Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(29), С. 19621 - 19628

Опубликована: Май 13, 2024

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order and catalytic asymmetric BCBs long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions divergent synthesis bridged bicyclic frameworks. The dppb ligand facilitates formal (5+3) vinyl oxiranes, yielding valuable eight-membered ethers with scaffolds in 100% regioselectivity. Cy-DPEphos promotes selective hetero-[2σ+2σ] to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, corresponding O-BCHeps 94–99% ee has achieved using chiral (S)-DTBM-Segphos, representing first cross-dimerization two strained rings. obtained are promising bioisosteres ortho-substituted benzenes.

Язык: Английский

---

Silver‐Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3‐Azabicyclo[3.1.1]heptanes

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(21)

Опубликована: Март 5, 2024

Abstract Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve saturated bioisosters to enhance the physicochemical properties and metabolic profiles candidates. Here we report a remarkably simple silver‐enabled strategy access polysubstituted 3‐azabicyclo[3.1.1]heptanes single operation from readily accessible bicyclobutanes (BCBs) isocyanides. The process is proposed involve formal (3+3)/(3+2)/retro‐(3+2) cycloaddition sequence. This novel protocol allows for rapid generation molecular complexity starting materials, products be easily derivatized, further enriching BCB chemistry growing set valuable sp 3 ‐rich building blocks.

Язык: Английский

---

Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst-Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(27), С. 18565 - 18575

Опубликована: Июнь 27, 2024

Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept "escape from flatland". However, adopting this into exploration pyridines remains elusive due to challenge incorporating a N atom such bridged structures. Herein, we report practical routes for divergent synthesis 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential readily accessible vinyl azides bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity tailored with BCBs is key achieving transformations. Ti

Язык: Английский

---

Three-dimensional saturated C(sp3)-rich bioisosteres for benzene

Nature Reviews Chemistry, Год журнала: 2024, Номер 8(8), С. 605 - 627

Опубликована: Июль 9, 2024

Язык: Английский

---

Switching between the [2π+2σ] and Hetero‐[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(29)

Опубликована: Май 11, 2024

Abstract The exploration of the complex chemical diversity bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over past two decades. Regiodivergent syntheses thiabicyclo[4.1.1]octanes (S‐BCOs) highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition bicyclobutanes (BCBs) 3‐benzylideneindoline‐2‐thione derivatives have been established. first hetero‐(4+3) BCBs, catalyzed by Zn(OTf) 2 , was achieved with broad substrate scope under mild conditions. In contrast, less electrophilic BCB ester undergoes Sc(OTf) 3 ‐catalyzed [2π+2σ] reaction 1,1,2‐trisubstituted alkenes, yielding BCHs spirocyclic quaternary carbon center. Control experiments preliminary theoretical calculations suggest that diastereoselective product formation may involve concerted between zwitterionic intermediate E ‐1,1,2‐trisubstituted alkenes. Additionally, nucleophilic ring‐opening mechanism.

Язык: Английский

---

Ti-Catalyzed Formal [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with 2-Azadienes to Access Aminobicyclo[2.1.1]hexanes

Organic Letters, Год журнала: 2024, Номер 26(8), С. 1745 - 1750

Опубликована: Фев. 20, 2024

Saturated bicyclic amines are increasingly targeted to the pharmaceutical industry as sp3-rich bioisosteres of anilines. Numerous strategies have been established for preparation bridgehead aminobicyclics. However, methods assemble bridge-amino hydrocarbon skeleton, which serves a meta-substituted arene bioisostere, limited. Herein, general approach access 2-aminobicyclo[2.1.1]hexanes (aminoBCHs) by titanium-catalyzed formal [2π + 2σ] cycloaddition bicyclo[1.1.0]butanes and 2-azadienes was developed. Simple derivatization aminoBCHs leads various medicinally agrochemically important analogues.

Язык: Английский

---

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(30), С. 21069 - 21077

Опубликована: Июль 16, 2024

The direct construction of bioisosteric compounds enriched in C

Язык: Английский

---

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

Asian Journal of Organic Chemistry, Год журнала: 2024, Номер 13(5)

Опубликована: Фев. 21, 2024

Abstract Within a medicinal chemist's toolbox, one of the most effective strategies to improve overall properties biologically active compound is bioisosteric replacement. Ever since first example replacing benzene with bicyclo[1.1.1]pentane (BCP) group was published in late 1990s, [1] chemistry community has continually been expanding scope such phenyl replacements. Recent interest from academia focused on novel synthetic access C( sp 3 )‐rich bicyclic hydrocarbons expanded ring sizes. Herein, we summarize some these transformations and reveal that rely strain releasing cycloadditions bicyclo[1.1.0]butane (BCB) bicyclo[2.1.0]pentane (housane). We have organized this review based mechanism release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed electron catalyzed polar cycloadditions.

Язык: Английский

---

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(23), С. 16237 - 16247

Опубликована: Май 29, 2024

As the chemistry that surrounds field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous develop alternative reactivity modes harness their unique properties access new regions chemical space. Herein, we report use photoredox catalysis promote single-electron oxidation bicyclo[1.1.0]butanes. The synthetic utility resulting radical cations is highlighted by ability undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. most notable feature this transformation breadth alkene classes can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken order better understand physical nature bicyclo[1.1.0]butyl thus provides a platform from further studies into applications these intermediates built upon.

Язык: Английский

---

Lewis Acid Catalyzed Cycloaddition of Bicyclobutanes with Ynamides for the Synthesis of Polysubstituted 2‐Amino‐bicyclo[2.1.1]hexenes

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(32)

Опубликована: Май 24, 2024

Abstract Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf) 3 ‐catalyzed [3+2] cycloaddition bicyclo[1.1.0]butanes (BCBs) with ynamides, yielding diverse array polysubstituted 2‐amino‐bicyclo[2.1.1]hexenes good excellent yields. These products offer valuable starting materials for the construction novel functionalized bicyclo[1.1.0]butanes. Preliminary mechanistic studies indicate that reaction involves nucleophilic addition ynamides bicyclo[1.1.0]butanes, followed by an intramolecular cyclization situ generated enolate keteniminium ion. We expect these findings will encourage utilization complex bioisosteres foster further investigation into BCB‐based chemistry.

Язык: Английский

---