A rhodium‐catalyzed allylation of trisubstituted alkenes with gem‐difluorinated cyclopropanes (gem‐DFCPs) has been developed to access all‐carbon tetrasubstituted olefins. This transformation exhibits robust functional group compatibility and utilizes gem‐DFCPs as versatile fluorine‐containing building blocks, delivering a diverse range of all‐carbon tetrasubstituted olefins in moderate to good yields. The synthetic utility of this strategy is further highlighted by its applicability to late‐stage functionalization.

The vinylcyclopropane-cyclopentene (VCP-CPent) rearrangement serves as a fundamental method for constructing five-membered carbocycles from vinylcyclopropanes. However, achieving enantioconvergent rearrangement of less activated VCPs remains a formidable challenge. Here we report a strategy to achieve enantioconvergent VCP-CPent rearrangement of vinyl gem-difluorocyclopropanes. Our strategy proceeds through a key vinyl fluoroallyl rhodium intermediate that is mechanistically distinct from those in previously reported pathways. Furthermore, we discovered a vessel-controlled chemodivergence in this rearrangement: the reaction forms gem-difluorocyclopentenes in plastic tubes and cyclopentenones in glass vials. This protocol demonstrates excellent chemoselectivity and enantioselectivity, delivering both products in high yields with excellent e.e. values. These products, which are difficult to synthesize by conventional methods, represent privileged scaffolds in synthetic and medicinal chemistry. Mechanistic investigations offer insights into this enantioconvergent rearrangement pathway and vessel-effected chemodivergence. In addition, preliminary biological activity study shows potential of gem-difluorocyclopentene as cyclopentenone bioisostere in medicinal chemistry.

Fluorinated four‐membered rings represent valuable structural motifs in bioactive molecules and pharmaceuticals; however, the asymmetric synthesis of such fluorinated frameworks bearing chiral quaternary carbon centers has not yet been achieved. Herein, we report a Rh‐catalyzed enantioselective defluoroarylation of gem ‐difluorinated cyclobutenes with aryl boronates, enabling the asymmetric construction of fluorinated cyclobutenes bearing chiral quaternary carbon centers with high enantioselectivity via an addition/β‐fluoride elimination process. In situ treatment with an additional distinct aryl boronate enables one‐pot bis‐defluoroarylation to give unsymmetrical diarylated cyclobutenes.

Abstract A ligand-controlled rhodium-catalyzed divergent defluorinative coupling of gem-difluorocyclopropanes with alcohols is reported. Monodentate phosphine ligands afford 1-alkoxy-1-arylpropan-2-ones via bis-defluorination in up to 83% yield, while bidentate ligands give Z-monofluoroalkenes via monodefluorination in up to 91% yield. Mechanistic studies reveal that alcohol acts as both an O-nucleophile and a hydride source. This work broadens the scope of the rhodium-catalyzed reaction of gem-difluorocyclopropanes and provides a unique catalytic strategy for controllable defluorination.

Deuterated compounds are significantly important in multiple domains. Herein, we report a mild and efficient method to synthesize deuterated gem-difluorinated cyclopropanes via base-catalyzed H/D exchange with an excellent level of deuterium incorporation. This approach was mediated by a catalytic amount of sodium tert-butoxide or potassium tert-butoxide with DMSO-d6 as the deuterium source. Mechanistic studies indicate that this reaction proceeds via an anionic pathway. The scale-up synthesis and the preserved deuterium incorporation in downstream transformations demonstrate the practical applicability of this method.

A rapid isocratic LC-MS/MS method for quantifying busulfan in human plasma was developed and validated. Plasma samples were processed by protein precipitation with acetonitrile using busulfan-d8 as internal standard. Separation...

Transition-metal-catalyzed cycloadditions of strained carbocycles have emerged as a powerful strategy for constructing complex molecular architectures through C-C bond reorganization. We previously reported a Rh-catalyzed (3 + 2) cycloaddition of gem-difluorinated cyclopropanes (gem-DFCPs) with internal olefins, which was initially interpreted to proceed via a conventional cycloaddition mechanism. Mechanistic interrogation, through control experiments and DFT calculations, now reveals that this transformation proceeds through a previously unrecognized pathway involving dual C-C/C-F bond activation. The unusual cyclization mechanism involves fluoroallylic substitution, carbocation-mediated intramolecular cyclization, and fluoride transfer. This revised mechanistic framework not only redefines the understanding of such cycloadditions but also directly inspires the development of new reactions.

