Electrophilic aldehyde acceptor

Most enzymes used by Nature for carbon-carbon bond formation and cleavage ( lyases ) catalyze a crossed aldol reaction in the form of a reversible, stereocontrolled addition of a nucleophilic ketone donor to an electrophilic aldehyde acceptor. Synthetically the most useful and most extensively studied enzymes use aldol donors comprising 2-carbon or 3-carbon fragments and can be grouped into fom categories depending on the structure of their nucleophilic component (Figme 5.2) (i) pyruvate-... 

Acceptor-monosubstituted diazomethanes can be further converted into other types of diazo compound. C-Acylation of diazoacetic esters generally requires very reactive acylating agents, such as acid chlorides [969,970] or bromides [971]. C-Alkylations of acyldiazomethanes are best accomplished by metallation followed by treatment with a carbon electrophile [972-977], C-alkylation can also occur without any base if sufficiently electrophilic aldehydes or ketones are used [973,978 -982] or if the alkylation proceeds intramolecularly [983]. 

As has already been mentioned, the low reactivity of enamine nucleophiles needs a highly electrophilic Michael acceptor for the reaction to proceed with good conversions in an acceptable time. In this context, the Michael reaction of aldehydes and ketones with nitroalkenes can be regarded as one of the most studied transformations in which the enamine activation concept has been applied. This reaction furnishes highly functionalized adducts with remarkable potential in organic synthesis, due to the synthetic versatility of the nitro group and the presence of the carbonyl moiety from the donor reagent. 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

Nitroalkenes are shown to be effective Michael acceptor B units In three sequential re fA + B + C couplingi in one reaction vessel. The sequence is initialed by enolate nucleophiles fA and is terminated by aldehydes or acrylate electrophiles fC. The utility of this protocol is for rapid assembly of complex stnictures from simple and readily available components. A short total synthesis of a pyrroLmdine alkaloid is presented in Scheme 10.16. ... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Typically, lyases are quite specific for the nucleophilic donor component owing to mechanistic requirements. Usually, approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospedfically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzymes, in general irrespective of the constitution or configuration of the substrate, which renders the enzymes highly predictable. On the other hand, most of the lyases allow a reasonably broad variation of the electrophilic acceptor component that is usually an aldehyde. This feature... 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

Some cation-radicals can appear as hydrogen acceptors. Thus, fullerene Cgg is oxidized to the cation-radical at a preparative scale by means of photoinduced electron transfer. As in the case of anion-radical, the fullerene Cgo cation-radical bears the highly delocalized positive charge and shows low electrophilicity. This cation-radical reacts with various donors of atomic hydrogen (alcohols, aldehydes, and ethers) yielding the fullerene 1,2-dihydroderivatives (Siedschlag et al. 2000). 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

Reaction with Further Electrophiles of Group IVA (Sl,Ge,Sn). IV-Silylated aziridines can be prepared from ethyleneimine by amination of chlorosilanes in the presence of an HC1 acceptor, by dehydrocondensation with an organosilicon hydride or by cleavage of a silicon—carbon bond in 2-furyl-, 2-thienyl-, benzyl-, or allylsilanes in the presence of an alkali metal catalyst (262—266). N-Silylated aziridines can react with carboxylic anhydrides to give acylated aziridines, eg, A/-acetylaziridine [460-07-1] in high yields (267). At high temperatures, A/-silylaziridines can be dimerized to piperazines (268). Aldehydes can be inserted... 

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