Enolization consequences

It is important that the indicator color, showing a small excess of strong base, not be discharged completely since the presence of any excess enol acetate or ketone will permit equilibration of the isomeric metal enolates. Consequently, the addition of this reactant is complete if further additions will discharge completely the color of the indicator. 

Diketones are converted into pyranones on treatment with malonyl dichloride, involving both C- and O-acylation (63JCS4483). The reaction between benzoylacetone and the acid chloride gives only one pyranone in accordance with a preferred direction of enolization consequent upon the unsymmetrical nature of the diketone a 5-acetyl-6-phenylpyranone results rather than the 5-benzoyl-6-methyl isomer. There is still some uncertainty as to whether the product is the 4-hydroxypyran-2-one (409) or the tautomer, but the former is considered to be the more likely. There is yet further controversy, since... 

Baldwin concluded that the remarkable difference between these two cycliza-tions results from stereoelectronic control of the alkylation of the amhi-dent nucleophile, i.e. the enolate ion. For such an ion, carbon alkylation requires approach of the electrophile perpendicular to the plane of the enolate, whereas oxygen alkylation requires approach in the plane of the enolate. Consequently, in the five-membered ring case, the C-alkylation process 196A 198 (which can be considered as a 5-Endo-trigonal process) is sterically difficult, but not the 0-alkylation process 196B 197 (a 5-Exo-tetrahedral process). 

Accordingly, trimethylsilyl enol ethers are enolate precursors (Figure 10.16). Fortunately, they can be prepared in many ways. For instance, silyl enol ethers are produced in the silylation of ammonium enolates. Such ammonium enolates can be generated at higher temperature by partial deprotonation of ketones with triethylamine (Figure 10.18). The incompleteness of this reaction makes this deprotonation reversible. Therefore, the regioselectivity of such deprotonations is subject to thermodynamic control and assures the preferential formation of the more stable enolate. Consequently, upon... 

A further investigation was carried out to determine whether the trends observed during the azidation studies of imide enolates (see previous section) were applicable to other types of enolates. Consequently dihydrocinnamate 1 was chosen as a typical ester enolate2. 

Having learned about the synthesis and properties of enolates, we can now turn our attention to their reactions. Like enols, enolates are nucleophiles, but because they are negatively charged, enolates are much more nucleophilic than neutral enols. Consequently, they undergo a wider variety of reactions. 

The Kunz group further demonstrated the asymmetric s)uithesis of )3-alkylated a-halogenated (Cl or Br) carboxylic acid derivatives. Eor this purpose, the Al-functionalized D-galactosamine-derived oxazolidinone 52 was treated with dialkylaluminum chloride, which was followed by addition of NXS (X = Cl, Br) to trap the intermediary enolate. Consequently, a variety of j8-branched a-halo carboxylic acid derivatives were obtained with good diastereoselectivities [63]. 

XXXI). It is possible, therefore, to determine independently the rate of racemization and enolization. It was found that the rate of racemization was about twice that of enolization. Consequently, racemization cannot be due solely to the intermediate formation of the neutral enol. 

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

Most of the currently applied protocols for rhodium-catalyzed conjugate addition chemistry involve the use of aqueous solvent systems which ensure catalytic turnover by protonation of the intermediate rhodium enolate. Consequently, tandem reaction sequences with electrophiles other than a proton are troublesome. In early investigations, Hayashi reported a rhodium/BINAP-catalyzed conjugate addition-aldol reaction under anhydrous conditions by use of 9-aryl-9-borabicyclo[3.3.1]no nanes (9-Ar-9-BBN) as aryl sources [117]. The reaction between tert-butyl vinyl ketone (145) with 9-(4-fluorophenyl)-9-BBN (146) and propionaldehyde (147) led to the formation of a syn/anti-mixiuve of 148 in a 0.8 to 1 ratio (Scheme 8.39). 

The steric requirement of the substituent R in EtCOR also plays a significant role in the control of enolate geometry. The smaller R groups favor the formation of Z-enolates, while bulkier R groups favor the formation of -enolate. Consequently, EtCOBu-f with all the RjBX (except RjBI) favor the formation of -enolborinate, either exclusively or predominantly (Table 20.5) [11]. 

The enol form is thus temporarily removed from the solution and the ferric chloride colouration produced by the enol form consequently disappears and the solution becomes colourless. Some of the unchanged keto form of the ester then passes into the enol form in order to restore the original equilibrium and the ferric chloride colouration therefore reappears. 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

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... 

A consequence of this mechanism is that the reaction is stereospecific with respect to the E- or Z-configuration of the enolate. The E-enolate will give the anti aldol product whereas the Z-enolate will give the syn aldol. 

If the equilibrium were established rapidly, reduction of the free ketone as it formed would result in a substantial loss of product. Lithium enolates are more covalent in character than are those of sodium and potassium and consequently are the least basic of the group. This lower thermodynamic basicity appears to be paralleled by a lower kinetic basicity several workers have shown that lithium enolates are weaker bases in the kinetic sense than are those of sodium and potassium." As noted earlier, conjugated enones... 

Carbohydrates undergo a number of isomerization and degradation reactions under both laboratory and physiological conditions. For example, a mixture of glucose, fructose, and mannose results when any one of them is treated with aqueous base. This reaction can be understood by examining the consequences of enolization of glucose ... 

The problem of nitrogen alkylation of enamines, which one encounters with alkyl halides, is of no consequence in alkylations with positively activated olefins, since the generation of amonium salts can be expected to be reversible in these cases. Thus such enamine alkylations are obviously attractive to the synthetic chemist. Their particular importance, however, arises from avoidance of the serious obstacles often found with parallel enolate anion reactions. 

Two different alkenes can be brought to reaction to give a [2 -I- 2] cycloaddition product. If one of the reactants is an o, /3-unsaturated ketone 11, this will be easier to bring to an excited state than an ordinary alkene or an enol ether e.g. 12. Consequently the excited carbonyl compound reacts with the ground state enol ether. By a competing reaction pathway, the Patemo-Buchi reaction of the 0, /3-unsaturated ketone may lead to formation of an oxetane, which however shall not be taken into account here ... 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

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