title: Shifting the energy landscape of multicomponent reactions using aziridine aldehyde dimers: a mechanistic study.
abstract: A multicomponent reaction between an aziridine aldehyde dimer, isocyanide, and l-proline to afford a chiral piperazinone was studied to gain insight into the stereodetermining and rate-limiting steps of the reaction. The stereochemistry of the reaction was found to be determined by isocyanide addition, while the rate-limiting step was found to deviate from traditional isocyanide-based multicomponent reactions. A first-order rate dependence on aziridine aldehyde dimer and a zero-order rate dependence on all other reagents have been obtained. Computations at the MPWPW91/6-31G(d) level supported the experimental kinetic results and provide insight into the overall mechanism and the factors contributing to stereochemical induction. These factors are similar to traditional isocyanide-based multicomponent reactions, such as the Ugi reaction. The computations revealed that selective formation of a Z-iminium ion plays a key role in controlling the stereoselectivity of isocyanide addition, and the carboxylate group of l-proline mediates stereofacial addition. These conclusions are expected to be applicable to a wide range of reported stereoselective Ugi reactions and provide a basis for understanding the related macrocyclization of peptides with aziridine aldehydes.
authors.affiliation: Brock University , St. Catharines, Ontario L2S 3A1, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Belding
authors.forename: Serge
authors.initials: S
authors.lastname: Zaretsky
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Rotstein
authors.forename: Andrei K
authors.initials: AK
authors.lastname: Yudin
authors.forename: Travis
authors.initials: T
authors.lastname: Dudding