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. 2015 Oct 2;80(19):9628-40.
doi: 10.1021/acs.joc.5b01384.

Asymmetric Redox-Annulation of Cyclic Amines

YoungKu Kang  1 , Weijie Chen  1 , Martin Breugst  2 , Daniel Seidel  1
Affiliations

Asymmetric Redox-Annulation of Cyclic Amines

YoungKu Kang et al. J Org Chem. .

Abstract

Cyclic amines such as 1,2,3,4-tetrahydroisoquinoline undergo regiodivergent annulation reactions with 4-nitrobutyraldehydes. These redox-neutral transformations enable the asymmetric synthesis of highly substituted polycyclic ring systems in just two steps from commercial materials. The utility of this process is illustrated in a rapid synthesis of (-)-protoemetinol. Computational studies provide mechanistic insights and implicate the elimination of acetic acid from an ammonium nitronate intermediate as the rate-determining step.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Selected Natural Products with THIQ and Tryptoline Substructures
Scheme 2
Scheme 2. Redox-Annulation
Scheme 3
Scheme 3. Scope of the Asymmetric Redox-Annulation
Reactions were performed on a 0.6 mmol scale. For products 6a/7a–6j/7j, yields correspond to combined, isolated yields of both diastereomers. For products 6k–t, yields correspond to isolated yields of the major diastereomer.
Scheme 4
Scheme 4. Divergent Regioselectivity in the Asymmetric Redox-Annulation
Reactions were performed on a 0.6 mmol scale.
Scheme 5
Scheme 5. Synthesis of (−)-Protoemetinol
Scheme 6
Scheme 6. Calculated Free Energies for the Uncatalyzed and Acetic-Acid-Catalyzed Annulation Reactions and Selected Transition-State Structures [kcal mol–1, M06-2X-D3/def2-QZVP/IEFPCM//M06-L-D3/6-31+G(d,p)/IEFPCM]
See this image and copyright information in PMC

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