Metal stabilization, enolates

As mentioned earlier, metal complexation not only allows isolation of the QM derivatives but can also dramatically modify their reactivity patterns.29o-QMs are important intermediates in numerous synthetic and biological processes, in which the exocyclic carbon exhibits an electrophilic character.30-33 In contrast, a metal-stabilized o-QM can react as a base or nucleophile (Scheme 3.16).29 For instance, protonation of the Ir-T 4-QM complex 24 by one equivalent of HBF4 gave the initial oxo-dienyl complex 25, while in the presence of an excess of acid the dicationic complex 26 was obtained. Reaction of 24 with I2 led to the formation of new oxo-dienyl complex 27, instead of the expected oxidation of the complex and elimination of the free o-QM. Such reactivity of the exocyclic methylene group can be compared with the reactivity of electron-rich enol acetates or enol silyl ethers, which undergo electrophilic iodination.34... 

Cationic vinylidene complexes can be considered to be metal-stabilized vinyl cations in purely organic chemistry, vinyl cations can be obtained by dissociation of the super leaving group, TfO-, from the esters obtained from enolate anions and Tf20. 

The Novartis Institute for BioMedical Research in Basel, Switzerland, and the University of Hull, UK, performed the diastereoselective alkylation of metal-stabilized enolates using a pressure-driven microreactor at — 100°C, whereby increased conversions and diastereoselectivity were observed compared to the batch process [20]. 

Another group of sugar epimerases, which uses a metal cofactor instead of NADH/NAD+, takes an entirely different approach to epimerization. L-ribulose 5-phosphate 4-epimerase, which is involved in the bacterial metabolism of arabinose, performs a retro-aldol cleavage of a C-C bond to yield a metal-stabilized enolate of dihydroxyacetone and glycoaldehyde phosphate, similar to the reaction catalyzed by class II aldolases [77-79]. The glycoaldehyde phosphate is thought to rotate, such that addition of the enolate generates the isomeric product. 

Epimerases and racemases may or may not employ enzyme cofactors (organic or inorganic) to activate the stereogenic center of the substrate. Common cofactor-stabilized intermediates include resonance-stabilized carbanions and metal-stabilized enolates. The substrate itself can be intrinsically activated if the stereogenic center is adjacent to a carbonyl or carboxylate group. A preponderance of racemases and epimerases act on activated substrates. A number of sugar and sugar nucleotide epimerases act on unactivated substrates. Double proton transfers may proceed, in principle, by either a one- or two-base mechanism. However, only two-base mechanisms have been observed for racemases. 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

Seebach s topological rule suggesting a preference of synclinal donor/acceptor orientations in a Newman projection along the forming bond cf. Figure 5.8, [60]). For ZfOj-enolates, additional stabilization can be had by metal chelation with the ether oxygen cf. Figure 6.4d). 

Addition Reactions of Metal Enolates of Non-stabilized Esters, Amides, and Ketones to Epoxides... 

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

One more example of metal ion catalysis will be considered briefly. In a now classic paper, Cox (1974) showed that the enolization of 2-acetylpyri-dine (but not 4-acetylpyridine) is catalysed by divalent transition metal ions. Proton abstraction by acetate ions is strongly accelerated by Zn2+, Ni2+ and Cu2+ ions and the transition state stabilization by these ions roughly parallels their abilities to bind to the substrate (Table A6.5). The three metal ions are significantly superior to the proton as electrophilic catalysts, no doubt because they can chelate to both the pyridine nitrogen and the... 

The preferential -configuration of the enol esters, derived from p-dicarbonyl compounds under phase-transfer conditions, contrasts with the formation of the Z-enol esters when the reaction is carried out by classical procedures using alkali metal alkoxides. In the latter case, the U form of the intermediate enolate anion is stabilized by chelation with the alkali metal cation, thereby promoting the exclusive formation of the Z-enol ester (9) (Scheme 3.5), whereas the formation of the ion-pair with the quaternary ammonium cation allows the carbanion to adopt the thermodynamically more stable sickle or W forms, (7) and (8), which lead to the E-enol esters (10) [54],... 

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. 

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