Enol hydroxycarbonylation

Within this section, the term aldol reaction includes additions of enols and enolates to carbonyl compounds. This section concentrates on aldol additions which deliver nonracemic, /i-hydroxycarbonyl compounds. The chiral information can be located ... 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

Oxidation of chiral sulfonimines (R"S02N=CHAr)and chiral sulfamyl-imines (R RNS02N=CHAr)affords optically active 2-sulfonyloxaziridines and 2-sulfamyloxaziridines, respectively. These chiral, oxidizing reagents have been used in the asymmetric oxidation of sulfides to sulfoxides (15-68% ee), 11-13 selenides to selenoxides (8-9% ee] enolates to a-hydroxycarbonyl compounds (8-37% ee) and in the asymmetric epoxidation of alkenes (15-40% ee)... 

To develop new electrophilic reagents, Ricci and coworkers have described the synthesis of trimethylsilyloxy and hydroxy compounds from magnesium enolates and bis(trimethyl-silyl)peroxide. Magnesium enolates, generated using magnesium diisopropylamide, (DA)2Mg, give the hydroxycarbonyl compounds in excellent yields (equation 72, Table 8). 

The addition of the nucleophilic carbanion-enolate, usually of an aldehyde, to the C=0 group of its parent compound is called an aldol condensation. The product is a /3-hydroxycarbonyl compound. In a mixed aldol condensation the carbanion-enolate of an aldehyde or ketone adds to the 0=0 group of a molecule other than its parent. The more general condensation diagramed above is termed an aldol-type condensation. Since the C, not the O, is the more reactive site in the hybrid, the enolate contributing structure is usually omitted when writing equations for these reactions. This is done even though the enolate is the more stable and makes the major contribution. 

The aldol reaction is well established in organic chemistry as a remarkably useful synthetic tool, providing access to p-hydroxycarbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in the previous section (Chap. 29.1). While some effective applications have been reported, most of the methodologies necessarily involve the preformation of latent enolates 2, such as ketene silyl acetals, using... 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

Another nucleophilic addition involving a charged nucleophile is the Aldol reaction. This involves the nucleophilic addition of enolate ions to aldehydes and ketones to form p-hydroxycarbonyl compounds ... 

In principle it also is possible to obtain the /3-hydroxycarbonyl compounds directly in neutral form rather than in form of their alkoxides (Figure 13.44, bottom). This is accomplished by the reaction of one carbonyl compound or of a mixture of two carbonyl compounds with a catalytic amount of MOH or MOR. Aldehyde enolates and ketone enolates are then formed in small amounts (see the Rule of Thumb at the beginning of Section 13.1.2). These enolates add to the C=0 double bond of the starting substrate molecules or, if a mixture of carbonyl compounds is employed, they add to the C=0 double bond of the more reactive of the carbonyl compounds. The alkoxides B of the aldol adducts are formed initially but are converted immediately and quantitatively into the aldols by way of protonation. 

It is for good reason that the bulky ketone substituent of enolate A contains a Me3SiO group, which is carried on into the. syw-configured aldol adduct its acid-catalyzed hydrolysis affords an OH group in the a-position of the C=0 double bond. Such an a-hydroxycarbonyl compound can be oxidatively cleaved with sodium periodate to afford a carboxylic acid (cf. Section 9.1.1). The mechanism of this oxidation is described later in connection with Fig-... 

Vedejs E, Engler DA, Telschow JE (1978) Transition-Metal Peroxide Reactions. Synthesis of a-Hydroxycarbonyl Compounds from Enolates. J Org Chem 43 188... 

Here, the name aldol refers to a /3-hydroxycarbonyl compound which is derived from the nucleophilic additions between enol (or enolate) 13 and ketone (or aldehyde) 14 (O Scheme 5). Sugars, as the chiral polyhydroxy aldehyde or ketone compounds, are natural substrates for these reactions. 

Diketones often are protected as enol ethers or enamines and these selectively functionalized compounds may be subjected to complementary transformations (Scheme 94). Also silylenes can be prepared from diketones and -hydroxycarbonyl compounds by reaction with dimethyldicyanosilane. Naturally, these blocking groups are relatively sensitive to hydrolysis. On the other hand, partial solvolysis can open a route to monoprotected derivatives (e.g. 101), usually blocked at the sterically less demanding carbonyl function as 0-silyl cyanohydrins (see Scheme 95). Deprotection is finally achieved with silver fluoride in THF. 

Aldol reaction Addition of an enol/enolate of a carbonyl compound to an aldehyde or ketone to form a (J-hydroxycarbonyl compound. 8... 

Davis, F. A., Vishwakarma, L. C., Billmers, J. G., Finn, J. Synthesis of a-hydroxycarbonyl compounds (acyloins) direct oxidation of enolates using 2-sulfonyloxaziridines. J. Org. Chem. 1984, 49, 3241-3243. 

