Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

Yidong Liu; Joseph A. Izzo; David McLeod; Sebastijan Ričko; Esben B. Svenningsen; Thomas B. Poulsen; Karl Anker Jørgensen

doi:10.1021/jacs.1c03923

Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

Yidong Liu, Joseph A. Izzo, David McLeod, Sebastijan Ričko, Esben B. Svenningsen, Thomas B. Poulsen, Karl Anker Jørgensen^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

Original language	English
Journal	Journal of the American Chemical Society
Volume	143
Issue	21
Pages (from-to)	8208-8220
Number of pages	13
ISSN	0002-7863
DOIs	https://doi.org/10.1021/jacs.1c03923
Publication status	Published - 2 Jun 2021

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@article{6c721c344e0847fba325ae907c10d0bb,

title = "Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols",

abstract = "Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change. ",

author = "Yidong Liu and Izzo, {Joseph A.} and David McLeod and Sebastijan Ri{\v c}ko and Svenningsen, {Esben B.} and Poulsen, {Thomas B.} and J{\o}rgensen, {Karl Anker}",

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year = "2021",

month = jun,

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doi = "10.1021/jacs.1c03923",

language = "English",

volume = "143",

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Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols. / Liu, Yidong; Izzo, Joseph A.; McLeod, David et al.
In: Journal of the American Chemical Society, Vol. 143, No. 21, 02.06.2021, p. 8208-8220.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

AU - Liu, Yidong

AU - Izzo, Joseph A.

AU - McLeod, David

AU - Ričko, Sebastijan

AU - Svenningsen, Esben B.

AU - Poulsen, Thomas B.

AU - Jørgensen, Karl Anker

PY - 2021/6/2

Y1 - 2021/6/2

N2 - Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

AB - Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

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DO - 10.1021/jacs.1c03923

M3 - Journal article

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AN - SCOPUS:85107711307

SN - 0002-7863

VL - 143

SP - 8208

EP - 8220

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 21

ER -

Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

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