Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 25, 2024

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because their extensive use as saturated bioisosteres arene in pharmaceutical industry. However, sharp contrast to racemic counterparts, assembling chiral structures an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by [4π + 2σ] cycloadditions bicyclo[1.1.0]butanes (BCBs) nitrones taking advantage a copper(II) complex Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up 99%), excellent enantioselectivity 99% ee). Density theory (DFT) calculation elucidates the origin reaction's mechanism BCB activation Cu(II) complex.

Language: Английский

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A solution to the anti-Bredt olefin synthesis problem

Science, Journal Year: 2024, Volume and Issue: 386(6721)

Published: Oct. 31, 2024

The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that conserved across diverse structural contexts. Nonetheless, these can be distorted, leading to heightened reactivity of the π-bond. Although π-bond-containing compounds bent well utilized synthetic chemistry, corresponding leveraging display twisting or pyramidalization remains underdeveloped. We report a study perhaps most notorious class geometrically distorted contain π-bonds: anti-Bredt olefins (ABOs). ABOs have been known since 1924, and conventional wisdom maintains difficult impossible access. provide solution this long-standing problem. Our also highlights strategic manipulation considerable distortion arising from presence constrained π-bonds.

Language: Английский

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Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity

Nature Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Language: Английский

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Recent Progress in Accessing Multi-functionalized Caged Hydrocarbons: En Route to Highly Functionalized Saturated (Bio)isosteres of Benzene Rings

Synthesis, Journal Year: 2024, Volume and Issue: unknown

Published: July 4, 2024

Abstract Recently, many saturated bioisosteres of the benzene ring have been developed, and their applications in drug development evaluated. Most these are caged hydrocarbons, which rigid skeletons three-dimensional spaces. Recent efforts to synthesize hydrocarbons enabled access multi-functionalized congeners that expected be (bio)isosteres benzenes. This short review summarizes recently reported methods for obtaining (typically more than disubstituted) hydrocarbons. 1 Introduction 2 Proposed Structures Caged Hydrocarbons as Saturated (Bio)isosteres Benzene Ring: A Brief Summary 3 Access Multi-functionalized Hydrocarbons: De Novo Synthetic Approaches 3.1 Bicyclo[1.1.1]pentanes (BCPs) 3.2 Bicyclo[2.1.1]hexanes (BCHs) 3.3 Bicyclo[3.1.1]heptanes (BCHeps) 3.4 Others 4 C–H Functionalization 5 Conclusion

Language: Английский

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Enantioselective [2π + 2σ] cycloaddition of bicyclobutanes with imines: An efficient approach to chiral 2-aza-bicyclo[2.1.1]hexanes

Chem Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 101295 - 101295

Published: March 1, 2025

Language: Английский

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3-Oxabicyclo[3.1.1]heptanes as Isosteres of meta-Substituted Benzene Rings

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Replacement of the aromatic rings in drug candidates with isosteric rigid sp3-rich scaffolds can improve physicochemical properties, increase chance progressing molecule development, and open new chemical space. Isosteres meta-substituted benzenes remain challenging due to difficulty mimicking exit vector angles bond distances. Herein, we report synthesis 1,5-disubstituted 3-oxabicyclo[3.1.1]heptanes (oxa-BCHeps), which serve as saturated isosteres phenyl a similar geometric arrangement. This structural motif be obtained under mild reaction conditions via acid-mediated isomerization (2-oxaspiro[3.3]heptan-6-yl)methanols using catalytic quantities pyridinium chloride (PyrHCl). We demonstrate utility this methodology by preparing various building blocks for use medicinal chemistry incorporating 3-oxa-BCHep into anticancer sonidegib, improving its such permeability, metabolic stability, solubility.

Language: Английский

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Enantioselective Dearomative [2π + 2σ] Photocycloaddition of Naphthalene Derivatives with Bicyclo[1.1.0]butanes Enabled by Gd(III) Catalysis

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

The cycloaddition reactions of bicyclo[1.1.0]butanes with alkenes, imines, nitrones, or aziridines have served as an efficient platform to create conformationally restricted saturated bicyclic scaffolds. However, the use readily available aromatics in such reactions, especially asymmetric manner, remains underexplored. Herein, we report a highly regio- and enantioselective dearomative [2π + 2σ] photocycloaddition reaction between naphthalene derivatives bicyclo[1.1.0]butanes, enabled by Gd(III) catalysis. Bicyclo[1.1.0]butanes naphthalenes adorned diverse array functional groups are well-tolerated under mild conditions, affording enantioenriched pharmaceutically important bicyclo[2.1.1]hexanes 30–96% yields 81–93% ee 12:1 → >20:1 rr. synthetic versatility this is further demonstrated facile removal directing group derivatizations dearomatized product. UV–vis absorption spectroscopy studies suggest involvement excited species process.

Language: Английский

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Monobromination of Cubane 1,4-Diester, A Synthetic Handle for Fluorosulfonylation and Giese-Type Reactions

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

The bromination of cubane 1,4-diester is described for the first time. versatility C-Br bond forging C-S and C-C bonds was demonstrated. fluorosulfonylation reaction allowed entry in click chemistry illustrated with nucleophiles, electrophiles, alkynes. grafting appendages amino acids dipeptides, enabling discrimination diesters via cyclization into "fused cubane-lactam" structures.

Language: Английский

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Modular Synthesis of Azidobicyclo[2.1.1]hexanes via (3 + 2) Annulation of α-Substituted Vinyl Azides and Bicyclo[1.1.0]butanes

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(20), P. 15151 - 15157

Published: Sept. 27, 2024

Here, we present a mild and rapid method to access azidobicyclo[2.1.1]hexanes via formal (3 + 2) cycloaddition of α-substituted vinyl azides bicyclo[1.1.0]butanes under Lewis acid catalysis. A wide range were tolerated conditions. Notably, the resulting cycloadducts could be transformed into structurally attractive 3-azabicyclo[3.1.1]heptenes through microwave-promoted rearrangement. The utilities highlighted by copper(I)-catalyzed Huisgen 1,3-dipolar tertiary alkyl azide further transformation ketone groups.

Language: Английский

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Blickpunkt Synthese: Ein nützlicher Antiaromat

Nachrichten aus der Chemie, Journal Year: 2024, Volume and Issue: 72(7-8), P. 65 - 67

Published: July 1, 2024

Abstract Cyclobutadien, der kleinste Antiaromat, ist sehr reaktiv. Es herzustellen und präparativ zu nutzen nicht einfach, aber Aufwand lohnt sich: Cyclobutadien eignet sich zum Beispiel für [4+2]‐Cycloadditionen, eine Cuban‐ Naturstoffsynthese.

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