with the Z isomer. The E isomer prefers to give the anti isomer (52a is 0.7 kcal mol" below 52b), while the Z isomer favors the syn product (52c is 1.4 kcal mol" below 52d) These results are consistent with experiments that show preference... 

FIGURE 2. AMI-calculated reaction path for the aldol reaction of acetaldehyde with propionalde-hyde, using complex 150b as a model for the intermediate boron enolate complex 150a. Reproduced from Y. Makino, K. Iseki, K. Fujii, S. Oishi, T. Hirano and Y. Kobayashi, Tetrahedron Lett., 36, 6527. Copyright 1995, courtesy of Elsevier... 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

This ester 131 forms the usual /( -enolate with LDA that can be trapped as the boron enolate 132. Reaction with acetaldehyde gives, as expected, an anti aldol (chapter 4). The major product is 133 in a 91 9 ratio with the other anti aldol. This diastereoisomer can be isolated in 75% yield. The absolute stereochemistry is decided by the chiral centre already in place in 132 - it remains as C-4 in 133. The next centre along (C-3) is controlled by C-4 and the relative stereochemistry of C-3 and C-4 is controlled by the geometry of the enolate. 

The reaction of ethanol with ammonia on zeolite catalysts leads to ethylamine. If, however, the reaction is carried out in the presence of oxygen, then pyridine is formed [53]. MFI type catalysts H-ZSM-5 and B-MFI are particularly suitable for this purpose. Thus, a mixture of ethanol, NH3, H2O and O2 (molar ratio 3 1 6 9) reacts on B-MFI at 330 °C and WHSV 0.17 h 1 to yield pyridine with 48 % selectivity at 24 % conversion. At 360 °C the conversion is 81% but there is increased ethylene formation at the expense of pyridine. Further by-products include diethyl ether, acetaldehyde, ethylamine, picolines, acetonitrile and CO2. When applying H-mordenite, HY or silica-alumina under similar conditions pyridine yields are very low and ethylene is the main product. The one-dimensional zeolite H-Nu-10 (TON) turned out to be another pyridine-forming catalyst 54]. A mechanism starting with partial oxidation of ethanol to acetaldehyde followed by aldolization, reaction with ammonia, cyclization and aromatization can be envisaged. An intriguing question is why pyridine is the main product and not methylpyridines (picolines). It has been suggested in this connection that zeolite radical sites induced Ci-species formation. 

It is the only known member of the group of acetaldehyde-dependent aldolases. In vivo, DERA catalyzes the reversible aldol reaction of acetaldehyde and G3P. The donor substrate specificity of this enzyme is not as strict as with the other aldolases. 

The reaction occurs with ketones as well. Acetone is a good example for us to use at the start of this chapter because it gives an important product, and as it is a symmetrical ketone, there can be no argument over which way it enolizes. Each step is the same as the aldol sequence with acetaldehyde, and the product is again a hydroxy-carbonyl compound, but this time a hydroxy-ketone. 

Barbas and coworkers disclosed the first example of diastereo- and enantioselctive aldol reactions of fluoroacetone with aromatic and aliphatic aldehydes catalysed by simple prolinol Ic. Notable advances in substrate scope and convenient procedures for the aldol reaction have been illustrated by Hayashi and coworkers, who demonstrated the ability of diatyl prolinols to catalyse the highly challenging self-aldol and cross-aldol reactions of acetaldehyde (Scheme 7.19). ... 

The first cross-aldol reaction of acetaldehyde with non-enolizable aldehydes was reported by Hayashi et al. [118]. The diarylprohnol-catalyzed reaction gave excellent results for aromatic aldehydes, e.g. high yields and enantioselectivities. 

Aldehyde donors were also employed successfully in the syntheses of convolutamydines E (77) and B (78) (80-82). The strategy was the same as depicted for the synthesis of (/ )- and (5)-convolutamydine A (32) (Scheme 9), but using acetaldehyde (79) instead of acetone (13) as the nucleophile in the cross-aldol reaction with dibromo-isatm 33 (Scheme 19). Nakamura et al. utilized catalyst 37, followed by a NaBH3CN-mediated reduction to obtain (/ )-convolutamydine E (77) in excellent yield and enantioselectivity. Chlorination of 77 then gave (l )-convolutamydine B (78) (Scheme 19) (80, 81). 

An elegant method for sequential aldol reactions performed in a one-pot reaction has been discovered for 2-deoxyribose-5-phosphate aldolase (Scheme 2.195) [1439]. When a (substituted) aldehyde was used as acceptor, condensation of acetaldehyde (as donor) led to the corresponding 3-hydroxy aldehyde as intermediate product. The latter, however, can undergo a second aldol reaction with another acetaldehyde donor, forming a P,8-dihydroxy aldehyde. At this stage, this aldol... 

The solution produced from the reaction of enones and dimethylcuprate undergoes aldol condensation with acetaldehyde in the presence of zinc chloride producing the )8-methyl a-(l-hydroxyethyl) ketones in acceptable yields (Heng and Smith, 1975). 

A more unusual sequence to the diene 93 starts with the cross-aldol reaction of acetaldehyde and isobytyraldehyde which leads to a highly versatile unsaturated alcohol 103 suitable for radical additions of carbon tetrachloride. The resulting product 104 is labile to bases and suffers a Grob -fragmentation of a carbon-carbon bond, splitting off formaldehyde [167] (Reaction scheme 62). 

Class I aldolase-like catalysis of the intermolecular aldol reaction with amines and amino acids in aqueous solution has been studied sporadically throughout the last century. Fischer and Marschall showed in 1931 that alanine and a few primary and secondary amines in neutral, buffered aqueous solutions catalyze the self-aldolization of acetaldehyde to give aldol (11) and crotonaldehyde (12) (Scheme 4.3, Eq. (1)) [41]. In 1941 Langenbeck et al. found that secondary amino acids such as sarcosine also catalyze this reaction [42]. Independently, Westheimer et al. and other groups showed that amines, amino acids, and certain diamines catalyze the retro-aldolization of diacetone alcohol (13) and other aldols (Scheme 4.3, Eq. (2)) [43-47]. More recently Reymond et al. [48] studied the aqueous amine catalysis of cross-aldolizations of acetone with aliphatic aldehydes furnishing aldols 16 (Scheme 4.3, Eq. (3)) and obtained direct kinetic evidence for the involvement of enamine intermediates. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

The utility of aqueous [ C2]acetaldehyde is illustrated by its Homer-Wadsworth-Emmons olefmation with diethyl (cyanomethyl)phosphonate under phase transfer conditions to give [3,4- C2]crotonitrile (16) in 83% radiochemical yield. Subsequent Michael addition of a-aminonitrile 17 produced the masked y-ketoacid derivative IS (Figure 8.6), which served as a key intermediate in the synthesis of [ " C2]C1930 (19). For the TiCLi-promoted aldol reaction with the propiophenone derivative 20, however, the use of anhydrous [ 2] acetaldehyde was essential. The reaction proceeded with excellent stereoselectivity, providing exclusively the racemic syn-diastereomers 21. Subsequent... 

Chen, W.-B., Du, X.-L., Cun, L.-F., Zhang, X.-M., and Yuan, W.-C. (2010) Highly enantioselective aldol reaction of acetaldehyde and isatins only with 4-hydroxydiarylprolinol as catalyst concise stereoselective synthesis of (R)-convolutamydines B and E, (-)-donaxridine and (R)-chimonamidine. Tetrahedron, 66, 1441-1446. 

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