Enolization power

Titanium(IV) is a powerful but selective Lewis acid which can promote the coupling of allylsilanes with carbonyl compounds and derivatives In the presence of titanium tetrachlonde, benzalacetone reacts with allyltnmethylsilane by 1,4-addition to give 4-PHENYL-6-HEPTEN-2-ONE. Similarly, the enol silyl ether of cyclopentanone is coupled with f-pentyl chloride using titanium tetrachlonde to give 2-(tert-PENTYL)CYCLOPENTANONE, an example of a-tert-alkylation of ketones. 

Amino substituents on a carbon-carbon double bond enhance the nucleophilicity of the p carbon to an even greater extent flian the hydroxyl group in enols. This is because of the greater electron-donating power of nitrogen. Such compounds are called enamines. ... 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

The Sn2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C-C bonds, thereby building up larger molecules from smaller precursors. We ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Schemes 28 and 29 illustrate Curran s synthesis of ( )-hirsutene [( )-1]. Luche reduction58 of 2-methylcyclopentenone (137), followed by acetylation of the resulting allylic alcohol, furnishes allylic acetate 138. Although only one allylic acetate stereoisomer is illustrated in Scheme 28, compound 138 is, of course, produced in racemic form. By way of the powerful Ireland ester enolate Clai-sen rearrangement,59 compound 138 can be transformed to y,S-unsaturated tm-butyldimethylsilyl ester 140 via the silyl ketene acetal intermediate 139. In 140, the silyl ester function and the methyl-substituted ring double bond occupy neighboring regions of space, a circumstance that favors a phenylselenolactonization reac-...

A powerful variation of the iron acetyl enolate aldol reaction utilizes the cnolate of complex 8 which bears a (pentafluorophenyl)diphenylphosphane ligand in place of the more usual triphenylphosphane47. The enolate species 9. prepared by treatment of 8 with lithium diiso-propylamide, reacts at — 78 °C with benzaldehyde to produce the aldol adduct 10 with a d.r. of 98.5 1.5. 

In this case, the enol form is not more stable than the keto form (115). The enol form is less stable, and converts to the keto form upon prolonged heating. It can, however, be kept at room temperature for long periods of time because the tautomerization reaction (12-3) is very slow, owing to the electron-withdrawing power of the fluorines. 

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

High antiscorbutic power is also reported to be shown by a derivative of L-ascorbic acid in which the enolic hydroxyl group at C2 is replaced by an amino group. 3,4-Isopropylidene-L-threonic acid (LX), prepared from 5,6-isopropylidene-L-ascorbic acid, is converted into the 2-acetyl-3,4-isopropylidene-L-threonyl chloride (LXI) and this is then allowed to react with the sodium derivative of ethyl malonate. 

Exploitation of time-resolved spectroscopy allows the direct observation of the reactive intermediates (i.e., ion-radical pair) involved in the oxidation of enol silyl ether (ESE) by photoactivated chloranil (3CA ), and their temporal evolution to the enone and adduct in the following way.41c Photoexcitation of chloranil (at lexc = 355 nm) produces excited chloranil triplet (3CA ) which is a powerful electron acceptor (EKelectron-rich enol silyl ethers (Em = 1.0-1.5 V versus SCE) to the ion-radical pair with unit quantum yield, both in dichloromethane and in acetonitrile (equation 20). 

From the reactions shown in Scheme 5, it is obvious that only those uronic acid derivatives whose elimination proceeds with the formation of enolic or aldehydic groups, or both, afford products capable of reducing the Cu(II) ion. Although such structures can be expected from hexo- and hepto-furanuronic, as well as from hep-topyranuronic, acid derivatives, glycosides of pentofuranuronic and of hexopyranuronic acid derivatives do not exhibit reducing properties. However, in view of this generalization, the zero reducing power observed for compound 26 requires a different explanation. 

Finally, production of tricyclic array 153 (Scheme 24) required cyclization of bicyclic ester 151 in which additional oxygenation was present in the olefinic appendage. The successful conversion to enol ether 152 demonstrated further the power of the method and led to the JKF fragment 153 [34b]. 

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

The intermediate enol silyl ether permits further regioselective substitutions such as bromination followed by dehydrobromination (Eq. 81)49> and alkylation (Eqs. 82 93) and 83 103)). Thus, in addition to activating the rearrangement, the oxygen substituent regioselectivity creates an enol silyl ether, a powerful enolate synthon. 

Silyl enol ethers are powerful intermediates in organic synthesis. Reactions of silyl enol ethers with various electrophiles provide effective methods for the synthesis of various carbonyl compounds. In this section we will briefly touch on the electrochemical reactions of silyl enol ethers and related compounds. The electrochemical behaviour of silyl enol ethers is expected to be closely related to that of allylsilanes and benzylsilanes because silyl enol ethers also have a silyl group ft to the re-system. 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

OTHER EXAMPLES OF KINETIC ISOTOPE EFFECTS. The power of kinetic isotope effects in enzymol-ogy is well illustrated in the work of Rose ° and Knowles deahng with hydrogen effects in proton transfer to and from carbon. Abstraction of a proton from a tetrahedral carbon is a fundamental step in many enzyme-catalyzed reactions. Intramolecular proton transfer as well as partial loss (wash-out) migrating protons have provided important clues in mechanistic investigations. Enol and enediolate formation constitute several... 

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