This minireview covers the literature of the last decade related to the stereochemistry of axially chiral molecules. The first section reviews the use of dynamic NMR and dynamic HPLC for the ranking of the steric size of common organic moieties. The second and third sections describe the recent advances in the preparation of new atropisomeric scaffolds, and in the asymmetric synthesis of stereogenic axes by means of atroposelective organocatalysis.
The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloadditiono f3 -alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unre-porteda xially chiral indole-quinoline biaryls. The methodology is also implementedf or the design and the preparation of challengingc ompounds exhibitingt wo stereogenic axes. DFT calculations shed light on the stereoselectivityo ft he central-to-axial chirality conversion,s howing unconventional behavior.Scheme1.Combining organocatalytice nantioselective Povarovc ycloadditions with the oxidative central-to-axial chirality conversion concept.
Catalytic addition of chiral enamines to azinium salts is a powerful tool for the synthesis of enantioenriched heterocycles. An unprecedented asymmetric dearomative addition of aldehydes to activated N-alkylpyridinium salts is presented. The process exhibits complete C-4 regioselectivity along with high levels of diastereo- and enantiocontrol, achieving a high-yielding synthesis of a broad range of optically active 1,4-dihydropyridines. Moreover, the presented methodology enables the synthesis of functionalized octahydropyrrolo[2,3-c]pyridines, the core structure of anticancer peptidomimetics.
The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.
A new protocol for the enantioselective direct α-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of α-heteroarylated aldehydes.
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