Named reactions: Frater - Seebach alkylation

14 June 2008 - OrgChem

The Fráter-Seebach alkylation is the stereoselective alkylation of chiral beta-hydroxy esters using superbases such as LDA or LiHMDS. This organic reaction was first reported by G. Fráter in 1979 (DOI DOI).

In the original Fráter publication the starting material is ethyl acetoacetate 1, stereoselectively converted to the beta-hydroxy ester 2 with Baker's yeast, converted to the dianion 3 with LDA and finally alkylated with iodomethane in HMPA to 4.

In the key step of this enolate alkylation the lithium ion present in the base coordinates to both oxygen atoms, effectively shielding one of the faces of the enolate complex. In this sense the reaction is an early example and predating the concept of memory of chirality.

Dieter Seebach in 1980 reported on a related reaction: the diastereoselective alkylation of an malic acid ester ( DOI) with the newly formed alkyl group in an anti relationship to the alcohol.

The Fráter procedure (almost identical to the original) was most recently employed in the total synthesis of 35-deoxy amphotericin B methyl ester (Carreira et al. 2008 DOI):