Aldol Reaction Methodology and Stereochemistry

E. M. Carreira, Aldol Reaction Methodology and Stereochemistry in Modem Carbonyl Chemistry, Ed. J. Otera, Wiley-VCH, Weinheim, 2000, 227-248. 

Carreira EM. Aldol reaction methodology and stereochemistry. In Otera J, editor. Modern carbonyl chemistry. New York Wiley 2000. p 227-248. 

Methodology and stereochemistry of aldol reactions with participation of heterocycles 00MI7. 

The Diels-Alder reaction, now more than 60 years old, has regained new prominence with the ability to use asymmetric technology to control relative and absolute stereochemistry while creating two new carbon-carbon bonds.1 3-5 6 As a result of the diversity of dienes and dienophiles, the application of asymmetric methodology to the Diels-Alder reaction has lagged behind other areas such as aldol reactions.3 However, considerable advances have been made in recent years through the use of chiral dienophiles and catalysts.3 6 21... 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

Attempts to extend this methodology to a-sulfinyl derivatives of other esters have been only moderately successful. As shown in Scheme 14, ester (215) may be deprotonated by r-butylmagnesium bromide and added to aldehydes, although not to ketones. The intermediate P-hydroxy-a-sulfinyl esters, in each case a mixture of diastereomers, are reduced to obtain diastereomeric mixtures of -hydroxy esters. The diastereomeric ratio of these materials does not reveal the degree of asymmetric induction in the original aldol reactions, because of the unknown stereochemistry of the desulf urization step. Aldols (216) were converted by a three-step process into secondary alcohols (217), which were found to have isomeric purities of 33.5% enantiomeric excess for R = Ph and 80% enantiomeric excess for R = n-heptyl. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

Diastereoselective radical allylations have been studied in many different contexts, and a plethora of information exists regarding stereocontrol in these reactions. Allylations have been performed using the traditional trapping and )9-elimination sequence occurring typically with allylstannanes as well as a stepwise atom transfer/ elimination sequence found to occur with allylsilanes. Stereochemistry is commonly controlled through the use of chiral auxiliaries or by 1,2-induction, and functionalized anh -aldol and amino acid products are available using this established methodology. 

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