Jun Zheng

Higher Fsp ³ often correlates with clinical success, driving the replacement of flat arenes with saturated carbocycles. Stereodefined 1,1,3‐trisubstituted cyclobutane and 1,2,4‐trisubstituted bicyclo[2.1.1]hexane (BCH) serve as bioisosteres for para ‐ and 1,2,4‐trisubstituted benzenes, respectively. Yet, general stereoselective routes to these frameworks remain underdeveloped. In this study, we report a photocatalytic transannular functional group migration (TFGM) strategy that enables highly diastereoselective synthesis of 1,1,3‐trisubstituted cyclobutanes from alkylidene cyclobutanes and diverse radical precursors at room temperature. The reaction proceeds through a rigid BCH‐type transition state, delivering exclusive cis ‐selectivity. The mild conditions accommodate broad functional group tolerance and support the migration of various groups, including heteroarenes, nitrile, aldehyde, oxime, and alkene derivatives. This platform further provides general and modular entry to 1,2,4‐trisubstituted BCHs via a base‐promoted 5‐exo‐tet cyclization and cross‐coupling sequence. The resulting BCH scaffolds are effective bioisosteres of 1,2,4‐trisubstituted benzenes, demonstrated by BCH‐Olaparib and BCH‐Fluzoparib—analogues of the anticancer drugs Olaparib and Fluzoparib. These analogues retain potent activity comparable to Olaparib in a panel of cancer cell lines (enhanced in breast and liver cells), and the preferred enantiomer of BCH‐Olaparib surpasses Olaparib in PARP1 inhibition, validating 1,2,4‐trisubstituted BCHs as faithful benzenoid bioisosteres for drug innovation.

Higher Fsp ³ often correlates with clinical success, driving the replacement of flat arenes with saturated carbocycles. Stereodefined 1,1,3‐trisubstituted cyclobutane and 1,2,4‐trisubstituted bicyclo[2.1.1]hexane (BCH) serve as bioisosteres for para ‐ and 1,2,4‐trisubstituted benzenes, respectively. Yet, general stereoselective routes to these frameworks remain underdeveloped. In this study, we report a photocatalytic transannular functional group migration (TFGM) strategy that enables highly diastereoselective synthesis of 1,1,3‐trisubstituted cyclobutanes from alkylidene cyclobutanes and diverse radical precursors at room temperature. The reaction proceeds through a rigid BCH‐type transition state, delivering exclusive cis ‐selectivity. The mild conditions accommodate broad functional group tolerance and support the migration of various groups, including heteroarenes, nitrile, aldehyde, oxime, and alkene derivatives. This platform further provides general and modular entry to 1,2,4‐trisubstituted BCHs via a base‐promoted 5‐exo‐tet cyclization and cross‐coupling sequence. The resulting BCH scaffolds are effective bioisosteres of 1,2,4‐trisubstituted benzenes, demonstrated by BCH‐Olaparib and BCH‐Fluzoparib—analogues of the anticancer drugs Olaparib and Fluzoparib. These analogues retain potent activity comparable to Olaparib in a panel of cancer cell lines (enhanced in breast and liver cells), and the preferred enantiomer of BCH‐Olaparib surpasses Olaparib in PARP1 inhibition, validating 1,2,4‐trisubstituted BCHs as faithful benzenoid bioisosteres for drug innovation.

Transition‐metal‐catalyzed carbene transfer reactions are powerful tools in organic synthesis, yet they traditionally rely on diazo compounds, which raise stability and safety concerns. While alternative precursors have emerged, a general, redox‐neutral, and atom‐economical platform for metallocarbenes generation remains a persistent challenge. Herein, we introduce carboxamide‐functionalized BCBs as versatile carbene precursors that undergo catalyst‐controlled chemodivergent reactions. Under nickel catalysis, cyclopropanation of multisubstituted alkenes proceeds via an acceptor‐type Ni‐carbene, affording azabicyclo[n.1.0] architectures bearing up to three contiguous stereocenters with excellent diastereocontrol. In contrast, copper catalysis promotes efficient and chemoselective formal C(sp ² )─H insertion to access allyl oxindoles. Both protocols exhibit broad substrate scope, high functional group tolerance, and exceptional atom economy, and their synthetic utility is highlighted through the preparation of core structures of bioactive compounds. Computational and experimental studies reveal that Ni‐carbene generation proceeds via a stepwise dual C─C cleavage, contrasting with the concerted dual cleavage and subsequent electrophilic aromatic substitution manifold established for the copper system.

