Diastereoselectivities in Reductions of α-Alkoxy Ketones Are Not Always Correlated to Chelation-Induced Rate Acceleration

Abstract

The chelation-control model is used to predict stereochemical outcomes of many organometallic reactions. Diastereoselectivity arises due to reaction with a chelated intermediate with sterically differentiated faces. Earlier studies with dimethylmagnesium established that the chelated intermediate is a minor component of the reaction mixture, so reaction with the chelated intermediate must be faster than reaction with a non-chelated intermediate. High diastereoselectivity and chelation-induced rate acceleration are correlated with some hydride reducing agents. There are examples in which diastereoselectivity is high, but chelation-induced rate acceleration is not observed, however. In other cases, chelation-induced rate acceleration is observed, but diastereoselectivity remains low. These experiments illustrate that a revision to the chelation-control model is needed.

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

“…It is unlikely that reduction of ketone 323 could occur by a βchelation-controlled reduction with NaBH 4 because this reagent does not generally conform to the chelation-control model. 70 In the case of an α-amino aldehyde, addition of an allylmagnesium reagent occurred with high diastereoselectivity (Scheme 128). 241 Addition to aldehyde 325 provided homoallylic alcohol 326, likely through a transition state resembling 327, where the NBn 2 group adopts the position expected for R L .…”

“…Steric approach control of stereoselectivity, combined with the emerging picture of how one can observe chelation control even without rate acceleration, 22,70 suggests a way to understand why allylmagnesium reagents can sometimes react with carbonyl compounds with high stereoselectivity. As observed with chelation-controlled additions of allylmagnesium reagents to chiral α-alkoxy ketones in nonpolar solvents, if the electrophile preferentially adopts a conformation where steric effects are different enough between the two faces of the electrophile, then a highly stereoselective reaction can ensue.…”

“…These arguments would also apply to many other modes of stereochemical control. For the purposes of this review, we have analyzed the results of reactions of allylmagnesium halides with chiral carbonyl compounds and imines using four distinct models: the Cram chelation model (as formulated by Eliel and Frye, − although with caveats obtained from more recent results , ), the Felkin–Anh model, the torsional strain model associated with additions to cyclic ketones, and the concept of steric approach control.…”

“…One final example reinforces the general caveats noted about the stereochemical models used by organic chemists (section ). In studies of hydride reduction reactions, it was demonstrated that the product expected from chelation control was formed without any evidence that it was either a result of a highly reactive chelated intermediate or that the major species in solution was a chelated intermediate . Therefore, it is important to remember that all that is required for stereoselectivity is that the diastereotopic faces of the carbonyl compound are sufficiently differentiated.…”

“…Reduction of this ketone proceeded with stereoselectivity that would be predicted using the Felkin–Anh model to give the desired stereoisomer ( 324 ). It is unlikely that reduction of ketone 323 could occur by a β-chelation-controlled reduction with NaBH 4 because this reagent does not generally conform to the chelation-control model …”