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

Portolani, Chiara; Centonze, Giovanni; Luciani, Sara; Pellegrini, Andrea; Righi, Paolo; Mazzanti, Andrea; Ciogli, Alessia; Sorato, Andrea; Bencivenni, Giorgio

doi:10.1002/ange.202209895

Cited by 6 publications

(2 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…51 Owing to the importance of N−N atropisomers and our interest in the search for novel strategies for synthesis of atropisomers, we performed the first catalytic stereoselective synthesis of hydrazides containing a rotationally stable N−N single bond. 3 Our catalytic strategy was based on the use of azodicarboxylate derivatives as a precursor of the N−N single bond. At the design stage, we reasoned that azodicarboxylates can act as reagents in two catalytic reactions that sequentially work together to increase the steric hindrance around the N−N single bond, affording rotationally stable chiral tetrasubstituted hydrazides.…”

Section: Enantio-and Diastereoselective Synthesis Of N−n Atropisomersmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

Conspectus 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 atropselect...

show abstract

Section: Enantio-and Diastereoselective Synthesis Of N−n Atropisomersmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The enantioselective synthesis of N─N atropisomers remained elusive until very recently when the Lu/Houk and the Liu groups independently developed an N-allylic alkylation reaction (31) or desymmetrization of an existing pyrrole ring (32). Subsequently, increasing attention has been paid to two categories of asymmetric synthetic strategies in this regard, namely, late-stage functionalization (33)(34)(35)(36)(37)(38) and de novo synthesis (39)(40)(41)(42), for the expedient construction of indole-based N─N atropisomers that are known as unique and vital skeletons in bioactive molecules, organic materials, and chiral ligands (Fig. 1) (43)(44)(45)(46).…”

Section: Introductionmentioning

confidence: 99%

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles

Wang,

Pan,

Wang

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o -iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

show abstract

Stereodivergent Construction of 1,3‐Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction

et al. 2023

View full text Add to dashboard Cite

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridiumcatalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.

show abstract

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

Cited by 6 publications

References 49 publications

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

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

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles

Stereodivergent Construction of 1,3‐Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction

Contact Info

Product

Resources

About