Organocatalytic Enantioselective Construction of Conformationally Stable C(sp2 )−C(sp3 ) Atropisomers

Giulio  Bertuzzi; Vasco Corti; Joseph Anthony Izzo; Sebastijan Ricko; Nicolaj Jessen; Karl Anker Jørgensen

doi:10.1021/jacs.1c12619

Organocatalytic Enantioselective Construction of Conformationally Stable C(sp² )−C(sp³ ) Atropisomers

Giulio Bertuzzi, Vasco Corti, Joseph Anthony Izzo, Sebastijan Ricko, Nicolaj Jessen, Karl Anker Jørgensen^*

^*Corresponding author for this work

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

Abstract

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

Original language	English
Journal	Journal of the American Chemical Society
Volume	144
Issue	2
Pages (from-to)	1056-1065
Number of pages	10
ISSN	0002-7863
DOIs	https://doi.org/10.1021/jacs.1c12619
Publication status	Published - Jan 2022

Keywords

ASYMMETRIC-SYNTHESIS
AXIAL CHIRALITY
CARBON
CONVERSION
ELEMENT
RESOLUTION
ROTATION

Access to Document

10.1021/jacs.1c12619

Cite this

@article{4ecec3b8a9d54203abf640274dc8d3b4,

title = "Organocatalytic Enantioselective Construction of Conformationally Stable C(sp2 )−C(sp3 ) Atropisomers",

abstract = "Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.",

keywords = "ASYMMETRIC-SYNTHESIS, AXIAL CHIRALITY, CARBON, CONVERSION, ELEMENT, RESOLUTION, ROTATION",

author = "Giulio Bertuzzi and Vasco Corti and Izzo, {Joseph Anthony} and Sebastijan Ricko and Nicolaj Jessen and J{\o}rgensen, {Karl Anker}",

year = "2022",

month = jan,

doi = "10.1021/jacs.1c12619",

language = "English",

volume = "144",

pages = "1056--1065",

journal = "Journal of the American Chemical Society",

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Organocatalytic Enantioselective Construction of Conformationally Stable C(sp² )−C(sp³ ) Atropisomers. / Bertuzzi, Giulio ; Corti, Vasco; Izzo, Joseph Anthony et al.
In: Journal of the American Chemical Society, Vol. 144, No. 2, 01.2022, p. 1056-1065.

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

TY - JOUR

T1 - Organocatalytic Enantioselective Construction of Conformationally Stable C(sp2 )−C(sp3 ) Atropisomers

AU - Bertuzzi, Giulio

AU - Corti, Vasco

AU - Izzo, Joseph Anthony

AU - Ricko, Sebastijan

AU - Jessen, Nicolaj

AU - Jørgensen, Karl Anker

PY - 2022/1

Y1 - 2022/1

N2 - Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

AB - Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

KW - ASYMMETRIC-SYNTHESIS

KW - AXIAL CHIRALITY

KW - CARBON

KW - CONVERSION

KW - ELEMENT

KW - RESOLUTION

KW - ROTATION

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DO - 10.1021/jacs.1c12619

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