J8-Hydroxy aldehydes

Originally, the term aldol condensation referred specifically to the reaction of an aldehyde (having an a-hydrogen) with an aldehyde/ketone to form a j8-hydroxy aldehyde (the aldol). The reverse reaction is often referred to as a retrograde aldol reaction, a retro-aldol condensation (or reaction), or an aldol cleavage. March categorizes aldol condensations into five classes. The first is condensation between two identical aldehydes... 

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. 

What four j8-hydroxy aldehydes would be formed by a crossed aldol reaction between the following compounds ... 

The mechanism of the base-catalyzed aldol reactions involves initial deprotonation of the a-hydrogen in base to create an enolate anion, which is a strong nucleophile that attacks another aldehyde or ketone molecule to give a carbonyl addition intermediate, which, in turn, reacts with water to create a j8-hydroxy aldehyde or ketone product and regenerates the original base. 

The mechanism of the acid-catalyzed aldol reaction involves an initial acid-catalyzed keto-enol tautomerization to provide the enol form protonation of a second molecule on the carbonyl oxygen creates an electrophilic oxonium ion that is then attacked by the nucleophilic enol, followed by loss of a proton to give the j8-hydroxy aldehyde or ketone product. 

The j8-hydroxy aldehyde or ketone products of aldol reactions are easily dehydrated and lose H2O to give an a,j8-unsaturated aldehyde or ketone. 

Aldol condensation (Section 19.1, Section 19.4C) An aldol reaction that forms an a,/3-unsaturated product by dehydration of the j8-hydroxy aldehyde or ketone aldol product. 

Water can add reversibly to a,)8-unsaturated aldehydes and ketones to yield j8-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. Related additions to a,j8-unsaturated carboxylic acids occur in numerous biological pathways, such as the citric acid cycle of food metabolism where cis-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

The j8-hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield a,)8-unsaturated products, or conjugated enones. In fact, it s this loss of water that gives the carbonyl condensation reaction its name, because water condenses out of the reaction when the enone product forms. 

The aldol reaction yields either a j8-hydroxy aldehyde/ketone or an a,/3-unsatu-rated aldehyde/ketone, depending on the experimental conditions. By learning how to think backward, it s possible to predict when the aldol reaction might be useful in synthesis. Whenever the target molecule contains either a /3-hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. 

The reversible reaction (usually base catalyzed) of two carbonyl compounds (/.e., two aldehydes, two ketones, or one of each), in which at least one compound has an a-hydrogen, to produce a j8-hydroxy carbonyl compound. 

The reaction of a-fluoro-/f-hydroxy-a-phenylsulfanyl esters 4, which can be readily synthesized from aldehydes and ethyl bromofluoroacetate, with diethylaminosulfur triduoride leads to the formation of a,o -difluoro-/I-phenylsulfanyl esters Instead of the expected substitution of the j8-hydroxy group by fluorine, a rearrangement via an episulfonium ion and addition of a fluoride ion % to the ester function gives the a,a-difluorinated product 5. The reaction proceeds under mild conditions with moderate to good yields. In the case of ethyl 2-fluoro-3-hydroxy-3-phenyl-2-(phcnylsulfanyl)propanoate only the nonrearranged product ethyl 2.3-di-fluoro-3-phenyl-2-(phenylsulfanyr)propanoate was isolated. 

If an a-bromo ester is treated with metallic zinc in the presence of an aldehyde or ketone, there is obtained a j8-hydroxy ester. This reaction, known as the Reformatsky reaction, is the most important method of preparing j8-hydroxy acids and their derivatives. For example ... 

Possibly, glyoxylase, which catalyses the conversion of j8-keto aldehydes to -hydroxy thiol esters, acts by an analogous sort of intramolecular hydride transfer. 

Enantioselective cyanomethylation. Cyanomethylzinc bromide, prepared by reaction of BrCH2CN with Zn/Cu, adds to aryl aldehydes in the presence of (S)-l (1 cquiv.) to give j8-hydroxy nitriles in 87-93% ee. If only 0.3 mol% of (S)-l is present the optical yield is markedly decreased (in the case of QHsCHO ec falls from 93 to 78%). Therefore, 1 serves both as a ligand and a catalyst. 

Lithio-l,3-dithianes add to the carbonyl group of aldehydes and ketones to provide mercaptal derivatives of a-hydroxy aldehydes or ketones (equation 55). The yields are normally quite high. Reaction with a,j8-unsaturated ketones has been observed to give only 1,2-addition however, Seebach and Lietz have reported 1,4-addition to occur in reactions with a,]8-unsaturated nitro derivatives (equation 56). In the case... 

