Re-Engineering Organocatalysts for Asymmetric Friedel–Crafts Alkylation of Indoles through Computational Studies

The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels–Alder reactions following a rational design approach. This result encouraged us to t...

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Bibliographic Details
Published in:Journal of organic chemistry 2020-08, Vol.85 (15), p.9969-9978
Main Authors: Gerosa, Gabriela G, Marcarino, Maribel O, Spanevello, Rolando A, Suárez, Alejandra G, Sarotti, Ariel M
Format: Article
Language:English
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Summary:The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels–Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel–Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.0c01256