Enolates reversible addition

The reverse trend is observed with (Z)-enolates. The reaction of the lithium enolate of cyclohexanone with ( )-(2-nitroethenyl)benzene gives a 75 25 mixture of the syn- and anti-adducts. In contrast, the same enolate undergoes addition of ( )-5-(2-nitroethenyl)-l,3-benzo-dioxole to give exclusively the yymaddition product in 93% yield2. 

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... 

The zinc-enolate cyclizations are not restricted to a-aminoesters as /3-aminoesters have also been successfully involved in such reactions275. The preformed lithium enolate generated by treatment of the /J-arninoester 423 with LDA had to be added dropwise to an ethereal solution of ZnBr2 in order to avoid a competing /3-elimination reaction induced by the zinc enolate. this reverse addition protocol was respected, a smooth carbocyclization reaction occurred and provided, after hydrolysis, the substituted 3-carbomethoxypyrrolidine 424 as a 87/13 mixture of diastereomers (equation 183). 

It has been suggested that poly-L-leucine (PLL)-catalysed epoxidation of substituted chalcones proceeds via a reversible addition of chalcone to a PLL-bound hydroperoxide, forming a fleeting hydroperoxy enolate species. The origin of enantioselectivity in this system has been rationalized.194... 

The formation constants of an actinium isopropyltropolonate complex were determined. Thermochemically relevant studies of thorium enolates generally involve bis(pentamethyl-cyclopentadienyl)thorium derivatives. Cp 2Th(Cl)(C(0)CFl2Bu-f) with an anionic acyl group that readily rearranges to the isomeric enolate Cp 2Th(Cl)OCH=CHBu-t. The Z-isomer is formed upon heating and the -isomer upon catalysis with Cp 2ThH2. Is the E or Z enolate thermodynamically more stable For the simple alkyl enolates MeCH=CHOR, the equilibration reaction of the Z- and E-isomers is nearly thermo-neutral . Consider the two species Cp 2Th(H)OCH(Bu-t)2 and Cp 2Th(H)0-2,6-C6H3 (Bu-f)2. The reversible addition of CO yields the rp- formyl derivative in reactions that are 19 4 and 25 6 kJmoR exothermic. These formyl species dimerize to form the classical enediolate, Cp 2Th(OR)OCH=CHO(OR)ThCp 2. This product is formed as the Z-isomer, plausibly thermodynamically preferred over the -isomer, much as (Z)-MeOCH=CHOMe is preferred over its E-counterpart by 6.0 0.2 kJmoR. ... 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

The regiospecificity of addition of substituted alkenes to azides is not as absolute as the preceeding examples with enamines, enol ethers, and acceptor-substituted alkenes may imply in all those cases the reverse addition product was not detected. This does not mean that it cannot be formed. Ouali et al. (1980) found cases in which both isomers were indeed obtained. Methyl acrylates with an acceptor substituent at... 

If the ester enolate reaction involves reversible addition while the cyclisation remains irreversible, it should be possible to use weaker bases than the generally used lithium amides for the condensation reaction. A situation of this type results when potassium enolates are used. In this case, the highly ionized oxygen-potassium bond renders the addition of the enolate to the imine reversible. As a result, we were able to prepare P-lactams via ester enolate imine condensation using potassium r-butoxide that has a pK of 16.5 (Scheme 16). ... 

A novel use of a wide range of nitriles as mediator has enabled the regioselective inter-molecular addition of unstabilized zinc ester enolates to 1-alkynes and l.S-enynes. " This reaction was made possible by a reversible addition of enolates to a nitrile (Blaise reaction), generating a zinc aza-enolate that, unlike zinc ester enolates, can add inter-molecularly to 1-alkynes and 1,3-enynes. Subsequent removal of the nitrile through a retro-Blaise reaction has generated the targeted addition product. 