Some interesting developments have been reported in the area of stereoselective a-substituted jS-hydroxy-ester synthesis (see also ref. 30). Masamune s group has described an alternative preparation of the E-vinyloxyborane (102) which condenses with aldehydes to give erythro-esters (103) of 97% stereochemical purity. By contrast, the Z-dicyclopentylboron analogue of (102) leads exclusively to threo-(103). The -enol ether (104) also reacts with aldehydes in the presence of TiCU to give threo-isomcrs of (103) unfortunately the Z-isomer of (104) reacts with little stereoselectivity, An alternative, completely selective, route to threo-(103) is by mono-alkylation of dianions derived from j8-hydroxy-esters. This latter method appears to have considerable potential in general synthesis. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to /3-hydroxy aldehydes/ketones and then to a,j8-unsaturated products after dehydration. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an imusually good donor (ethyl acetoacetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-membered rings. 

Step Q of Figure 29.7 Cleavage Fructose 1,6-bisphosphate is cleaved in step 4 into two 3-carbon pieces, dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). The bond between C3 and C4 of fructose 1,6-bisphosphate breaks, and a C=0 group is formed at C4. Mechanistically, the cleavage is the reverse of an aldol reaction (Section 23.1) and is catalyzed by an aldolase. A forward aldol reaction joins two aldehydes or ketones to give a j8-hydroxy carbonyl compound, while a retro-aldol reaction such as that occirrring here cleaves a j8-hydroxy carbonyl compound into two aldehydes or ketones. 

As mentioned above, the use of lithium bases in the HW reaction allows the reaction to be divided into two discrete steps [39] 1) the HW addition of a lithiated phosphine oxide to an aldehyde (or ketone) to produce a j8-hydroxy phosphine oxide, and 2) the HW elimination of a phosphinic acid to afford an alkene (Scheme 1.14). Careful manipulation of each step then allows control of the overall sequence. While the overall mechanism of the Horner-Wittig reaction is similar to that of the HWE reaction (Scheme 1.6), some additional discussion is required to understand its stereochemical outcome. The HW reaction can be carried out without isolation of the intermediate yS-hydroxy phosphine oxides in cases where a nonlithium base is used and is able to stabilize the negative charge of the phosphorus a-carbanion 9. Under these conditions, reaction of an aldehyde with the phosphine oxide to give intermediates 10 and 11 is reversible. The -alkene is then formed preferentially since elimination of intermediate 11 occurs much faster than that of 10. 

Stereoselective synthesis of 1,4-disubstituted 1,3-dienes from aldehydes has also been reported [232, 233]. The stereoselective synthesis of j8-hydroxy-a-(l-alkenyl)-... 

Ketone 55 and aldehyde 54 were then joined via a crossed aldol condensation. The resulting alcohol was oxidized to give 56. The enolate derived from /3-dicarbonyl 56 was O-acylated at C9. The C7 carbonyl group was reduced to the alcohol oxidation state with concomitant reductive cleavage of the enol acetate. Treatment of the resulting j8-hydroxy ketone with mesyl chloride gave 57. 

The special reactivity of the benzylic position is also seen in the mild conditions required for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. For example, manganese dioxide, MnOa, performs this oxidation selectively in the presence of other (nonbenzylic) hydroxy groups. (Recall that Mn02 was used in the conversion of allylic alcohols into a,j8-unsaturated aldehydes and ketones see Section 17-4.)... 

In the presence of a strong base such as LDA, the a-carbon of acetic acid esters can react with the carbonyl group of aldehydes or ketones to give j8-hydroxy esters, which may or may not be dehydrated to a,j8-unsaturated esters. This type of reaction has been exploited for the preparation of racemic [2- C]mevalonolactone (64) (Figure 6.25) and the benzofuran[l- C]acetamide PD 126,212 (67)". In the first case a-deprotonated trimethyl-silyl [2- C]acetate was treated with l-trimethylsilyloxy-3-butanone. Acidic work-up resulted in hydrolytic cleavage of the TMS groups and formation of the lactone system... 

An alternative to 138 and 122 is (R)- or (5)-2-hydroxy-l,2,2-triphenylethyl acetate ((/ )-or (5)-HYTRA) (14.3). a chiral acetate which does not need an auxiliary heteroatomic substituent. Compound 143 is readily available through acylation of 1,2,2-triphenyl-1,2-ethandiol with acetyl chloride or acetic anhydride. Its dianion, generated by double deprotonation with LDA and transmetallation with MgBr2 or Mgl2, reacts with aliphatic and aromatic aldehydes to give )8-hydroxy acid derivatives with diastereomeric ratios ranging from 92 8 to 98 2 . The crude adducts can be readily purified by crystallization. Removal of the auxiliary can be accomplished either hydrolytically (KOH, aq. MeOH) or transesterification (MeONa, MeOH/THF) to provide the respective j8-hydroxy acid/ester in enantiomerically pure form. 

Bakers yeast is used almost exclusively for reduction, principally of ketones, by a dehydrogenase which usually follows the Prelog-Cram rule. As with chemical reductions, highest enantioselectivity obtains with aromatic aldehydes and aryl methyl ketones. /3-Keto esters arc also reduced with high canantiosclectivity by yeast. Some j8-kcto acids can also be reduced efficiently to (R)-jS-hydroxy acids. 

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