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Metal-, and Organocatalyst-Free One-Pot Assembly of Chiral Aza-Tricyclic Molecules: Creating Six Contiguous Stereocenters from 2-D-Structures and an Amino Acid

preprint
submitted on 04.08.2020 and posted on 05.08.2020 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 Practically, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for desired reactions. As a result, developing a method that enables rapid assembly of chiral complex molecules under metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward route 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 (“subcatalyst”) dual role of the intermediate enhances the coordinational proximity of the chiral substrate and catalyst in the key Aza-Michael/Michael cascade resulting in a substantial steric discrimination and an excellent overall diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not present in the reaction’s initial components, which renders a chiral catalyst-free process, it is strategically produced to promote sequential self-catalyzed reactions. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules and aid for the quest to create next generation of therapeutic agents.

History

Email Address of Submitting Author

dtdung82@hus.edu.vn

Institution

Vietnam National University, University of Science, Hanoi

Country

Vietnam

ORCID For Submitting Author

0000-0002-5717-4285

Declaration of Conflict of Interest

No conflict of interest

Version Notes

First version

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