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. 2015 Oct 1;6(10):5446-5455.
doi: 10.1039/c5sc01958c. Epub 2015 Jul 7.

Mechanistic investigation of aziridine aldehyde-driven peptide macrocyclization: the imidoanhydride pathway

Serge Zaretsky  1 , Jennifer L Hickey  1   2 , Joanne Tan  1 , Dmitry Pichugin  3 , Megan A St Denis  1   2 , Spencer Ler  1 , Benjamin K W Chung  1 , Conor C G Scully  1 , Andrei K Yudin  1
Affiliations

Mechanistic investigation of aziridine aldehyde-driven peptide macrocyclization: the imidoanhydride pathway

Serge Zaretsky et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1. Comparison of the mixed anhydride versus the imidoanhydride intermediates in a multicomponent reaction.
Scheme 1
Scheme 1. Pendant aziridine nucleophile intercepts the mixed anhydride intermediate in the disrupted Ugi reaction to generate aziridine amide-bearing piperazinones.
Scheme 2
Scheme 2. Substrate-dependent selectivity of peptide macrocyclization monitored by 13C NMR.
Fig. 2
Fig. 2. 1H–13C HSQC NMR of 18C showing the three newly incorporated signals that did not correspond to the chemical shifts observed in aziridine amide-bearing macrocycles.
Scheme 3
Scheme 3. Structure elucidation of a bridged-amidine peptide by 1H–13C HMBC NMR and 15N NMR.
Scheme 4
Scheme 4. Formation of amidine peptide products along with PHα epimerization.
Scheme 5
Scheme 5. Multicomponent reaction of α-amino amides with aziridine aldehyde dimers and tert-butyl isocyanide to form amidine products.
Scheme 6
Scheme 6. Götz's polyglycine peptide cyclization by Ugi MCR.
Scheme 7
Scheme 7. A stepwise pathway with a nitrilium intermediate towards the formation of a cyclic mixed anhydride.
Scheme 8
Scheme 8. Formation of an imidoanhydride in the disrupted Ugi reaction by a concerted diastereoselective process.
Scheme 9
Scheme 9. Nucleophilic attack by the pendent aziridine in imidoanhydrides leads to aziridine amidines, which may undergo further transformations to generate the characterized amidine and bridged-amidine products.
Scheme 10
Scheme 10. Proposed pathway for macrocyclization of peptides in the MCR with aziridine aldehyde dimers and isocyanides.
Fig. 3
Fig. 3. Unfavourable substrates for achieving the desired macrocyclic product.
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