Stereocontrol during the formation of 2-C mono-arylated pseudo-prolines by aromatic stacking interaction

Article abstract of DOI:10.1016/S0040-4020(98)01039-4

When treated with anisaldehyde dimethylacetal the O-benzyl ester protected dipeptide Fmoc-NMeIle-Thr-OBzl(2, cf. Scheme 3), cyclizes to the 2- C(S) epimer 3b assigned by NMR spectroscopy to chirality (R) at the 2-C position of the resulting substituted 1,3-oxazolidine (ΨPro) unit, while in the acetalization of the corresponding O-methylester Fmoc-NMeIle-Thr-OMe (6), the 2-C(S) epimer 7a is predominantly formed stereoselectively and in quantitative yield. The course of the reaction can be rationalized by aromatic stacking interactions involving the benzyl ester and aryl ether groups in a transition state close to a product structure of (R) chirality, whereas the lack of such interactions in the case of the methyl ester can be used to direct the acetalization towards the 2-C(S) epimer.