Transition‐metal‐catalyzed carbene transfer reactions are powerful tools in organic synthesis, yet they traditionally rely on diazo compounds, which raise stability and safety concerns. While alternative precursors have emerged, a general, redox‐neutral, and atom‐economical platform for metallocarbenes generation remains a persistent challenge. Herein, we introduce carboxamide‐functionalized BCBs as versatile carbene precursors that undergo catalyst‐controlled chemodivergent reactions. Under nickel catalysis, cyclopropanation of multisubstituted alkenes proceeds via an acceptor‐type Ni‐carbene, affording azabicyclo[n.1.0] architectures bearing up to three contiguous stereocenters with excellent diastereocontrol. In contrast, copper catalysis promotes efficient and chemoselective formal C(sp ² )─H insertion to access allyl oxindoles. Both protocols exhibit broad substrate scope, high functional group tolerance, and exceptional atom economy, and their synthetic utility is highlighted through the preparation of core structures of bioactive compounds. Computational and experimental studies reveal that Ni‐carbene generation proceeds via a stepwise dual C─C cleavage, contrasting with the concerted dual cleavage and subsequent electrophilic aromatic substitution manifold established for the copper system.

Bicyclo[2.1.1]hexanes (BCHs) have emerged as promising three‐dimensional bioisosteres of benzenoids, garnering considerable interest from both synthetic and medicinal chemistry communities. In this study, we disclose a photoinduced intermolecular [2 σ + 2 π ] cycloaddition reaction between bicyclo[1.1.0]butanes (BCBs) and alkenes, mediated by an unprecedented Ti(Salen) photocatalytic system. Under violet light irradiation (390 nm), the photoexcited Ti(Salen) complex promotes the cleavage of the central CC bond in BCBs, enabling subsequent alkene insertion to afford polysubstituted BCHs with high efficiency. This Ti‐catalyzed protocol features a broad substrate scope, good functional group compatibility, and mild reaction conditions. The operational simplicity and scalability of this transformation are further demonstrated by the concise synthesis of BCH‐Lumacaftor—a conformationally restricted analog of the FDA‐approved drug Lumacaftor—highlighting its potential for pharmaceutical applications.

Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept of "escape from flatland". However, adopting this concept into the exploration of bioisosteres of pyridines remains elusive due to the challenge of incorporating a N atom into such bridged bicyclic structures. Herein, we report practical routes for the divergent synthesis of 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential bioisosteres of pyridines from the readily accessible vinyl azides and bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity of vinyl azides tailored with BCBs is the key to achieving divergent transformations. Ti^III-catalyzed single-electron reductive generation of C-radicals from BCBs allows a concise (3 + 3) annulation with vinyl azides, affording novel 2-aza-BCHepe scaffolds. In contrast, scandium catalysis enables an efficient dipolar (3 + 2) annulation with vinyl azides to generate 2-azidobicyclo[2.1.1]hexanes, which subsequently undergo a chemoselective rearrangement to construct 3-aza-BCHepes. Both approaches efficiently deliver unique azabicyclo[3.1.1]heptene scaffolds with a high functional group tolerance. The synthetic utility has been further demonstrated by scale-up reactions and diverse postcatalytic transformations, providing valuable azabicyclics including 2- and 3-azabicyclo[3.1.1]heptanes and rigid bicyclic amino esters. In addition, the related sp²-hybridized nitrogen atom and the similar geometric property between pyridines and corresponding aza-BCHepes indicate that they are promising bioisosteres of pyridines.

This work reports a one-pot asymmetric synthesis of spirocyclopropyl propionaldehydes/propanols via β,γ-bifunctionalization of propanols through the synergistic effect of a secondary amine catalyst and an oxidant.

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