Shifting the Energy Landscape of Multicomponent Reactions Using Aziridine Aldehyde Dimers: A Mechanistic Study

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• 作者：Lee Belding ; Serge Zaretsky ; Benjamin H. Rotstein ; Andrei K. Yudin ; Travis Dudding
• 刊名：Journal of Organic Chemistry
• 出版年：2014
• 出版时间：October 17, 2014
• 年：2014
• 卷：79
• 期：20
• 页码：9465-9471
• 全文大小：499K
• ISSN：1520-6904

文摘

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.