Stereoselectivity thermodynamic control

The surprising selectivity in the formation of 4 and 5 is apparently due to thermodynamic control (rapid equilibration via the 1,3-boratropic shift). Structures 4 and 5 are also the most reactive of those that are present at equilibrium, and consequently reactions with aldehydes are very selective. The homoallylic alcohol products are useful intermediates in stereoselective syntheses of trisubstituted butadienes via acid- or base-catalyzed Peterson eliminations. 

The Pummerer reaction346 of conformationally rigid 4-aryl-substituted thiane oxides with acetic anhydride was either stereoselective or stereospecific, and the rearrangement is mainly intermolecular, while the rate-determining step appears to be the E2 1,2-elimination of acetic acid from the acetoxysulfonium intermediates formed in the initial acetylation of the sulfoxide. The thermodynamically controlled product is the axial acetoxy isomer, while the kinetically controlled product is the equatorial isomer that is preferentially formed due to the facile access of the acetate to the equatorial position347. The overall mechanism is illustrated in equation 129. 

Evans Jr. and coworkers reported a similar olefination reaction employing spirooxyphosphoranes of type 66. Upon treatment with a strong base (LiHMDS) and subsequent addition of benzaldehyde, the reaction proceeded to form anionic P(VI) intermediates (67,6 -106 to -116 ppm) that decomposed at room temperature to form the corresponding olefins and spiropentaoxyphosphoranes [ 105]. The stereoselectivity (E Z ratio) of the double bond-forming reaction depended upon the conditions evidence indicated the possibility of kinetic or thermodynamic control (Scheme 21). 

There are very few examples of asymmetric synthesis using optically pure ions as chiral-inducing agents for the control of the configuration at the metal center. Chiral anions for such an apphcation have recently been reviewed by Lacour [19]. For example, the chiral enantiomerically pure Trisphat anion was successfully used for the stereoselective synthesis of tris-diimine-Fe(ll) complex, made configurationally stable because of the presence of a tetradentate bis(l,10-phenanthroline) ligand (Fig. 9) [29]. Excellent diastereoselectivity (>20 1) was demonstrated as a consequence of the preferred homochiral association of the anion and the iron(ll) complex and evidence for a thermodynamic control of the selectivity was obtained. The two diastereoisomers can be efficiently separated by ion-pair chromatography on silica gel plates with excellent yields. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Trimethyl aconitate can be cyclodimer-ized in 75% yield and a high stereoselectivity to a pentamethyl l-(2-methoxy-2-oxoethyl)- ,2,3,4,5-cyclopentane pentacar-boxylate. Product formation is initiated by an electrogenerated base that induces a catalytic cycle of two successive Michael additions. The most stable out of 16 possible diastereomers is formed, which indicates that the tandem Michael addition is thermodynamically controlled [282]. 

The directing effect of the amide group can then be used a second time in the lateral lithiation of 503 to give an organolithium 507 which adds to the imine 508 in a stereoselective manner, probably under thermodynamic control (imine additions of laterally lithiated amides appear to be reversible). Warming the reaction mixture to room temperature leads to a mixture of 509 and some of the (ultimately required) cyclized product... 

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. 

Both type A and B transformations are kinetically controlled and, therefore, the stereochemical result is based on an energetic comparison of transition states. By contrast, there is a large group of reactions where stereoselective bond formation occurs under thermodynamic control, and the stereoselectivity stems from the energy difference of the stereoisomeric products. Section 2.3.6. describes some pertinent examples. 

All of the stereoselective transformations described so far originate from kinetic control. Therefore, the ratio of stereoisomers obtained does not reflect their relative energies and, provided that the reaction conditions allow a subsequent equilibration, this ratio may change during prolonged reaction periods. The two principal possibilities arising from thermodynamically controlled (equilibrating) conditions and are shown below. 

Hence to achieve high stereoselectivity with these systems, one has to rely on thermodynamic control. 

However, orbital factors may override thermodynamic control. For example, the regiochemistry of nucleophilic attack on the bridged norcaradiene radical cation 122 shows a significant deviation from thermodynamic control. Although attack on the cyclopropane ring should be favored by both release of ring strain and formation of delocalized free radicals (cf. Scheme 6.8), methanol attacks 122 " selectively at C2 (and C5), generating 123 and 124. There is little stereoselectivity Products derived from 123 and 124 were formed in comparable yields. ... 

The stereoselectivity of cyclization reactions conducted under conditions of thermodynamic control can often be reliably predicted by estimation or calculation of the energy differences between the diastereomers of the cyclization product (H) or its immediate precursor (G). It has been shown that, even in cases where the (G) to (H) step is not reversible, thermodynamic control of the diastereomer ratio can be influenced through the use of cyclization substrates in which the neutralization step (G to H) is the slow step, thus allowing for equilibration of the diastereomers of (G). Thermodynamic equilibration of dia-stereomeric products will occur only if the reaction reverses to starting materials (A), or interconversion of the diastereomers of the intermediates (B) or (C) occurs in some other way (e.g. the C to D interconversion can equilibrate diastereomers if E = X). 

Attempts to reduce the quaternary salts of 4-oxo-4//-pyrido[l,2-a]-pyrimidines with sodium borohydride or lithium aluminum hydride remained unsuccessful.137 At the same time the 6,7,8,9-tetrahydro quaternary salts may readily be reduced with sodium borohydride to the 1-alkyl-l,6,7,8,9,9a-hexahydro derivatives.75-77,133 1481269 270 Sodium borohydride reduction of the 1,6- and l,7-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidinium salts proceeds stereoselectively and yields the thermodynamically controlled product.271 The l-methyl-3-carbamoyl-4-oxo-l,6,7,8,9,9a-hexahydropyrido[l,2-a]pyrimidines were also prepared by the catalytic (Pd/C) hydrogenation of the 1,6,7,8-tetrahydro derivatives,270-272 but this reaction led to a diastereoisomeric mixture.271... 

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