Enolate Enol Nucleophiles

In the past two ChemActivities we have focused on reactions such as H the one at right, in which a basic species acts as a nucleophile, making a bond to a carbonyl carbon.  

Such a species can also act as a base. Shown below are three possible acid-base reactions of this pair. 

Draw the product of each set of curved arrows. (Include all important resonance structures.) 

Only one of these three acid-base reactions is favorable. Which one Explain your reasoning. 

(Check your work.) Is your answer above consistent with Memorization Task 25.1  

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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. ... 

Three types of synthases catalyze the addition of phosphoenolpyruvate (PEP) to aldoses or the corresponding terminal phosphate esters. By concurrent release of inorganic phosphate from the preformed enolate nucleophile, the additions are essentially irreversible. None of the enzymes are yet commercially available and little data are available oil the individual specificities for the aldehydic substrates. A bacterial NeuAc synthase (EC 4.1.3.19) has been used for the microscale synthesis of A -acetylncuraminic acid from Af-acetyl-D-mannosamine31 and its 9-azido analog from 2-acetamido-6-azido-2,6-dideoxy-D-mannose32. 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

Most allylic substitution reactions catalyzed by other metals are selective for the formation of branched products. Although this had been demonstrated for a large portion of the d-block before Takeuchi s work with iridium, most of the progress in this area was restricted to stabilized enolate nucleophiles. 

Scheme 13 Allylic substitution with unstabilized enolate nucleophiles...

In addition, unstabilized enolate nucleophiles have been generated by decarboxylation of (3-ketocarboxylates. In this case, no additives are required to activate the nucleophile, but the highest yields and selectivities were obtained in the presence of two equivalents of DBU [82]. Although reactions of allylic carbonates containing aromatic, heteroaromatic, and aliphatic substituents occurred, only reactions to form aryl ketone products were published. 

Mannich and Mannich-like reactions are widely used for the chemical synthesis of heterocycles, and in alkaloid biosynthesis in plants. One such reaction important in nature is a biological equivalent of the Pictet-Spengler tetrahydroisoquinoline synthesis (see Section 11.10.4), and offers a slight twist, in that the enol nucleophile is actually a phenol. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Synthetic studies for sialic acid and its modifications have extensively used the catabolic enzyme N-acetylneuraminic acid aldolase (NeuA E.C. 4.1.3.3), which catalyzes the reversible addition of pyruvate (70) to N-acetyl-D-mannosamine (ManNAc, 11) to form the parent sialic acid N-acetylneuraminic acid (NeuSNAc, 12 Scheme 2.2.5.23) [1, 2, 45]. In contrast, the N-acetylneuraminic acid synthase (NeuS E.C. 4.1.3.19) has practically been ignored, although it holds considerable synthetic potential in that the enzyme utilizes phosphoenolpyruvate (PEP, 71) as a preformed enol nucleophile from which release of inorganic phosphate during... 

A range of enolate nucleophiles have been added to trimethylsilyl-substituted cyclohexadienyl complexes (49 Scheme 18) and (51 equation 49) and related compounds. Again, high yields are obtained and stereodirection by the Fe(CO)3 group is very powerful.13... 

The aldol condensation is the reaction of an aldehyde or ketone enolate with an aldehyde or ketone to give a /3-hydroxy aldehyde or ketone. A simple aldol reaction is one in which the enolate nucleophile is derived from the carbonyl electrophile. Very often the /3-hydroxy carbonyl product dehydrates to give an... 

If die enolate nucleophile is derived from an aldehyde or ketone different than die carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone etiolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead. 

There are many odier named reactions that follow die same general features but differ as to die type of enolate or the carbon electrophile. These include the Reformatski reaction, the Darzens reaction, and the Dieckmann ring closure. They were in widespread use for many years and were named as a convenient way to characterize the reactants employed and type of product which results. The reason that diere are so many variations on the same theme is that control of the reaction products depends on die ability to generate a particular enolate nucleophile and... 

Today reactions of etiolates are usually carried out much differently by utilizing very strong, nonnucleophilic bases for generating the enolate nucleophile. Instead of having only small equilibrium concentrations of an enolate produced in solution, the use of strong, nonnucleophilic bases like LDA, KHMDS, and KH that have pAYs >35 permits carbonyl compounds, whose a protons have pA"a s of 20-25, to be converted completely to enolate anions. Doing so completely converts the carbonyl compound into a nucleophile which cannot condense with itself and is stable in solution. This enolate can then be reacted with a second carbonyl compound in a subsequent step to give product ... 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

The foregoing classification is of fundamental significance for the understanding of enolate chemistry. For every pair of C,H acid and base, one needs to know whether the combination effects quantitative or partial enolate formation. If deprotonation is only partial, then the unreacted substrate may represent an electrophile that can react with the enolate nucleophile. In such a case, it depends on the specific circumstances whether an enolate reacts with any remaining substrate or whether it reacts only with an added different electrophile. The occurrence of a reaction between enolate and unreacted substrate is avoided if the C,H acid is deprotonated completely with a stoichiometric amount of a sufficiently strong base. 

The acetoacetic ester synthesis is used to prepare methyl ketones such as this. In this example, a butyl group must be attached to the enolate nucleophile. 

This part of the mechanism is just like the mechanism for the addition reactions of Chapter 18. The enolate nucleophile adds to the carbonyl carbon of a second aldehyde molecule, and the negative oxygen removes a proton from water. This step regenerates hydroxide ion, so the reaction is base catalyzed. 

Often, it is desirable to conduct an aldol condensation in which the nucleophile and the electrophile are derived from different compounds. In general, such mixed aldol condensations, involving two different aldehydes, result in the formation of several products and for this reason are not useful. For example, the reaction of ethanal and propanal results in the formation of four products because there are two possible enolate nucleophiles and two carbonyl electrophiles ... 

The enolate nucleophile adds to the /3-carbon of an a,/3-unsatu rated ketone (or ester or nitrile), which is called the Michael acceptor. 

Enolate nucleophiles have exactly the same opportunity to attack the carbonyl group directly as do the simple nucleophiles discussed in Chapter 10 and the same factors govern the eventual outcome... 

In this area, Krische and co-workers have developed a family of catalytic transformations based on the use of enones as latent enolates. Nucleophilic activation of the enone is induced via carbometallation, nucleophilic organocatalysis or hydrometallation. The following examples illustrate some aspects of these new catalytic conjugate addition/electrophilic trapping reactions. 

Step 2 Addition of the enol nucleophile to the protonated carbonyl compound. 

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