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/anie.202209895

Cited by 44 publications

(23 citation statements)

References 52 publications

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“… 2022 61 e202209895 . 3 This study demonstrates the effective use of sequential catalysis in the enantio- and diastereoselective synthesis of a novel class of N–N atropisomers. The catalyst permutation enables the synthesis of diastereoisomers in a stereodivergent manner.…”

Section: Key Referencesmentioning

confidence: 84%

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

confidence: 99%

“…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%

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

et al. 2022

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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...

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Section: Key Referencesmentioning

confidence: 84%

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

confidence: 99%

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

confidence: 99%

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

et al. 2022

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“…As part of their new enantioselective approach to atropisomeric hydrazides, Bencivenni and coworkers reported the asymmetric α-hydrazination of branched aldehydes catalyzed by primary amine C30 . The one-pot N -alkylation of the resulting NH hydrazides 2d under PTC conditions using catalyst C40 led to hydrazides 19 featuring a rotationally restricted N - N bond that may present axial chirality ( Scheme 8 ) [ 56 ]. Products 19 with ( S , Ra ) configuration are obtained in generally good diastereomeric ratios and excellent enantioselectivity.…”

Section: Methods Based On Enamine Activationmentioning

confidence: 99%

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

et al. 2023

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Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp2 carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward.

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“…Currently, this research area is still in its infancy and only few types of NÀ N axially chiral scaffolds have been constructed (Scheme 1a), mainly including 1-aminopyrroles, [24] 3-aminoquinazolinones, [24,26] bispyrroles, [25, 27, 8c] and hydrazides. [28,29] In early 2022, our group also conducted the synthesis of axially chiral N,N'pyrrolylindoles using a chiral Brønsted acid (B*À H)-catalyzed enantioselective Paal-Knorr reaction of N-aminoindoles with 1,4-diketones (Scheme 1b). [8c] However, that work did not address the challenges in constructing axially chiral N,N'-bisindoles, which led us to further study the catalytic enantioselective synthesis of axially chiral N,N'bisindoles and their promising applications.…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Enantioselective Synthesis of Axially ChiralN,N′‐Bisindoles

Chen

Wang

et al. 2023

Angewandte Chemie

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This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles via chiral phosphoric acid‐catalyzed formal (3+2) cycloadditions of indole‐based enaminones as novel platform molecules with 2,3‐diketoesters, where de novo indole‐ring formation is involved. Using this new strategy, various axially chiral N,N′‐bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′‐bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′‐bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.

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

Cited by 44 publications

References 52 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

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

Organocatalytic Enantioselective Synthesis of Axially ChiralN,N′‐Bisindoles

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