The development of safe and economical catalytic hydrogenation is a persistent challenge. The direct use of abundant alkanes as hydrogen donors under mild conditions is particularly desirable, yet conventional alkane dehydrogenation approaches for this purpose typically require harsh conditions (150°C-200°C) and tolerate a limited range of olefin substrates. Here, we report a cooperative palladium/photoredox catalytic system that enables the hydrogenation of unactivated olefins at room temperature using simple alkanes as the hydrogen source. This dual catalysis merges a photocatalyzed hydrogen atom transfer (HAT) from alkanes with a palladium-catalyzed hydrogen transfer, achieving efficient olefin hydrogenation. Mechanistic studies support a radical-mediated pathway and confirm alkanes as the hydrogen source. This operationally simple method exhibits broad substrate scope and functional group tolerance, allowing for the late-stage modification of complex molecules under mild conditions. This work establishes a general strategy for alkane utilization as convenient and versatile hydrogen donors, offering a mild alternative to traditional hydrogenation methods that generally rely on H2 gas.

This study introduces a traceless linker strategy for pentadehydro-Diels–Alder (PDDA) cyclization, in which the sulfide/sulfone linker is strategically repurposed as a diene surrogate. As excellent electron-donating dienes, these linkers react with electron-deficient alkenes and alkynes, resulting in a series of highly selective cyclization products. This cascade reaction efficiently integrates the PDDA reaction with linker transformation, formally eliminating the need for permanent structural constraints. By exploiting the intrinsic reactivity of the linker, this strategy offers a robust and versatile approach to constructing complex polycyclic aromatic architectures, providing a powerful tool for organic synthesis.

Vinyl cyclopropanes (VCPs) serve as important three- and five-carbon synthons in organic synthesis; however, functionalization of their two inherently inactive sites remains a significant challenge. To address this, we designed a Rh-catalyzed ring-opening/β-F elimination of vinyl gem-difluorocyclopropanes (VCPdFs) to generate vinylic allyl rhodium intermediates, thereby unlocking novel reactivity of VCP derivatives. In this work, we report a rhodium-catalyzed enantioconvergent rearrangement of racemic VCPdFs that efficiently produces diverse chiral cyclopentenes in chemdivergent manner, including cyclopentenones and gem-difluorocyclopentenes that are challenging to access via conventional methods. This protocol demonstrates excellent chemoselectivity and enantioselectivity, delivering both products in high yields with excellent ee values. The rationalized mechanistic discussion elucidates the reaction pathways and selectivity, all of which are well-supported by experimental evidence. In addition, several chiral cyclopentenones demonstrate therapeutic potential against bladder cancer.

Synthesis of axially chiral alkylidenecyclobutanes exists sustained challenges by virtue of the compatibility of an efficient asymmetric catalytic system and the meticulous retention of its inherent strained ring structure. We herein disclose an enantioselective carbene cross-coupling reaction of cyclobutanecarbaldehyde-derived N‑tosylhydrazones with organohalides enabled by a combination of palladium catalysis and the modified sulfinamide phosphine ligand (Sadphos). This reaction proof the concept that axial chirality can be constructed on a strained metal carbene intermediate precisely through a sequential process of enantio-determined migratory insertion and β-H elimination. A variety of alkylidenecyclobutanes with heteroatom-substituted stereocenter, tertiary carbon stereocenter, and all-carbon quaternary stereocenter for particular, can be synthesized collectively with excellent yields and high enantioselectivities. Both the two enantiomers can be obtained via selecting the corresponding either cis or trans hydrazone substrates in a stereospecific manner. The synthetic applications of this asymmetric carbene coupling reaction are further demonstrated by the access of enantioenriched free amine by hydrolysis smoothly (99% ee) and the downstream transformations to reach versatile nitrogen-containing heterocycles without any enantiopurity erosion (99% ee).

Herein, a metal‐free and general platform for the direct (di‐ or mono‐)selenylation at the C3 and C5 position of pyridones via bromide catalysis, using Se powder and boronic acids as the selenyl precursors, was successfully disclosed. This strategy proceeded with high site‐selectivity under the directing group‐free and transition‐metal‐free conditions. Simple catalytic system, high efficiency, operational simplicity, excellent functional group tolerance, strong chemical‐oxidant free, and easily scale‐up, were shown in this method. Furthermore, the mechanistic experiments indicated that a radical pathway was possibly involved.

