Acetaldehyde crossed aldol reaction with

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). 

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... 

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. 

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. 

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. 

An important contribution to the field of direct aldol reaction was put forward by MacMillan who reported on the enantioselective direct cross aldol reaction (Scheme 2.119) [31]. Two aldehydes are brought to reaction with 10mol% prohne to produce selectively the anfi-aldol product. If different aldehydes are used, the one that contains a sterically more crowded side chain acts as the carbonyl component, whereas simple aldehydes, in most cases acetaldehyde or even acetone, act as nucleophiles. The advantage of such organocatalytic aldol reactions is the fact that aldehydes can be used, which is practically prohibited if enolates or... 

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 base-catalyzed reaction of acetaldehyde with excess formaldehyde [50-00-0] is the commercial route to pentaerythritol [115-77-5]. The aldol condensation of three moles of formaldehyde with one mole of acetaldehyde is foUowed by a crossed Cannizzaro reaction between pentaerythrose, the intermediate product, and formaldehyde to give pentaerythritol (57). The process proceeds to completion without isolation of the intermediate. Pentaerythrose [3818-32-4] has also been made by condensing acetaldehyde and formaldehyde at 45°C using magnesium oxide as a catalyst (58). The vapor-phase reaction of acetaldehyde and formaldehyde at 475°C over a catalyst composed of lanthanum oxide on siHca gel gives acrolein [107-02-8] (59). 

Polyacetal resins have a repeating unit of -O-CH2-. They are strong, stiff polymers for valves, hoses, and tube connectors. Pentaerythritol finds end-uses in alkyd resins and explosives (pentaerythritol tetranitrate). To appreciate this synthesis, the student should review two condensation reactions, the crossed aldol and the crossed Cannizzaro. Acetaldehyde reacts with 3 mol of formaldehyde in three successive aldol condensations. This product then undergoes a Cannizzaro reaction with formaldehyde. 

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. 

Cross-aldol condensations have been performed with alkaline earth metal oxide, as base catalysts. A limitation of the cross-aldol condensation reactions is the formation of by-products throught the self-condensation of the carbonyl compounds, resulting in low selectivities for the cross-aldol condensation product. Thus, the cross-condensation of heptanal with benzaldehyde, which leads to jasminaldehyde (a-M-amylcinnamaldehyde), with a violet scent, has been performed with various solid base catalysts/13,541 particularly MgO, which gave excellent conversions of heptanal (97 %) at 398 K in the absence of a solvent (but the selectivity to jasminaldehyde was only 43 %). A low selectivity was also reported (40 %) for the cross-aldol condensation of acetaldehyde and heptanal catalysed by MgO.[55]... 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

The use of Ln(OTf)3 in the activation of aldehydes other than formaldehyde was also investigated [18], Several examples of the present aldol reaction of silyl enol ethers with aldehydes are listed in Table 14-1. In every case, the aldol adducts were obtained in high yields in the presence of a catalytic amount of Yb(OTf)3, Gd(OTf)3, or Lu(OTf)3 in aqueous media. Diastereoselectivities were generally good to moderate. One feature in the present reaction is that water-soluble aldehydes, for instance, acetaldehyde, acrolein, and chloroacetaldehyde, can be reacted with silyl enol ethers to afford the corresponding cross aldol adducts in high yields (entries 5-7). Some of these aldehydes are commercially supplied as water solutions and are appropriate for direct use. Phenylglyoxal monohydrate also worked well (entry 8). It is known that water often interferes with the aldol reactions of aldehydes with metal enolates and that, in the cases where such water... 

Until now, we have focused on symmetrical aldol reactions, that is, aldol reactions that occur between two identical parmers. In this section, we explore crossed aldol, or mixed aldol, reactions, which are aldol reactions that can occur between different parmers. As an example, consider what happens when a mixture of acetaldehyde and propionaldehyde is treated with a base. Under these circumstances, four possible aldol products can be formed (Figure 22.3). The... 

As with to FSA and GO, the most significant feature of DERA is the ability to catalyze self- and cross-aldol additions of acetaldehyde. Therefore, the first aldol addition furnishes another aldehyde that can be used as acceptor by DERA, or in combination with other aldolases, for cascade aldol reactions (Scheme 10.31) [25-27,195]. 

Recent developments in this area have considerably expanded the scope of the process to include a wide range of ketone and aldehyde components [98-100). Direct proline-catalyzed cross-coupling aldol reactions from ketones (Equation 16) [98] and aldehydes (Equation 17) [101] have been reported. Moreover, domino processes are possible thus, the proline-catalyzed aldol addition reaction of acetaldehyde proceeds through a double aldol addition and elimination to give useful building blocks for asymmetric synthesis (Equation 18) [100], As with any catalytic process, these processes are in essence multivariable problems, consisting of multiple steps and reactive intermediates, the reactivities and stabilities of which are finely balanced. 

Reduction. The familiar preparation of pentaerythritol from acetaldehyde and formaldehyde involves aldolization and crossed Cannizzaro reduction. In the same way, cyclohexanone reacts with 5 moles of formaldehyde to give the pentaol (3). The reaction is conducted by adding calcium oxide (1,25 moles) to a stirred mixture O OH... 

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