Catalysis enolization

A specially interesting case of the blocked carbonyl compound is the lactone or cyclic ester. Open-chain esters do not give aldol reactions they prefer a different reaction that is the subject of the next chapter. But lactones are in some ways quite like ketones and give unsaturated carbonyl products under basic catalysis. Enolization is unambiguous because the ester oxygen atom blocks enolization on one side. 

The availibility of three geometric isomers of our artificial enzyme lets us examine other reactions that can show bifunctional catalysis. Enolization of a ketone— and its addition to an aldehyde group in an aldol condensation—are two cases examined so far in which an isomer of our catalyst is preferred that is not the one that was best in the ribonuclease mimic. The geometric preference indicates something novel about the geometry of enolization reactions. 

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. 

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

The chemoselective desilylation of one of the two different silyi enoi ethers in 10 to give the monosilyl enol ether II is realized by the Pd-catalyzed reaction of Bu3SnF. The chemoselectivity is controlled by steric congestion and the relative amount of the reagent[7,8]. An interesting transformation of the 6-alkoxy-2,3-dihydro-6//-pyran-3-one 12 into the cyclopentenone derivative 13 proceeds smoothly with catalysis by Pd(OAc)2 (10 mol%)[9]. 

NaH must be used when the starting thiazolones are not easily enolized (453, 467). Phase-transfer catalysis could be helpful for this t pe of reactivity. 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

Reactions 33 and 35 constitute the two principal reactions of alkyl hydroperoxides with metal complexes and are the most common pathway for catalysis of LPOs (2). Both manganese and cobalt are especially effective in these reactions. There is extensive evidence that the oxidation of intermediate ketones is enhanced by a manganese catalyst, probably through an enol mechanism (34,96,183—185). 

Ketones with labile hydrogen atoms undergo enol acetylation on reaction with ketene. Strong acid catalysis is required. If acetone is used, isoptopenyl acetate [108-22-5] (10) is formed (82—85). Isopropenyl acetate is the starting material for the production of 2,4-pentanedione (acetylacetone) [123-54-6] (11). 

CS indicated that the enolate of acetyl-CoA is significantly more stable than the enol or a proton-sharing enolic form and thus do not support the proposal that a low barrier hydrogen bond is involved in catalysis in CS. This study demonstrates the practial application of high level QM-MM studies to the elucidation of mechanistic details of an enzymatic reaction that are otherwise unclear. 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

Solutions of unstable enols of simple ketones and aldehydes can also be generated in water by addition of a solution of the enolate to water. The initial protonation takes place on oxygen, generating the enol, which is then ketonized at a rate that depends on the solution pH. The ketonization exhibits both acid and base catalysis. Acid catalysis involves C-protonation with concerted 0-deprotonation. 

In agreement with expectation for a rate-determining proton transfer, the reaction shows general acid catalysis. Base-catalyzed ketonization occurs by C-protonation of the enolate. 

The selectivity is probably impaired by bromination at C-2 and C-9. Bromination under buffered conditions of the A -enol acetate prepared from acetic anhydride with perchloric acid catalysis may give better results. See also ref. 55 for a similar bromination. 

Similarly, with two equivalents of DDQ, A -3-ketones give A -3-ketones in good yield ( 70%), without isolation of the intermediate A -3-ke-tone/ These trienones are also obtainable directly from A -3-alcohols with three equivalents of DDQ in refluxing dioxane (20 hr), and the overall yield ( 50%) compares favorably with less direct methods. The direct formation of A -3-ketones from A -3-ketones with acid catalysis is not successful. Enol derivatives have proven to be useful for the preparation... 

The use of A -enol ethers as substrates for dehydrogenation is often attractive. Aqueous acetone at room temperature gives yields ranging from 70 to 88% other systems with acid catalysis have also been used, e.g. ... 

The reaction can be performed with base catalysis as well as acid catalysis. The former is more common here the enolizable carbonyl compound 1 is depro-tonated at the a-carbon by base (e.g. alkali hydroxide) to give the enolate anion 5, which is stabilized by resonance ... 

Keto-enol tautomerism of carbon) ] compounds is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the carbonyl oxygen atom to give an intermediate cation that Joses H+ from its a carbon to yield a neutral enol (Figure 22.1). This proton loss from the cation intermediate is similar to what occurs during an El reaction when a carbocation loses H+ to form an alkene (Section 11.10). 

As an alternative to lithium enolates. silyl enolates or ketene acetals may be used in a complementary route to pentanedioates. The reaction requires Lewis acid catalysis, for example aluminum trifluoromethanesulfonate (modest diastereoselectivity with unsaturated esters)72 74 antimony(V) chloride/tin(II) trifluoromethanesulfonate (predominant formation of anti-adducts with the more reactive a,/5-unsaturated thioesters)75 montmorillonite clay (modest to good yields but poor diastereoselectivity with unsaturated esters)76 or high pressure77. 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

This valuable method utilizes the O-TMS enol ethers derived from either pentane-2,4-dione or methyl acetoacetate, the former being the more reactive. Even t-alcohols are rapidly and quantitatively silylated in DMF at room temperature. A similar technique can be used to introduce the TBDMS group, although here ptsa catalysis is required (4). 

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

Recently, Akiyama et al. reported an enantiocontrolled [3+2] cycloaddition of chirally modified Fischer alkenylcarbene complexes 180 with aldimines 181 under Lewis-acid catalysis (Sn(OTf)2) to afford enantiomerically pure 1,2,5-trisubstituted 3-alkoxypyrrolines 182 (Scheme 40) [121]. The mode of formation of these products 182 was proposed to be a [4+2] cycloaddition, with the complexes 180 acting as a 1-metalla- 1,3-diene with subsequent reductive elimination. Upon hydrolysis under acidic conditions, the enol ethers give the enantiomerically pure 3-pyrrolidinones 183 (Table 9). 

The molecular mechanism of the enantioselective protonation reaction by antibody 14D9 was revealed by a crystal structure analysis [19[. A catalytic carboxyl group AspH 101 was found at the bottom of the catalytic pocket and found to be necessary for catalysis by mutagenesis to Asn or Ala. The mechanism or protonation involves an overall syn addition of water to the enol ether in a chiral binding pocket ensuring complete enantioselectivity (Figure 3.4). 

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