The synthesis of axially chiral alkylidenecyclobutanes remains challenging due to the requirement of both an efficient asymmetric catalytic system and preservation of its inherent strained ring structure. We herein disclose an enantioselective carbene cross-coupling reaction of cyclobutanecarbaldehyde-derived N-tosylhydrazones with aryl bromides, enabled by palladium catalysis in combination with an elaborately modified sulfinamide phosphine ligand (Sadphos). This method demonstrates the feasibility of constructing axial chirality on a strained metal carbene intermediate precisely through a sequential process of enantiodetermined migratory insertion followed by central-to-axial-chirality-transfer β-H elimination. The reaction provides access to diverse alkylidenecyclobutanes featuring a heteroatom-substituted, tertiary and all-carbon quaternary stereocenter with excellent yields (up to 95%) and high enantioselectivities (up to 95% ee). Moreover, both enantiomers can be selectively obtained by choosing either cis- or trans-cyclobutane substrates in a stereospecific manner.

In this work, we report the cyclization of sulfur-linked tetraynes under 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radical conditions, leading to the formation of novel pentadehydro-Diels-Alder-type addition products. Through this study, we expand the scope of radical-mediated cyclization reactions of polyyne compounds. The results offer new opportunities for the development of radical-based synthetic methodologies.

The C—F bond transformation of gem-difluorinated cyclopropanes without cleavage of the highly strained C—C bond is an intractable challenge.The synthesis of cyclopropanone ketals via double defluorination of gem-difluorinated cyclo-propanes under transition-metal free and basic conditions has been developed.A broad range of gem-difluorinated cyclopro-panes and alcohols are amenable in present reaction to permit the synthesis of corresponding products in high yields.The reaction is elucidated to proceed via elimination and addition other than direct substitution based on the mechanistic studies.This transformation not only provides a new strategy for the construction of cyclopropanone ketals,but also reveals a new paradigm on C—F bond transformation without ring-opening ofgem-difluorinated cyclopropanes.

gem-Difluorocyclopropanes (gem-DFCPs) have gained significant attention as versatile fluorinated synthons in organic synthesis due to their unique structural and electronic properties. Recent advancements have demonstrated the utility of gem-DFCPs in transition-metal-catalyzed cross-coupling reactions with indoles, enabling the synthesis of monofluoroallylic indole derivatives. In this study, a transition-metal-free double indolylation of gem-DFCPs was developed, preserving the cyclopropane core and facilitating the direct incorporation of two indole units. This method, optimized under mild conditions using NaOtBu and DMSO, provides access to gem-diindolylcyclopropanes with high yields and broad substrate scope. Mechanistic studies, including deuterium-labeling experiments, suggest a base-mediated elimination and nucleophilic addition pathway. The scalability and postfunctionalization potential of the products highlight the synthetic utility of this transformation, particularly in the late-stage modification of bioactive molecules. This research expands the synthetic toolbox for constructing densely functionalized cyclopropane architectures with potential pharmaceutical relevance.

Axially chiral cycloalkanes have recently emerged as compelling scaffolds with broad utility in asymmetric catalysis and molecular design. This graphical review provides a concise overview of synthetic strategies for constructing axially chiral cycloalkanes. Representative methods summarized include asymmetric allylic substitution, alkene insertion, carbene cross-coupling, carbonyl condensation/reduction, [2+2] cycloaddition, and deracemization. We offer fundamental insights into this emerging field, aiming to facilitate future research toward novel chiral frameworks.

Metal carbenes are versatile motifs that serve not only as catalysts but also as key intermediates in modern organic synthesis. Although considerable attention has been devoted to metal carbenes in non-strained systems, strained metal carbenes, which integrate high-energy strained ring systems with metal carbenes, exhibit distinct reactivity and selectivity in carbene-involved transformations. This feature article systematically reviews recent advances in this emerging field of strained metal carbene chemistry, which are categorized by carbene precursors, including N-sulfonylhydrazones, [1.1.1]propellane, and strained methylenecyclobutane derivatives. It aims to highlight developments and applications of strained metal carbene species, with a particular emphasis on reaction mechanistic insights, selectivity control, and merits and limitations of each strategy, alongside their potential implications for synthetic and medicinal chemistry. We hope that this review will stimulate further innovation among researchers in strained metal carbene chemistry and beyond.

Cyclobutane derivatives are important motifs in natural products and bioactive compounds. Owing to their inherent strain, the asymmetric synthesis of cyclobutanes remains a formidable challenge. With the development of various stereospecific transformations of alkylboronic esters, chiral cyclobutylboronates are expected to serve as promising synthetic intermediates for accessing chiral cyclobutane derivatives. However, obtaining highly enantioenriched cyclobutylboronates poses a daunting task in the field of organic synthesis. In this context, we highlight recent significant advances in the synthesis of chiral cyclobutylboronates. 1 Introduction 2 Enantioselective Borylation of Cyclobutenes 3 Enantioselective Borylation of Cyclobutanes 4 Other Methods 5 Conclusions