Chiral auxiliaries cyclocondensations

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

Methods to control the absolute stereochemistry of the products obtained from the cyclocondensation reaction have also been developed. The use of both chiral auxiliary based methods and chiral catalysts have been investigated. The first and most straightforward method of controlling absolute stereochemistry is the use of a chiral and optically pure aldehyde. All of the methodology developed for the control of relative stereochemistry can then be directly applied to give optically pure cyclocondensation products. In many cases, however, the synthesis of optically pure aldehydes is difficult (if not impossible) due to their tendency to undergo racemization under the reaction conditions. This method also suffers from the fact that only chiral aldehydes can be used in the cyclocondensation reaction to get optically pure products simple and readily available achiral aldehydes can not be used. 

To achieve high stereoselectivity applicable to any aldehyde in the cyclocondensation reaction the use of double diastereofacial selectivity has been investigated. These studies revealed an interesting relationship between the chiral catalyst used in the reaction and the chiral auxiliary. Contrary to the notion that the selectivity of a chiral diene and chiral dienophile are enhanced only in a matched pair, the interactivity of a chiral catalyst with a chiral diene where the two individual components have an opposite facial preference seems to give a high degree of asymmetric induction in the cyclocondensation reaction. ... 

A variety of methods are now available to control the relative and absolute stereochemistry of the cyclocondensation reaction of activated dienes with aldehydes. Chiral aldehydes that posses a high degree of diastereofacial selectivity with a variety of dienes can be used and the stereoselectivity controlled by the choice of diene, aldehyde and catalyst. Chiral dienes in combination with chiral catalysts can also be used in an unusual process of double diastereofacial selectivity. The resulting adducts can be purified and eliminated to give optically pure dihydropyrones. The chiral auxiliary can be isolated and reused if... 

The analogous cyclocondensation of the alkaloid (-)-ephedrine with urea gives (4i ,55)-l,5-dimethyl-4-phenylimidazolidin-2-one 2. This compound can be used as a chiral auxiliary for asymmetric syntheses [124] ... 

Hydroxy-4-phenyl-P-lactams. The lithium enolate of (silyloxy)acetates (2) couple with the N-(trimethylsilyl)imine 3 to give 3-hydroxy-4-aryl- -lactams (4). The stereoselectivity depends in part on the size of the silyloxy group but mainly on the ester group. Use of either (+)- or (—)-/ra/w-2-phenyl-l-cyclohexyl (I) as the chiral auxiliary results entirely in a cw-/3-lactam (4) in 80% yield and 96-98% ee. Use of (-)-menthyl or of Oppolzer s D-isobornyl auxiliary (12,103-104) results in lower yields and enantioselectivity. The cyclocondensation with the ester 2 from (-)-l results in (3R,4S)-4 in 96% ee. On desilylation and acid hydrolysis, this lactam provides (2R,3S)-... 

In addition to providing excellent diastereoselection in the cyclocondensation process, the chiral oxa-zolidinone auxiliary can be reductively removed to give the enantiomerically pure 3-amino-3 lactam in good overall yields (Scheme 16). Homochiral 1,4-imidazolidinones also give cis 3-lactams with excellent induction when the asymmetric carbon atom is next to the nitrogen atom (15 in Scheme 17). High inductions can also be observed with a -y-lactam (16), but the cycloaddition yields a mixture of cis and trans isomers. The level of diastereoselection is much lower with imide synthons (17). 

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