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.

We synthesized bis-aryl carbazole borane derivatives having emissive properties and axial chirality. The resolution of a thermally stable atropisomeric pair (compound 1b ), due to a B–C chiral axis, was achieved by chiral stationary-phase high-performance liquid chromatography (CSP-HPLC). Complete photophysical properties of all compounds were measured and simulated by time-dependent density functional theory (TD-DFT) calculations of the complete fluorescence cycle, and circularly polarized luminescence spectra were obtained for the atropisomers of compound 1b , whose absolute configuration was derived using a TD-DFT simulation of the electronic circular dichroism (ECD) spectra.

In this work, a new chemodivergent domino approach for the preparation of various saturated heterocycles, based on phase‐transfer catalysis (PTC), is presented. The versatile nature of doubly electrophilic substrates, showing both a Michael acceptor and a ketone, tethered by a heteroatom, enables three different domino reaction pathways. The nucleophile dictates the chemoselectivity of the reaction. Sulfa‐Michael/aldol, cyanide addition/oxa‐Michael and Michael/H‐shift/aldol processes, along with the variation of the tethering heteroatom, results in the formation of six different classes of saturated heterocycles. DFT calculations account for the observed chemo‐ and diastereoselectivity of the two most productive processes. Moreover, an extensive investigation on the sulfa‐Michael/aldol pathway was carried out, ultimately leading to the development of a new enantioselective domino approach to multi‐substituted piperidines based on PTC.

Atorvastatins play an important role in the inhibition of HMG-CoA reductase, an enzyme present in the liver that takes part in the biosynthesis of cholesterol. In this article, we report the total synthesis of a lactone–atorvastatin prodrug with additional atropisomeric features. Conformational and experimental studies of model compounds were designed to test the stability of the chiral axis. Docking calculations were performed to evaluate the constant inhibition of a library of atorvastatins. Full synthesis of the best candidate was achieved and thermally stable atropisomeric lactone–atorvastatin was obtained. The absolute configuration of the chiral axis of the atropisomers was assigned by means of chiroptical ECD spectroscopy coupled with TD-DFT calculations.