The conjugate bases of carbonyl compounds, enolates, react with ketones and aldehydes in the aldol reaction. The reaction is usually executed in two stages. First, the enolate is generated, usually by deprotonation of the carbonyl compound at low temperature with a strong base such as LDA, KHMDS, or LiHMDS, but not always. Then the electrophilic carbonyl compound is added to the reaction mixture. Under these conditions, the reaction usually stops at the /3-hydroxycarbonyl stage. The nucleophilic component may be any carbonyl compound, or even a nitrile, a sulfonyl compound, or a nitro compound (honorary members of the carbonyl family). 

The F-alkyl ketone enolates were readily prepared by dephosphorylation of the corresponding 1-substituted F-l-aUcenyl phosphates with DIBAL at 0°C for a few minutes (Scheme 6.29) [50]. The resulting diisobutylaluminum enolate undergoes aldol reaction with benzaldehyde to give fhe -hydroxycarbonyl compound in a reasonable yield. 

The first highly enantioselective construction of a-methyl-p-hydroxycarbonyl units, described by Masamune et al., used alkenyloxyboranes (29) prepared by enolization of ethyl ketone (30) derived in three steps from enantiomerically pure mandelic acid. Various dialkylboryl triflates are used with diiso-propylethylamine for enolization. The alkenyloxyboranes (29) exhibit striking stereoselectivity as chiral reagents in reactions with representative aldehydes. With judicious choice of the alkyl ligands on the... 

The 2-sulfonyloxaziridine (57) is a more selective oxidant than peracids. The reagent has been employed in the oxidation of sulfides to sulfoxides, disulfides to thiolsulfinates, selenides to selenoxides, thiols to sulfenic acids, organometallic reagents to alcohols and phenols, ketone and ester enolates to a-hydroxycarbonyl compounds (equation 31)41. The oxidation of chiral amide enolates gives optically active a-hydroxy carboxylic acids with 93-99% enantiomeric excess42. 

Dimethyldioxirane, together with acetone, is removed from the reaction vessel by distillation. The yellow 0.1-0.2 M solution can be used as an oxidizing agent, e.g. for the epoxidation of olefins [19], for the oxidation of enolates to a-hydroxycarbonyl compounds and for the oxidation of primary amines into nitro compounds ... 

Following route II, it can be seen that the primary H2O addition to the fiiran C-2/C-3 bond can also occur in an opposite direction to a, i.e. according to the retrostep d. This leads to the intermediate 7 for which the bond cleavage O/C-2 (e) is retroanalytically rationalized and leads to the y-hdXo-p-hydroxycarbonyl system 9. A retroaldol operation (g) provides the same starting materials 10 and 11 as the retrosynthesis I route II, however, suggests as the first step aldol addition of 10 and 11 to give 9 followed by intramolecular Sn cyclization of the enolate 9 to the dihydrofuran 7 and conversion into fiiran by dehydration. 

In an aldol reaction, the enolate of one compound reacts with the electrophilic carbonyl carbon of the other carbonyl compound. A problem can arise when the other regioisomeric enolate can form easily or when the electrophilic carbonyl compound is enolizable. In addition, the product is enolizable and the wrong carbonyl compound could act as the electrophile therefore a mixture of products or predominantly the undesired product may result. An added complication arises when more than one chiral centre is present in the product and therefore two diastereomeric products can be formed. The course of the reaction between unlike components must be directed so that only the product required is obtained, or at least is formed predominantly. In addition, the stereochemical course of the reaction must be controlled. These difficulties have been overcome as a result of intensive study of the aldol reaction, spurred on by the presence of the (3-hydroxycarbonyl functional group in the structures of many naturally occurring compounds such as the macrolides and ionophores. 

The normal product of an aldol reaction between an aldehyde and a monocarbonyl compound is a -hydroxycarbonyl compound and in many cases a mixture of stereoisomers of the product is formed (1.62). The use of preformed enolates and conditions that are now well established allows control of the stereochemical outcome of aldol reactions. Under appropriate conditions predominantly the syn or... 

Titanium-based Lewis acids are widely used in the Mukaiyama reaction, i. e. the condensation of an enol silane and an aldehyde, giving 3-hydroxycarbonyl derivatives. In this context, BINOL-derived chiral titanium complexes were used in the condensation of thioester-derived ketene silyl acetals with a large range of aldehydes, in high yields and enantioselectivities (Scheme 7.39). ... 

The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a p-hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol. 

Carbanions and related intermediates react with a variety of carbon electrophiles, such as alkyl halides and carbonyl compounds, forming carbon-carbon bonds. In this capacity, these intermediates are a cornerstone of organic synthesis. A classic example of a carbanion reaction is the aldol reaction. In this, an enolate reacts with a carbonyl compound to yield a -hydroxycarbonyl compound, as shown in the example below ... 

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