Stereoselective synthesis of atropisomeric amides enabled by intramolecular acyl transfer

TY - JOUR

T1 - Stereoselective synthesis of atropisomeric amides enabled by intramolecular acyl transfer

AU - Wootton, Jack M

AU - Roper, Natalie J

AU - Morris, Catrin E

AU - Maguire, Victoria E

AU - Duff, Lee C

AU - Waddell, Paul G

AU - Whitwood, Adrian C

AU - Gammons, Richard J

AU - Miah, Afjal H

AU - Lynam, Jason M

AU - Armstrong, Roly J

AU - Unsworth, William P

N1 - © 2025 The Author(s).

PY - 2025/1/23

Y1 - 2025/1/23

N2 - C-N atropisomeric amides are important compounds in medicinal chemistry and agrochemistry. Atropselective methods for their synthesis are therefore important. In this study, a novel strategy to make C-N atropisomeric amides based on intramolecular acyl transfer via a tethered Lewis basic pyridine or tertiary amine group is reported. The reactions operate under kinetic control and in most cases are highly atropselective, with the products isolable as pure, single diastereoisomers following chromatography. The kinetically favored atropisomer can also be isomerised into the alternative thermodynamically favored atropisomer upon heating. The kinetic and thermodynamic outcomes are supported by computational studies, while additional mechanistic studies support operation via initial fast acylation of the Lewis basic group, followed by rate-determining acyl transfer, which also enables control over the atropisomer formed.

AB - C-N atropisomeric amides are important compounds in medicinal chemistry and agrochemistry. Atropselective methods for their synthesis are therefore important. In this study, a novel strategy to make C-N atropisomeric amides based on intramolecular acyl transfer via a tethered Lewis basic pyridine or tertiary amine group is reported. The reactions operate under kinetic control and in most cases are highly atropselective, with the products isolable as pure, single diastereoisomers following chromatography. The kinetically favored atropisomer can also be isomerised into the alternative thermodynamically favored atropisomer upon heating. The kinetic and thermodynamic outcomes are supported by computational studies, while additional mechanistic studies support operation via initial fast acylation of the Lewis basic group, followed by rate-determining acyl transfer, which also enables control over the atropisomer formed.

U2 - 10.1039/d4sc05760k

DO - 10.1039/d4sc05760k

M3 - Article

C2 - 39886439

SN - 2041-6520

JO - Chemical Science

JF - Chemical Science

ER -