Organocatalytic Enantioselective α-Nitrogenation of α,α-Disubstituted Aldehydes in the Absence of a Solvent

Torregrosa-Chinillach, Alejandro; Carral-Menoyo, Asier; Gómez‐Bengoa, Enrique; Chinchílla, Rafael

doi:10.1021/acs.joc.2c01919

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…Very recently, Gómez-Bengoa, Chinchilla and co-workers reported a solvent-free catalytic α-hydrazination of branched aldehydes with azodicarboxylates in the absence of solvents that proceeds in usually high yields and enantioselectivities using 20 mol% of the primary amine catalyst C37 and acetic acid as the cocatalyst ( Scheme 7 ) [ 54 ]. The bifunctional activation mode imparted by the new catalyst ( TS-3 ) was supported on computational DFT studies.…”

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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Section: Methods Based On Enamine Activationmentioning

confidence: 99%

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

et al. 2023

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“…b Chiral catalysts used in the electrophilic and nucleophilic amination 52 . c Calculated transition states in Chinchilla’s solvent-free procedure 58 . d Synthesis of α,α-disubstituted α-amino esters via 1,4-acyl transfer 64 .…”

Section: Synthesis Of αα-Disubstituted α-Aas Via C-n Bond Formationmentioning

confidence: 99%

“…Later, Chinchilla and co-workers developed a solvent-free procedure for the metal-free asymmetric α-amination of α,α-disubstituted aldehydes 58 . A carbamate-protected derivative of cyclohexa-1,2-diamine was used for this purpose which had already been used by the same group in their enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides 59 .…”

Section: Synthesis Of αα-Disubstituted α-Aas Via C-n Bond Formationmentioning

confidence: 99%

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Challenges and recent advancements in the synthesis of α,α-disubstituted α-amino acids

Zhang,

Vanderghinste,

Wang

et al. 2024

Nat Commun

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Abstractα,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO2 fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives.

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