It is self-evident that the transition state hypotheses discussed above are exclusively relevant to kinetically controlled aldol additions. Although this type of reaction control is the rule when preformed enolates are used, one should be aware that the reversibility of aldol additions cannot be excluded a priori and in any instance. In aldol reactions of preformed enolates, reversibility becomes noticeable in equilibration of syn aldolates with anti aldolates rather than in an overall low yield as found in the traditional aldol reaction. Considering the chair conformations of the syn and the anti aldolates, the former seem to be thermodynamically less stable, because of the axial position of the a-substituent R. This situation is avoided in the anti adduct (Eq. 

Another early solution to the acetate aldol problem came from the so-called Davies-Liebeskind enolates already mentioned in the context of enolate alkylation. As elaborated independently by the groups of Davies [138] and Liebeskind [139], the deprotonation of the chiral acetyl iron complex 124b, transmetallation of the lithium enolate, and addition to aldehydes lead to the predominant formation of diastereomers 279, as proved by a crystal structure analysis. The diastereoselectivity strongly depends on the transmetallation, the best results being obtained with diethylaluminum chloride. With other additives, the topicity is reversed, and the diastereomer 280 is obtained as the major product. The decomplexation of the adducts leads to P-hydroxycarboxylic acids (Scheme 4.64). 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Both parts of the Lapworth mechanism enol formation and enol halogenation are new to us Let s examine them m reverse order We can understand enol halogenation by analogy to halogen addition to alkenes An enol is a very reactive kind of alkene Its carbon-carbon double bond bears an electron releasing hydroxyl group which makes it electron rich and activates it toward attack by electrophiles... 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Cleavage reactions of carbohydrates also occur on treatment with aqueous base for prolonged periods as a consequence of base catalyzed retro aldol reactions As pointed out m Section 18 9 aldol addition is a reversible process and (3 hydroxy carbonyl com pounds can be cleaved to an enolate and either an aldehyde or a ketone... 

Reversible electron addition to the enone forms the radical anion. Rate determining protonation of the radical anion occurs on oxygen to afford an allylic free radical [Eq. (4b) which undergoes rapid reduction to an allylic carbanion [Eq. (4c)]. Rapid protonation of this ion is followed by proton removal from the oxygen of the neutral enol to afford the enolate ion [Eq. (4c)]. 

During the course of base-catalyzed exchange in O-deuterated alcohols, the vinylic hydrogen in the a position to the ketone is replaced by deuterium, in addition to the hydrogens activated by enolization. Thus, under these conditions the exchange of androst-l-en-3-one (16, R = H) gives a trideuterio derivative (18) instead of the expected 4,4-d2 analog (16, R = D). " (For other examples see compounds 13, 19, 21, 23, 26 and 27.) Incorporation of this deuterium is due to rapidly reversible alcohol addition (16 -+17) and elimination (17 18) which competes with the enolization step. " ... 

Normally, phenylhydrazine reacts with the enol form of 1,1,1-trifluorometh-ylpentane-2,4-dione to give 5-methyl-l-phenyl-3-tnfluoromethylpyrazole as the major product. However, the use of pyrrolidine as a transient carbonyl-blocking group can completely reverse the regiochemistry of the addition and leads to 3-methyl-l-phenyl-5-trifluoromethylpyrazole [102] (equation 88)... 

Various competitive reactions can reduce the yield of the desired Michael-addition product. An important side-reaction is the 1,2-addition of the enolate to the C=0 double bond (see aldol reaction, Knoevenagel reaction), especially with a ,/3-unsaturated aldehydes, the 1,2-addition product may be formed preferentially, rather than the 1,4-addition product. Generally the 1,2-addition is a kinetically favored and reversible process. At higher temperatures, the thermodynamically favored 1,4-addition products are obtained. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Glycolysis is a ten-step process that begins with isomerization of glucose from its cyclic hemiacetal form to its open-chain aldehyde form—a reverse nucleophilic addition reaction. The aldehyde then undergoes tautomerixa-tion to yield an enol, which undergoes yet another tautomerization to give the ketone fructose. 

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

A somewhat tedious extension of this methodology, which guarantees good induced stereoselectivity, relies on the reversible introduction of an a-substituent which is removed after the aldol addition is performed. For this purpose, the corresponding derivative of (methyl-thio)acetic acid is converted into the boron enolate and subsequently reacted with aldehydes. The... 

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