Unexpected Contrasteric Alkylation Leading to a Model for Five-Membered Ring Enolate Alkylation: Short Stereoselective Synthesis of (+/-)-Acetomycin

Article abstract of DOI:10.1021/jo00121a025

It is well established that the alkylation of cyclic enolates 1 bearing an asymmetric center at the β-position should provide mainly lactones 2 where the electrophile (E(+)) ends up trans to the β-substituent (R₂).Our interest in such processes lies in the fact that according to this principle, alkylation of 1a with methyl iodide should provide direct access to (+/-)-acetomycin (2a).However, this reaction unexpectedly afforded the contrasteric alkylation product 3a ((+/-)-3-epi-acetomycin) with high diastereoselectivity.To elucidate this observation, alkylation studies have been carried out on various enolates 1.As normally expected, when R₂ and R₃ are alkyl groups, only product 2 is obtained.On the other hand, when R₃ is an acetoxy group or an alkoxy group and methyl iodide is used as electrophile, the contrasteric products 3 are predominant.With sterically more demanding electrophiles, the "normal" alkylation products 2 are obtained in moderate to extremely high selectivity.Thus, the use of 1,3-dithienium tetrafluoroborate, a bulky methyl equivalent, allowed us to complete a stereoselective syntheses of (+/-)-acetomycin.These results led to the elaboration of a model for five-membered ring enolate alkylation based on steric and stereoelectronic effects, as well as ring conformations.