On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides.

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms.

Enantioselective Strategies for The Synthesis of N-N Atropisomers.

Axially chiral compounds have been always considered a laboratory curiosity with rare prospects of being applied in asymmetric synthesis. Things have changed very quickly in the last twenty years when it was understood the important role and the enormous impact that these compounds have in medicinal, biological and material chemistry. The asymmetric synthesis of atropisomers became a rapidly expanding field and recent reports on the development of N-N atropisomers strongly prove how this research field is a hot topic open to new challenges and frontiers of asymmetric synthesis. This review focuses on the recent advances in the enantioselective synthesis of N-N atropisomers highlighting the strategies and breakthroughs to obtain this novel and stimulating atropisomeric framework.

Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds.

Asymmetric synthesis using organic catalysts has evolved since it was first realized and defined. Nowadays, it can be considered a valid alternative to transition metal catalysis for synthesizing chiral molecules. According to the literature, the number of asymmetric organocatalytic processes associated with atropisomer synthesis has rapidly increased over the past 10 years because organocatalysis addresses the challenges posed by the most widespread strategies used for preparing axially chiral molecules with satisfactory results.These strategies, useful to prepare a wide range of C-C, C-heteroatom, and N-N atropisomers, vary from kinetic resolution to direct arylation, desymmetrization, and central-to-axial chirality conversion. In this field, our contribution focuses on determining novel methods for synthesizing atropisomers, during which, in most cases, the construction of one or more stereogenic centers other than the stereogenic axis occurred. To efficiently address this challenge, we exploited the ability of catalysts based on a cinchona alkaloid scaffold to realize enantioselective organic transformations. Desymmetrization of N-(2-tert-butylphenyl) maleimides was one of the first strategies that we pursued for preparing C-N atropisomers. The main principle is based on the presence of a rotationally hindered C-N single bond owing to the presence of a large tert-butyl group. Following the peculiar reactivity of this type of substrate as a powerful electrophile and dienophile, we realized several transformations.First, we investigated the vinylogous Michael addition of 3-substituted cyclohexenones, where a stereogenic axis and two contiguous stereocenters were concomitantly and remotely formed and stereocontrolled using a primary amine catalyst. Subsequently, we realized desymmetrization via an organocatalytic Diels-Alder reaction of activated unsaturated ketones that enabled highly atropselective transformation with efficient diastereoselectivity, thereby simultaneously controlling four stereogenic elements. Employing chiral organic bases allowed us to realize efficient desymmetrizations using carbon nucleophiles, such as 1,3-dicarbonyl compounds, cyanoacetates, and oxindoles. These reactions, performed with different types of catalysts, highlighted the versatility of organocatalysis as a powerful strategy for atropselective desymmetrization of pro-axially chiral maleimides.Hereafter, we studied the Friedel-Crafts alkylation of naphthols with indenones, a powerful method for enantioselective synthesis of conformationally restricted diastereoisomeric indanones. We realized the first axially chiral selective Knoevenagel condensation using cinchona alkaloid primary amine as the catalyst. This reaction provided a powerful method to access enantioenriched olefins containing the oxindole core. Subsequently, we initiated an intense program for the computational investigation of the reaction mechanism of our atropselective processes. An understanding of the catalytic activity for vinylogous atropselective desymmetrization as well as of the role played by the acidic cocatalyst used for the experimental work was achieved.Recently, we have garnered interest in the novel frontiers of atropselective synthesis. As observed in recent publications, there is considerable interest in the development of methods for preparing N-N atropisomers, an emerging topic in the field of atropselective synthesis. We focused on the synthesis of hydrazide atropisomers by developing a one-pot sequential catalysis protocol based on two sequential organocatalytic reactions that provided high stereocontrol of two contiguous stereogenic elements.

Synthesis of Atropisomeric Hydrazides by One-Pot Sequential Enantio- and Diastereoselective Catalysis.

The first catalytic enantioselective and diastereoselective synthesis of atropisomeric hydrazides was achieved using a sequential catalysis protocol. This strategy is based on a one-pot sequence of two organocatalytic cycles featuring the enamine amination of branched aldehydes followed by nitrogen alkylation under phase-transfer conditions. The resulting axially chiral hydrazides were obtained directly from commercially available reagents in high yields and with good stereocontrol. The permutation of organocatalysts allowed easy access to all stereoisomers, enabling a stereodivergent approach to enantioenriched atropisomeric hydrazides.