Facial control by the enolate
Facial selectivity can also be imposed by a stereocentre in the enolate. If the aldehyde and the enolate are both chiral, their preferences add up (matched pair) or oppose each other (mismatched pair): this is double stereodifferentiation.
The stereocentre may be at any of the positions adjacent to the enolate or enolate equivalent, and its configuration orients the approach of the aldehyde. The outcome cannot be generalized with a simple rule like Felkin’s: each type of reaction must be analysed, because it depends on the metal, the transition state and the preferred conformation of the enolate (for example, on A1,3 allylic strain). Enolates of chiral ethyl ketones derived from lactic acid or from 3-hydroxy-2-methylpropanoate, with the hydroxyl protected, are widely used examples in polyketide synthesis.
Double stereodifferentiation
If the aldehyde and the enolate are both chiral, each imposes a preference for one absolute configuration. The combined interaction of the stereocentres in both components is called double stereodifferentiation or double asymmetric induction (Masamune, 1985):
| Pair | Preferences | Selectivity |
|---|---|---|
| matched | aldehyde and enolate favour the same diastereomer | higher than that of either component alone (roughly the product of both) |
| mismatched | they favour different diastereomers | lower; the more selective component prevails |
If one of the components is much more selective than the other, such as an enolate with a good chiral auxiliary, it imposes its preference even in the mismatched pair. This is the strategy of reagent control, which allows any of the diastereomers to be prepared from the same chiral aldehyde by choosing the enantiomer of the enolate.