Enols from enolate reprotonation

Removal of an a-proton from a P,y-unsaturated ketone generates an enolate anion, and this might be transformed back to the P,y-unsaturated compound by reprotonation at the a-position. However, this does not occur because the enolate anion now has conjugated double bonds, and we can propose an alternative mechanism for reprotonation, invoking... 

This is an equilibrium reaction, and it raises a couple of points. First, there are two a-positions in the ketone, so what about the COCH3-derived enolate anion The answer is that it is formed, but since the CH3 group is not chiral, proton removal and reprotonation have no consequence. Racemization only occurs where we have a chiral a-carbon carrying a hydrogen substituent. Second, the enolate anion resonance structure with charge on carbon is not planar, but roughly tetrahedral. If we reprotonate this, it must occur from just one side. Yes, but both enantiomeric forms of the carbanion will be produced, so we shall still get the racemic mixture. 

At higher concentrations of acetaldehyde, bimolecular trapping of the enolate in Scheme 4.7 will become faster, so, at some stage, this will compete effectively with the reprotonation of the enolate. When the bimolecular capture of enolate by another acetaldehyde molecule becomes much faster than the reprotonation of the enolate, i.e. when /c4[CH3CHO] k, 1 + k-2[H+] + /c 3[BH+], another limiting approximation to the complex rate equation predicted from the mechanism (Equation 4.17) is obtained, Equation 4.19 ... 

The mechanism for basic hydrolysis begins with attack by hydroxide on the electrophilic carbon of the cyano group. Protonation gives the unstable enol tautomer of an amide. Removal of a proton from oxygen and reprotonation on nitrogen gives the amide. Further hydrolysis of the amide to the carboxylate salt involves the same base-promoted mechanism as that already discussed. 

Another base-catalyzed side reaction is the enediol rearrangement, which moves the carbonyl group up and down the chain, as shown in Mechanism 23-3. If the enolate ion (formed by removal of a proton on C2) reprotonates on the Cl oxygen, an enediol intermediate results. Removal of a proton from the C2 oxygen and reprotonation on Cl gives fructose, a ketose. 

Diethyl malonate adds to diethyl fumarate in a conjugate addition reaction promoted by sodium ethoxide in dry ethanol to give a tetraester, Diethyl fumarate is an excellent Michael acceptor because two ester groups withdraw electrons from the alkene, The mechanism involves deprotonation of the malonate, conjugate addition, and reprotonation of the product enolate by ethanol solvent, In this reaction two ester groups stabilize the enolate and two more promote conjugate addition. 

The kinetic reprotonation by a series of carbonyl-based acids, of the lithium enolate obtained from 2,4-dimethyltetralone either by LDA-mediated deprotonation or by cleavage of its silyl enol ether, was studied by Eames (Scheme 71)352. The diastereoselective ratio, close to the thermodynamic value, obtained with methanol (pKa = 29 in DMSO) is probably due to equilibration. The difference observed in the presence of an additive was interpreted as the result of a fine balance between the coordinating ability, the intrinsic acidity, and probably the concentration of the enolic form of the cyclic and linear dicarbonyl acidic compounds. 

C-3 hydrogen to form the biradical 134 which partitions between disproportion to enol and reversal to starting material, has been questioned on a number of grounds 101). An alternative which has been suggested is that excited triplet states of these diones have zwitterionic character involving some positive charge on C-2 which facilitates loss of a proton from C-3 followed by reprotonation on oxygen. A bimolecular mechanism is not consistent with the observed results. 

HMPT). These results were explained by a postenohzation complex 210 (Figure 10.19), in which the protonated amide base is still in close contact with the enolate. The attack of the methyl iodide preferentially takes place from the less hindered it-face of the double bond. With LHMDS, the approach of the electrophile is hindered by the bulky TMS-groups, and an internal proton return from the amide base to the enolate becomes a competing process. The consequences of the reprotonation are low yields of methylated products and the recovery of the corresponding amount of starting material. 

Oxaloacetate is activated by the transfer of a proton from His 320 to its carbonyl carbon atom. (3) Simultaneously, the enol of acetyl CoA attacks the carbonyl carbon of oxaloacetate to form a carbon-carbon bond linking acetyl CoA and oxaloacetate. His 274 IS reprotonated. Citryl CoA is formed. His 274 participates again as a proton donor to hydrolyze the thioester (not shown), yielding citrate and CoA. 

