Organocatalytic enantioselective synthesis of acyclic pyrimidine nucleosides by aza-Michael reaction

Lee, Su-Jeong; Ahn, Jun-Gi; Seo, Jung Hun; Ha, Heun‐Jong; Cho, Chang-Woo

doi:10.1039/c8ob02754d

Cited by 9 publications

(2 citation statements)

References 51 publications

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“…As the first choice, we selected the widely recognized Hayashi-Jørgensen catalyst AM1 due to its well-established reputation for exhibiting high generality and applicability, particularly in organocatalytic CÀ N bond formation of enals. [29,[39][40][41][42][43] Contrary to expectations, the catalyst performance was unsatisfactory, regardless of the presence of benzoic acid as a cocatalyst (Table 1, entry 1-2). This outcome strongly indicated that the activation of the ketone functionality on reagent 2 a was a fundamental requirement for achieving at least moderate yield.…”

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confidence: 65%

“…In our pursuit of optimizing the yield and enantioselectivity of product 3 a , we conducted a screening of various catalysts in the domain of iminium catalysis, focusing on enals 1 a – w as the substrate class. As the first choice, we selected the widely recognized Hayashi‐J ø rgensen catalyst AM1 due to its well‐established reputation for exhibiting high generality and applicability, particularly in organocatalytic C−N bond formation of enals [29,39–43] . Contrary to expectations, the catalyst performance was unsatisfactory, regardless of the presence of benzoic acid as a cocatalyst (Table 1, entry 1–2).…”

Section: Figurementioning

confidence: 99%

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Synthesis of Chiral Diazabicycloalkanes via Organocatalytic aza‐Michael/Aldol Reaction

Scharinger,

Weil,

Schnürch

et al. 2023

Adv Synth Catal

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We introduce a strategy for the one‐step synthesis of chiral diazabicycloalkanes that delivers the annulated ring system in a single reaction step. The method entails a direct aza‐Michael/aldol reaction of enals in conjunction with modified oxopropanamides and establishes the chiral center via iminium‐enamine tandem catalysis. For this purpose, we developed simple diphenylethylendiamine frameworks as dual activation organocatalyst, effectively engaging both the substrate and reagent, thus leading to yields of 31–86% and enantioselectivities in the range of 80–98%. The final product features not only the diazabicycloalkane moiety but includes also additional functionalities, such as aldehyde motives that can be modified in situ without loss of enantioselectivity, and an sp2‐bearing methyl group. Our approach accommodates a wide array of enals with high functional group tolerance. Additionally, we demonstrated the adjustability of enantioselectivity and yield by modulating the acid cocatalyst‘s quantity, thus offering multiple optimization possibilities.

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confidence: 65%

Section: Figurementioning

confidence: 99%

Synthesis of Chiral Diazabicycloalkanes via Organocatalytic aza‐Michael/Aldol Reaction

Scharinger,

Weil,

Schnürch

et al. 2023

Adv Synth Catal

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Enantioselective Organocatalyzed aza‐Michael Addition Reaction of 2‐Hydroxybenzophenone Imines to Nitroolefins under Batch and Flow Conditions

et al. 2021

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Herein, an asymmetric organocatalytic aza‐Michael addition reaction of ketimines to nitroolefins is presented. The use of 2‐hydroxybenzophenone imine improves the enantioselective addition of N‐centered nucleophiles to nitroalkenes by means of intramolecular hydrogen bond formation at the imine moiety. Moreover, the versatility of the process is demonstrated under both batch and flow conditions, showing the synthesis of a large variety of nitroamine derivatives with excellent yields and enantioselectivities. In addition, we applied this methodology to the formal synthesis of VNI, a drug‐like scaffold for the treatment of Chagas disease.

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Enantioselective Michael addition using 4(3H)‐pyrimidinone

Chen

Huang

Cheng

et al. 2022

J Chinese Chemical Soc

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The framework of 4-pyrimidinones is prevalent in biologically and medicinally important molecules. Here we report that chiral N-substituted 4-pyrimidinones were prepared by an enantioselective, organocatalytic aza-Michael addition of 4 (3H)-pyrimidinone (4-hydroxypyrimidine) to α,β-unsaturated 1,4-dicarbonyl compounds for the first time. The reactions were optimized by the choice of solvents, screening Cinchona alkaloid-based bifunctional catalysts, and Michael acceptors to achieve good yields and enantioselectivities.

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Organocatalytic enantioselective synthesis of acyclic pyrimidine nucleosides by aza-Michael reaction

Abstract: Organocatalytic enantioselective synthesis of acyclic pyrimidine nucleosides was achieved by the aza-Michael reaction of pyrimidines as N-centered nucleophiles to α,β-unsaturated aldehydes.

Cited by 9 publications

References 51 publications

Synthesis of Chiral Diazabicycloalkanes via Organocatalytic aza‐Michael/Aldol Reaction

Synthesis of Chiral Diazabicycloalkanes via Organocatalytic aza‐Michael/Aldol Reaction

Enantioselective Organocatalyzed aza‐Michael Addition Reaction of 2‐Hydroxybenzophenone Imines to Nitroolefins under Batch and Flow Conditions

Enantioselective Michael addition using 4(3H)‐pyrimidinone

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