An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds

Jonas Faghtmann; Macarena Eugui; Johannes Nygaard Lamhauge; Signe Sofie Pladsbjerg Andresen; Anne Rask Østergaard; Esben Bjerregaard Svenningsen; Thomas B. Poulsen; Karl Anker Jørgensen

doi:10.1002/chem.202401156

An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds

Jonas Faghtmann, Macarena Eugui, Johannes Nygaard Lamhauge, Signe Sofie Pladsbjerg Andresen, Anne Rask Østergaard, Esben Bjerregaard Svenningsen, Thomas B. Poulsen, Karl Anker Jørgensen^*

^*Corresponding author af dette arbejde

Institut for Kemi

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C−C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

Originalsprog	Engelsk
Artikelnummer	e202401156
Tidsskrift	Chemistry - A European Journal
Vol/bind	30
Nummer	32
Antal sider	7
ISSN	0947-6539
DOI	https://doi.org/10.1002/chem.202401156
Status	Udgivet - jun. 2024

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10.1002/chem.202401156Licens: CC BY-NC-ND

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Faghtmann, J., Eugui, M., Nygaard Lamhauge, J., Sofie Pladsbjerg Andresen, S., Rask Østergaard, A., Bjerregaard Svenningsen, E., B. Poulsen, T., & Anker Jørgensen, K. (2024). An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds. Chemistry - A European Journal, 30(32), Artikel e202401156. https://doi.org/10.1002/chem.202401156

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title = "An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds",

abstract = "A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C−C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.",

keywords = "3-oxidopyridinium betaine, asymmetric catalysis, cascade reaction, hydroazulene, organocatalysis, Stereoisomerism, Azulenes/chemistry, Humans, Cell Line, Tumor, Molecular Structure, Catalysis, Cycloaddition Reaction",

author = "Jonas Faghtmann and Macarena Eugui and {Nygaard Lamhauge}, Johannes and {Sofie Pladsbjerg Andresen}, Signe and {Rask {\O}stergaard}, Anne and {Bjerregaard Svenningsen}, Esben and {B. Poulsen}, Thomas and {Anker J{\o}rgensen}, Karl",

year = "2024",

month = jun,

doi = "10.1002/chem.202401156",

language = "English",

volume = "30",

journal = "Chemistry - A European Journal",

issn = "0947-6539",

publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",

number = "32",

}

An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds. / Faghtmann, Jonas; Eugui, Macarena; Nygaard Lamhauge, Johannes et al.
I: Chemistry - A European Journal, Bind 30, Nr. 32, e202401156, 06.2024.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds

AU - Faghtmann, Jonas

AU - Eugui, Macarena

AU - Nygaard Lamhauge, Johannes

AU - Sofie Pladsbjerg Andresen, Signe

AU - Rask Østergaard, Anne

AU - Bjerregaard Svenningsen, Esben

AU - B. Poulsen, Thomas

AU - Anker Jørgensen, Karl

PY - 2024/6

Y1 - 2024/6

N2 - A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C−C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

AB - A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C−C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

KW - 3-oxidopyridinium betaine

KW - asymmetric catalysis

KW - cascade reaction

KW - hydroazulene

KW - organocatalysis

KW - Stereoisomerism

KW - Azulenes/chemistry

KW - Humans

KW - Cell Line, Tumor

KW - Molecular Structure

KW - Catalysis

KW - Cycloaddition Reaction

UR - http://www.scopus.com/inward/record.url?scp=85191745321&partnerID=8YFLogxK

U2 - 10.1002/chem.202401156

DO - 10.1002/chem.202401156

M3 - Journal article

C2 - 38564298

AN - SCOPUS:85191745321

SN - 0947-6539

VL - 30

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 32

M1 - e202401156

ER -

An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds

Abstract

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