Chair-like transition structures aldol reactions

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

The basic principles of the mechanism of this Lewis-base-catalyzed aldol reaction have already been described in Section 6.2.1.1. With regard to the course of the enantio- and diastereoselective formation of aldol adducts with two stereogenic centers, it is proposed that synthesis of anti-products proceeds via a chair-like transition structure. A distinctive feature of the cationic transition state complex is a hexacoordinated silicon atom bearing two chiral phosphoramide molecules as ligands (Scheme 6.30). 

In connection with the synthesis of podophyllum lignans, ester (62) was deprotonated and the resulting enolate condensed with 3,4,5-trimethoxybenzaldehyde to give a 1 1 mixture of diastereomeric aldols (equation 68). The structure of (63) was established by X-ray analysis the other diastereomer was assigned the 2,3-anti relative stereochemistry (64) on circumstantial evidence. It was suggested that the 1 1 mixture of isomeric products results from a 1 1 mixture of the ( )- and (Z)-enolate, each of which shows complete simple and diastereofacial selectivity in its reactions with 3,4,5-trimethoxybenzaldehyde. For this to be true, it is also necessary that the ( )-enolate reacts through a non-Zimmerman , boat-like transition state, whereas the (Z)-enolate reacts through the normal chair-like transition state. 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

Possible transition states for the reactions of type I and III crotyl organometallics with aldehydes are depicted in Scheme 7. Most of the available stereochemical evidence suggests that these reactions proceed preferentially through transition state (12) in which the metal is coordinated to the carbonyl oxygen syn to the smallest carbonyl substituent, H. This necessitates that R of RCHO adopt an equatorial position if the transition state is chair-like, an arrangement that is structurally similar to the Zimmerman-Traxler model commonly invoked for many aldol reactions. Transition states (13) and (14), however, may potentially intervene and are frequently cited to rationalize the production of minor diastereomers (17). 

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