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A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

revised on 24.05.2021, 16:34 and posted on 25.05.2021, 07:42 by Dung Do

Development of a rapid synthesis of complex molecules from simple building blocks under a metal-and organocatalyst-free condition is both conceptually and chemically challenging. Here, we developed a hidden catalysis that allow the straightforward assembly of enantiopure aza-tricyclic molecules containing six contiguous stereocenters from aminophenols, α,β-unsaturated aldehydes and α-amino acids. Without using a metal or an organocatalyst, our approach relies on a temporary formation of a spiroimidazolidinone intermediate and its participation in a sequential aza-Michael/Michael reaction as both a substrate and a catalyst under an iminium/enamine catalysis. The formation of the putative iminium intermediate was supported by spectroscopic data and its interruptive reduction derivative was isolated and fully characterized. Whereas a conventional catalyst is always present and does not undergo a permanent chemical change in a classic catalysis, the spiroimidazolidinone intermediate is conceptualized as a sub-catalyst as it is only temporary produced from precursors and catalyzes its own consumption. This unique substrate-catalyst (sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric discrimination in the transition state and an excellent overall diastereoselectivity (>20:1 dr). It allows the use of an amino acid precursor as the sole chirality genesis and avoids the use of transition metals or organocatalysts. An enantiomer of an aza-tricyclic imidazolidinone can be prepared from a commercially available amino acid precursor. The aqueous-based reaction is practical and scalable for multi-gram synthesis. The success of implementing this sub-catalysis concept in the synthesis will pave the way for many efficient chiral catalyst-free preparations of chiral complex molecules.


Email Address of Submitting Author


Vietnam National University, University of Science, Hanoi



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest

Version Notes

Third version

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