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. 2022 Nov 13;27(22):7819.
doi: 10.3390/molecules27227819.

Catalytic Enantioselective Synthesis of N-C Axially Chiral N-(2,6-Disubstituted-phenyl)sulfonamides through Chiral Pd-Catalyzed N-Allylation

Sota Fukasawa  1 , Tatsuya Toyoda  1 , Ryohei Kasahara  1 , Chisato Nakamura  1 , Yuuki Kikuchi  1 , Akiko Hori  2 , Gary J Richards  2 , Osamu Kitagawa  1
Affiliations

Catalytic Enantioselective Synthesis of N-C Axially Chiral N-(2,6-Disubstituted-phenyl)sulfonamides through Chiral Pd-Catalyzed N-Allylation

Sota Fukasawa et al. Molecules. .

Abstract

Recently, catalytic enantioselective syntheses of N-C axially chiral compounds have been reported by many groups. Most N-C axially chiral compounds prepared through a catalytic asymmetric reaction possess carboxamide or nitrogen-containing aromatic heterocycle skeletons. On the other hand, although N-C axially chiral sulfonamide derivatives are known, their catalytic enantioselective synthesis is relatively underexplored. We found that the reaction (Tsuji-Trost allylation) of allyl acetate with secondary sulfonamides bearing a 2-arylethynyl-6-methylphenyl group on the nitrogen atom proceeds with good enantioselectivity (up to 92% ee) in the presence of (S,S)-Trost ligand-(allyl-PdCl)2 catalyst, affording rotationally stable N-C axially chiral N-allylated sulfonamides. Furthermore, the absolute stereochemistry of the major enantiomer was determined by X-ray single crystal structural analysis and the origin of the enantioselectivity was considered.

Keywords: N-allylation; asymmetric catalyst; atropisomers; axial chirality; palladium; sulfonamides.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Catalytic enantioselective synthesis of various N-C axially chiral compounds I–III.
Scheme 2
Scheme 2
Catalytic enantioselective synthesis of N-C axially chiral N-(2,6-disubstituted-phenyl)sulfonamides 2 though chiral Pd-catalyzed N-allylation.
Figure 1
Figure 1
X-ray single crystal structure of 2o (major enantiomer).
Figure 2
Figure 2
Origin of enantioselectivity in N-allylation with (S,S)-Trost ligand.
Figure 3
Figure 3
Rotational stability of several sulfonamides bearing ortho-substituents.
Scheme 3
Scheme 3
Enantioselective double N-allylation with bis-sulfonamide substrate 4.
Scheme 4
Scheme 4
Product distribution based on Horeau principle in double asymmetric reaction.
See this image and copyright information in PMC

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