The keto-sugar nucleotide dTDP-L-rhamnose is synthesized from dTDP-4-keto-6-deoxy-D-glucose by dTDP-i-rhamnose synthase [104, 105). The enzyme consists of two components, a cofactor independent epimerase and an NADH-dependent reductase. The epimerase component is inactive without the reductase component. The mechanism involves epimerization of two stereocenters flanking a carbonyl group, via sequential deprotonation/reprotonation, with two enol intermediates. Complete solvent isotope incorporation into both epimerized stereocenters was observed, and primary substrate-derived KIEs have been determined [104],... 

An unusual case of internal proton return in a highly chirotopic environment was reported for the L-alanine derivative ( + )-2. On deprotonation with less than one equivalent of LDA in the presence of lithium bromide, and alkylation with iodomethane, 3 is isolated in which the methyl group has entered the ring from the less hindered side (sec also Section 2.1.4.2.). However, complete epimerization of the side chain occurred during this alkylation reaction. Deprotonation first produces the ester enolate. This enolate is selectively reprotonated from the less hindered side by internal proton transfer which produces the starting material for the alkvla-tiony5a. 

The lithium enolate derived from (2S//5)-l-tert-butoxycarbonyl-2-tcrt-butyl-3-methyl-4-imida-zolinone [(S)-l or (7J)-1], an optically active derivative of glycine, is stercosclectively attacked by electrophiles from the less hindered side. Alkylation of (S)-l yields the (S,S)-isomer which can be hydrolyzed to the (S)-amino acid. If, however, the (S.S)-isomer is again deprotonated then reprotonated, complete inversion (>92%) gives the (S,7J)-isomer, which consequently yields the (TJ)-amino acid on hydrolysis110 1106. 

The resulting enol intermediate 26 is reprotonized in a stereospecific mode affording the l(5) enantiomer the proton used for reprotonation at C-3 is introduced from bulk water. The stereochemistry of the rearrangement reaction has been studied in some detail. ... 

The phrase conducted tour mechanism was coined by Cram to describe the removal of a proton by a base and its subsequent return to a different face of the same molecule from which it was removed [Ij. Originally, the conducted tour mechanism was postulated to explain the observation that rates of racemization of deuterated carbon acids were faster than hydrogen-deuterium exchange in solutions of potassium r rr-butoxide/rerf-butyl alcohol. Thus, the basic catalyst takes hydrogen or deuterium on a conducted tour of the substrate from one face of the molecule to the [other] (ref. [1], p. 101). This process was envisioned as a rotation of the carbanion within the solvent cage. We now recognize that the secondary amine forms a mixed aggregate with the enolate, such that the reprotonation (and perhaps conformational motion) is intrasupramolecular. ... 

In solution, isotopic incorporation of deuterium from deuterated solvents into metal-bound hydrogen is common, e.g., reaction of acetone-reaction occurs between the Os complex and acetone even at reflux temperature thus the isotopic exchange with acetone-isotopic exchange may therefore occur via a deprotonation/reprotonation pathway coupled with a keto-enol tautomerization. 

When the acidic H on the carbon alpha to the carbonyl group is removed from either of these ketones, the same planar enolate anion is formed. When this enolate anion is reprotonated, the proton can add from either side, so an equilibrium mixture of the two ketones is formed. The stereoisomer on the left, with the fert-butyl group and the ethyl group cis, is the major component of the equilibrium mixture because it has both groups equatorial. The frans-isomer is less stable because it has the ethyl group in the axial position. 

Expectedly, since more highly substituted alkenes are more stable than less (Chapter 6), if equilibration of the enolate anions (through reprotonation and subsequent deprotonation) is permitted, alkylation will occur on the more highly substituted carbon (Figure 9.13). This is said to be the thermodynamic product since equilibration has occurred. Alternatively, when the rates of proton abstraction from one side or the other govern the product ratio (because the enolate anions do not have time to equilibrate before reacting), the product mixture reflects this and the kinetic product is obtained (Figure 9.13). 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

Alternatively, demetallation to give enol ethers 839 can be achieved by treatment with pyridine (Scheme 8.14). Under these conditions, as pyridine is a weak base, an equilibrium is established between the carbene 8.35 and its anion 837. The anion, however, can also reprotonate on chromium to give a chromium hydride 838. This is followed by reductive elimination. The enol ether 839 is obtained as its Z-isomer, a consequence of the carbene anion having S-geometry to keep the alkyl group away from the bulky Cr(CO)s moiety the chromium is converted into a pyridine complex. 

FIGURE 19.32 Reprotonation of the enolate from the two equivalent faces must give a pair of enantiomers. 

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