Aldehydes aldol condensation with carbonyl

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

The third hypothesis (C) is that reaction takes place through an aldol condensation between the ethyl acetoacetate and the carbonyl form of the sugar. There is some precedent indicating that it is possible for /3-ketonic esters to undergo aldol condensation. These compounds react mole to mole with the aliphatic aldehydes and afford unsaturated substances, which could be formed via an aldol condensation with subsequent dehydration. 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

Tab. 13.7 Representative a,/MJnsaturated Carbonyl Compounds Generated by Aldol Condensations of Carbonyl Compounds with Selected Aldehydes (M = Na or K )...

The addition of dialkylaminostannanes to aldehydes and ketones often gives a mixture of tin-free products derived from addition and elimination reactions of the monomeric carbonyl compound and of its products of base-catalysed aldol condensation. With appropriate substituents, however, reasonable yields of the enamines can be isolated, for example 38... 

The aldol condensation involves the reaction of two molecules of an aldehyde or ketone that has alpha hydrogens. Abstraction of an alpha hydrogen by base produces a carbanion which attacks the carbonyl carbon of the other molecule by base-initiated nucleophilic addition an alcohol group is formed. Often the alcohol dehydrates to form the final product, an unsaturated aldehyde or ketone. In a crossed aldol condensation, a carbonyl compound with alpha hydrogens reacts with one without alpha hydrogens. 

Rearrangement of a-pinene oxide, catalysed by zinc chloride or bromide, gives a product known as a-campholenic aldehyde. Aldol condensation of this with a second aldehyde or a ketone gives an a, (3-unsaturated carbonyl compound that can then be reduced to an... 

Hydroxy aldehydes. On treatment with MeLi and then (BuO)4Ti, silyl enol ethers of aldehydes form enoxytitanates that condense with carbonyl compounds. It should be emphasized that in conventional aldol reactions aldehydes behave as acceptors. In this method, the donor role is established. 

A.ii. Diastereoselection in the Aldol Condensation. In addition to the alkylation reaction, enolates react with other carbonyl compounds to give aldol or Claisen products, as discussed in previous sections. An aldol condensation with the enolate of 1-phenyl-1-propanone and benzaldehyde generates two new stereocenters and gives two racemic diastereomers (four stereoisomers). These two diastereomers are the racemic anti diastereomer (340 and 343) and the racemic syn diastereomer (341 and 342). Diastereoselectivity in this reaction is dependent on the reaction conditions and the enolate and aldehyde partners, and this section will explore the origins of that diastereoselection. 

This case study highlights the formidable challenge posed by epimerization en route to the synthesis of nonpeptidic fragments of cyclic peptide natural products. (3S,4R,7S)-HTMMD was prepared from (R)-4-methyl-5-valerolactone 74 in nine steps (Scheme 8.6a). After convenient synthesis of aldehyde 77 and its asymmetric aldol condensation with the ketene acetal 79, HTMMD skeleton 80 was isolated as a single isomer. After installation of allyl ester, the alcohol was coupled with Fmoc-Ala-Cl in the presence of DMAP/DIPEA (4-dimethylaminopyridine/diisopropylethylamine) followed by fluorenylmethyloxy-carbonyl (Fmoc) deprotection to afford the ester segment 81b in excellent yield. The amount of DMAP and temperature (—15 °C) were critical to avoid racemiza-tion. Modified Tsunoda s diastereoselective aza-Claisen rearrangement [145] was used as the key step in the 13-step synthesis of N-methylhydroxyisoleucine 86b... 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

Aldol condensation offers an effective route to a p unsaturated aldehydes and ketones These compounds have some interesting properties that result from conjugation of the carbon-carbon double bond with the carbonyl group As shown m Figure 18 6 the rr systems of the carbon-carbon and carbon-oxygen double bonds overlap to form an extended rr system that permits increased electron delocalization... 

AldolRea.ctlons, In the same way, hydroxybenzaldehydes react readily with aldehydes and ketones to form a,P-unsaturated carbonyl compounds in the Claisen-Schmidt or crossed-aldol condensation (60). 

For synthetic purposes, aldol-rype condensations of aldehydes with esters or amides are potentially of great utility because the carbonyl group is easily transformed either by further additions or by oxidation or reduction. Deprotonation of an ester [7, 19, 20] or amide of fluoroacetic acid [9, 27] has led to aldol condensations in high yields (equation 17) (Table 7)... 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

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. 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

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