Enolates stereoisomerism

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

Assuming that a carbonyl compound 1 with a substituent Y (which may be either a heteroatomic substituent or an alkyl group) forms enolate 2 exclusively, and that the aldehyde 3 functions as the only carbonyl-active component12, four stereoisomeric products 4a, 4b, 5a, 5 b may result. 

The effect of HMPA on the reactivity of cyclopentanone enolate has been examined.44 This enolate is primarily a dimer, even in the presence of excess HMPA, but the reactivity increases by a factor of 7500 for a tenfold excess of HMPA at -50° C. The kinetics of the reaction with CH3I are consistent with the dimer being the active nucleophile. It should be kept in mind that the reactivity of regio- and stereoisomeric enolates may be different and the alkylation product ratio may not reflect the enolate composition. This issue was studied with 2-heptanone.45 Although kinetic deprotonation in THF favors the 1-enolate, a nearly equal mixture of C(l) and C(3) alkylation was observed. The inclusion of HMPA improved the C(l) selectivity to 11 1 and also markedly accelerated the rate of the reaction. These results are presumably due to increased reactivity and less competition from enolate isomerization in the presence of HMPA. 

The preference for chairlike TSs has been confirmed by using deuterium-labeled enolates prepared from the corresponding silyl enol ethers. The ratio of the location of the deuterium corresponds closely to the ratio of the stereoisomeric enolates for several aldehydes.4... 

The enolates derived from cyclic ketones are necessarily /(-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products. The stereoselectivity is about 5 1 in favor of the anti isomer under optimum... 

The general trend is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. There also are some advantages in terms of access to both stereoisomeric enol derivatives. Another important characteristic of boron enolates is that they are not subject to internal chelation. The tetracoordinate dialkylboron in the cyclic TS is not able to accept additional ligands, so there is no tendency to form a chelated TS when the aldehyde or enolate carries a donor substituent. Table 2.2 gives some typical data for boron enolates and shows the strong correspondence between enolate configuration and product stereochemistry. 

For many ketones, stereoisomeric as well as regioisomeric enolates can be formed, as is illustrated by entries 6, 7, and 8 of Scheme 1.3. The stereoselectivity of enolate formation, under conditions of either kinetic or thermodynamic control, can also be controlled to some extent. We will return to this topic in more detail in Chapter 2. 

Because the aldol reaction is reversible, it is possible to adjust reaction conditions so that the two stereoisomeric aldol products equilibrate. This can be done in the case of lithium enolates by keeping the reaction mixture at room temperature until the product composition reaches equilibrium. This has been done, for example, for the product from the reaction of the enolate of ethyl /-butyl ketone and benzaldehyde. 

The general trend then is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. They also have the advantage of providing access to both stereoisomeric enol derivatives. Table 2.3 gives a compilation of some of the data on stereoselectivity of aldol reactions with boron enolates. 

Enoate 3-substitution and 3-disubstitution cause a decrease in the rate of the initial conjugate addition step of the reaction sequence that is directly related to the steric bulk of the substituent.103,105 Equation (24) provides a representative case in the a-alkylation of enoates by means of conjugate amination-enol-ate alkylation followed by dehydroamination.106 When 3-substitution results in stereoisomeric ( )- and (Z)-alkenoate substrates, tandem difunctionalization typically proceeds with greater facility for ( )-isomers.64103 Obviously, when the double bond of the ester is part of a medium-sized ring, an ( )-alke-noate geometry is mandated in such cases, tandem vicinal difunctionalization proceeds with uniformly excellent results (equation 25).25... 

The stereoisomeric features of the intermediates and of the product of this reaction should be noted. Thus the silyl enol ether (14) can only have the (El-configuration. The product (16) has two chiral sites ( ) and the aldol is therefore a mixture of erythro/threo ketols in this case the ratio is 23 69. 

Stereochemical integrity may also be lost when the reaction of a stereoisomer occurs via an intermediate which retains a stereogenic element, but whose bonding permits interconversion of stereoisomers faster than its conversion of stereoisomeric products. [2 + 21-Cycloaddition of TCNE and cis-propenyl methyl ether [30] yields cis- and trans-adducts, 22 in Scheme 9.13, in ratios which depend on the solvent (84 16 in favour of the cis-adduct in acetonitrile). The dipolar 23 was proposed as an intermediate. The initial bonding destroys the double bond character between Cl and C2 of the enol ether reactant, and the much... 

The kinetically controlled nucleophilic addition of preformed lithium enolates onto carbonyl compounds is reversible with a low activation barrier, and the thermal conditions are likely to have a major impact on the stereoisomeric ratio of the final aldols through the retroaldolization and the thermodynamic equilibration of lithium enolates76. The tendency of aldolates to undergo retroaldolization increases with the stability of enolates, and when going from lithium to potassium. On the other hand, boron enolates usually undergo completely irreversible aldol reaction511,512. 

A very useful intermediate for the attachment of further functionalities to Cgo is obtained by reaction of the fullerene with 2-[(trimethylsilyl)oxy]buta-1,3-diene, followed by hydrolysis of the resulting silyl enol ether under formation of a fullerene-fused cyclohexanone (214) which is reduced to the racemic alcohol ( )-215 (Scheme 1.18).374 Because of their great synthetic potential, silyloxy-substituted dienes, such as Danishefsky diene type systems,375-377 have been widely used in the preparation of fullerene derivatives, mostly in the form of stereoisomeric mixtures.378-383... 

Isomeric enols have different acidity. The more stable (El-enol of phenylacetaldehyde (53) was found to be more acidic (pAla ) than its less stable (pAIe) stereoisomeric (Z)-enol. This was presumably due to the less sterically demanding ( )-enol or ( l-enolate being better solvated in water than the corresponding (Z)-stereoisomers. Increasing the... 

In their study of the stereochemistry of the 1,3-dipolar cycloaddition of azides to enol ethers (c/. Section 4.11.5.2.2), Huisgen and Szeimies (65CB1153) have reported NMR spectral data for some A -l,2,3-triazolines. On the basis of the chemical shifts and coupling constants of H-4 and H-5, structural assignment of the stereoisomeric triazolines (28) and (29) was made as shown. 

In studies directed towaids the synthesis of the fungal isonitrile antibiotic isonitrin B (103), a cy-clopentanoid metabolite related to trichoviridine (104), various trialkylsilyl enol ethers were irradiated with propionaldehyde to produce equimolar amounts of stereoisomeric bicyclic oxetanes (105). The corresponding silyl dienol ethers, however, gave little oxetane product owing to preferential diene photopolymerization. The use of vinyl epoxide derivatives such as (106), however, offers a possible access to the epoxycyclopentanoid system with simultaneous control of the face selectivity of the photoaddition by the epoxide moiety. 

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