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

revised on 09.12.2020, 18:01 and posted on 10.12.2020, 07:25 by Dung Do

Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.1 In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a special chiral spiroimidazolidinone cyclohexadienone intermediate, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an α,β-unsaturated aldehyde under an iminium/enamine catalysis. The enhanced co-ordinational proximity of the chiral substrate and catalyst in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from N-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient 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

Second version