Acetaldehyde aldol reaction

The simplest possible aldehyde donor, acetaldehyde, can also be used as the donor Very recently, Hayashi and coworkers discovered how to use acetaldehyde in crossed-aldol reactions - the trick is to use diarylprohnol as the catalyst and to optimize the reaction conditions carefully to prevent oligomerization of acetaldehyde. However, so far the acetaldehyde aldol reactions appear to be limited to aromatic aldehyde acceptors [205],... 

Aldehydes fiad the most widespread use as chemical iatermediates. The production of acetaldehyde, propionaldehyde, and butyraldehyde as precursors of the corresponding alcohols and acids are examples. The aldehydes of low molecular weight are also condensed in an aldol reaction to form derivatives which are important intermediates for the plasticizer industry (see Plasticizers). As mentioned earlier, 2-ethylhexanol, produced from butyraldehyde, is used in the manufacture of di(2-ethylhexyl) phthalate [117-87-7]. Aldehydes are also used as intermediates for the manufacture of solvents (alcohols and ethers), resins, and dyes. Isobutyraldehyde is used as an intermediate for production of primary solvents and mbber antioxidants (see Antioxidaisits). Fatty aldehydes Cg—used in nearly all perfume types and aromas (see Perfumes). Polymers and copolymers of aldehydes exist and are of commercial significance. 

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. 

Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction. For example, treatment of acetaldehyde with a base such as sodium ethoxide or sodium hydroxide in a protic solvent leads to rapid and reversible formation of 3-hydroxybutanal, known commonly as aldol (aidehyde + alcohol), hence the general name of the reaction. 

In general, a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products. For example, base treatment of a mixture of acetaldehyde and propanal gives a complex product mixture containing two "symmetrical" aldol products and two "mixed" aldol products. Clearly, such a reaction is of no practical value. 

It is often said that the property of acidity is manifest only in the presence of a base, and NMR studies of probe molecules became common following studies of amines by Ellis [4] and Maciel [5, 6] and phosphines by Lunsford [7] in the early to mid 80s. More recently, the maturation of variable temperature MAS NMR has permitted the study of reactive probe molecules which are revealing not only in themselves but also in the intermediates and products that they form on the solid acid. We carried out detailed studies of aldol reactions in zeolites beginning with the early 1993 report of the synthesis of crotonaldehyde from acetaldehyde in HZSM-5 [8] and continuing through investigations of acetone, cyclopentanone [9] and propanal [10], The formation of mesityl oxide 1, from dimerization and dehydration of... 

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... 

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

The namesake aldol reaction is the formation of an addition compound, aldol, from two molecules of acetaldehyde, when this aldehyde is treated with aqueous sodium hydroxide. The terminology aldol comes from the functional groups in the product, aldehyde and alcohol. 

An alternative approach to mixed aldol reactions, and the one usually preferred, is to carry out a two-stage process, forming the enolate anion first using a strong base like EDA (see Section 10.2). The first step is essentially irreversible, and the electrophile is then added in the second step. An aldol reaction between butan-2-one and acetaldehyde exemplifies this approach. Note also that the large base EDA selectively removes a proton from the least-hindered position, again restricting possible combinations (see Section 10.2). 

Proline Aldol reaction of a-benzyloxy acetaldehyde Strong (+)NLE 63... 

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... 

A side reaction occurring with acetaldehyde and higher aldehydes containing a-hydro-gens is aldol condensation [Hashimoto et al., 1976, 1978 Yamamoto et al., 1978], Aldol reaction can be extensive at ambient temperatures and higher but is avoided by polymerization at low temperature. 

The product of the PNP enzyme, FDRP 9 has been purified and characterised. The evidence suggests that FDRP 9 is then isomerised to 5-fluoro-5-deoxyribulose-1-phosphate 10, acted upon by an isomerase (Scheme 7). Such ribulose phosphates are well-known products of aldolases and a reverse aldol reaction will clearly generate fluoroacetaldehyde 11. Fluoroacetaldehyde 11 is then converted after oxidation to FAc 1. We have also shown that there is a pyridoxal phosphate (PLP)-dependent enzyme which converts fluoroacetaldehyde 11 and L-threonine 12 to 4-FT 2 and acetaldehyde in a transaldol reaction as shown in Scheme 8. Thus, all of the biosynthetic steps from fluoride ion to FAc 1 and 4-FT 2 can be rationalised as illustrated in Scheme 7. 

The aldol reaction of 3-pentanone with acetaldehyde provides an example52 of control by an external chiral ligand 9. The relative configuration at the newly created stereogenic centers (syn vs. anti) of the adduct 10 was determined by NMR, while the absolute configuration was assigned by a chemical correlation (see p 452)101 -I02. 

To increase the stereoselectivity of the aldol reaction, successful reaction of dibromo-/3 -lactams with methylmagnesium bromide followed by addition of acetaldehyde has been studied (equation 10/ . 

The key step in the synthetic routes described in Section 6.4.1 is the DERA-cata-lyzed tandem aldol reaction of chloroacetaldehyde (CIAA) with two equivalents of acetaldehyde (AA) to lactol 1 proceeding via a monoaldol intermediate (S)-4-chloro-3-hydroxybutanal 7 and the open form of lactol 1 6-chloro-(3R,5S)-dihydroxyhex-anal (8) (Scheme 6.4). 

Scheme 6.4 DERA-catalyzed stereoselective tandem aldol reaction, using chloroacetaldehyde and 2 equivalents of acetaldehyde, yielding (3R,5S)-6-chloro-2,4,6-trideoxyhexapyranoside (1).

As depicted in Figure 6.8 the stability screening was based on DERA activity assay, the retro-aldol reaction of 2-deoxy-D-ribose 5-phosphate to acetaldehyde and D-glyceraldehyde 3-phosphate. D-glyceraldehyde 3-phosphate is further converted by the auxiliary enzymes triose phosphate isomerase and glycerol phosphate dehydrogenase. As the latter reaction consumes NADH it can be measured spectro-pho to metrically by the decrease in absorbance at 340 nm. 

Munson and Haw (151) reported the first in situ NMR study of acetaldehyde in a zeolite. Figure 27 shows 13C spectra of this species reacting on HZSM-5 in the presence of water to form crotonaldehyde with high selectivity (an example of aldol condensation). We later reported a very detailed study of the aldol reactions of acetone and cyclopentanone on various zeolites (Scheme 4) (147). Dimerization of acetone followed by dehydration gives mesityl oxide (31), and the I3C isotropic shifts of this conjugated ketone are strongly dependent on state of protonation. Farcasiu and Ghen-ciu (152,153) have reported extensive measurements of the 13C shifts of 31... 

Aldol reactions of sugar enolates have provided a good entry to C-C double bond branched-chain sugars [178]. As already mentioned, condensation of aldehydes, such as acetaldehyde or propionaldehyde, gives a mixture of aldol 120 of R,S configuration at the... 

Alcohols from an aldol reaction may be linear if acetaldehyde is a reactant, but usually aldol alcohols are branched primary alcohols. An aldol condensation sometimes is done with an OXO reaction. The combined process is called the ALDOX process. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

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... 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

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