Abstract
Aziridine aldehyde dimers, peptides, and isocyanides participate in a multicomponent reaction to yield peptide macrocycles. We have investigated the selectivity and kinetics of this process and performed a detailed analysis of its chemoselectivity. While the reactants encompass all of the elements of the traditional Ugi four-component condensation, there is a significant deviation from the previously proposed mechanism. Our results provide evidence for an imidoanhydride pathway in peptide macrocyclization and lend justification for the diastereoselectivity and high effective molarity observed in the reaction.
Highlights
The vast majority of chemical processes rely on polar reactions between nucleophilic (Nu) and electrophilic (E) functional groups.[1,2,3,4] Interactions between HOMO and LUMO orbitals of the Nu- and E-containing reagents result in a wide variety of reactive intermediates.[5,6,7,8] One of the long-standing interests of our research program has been to evaluate underexplored reactive intermediates and to seek their application in the synthesis of macrocycles.[1]
We obtained a crystal structure of 28, which matched the proposed structure of the bridged-amidine with the hypothesized stereochemistry (Scheme 5). These results indicate that a multicomponent reaction is possible between the proline amide, aziridine aldehyde dimer, and isocyanide
Our results suggest that the imidoanhydride pathway, in conjunction with the pendant nucleophilic aziridine of the aziridine aldehyde dimer, is an empowering engine of macrocyclization
Summary
The vast majority of chemical processes rely on polar reactions between nucleophilic (Nu) and electrophilic (E) functional groups.[1,2,3,4] Interactions between HOMO and LUMO orbitals of the Nu- and E-containing reagents result in a wide variety of reactive intermediates.[5,6,7,8] One of the long-standing interests of our research program has been to evaluate underexplored reactive intermediates and to seek their application in the synthesis of macrocycles.[1] To facilitate the discovery of such entities, we have focused on kinetically amphoteric molecules.[9] Over the years, we have contributed to this area by methodically separating the Nu and E nodes by one or more atoms and evaluating the resulting molecules in various contexts. Our ongoing studies stress the importance of seeking topologically different combinations of Nu and E nodes in amphoteric molecules.[9]
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