Aldol cyclization, kinetic control

The first results which indicate that stereoelectronic effects play an important role in the aldol condensation were reported by Hajos and Parrish (6) who found that (a) triketone J8 cyclizes to the bicyclo[3.2.1]octane ketol on treatment with piperidinium acetate in water and (b) ketol 19 undergoes an epimerization at C-4 yielding the more stable isomeric ketol 20 on treatment with piperidine. The authors concluded that the formation of ketol 19 from 18 under kinetically controlled conditions is the result of... 

It is noteworthy that - in principle - other cyclization products can also result from the diketone 129. Evidently, conjugation to the aromatic ring stabilized the enolate formed by deprotonation of the acetyl side chain at C-1 of 129 in such a way that this anion reacted as the nucleophile in kinetically controlled aldol reactions. 

The mode of intramolecular aldol cyclization of 1,5-diketones (113) has been shown to be strongly dependent on reaction conditions. Treatment of (113) with strong bases (e.g. LDA) in aprotic solvents leads to the kinetically controlled product... 

Whereas in principle the reaction of (487) with alkali may give rise to either tetra-substituted (488) or trisubstituted (489) enones, the latter have not been obtained from such a reaction in the cyclopentenone series. This could arise if (488) is the kinetic product or if (489) is formed reversibly with (488) as the kinetic product. When (489 R = Pr") was exposed to reaction conditions which convert (487) into (488) the starting material was recovered unchanged. Also, under cyclization conditions aldol (490) gave only (489 R = Pr") (487 R = Pr") was cyclized to a 94 6 mixture of (488 R = Pr") and (489 R = Pr"). Reversibility of enolate formation was demonstrated by quenching a reaction run in deuteriated solvent, when [ Hg] (487 R = Pr ) was recovered. It was concluded that under the reaction conditions kinetic control operates at the aldol step, with the transition state for cyclization of the eno-... 

There are different approaches for stereocontrol for the Robinson annulation the control can either arise fi-om the inherent nature of the starting ketone and/or the vinyl ketones substituents in combination with the reaction conditions, or by the use of a chiral catalyst. In the first case, an example is the stereoselective aldol cyclization to give the ketol intermediate 50. In this case the cyclization is kinetically controlled under protic basic conditions of sodium ethoxide and ethanol as it gives the cw-fused adduct rather than the more stable trans-fased ketol, which is not detected at any time during the reaction. 

Intramolecular acid-catalysed aldol cyclization of 2,3,7-triketoesters forms 1,2-anti-and 1,2-i yn-tetrasubstituted cyclopentanones with high diastereoselectivities under kinetic control, when catalysed by Lewis and Brpnsted acid catalysts, respectively. 0... 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

FDP aldolase exhibits kinetic diastereoselectivity with unnatural chiral aldehyde acceptor substrates. However, even though there is significant discrimination ( 20 1) between the d- and t-enantiomers of the natural substrate Gly 3-P12S1, this is usually not the case with unnatural aldehydes. In fact, resolutions of racemic aldehydes are normally only successful if carried out under thermodynamic control. Often the aldol products can cyclize via formation of a hemiketal, leading to... 

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