Accessing unnatural α-amino acids with tetrasubstituted stereogenic centers<i>via</i>catalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

Yasukawa, Naoki; Nakamura, Shuichi

doi:10.1039/d3cc02236f

Cited by 11 publications

(3 citation statements)

References 213 publications

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“…Overall, these advances via addition at ketimines provided more structural diversity of afforded α,α-disubstituted α-AAs through reaction with previously challenging reagents such as styrenes and allenes. Moreover, during the preparation of our manuscript, another extensive review about the catalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides to access unnatural α-AAs was published 82 .…”

Section: Synthesis Of αα-Disubstituted Amino Acids Via the C-c Bond F...mentioning

confidence: 99%

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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Section: Synthesis Of αα-Disubstituted Amino Acids Via the C-c Bond F...mentioning

confidence: 99%

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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“…We hypothesized that α-thio-substituted chiral aminonitriles could be obtained by using α-iminonitriles as a novel precursor of amino acid derivatives (Scheme d, right). Nevertheless, methods for the stereoselective construction of a chiral amines-bearing tetrasubstituted carbon center via asymmetric nucleophilic addition reaction to preformed ketimines are still limited, mainly due to the challenges associated with the formation of a highly hindered chiral center . Our research group recently reported the first enantioselective reaction of N -cyanoimines to construct β-amino acid derivatives in the use of hydrogen-bonding-donor (HBD) catalysts (Scheme c) .…”

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Construction of an α-Thio-Substituted α-Aminonitriles-Bearing Tetrasubstituted Carbon Center

Oyamada,

Fujii,

Takehara

et al. 2024

ACS Catal.

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Chiral unnatural amino acids (UAAs) are important structural units that are commonly found in a wide range of natural products and bioactive molecules. Chiral α-aminonitriles, which are one of the most important precursors for chiral α-amino acid synthesis, are widely accessible via the asymmetric Strecker reaction. However, the construction of α-heteroatom-substituted α-aminonitriles presents a challenge due to the lack of reactivity of electrophiles (ester, amide, thioamide, etc.) and their ability as leaving groups. Therefore, a practical and robust approach to their enantioselective synthesis is highly desirable. We herein describe an efficient method for the preparation of chiral α-heteroatom-substituted α-aminonitriles containing a tetrasubstituted stereogenic carbon center. This protocol displayed a broad substrate scope for both reactants in high yield and with high enantioselectivity. Several mechanistic studies revealed that the presence of nitrile is crucial for enhancing the reactivity and controlling the selectivity of the reaction. This work not only provides N,S-and N,Se-ketal motifs but also a powerful strategy for overcoming the limitation of synthesizable α-aminonitriles.

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“…Comparatively, β-electron-withdrawing group (ester or carbonyl)-tethered acrylamide usually acts as a N , C α -1,3-synthon in chiral amine-catalyzed asymmetric cascade aza-Michael/Michael reaction with α, β-unsaturated aldehydes, as well as Lewis base-catalyzed formal [3 + 2]-annulation reactions with nitro-heteroarenes or isocyanates . On the other hand, cyclic N -sulfonyl imines exhibit versatile reaction activity in organocatalytic, metal-catalyzed, or radical-mediated cycloaddition reactions, which provide straightforward, powerful, and atom-economical methods to a wide range of diverse pharmacologically sultam or sulfamidate-fused nitrogen-containing heterocycles . Based on our achievements in the field of heterocyclic chemistry involving N -alkoxy α-halohydroxamate or acrylamide, and in line with our continuous efforts in annulation reactions, we have successfully established an Et 3 N-catalyzed aza-Mannich reaction triggered cascade annulation reaction of β-oxo-acrylamides with cyclic N -sulfonyl imines, leading to the formation of highly functionalized sulfamide-fused imidazolidinone derivatives (Scheme f).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Polycyclic Imidazolidinones via Cascade [3 + 2]-Annulation of β-Oxo-acrylamides with Cyclic N-Sulfonyl Imines

Xie,

Zhao,

Wang

et al. 2023

J. Org. Chem.

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An Et3N-catalyzed cascade [3 + 2]-annulation of β-oxo-acrylamides with cyclic N-sulfonyl ketimines or sulfamate-derived imines is developed under mild reaction conditions, which provides a concise and efficient route to access valuable sultam- or sulfamidate-fused imidazolidinone derivatives in good to excellent yields (80–95% yields) with excellent diastereoselectivities (>20:1 drs). The current protocol features atom economy, a transition-metal-free process, and broad functional group tolerance. Moreover, the asymmetric variant of the [3 + 2]-cycloaddition reaction was achieved in the presence of diphenylethanediamine or quinine-based bifunctional squaramide organocatalysts C-1 and C-11, giving the corresponding chiral polycyclic imidazolidinones in 68–90% yields with 25–94% ees and >20:1 drs in all cases.

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Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

Abstract: Catalytic enantioselective synthesis methodologies have been actively explored and developed owing to the significance of chiral molecules and their utilities. In particular, unnatural α-amino acids with tetrasubstituted stereogenic carbon centers...

Cited by 11 publications

References 213 publications

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

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

Catalytic Enantioselective Construction of an α-Thio-Substituted α-Aminonitriles-Bearing Tetrasubstituted Carbon Center

Synthesis of Polycyclic Imidazolidinones via Cascade [3 + 2]-Annulation of β-Oxo-acrylamides with Cyclic N-Sulfonyl Imines

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