A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold

Casper L. Barløse; Niklas L. Østergaard; René S. Bitsch; Marc V. Iversen; Karl Anker Jørgensen

doi:10.1002/anie.202106598

A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold

Casper L. Barløse, Niklas L. Østergaard, René S. Bitsch, Marc V. Iversen, 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

An enantioselective methodology to construct trans-Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans-Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels–Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent S_N2-like reaction at a tertiary center to obtain the trans-Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

Original language	English
Journal	Angewandte Chemie - International Edition
Volume	60
Issue	33
Pages (from-to)	18318-18327
Number of pages	10
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.202106598
Publication status	Published - Aug 2021

Keywords

asymmetric synthesis
cycloaddition
halogen effect
organocatalysis
trans-Diels–Alder

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10.1002/anie.202106598

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@article{1e357129a6fc44cab8332be270153bb2,

title = "A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold",

abstract = "An enantioselective methodology to construct trans-Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans-Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels–Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN2-like reaction at a tertiary center to obtain the trans-Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.",

keywords = "asymmetric synthesis, cycloaddition, halogen effect, organocatalysis, trans-Diels–Alder",

author = "Barl{\o}se, {Casper L.} and {\O}stergaard, {Niklas L.} and Bitsch, {Ren{\'e} S.} and Iversen, {Marc V.} and J{\o}rgensen, {Karl Anker}",

note = "Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

year = "2021",

month = aug,

doi = "10.1002/anie.202106598",

language = "English",

volume = "60",

pages = "18318--18327",

journal = "Angewandte Chemie - International Edition",

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publisher = "Wiley - VCH Verlag GmbH & CO. KGaA",

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A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold. / Barløse, Casper L.; Østergaard, Niklas L.; Bitsch, René S. et al.
In: Angewandte Chemie - International Edition, Vol. 60, No. 33, 08.2021, p. 18318-18327.

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

TY - JOUR

T1 - A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold

AU - Barløse, Casper L.

AU - Østergaard, Niklas L.

AU - Bitsch, René S.

AU - Iversen, Marc V.

AU - Jørgensen, Karl Anker

PY - 2021/8

Y1 - 2021/8

N2 - An enantioselective methodology to construct trans-Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans-Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels–Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN2-like reaction at a tertiary center to obtain the trans-Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

AB - An enantioselective methodology to construct trans-Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans-Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels–Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN2-like reaction at a tertiary center to obtain the trans-Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

KW - asymmetric synthesis

KW - cycloaddition

KW - halogen effect

KW - organocatalysis

KW - trans-Diels–Alder

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DO - 10.1002/anie.202106598

M3 - Journal article

C2 - 34080269

AN - SCOPUS:85109670573

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

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ER -

A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels–Alder Products Having the Norcarane Scaffold

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