Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Опубликована: Апрель 1, 2024

The exploration of C(sp3)-rich three-dimensional (3D) scaffolds as bioisosteres for planar aromatics has garnered increasing attention. While the bioisosterism benzenes been extensively studied, pyridines, second most prevalent aromatic compounds in pharmaceuticals, faces additional challenges and encountered surprisingly limited success. In this study, we propose unprecedented 2-azabicyclo[3.1.1]heptenes effective 1,3,5-trisubstituted pyridines terms not only 3D conformation but also basicity. We develop a pyridine-boryl radical-catalyzed [3π + 2σ] cycloaddition reaction vinyl azides with bicyclo[1.1.0]butanes (BCBs) an efficient synthetic approach. Synthetic manipulation products reveals valuable handles, allowing modular synthesis various pyridine bioisosteres.

Язык: Английский

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In(OTf)₃-Catalyzed (3 + 3) Dipolar Cyclization of Bicyclo[1.1.0]butanes with N-Nucleophilic 1,3-Dipoles: Access to 2,3-Diazabicyclo[3.1.1]heptanes, 2,3-Diazabicyclo[3.1.1]heptenes, and Enantiopure 2-Azabicyclo[3.1.1]heptanes

ACS Catalysis, Год журнала: 2024, Номер unknown, С. 17837 - 17849

Опубликована: Ноя. 18, 2024

The investigation into the synthesis of azabicyclo[3.1.1]heptanes (azaBCHeps) as bioisosteres to flat aza-aromatics has garnered increasing attention, while it encounters significant challenges. Herein, we have demonstrated In(OTf)3-catalyzed (3 + 3) dipolar cyclization bicyclo[1.1.0]butanes (BCBs) with hydrazones and π-allyl-iridium 1,3-dipoles, engendering a diverse array azaBCHeps. BCBs furnished densely substituted 2,3-diazabicyclo[3.1.1]heptanes 2,3-diazabicyclo[3.1.1]heptenes under nitrogen oxygen atmospheres, respectively. A combination experimental computational investigations lends robust support for proton-transfer-interposed sequential mechanism. More importantly, by integrating In(OTf)3/iridium relay catalysis, enantiopure 2-azabicyclo[3.1.1]heptanes were constructed through aza-π-allyl-iridium in situ generated from N-allyl carbonates. Both methodologies exhibit mild reaction conditions good tolerance various functional groups. Moreover, copious derivatization products highlights utility newly synthesized heterobicyclic motifs versatile building blocks synthetic chemistry.

Язык: Английский

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1‐Azaspiro[3.3]heptane as a Bioisostere of Piperidine**

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(51)

Опубликована: Окт. 11, 2023

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes the Graf isocyanate, ClO2 S-NCO, to give spirocyclic β-lactams. Reduction β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation this core into anesthetic drug bupivacaine instead piperidine fragment resulted in a new patent-free analogue high activity.

Язык: Английский

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Recent Progress in (3+3) Cycloadditions of Bicyclobutanes to Access Bicyclo[3.1.1]heptane Derivatives

Synlett, Год журнала: 2024, Номер unknown

Опубликована: Авг. 28, 2024

Abstract The synthesis of bicyclo[3.1.1]heptane (BCHeps) derivatives, which serve as three-dimensional (3D) bioisosteres benzenes and are the core skeleton several terpene natural products, is garnering growing interest. (3+3) cycloadditions bicyclobutanes (BCBs) represent an attractive method for efficiently accessing (hetero)BCHep skeletons with 100% atom economy. Herein, we give a brief summary recent achievements in this approach diverse BCHep emphasizing our progress initial palladium-catalyzed vinyl oxiranes. 1 Introduction 2 Radical Cycloaddition Reaction 3 Polar 4 Palladium-Catalyzed Enantioselective 5 Conclusion

Язык: Английский

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Lewis-Acid-Catalyzed Dearomative [4π + 2σ] Cycloaddition of Bicyclobutanes with Isoquinolinium Methylides for the Synthesis of Ring-Fused Azabicyclo[3.1.1]heptanes

Organic Letters, Год журнала: 2024, Номер 26(43), С. 9311 - 9315

Опубликована: Окт. 17, 2024

Dearomative cycloadditions are valuable for efficiently generating three-dimensional molecular complexity. However, despite recent reports of bicyclobutanes (BCBs) the synthesis aza-bicyclo[3.1.1]heptanes (aza-BCHeps), which bioisosteres

Язык: Английский

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