Accounts of Chemical Research最新文献

{"title":"Total Synthesis of Polycyclic Natural Products via Photoenolization/Diels–Alder Reaction","authors":"Baochao Yang, Min Hou and Shuanhu Gao*, ","doi":"10.1021/acs.accounts.5c0008410.1021/acs.accounts.5c00084","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00084https://doi.org/10.1021/acs.accounts.5c00084","url":null,"abstract":"<p >Polycyclic ring systems represent the most common structural features of drug molecules and natural products. Chemical synthesis of complex polycyclic molecules with multiple stereogenic centers, especially quaternary carbon stereocenters, has been a significant challenge in the field of total synthesis. Due to the low reactivities of the substrates and congested chemical environments, the efficient establishment of polycyclic rings and enantioselective construction of quaternary carbon stereocenters are still ongoing challenges. In our laboratory, we are devoted to developing new methodologies and strategies for the total syntheses of bioactive polycyclic natural products and the exploration of their biological potentials. The photoenolization/Diels–Alder (PEDA) reaction has been recognized as a powerful strategy to increase synthetic efficiency and address the aforementioned issues. Over the past several years, our group systematically reinvestigated this reaction in terms of its reactivity and stereoselectivity and developed a unique dinuclear metal-promoted reaction process for constructing fused or spiro polycyclic rings bearing quaternary carbon stereocenters. During the course of this investigation, we have come to realize how to rationally design the synthetic route based on the PEDA reaction and successfully implement the synthetic projects.</p><p >In this Account, we summarize our endeavors and journeys in the development and application of the PEDA reaction to the total synthesis of topologically complex natural products in order to draw attention to its broad utility and encourage further uptake. In the first part, we provide the details on the investigation of the PEDA reaction to address the issues of reactivity, diastereoselectivity, and enantioselectivity. An enantioselective PEDA reaction involving Ti(O<i>i</i>-Pr)<sub>4</sub> and TADDOL-type ligands was developed. This reaction enables the sterically bulky dienophiles to interact with the transient photoenolized hydroxy-<i>o</i>-quinodimethanes, delivering a wide range of polycyclic rings with single or vicinal quaternary carbon stereocenters in good yields with excellent enantioselectivities. In the second part, we showcase the synthetic potential of PEDA reaction in total synthesis of natural products. The fused tricyclic ring systems, bearing <i>gem</i>-dimethyl groups or quaternary carbon stereocenters located at the ring junction, were efficiently constructed by Ti(O<i>i</i>-Pr)<sub>4</sub>-promoted PEDA reactions, which enabled the syntheses of three different types of natural products, including aromatic polyketides (anthrabenzoxocinones, fasamycins/naphthacemycins, and benastatins), meroterpenoid (oncocalyxone B), and halenaquinones (xestoquinone, adociaquinones A and B). To access structurally more complex triterpenoids, namely, perovskones and hydrangenones, the asymmetric PEDA reaction was developed to build a tricyclic ring along with three contiguous quaternary","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1308–1322 1308–1322"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aromatic Metamorphosis: Skeletal Editing of Aromatic Rings","authors":"Hideki Yorimitsu*, ","doi":"10.1021/acs.accounts.5c0009110.1021/acs.accounts.5c00091","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00091https://doi.org/10.1021/acs.accounts.5c00091","url":null,"abstract":"<p >Aromatic rings are fundamental structural motifs found in natural products, synthetic intermediates, pharmaceuticals, agrochemicals, and functional materials. While transformations at the periphery of these rings are well-established, modifying their core frameworks has remained an underexplored frontier. Our group has pioneered the concept, termed “aromatic metamorphosis”, enabling skeletal transformations of aromatic rings by replacing an endocyclic atom with a different atom or inserting an atom into aromatic rings, which leads to novel synthetic strategies and diverse molecular architectures.</p><p >The concept of aromatic metamorphosis was first demonstrated in the stepwise conversion of dibenzothiophenes and dibenzofurans into triphenylenes. These transformations, facilitated by palladium and nickel catalysts, involve the strategic activation of robust C–S and C–O bonds as the key steps. Next, the approach was extended to the two-step conversions of dibenzothiophenes into carbazoles, dibenzophospholes, fluorenes, etc., which involve oxidation into the corresponding sulfones and subsequent sequential inter- and intramolecular nucleophilic aromatic substitution reactions. These new synthetic routes have provided efficient access to optoelectronic materials. Especially, the S<sub>N</sub>Ar-based aromatic metamorphosis facilitated the construction of a heterohelicene library with systematic variation in endocyclic atoms. This strategy has revolutionized the way molecular libraries are constructed and enables the rapid discovery of functional molecules.</p><p >In addition to the endocyclic substitutions, ring-expanding aromatic metamorphosis through atom insertion has also been explored. We developed nickel-catalyzed boron insertion into benzofurans, generating benzoxaborins, which are important scaffolds for medicinal chemistry. This novel catalytic transformation has been successfully scaled to industrial synthesis by companies, which demonstrates the practical utility of aromatic metamorphosis. Furthermore, manganese-catalyzed and lithium–metal-promoted methodologies have expanded the ranges of heteroatoms inserted and aromatic frameworks cleaved, providing methods to access heterocycles with a diversity in element compositions.</p><p >Reductive dilithiation of thiophenes efficiently yields 1,4-dilithiobutadienes, which react with a variety of electrophiles to produce a series of nonbiogenic heteroles, such as boroles, phospholes, and siloles. In principle, this method should allow the sulfur atom in readily available thiophenes to be replaced with any atom and is therefore considered an ideal example of aromatic metamorphosis in terms of rapid construction of diverse chemical spaces with a variety of elements.</p><p >Aromatic metamorphosis proposes many new synthons and retrosynthetic disconnections that defy the conventional wisdom of organic synthesis. By making full use of metamorphosing the aromatic skeleton, a library with skeletal ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1323–1334 1323–1334"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative Chemical Strategies for Advanced CRISPR Modulation.","authors":"Xingyu Liu, Enyi Zhou, Qianqian Qi, Wei Xiong, Tian Tian, Xiang Zhou","doi":"10.1021/acs.accounts.5c00052","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00052","url":null,"abstract":"<p><p>ConspectusOver the past decade, RNA-guided gene editing technologies, particularly those derived from CRISPR systems, have revolutionized life sciences and opened unprecedented opportunities for therapeutic innovation. Despite their transformative potential, achieving precise control over the activity and specificity of these molecular tools remains a formidable challenge, requiring advanced and innovative regulatory strategies. We and others have developed new approaches that integrate chemical ingenuity with bioorthogonal techniques to achieve remarkable precision in CRISPR regulation. One key innovation lies in the chemical modulation of guide RNA (gRNA), significantly expanding the CRISPR toolkit. Strategies such as CRISPR-ON and CRISPR-OFF switches rely on selective chemical masking and demasking of gRNA. These approaches use either bulky chemical groups to preemptively mask RNA or minor, less obstructive groups to fine-tune its function, followed by bioorthogonal reactions to restore or suppress activity. These methodologies have proven to be pivotal for controlled gene editing and expression, addressing the challenges of precision, reversibility, and dynamic regulation.Parallel to these advances, the development of mesoporous metal-organic frameworks (MOFs) has emerged as a promising solution for RNA deprotection and activation. By serving as catalytic tools, MOFs enhance the versatility and efficiency of CRISPR systems, pushing their applications beyond the conventional boundaries. In addition, the synthesis of novel small molecules for regulating CRISPR-Cas9 activity marks a critical milestone in the evolution of gene therapy protocols. Innovative RNA structural control strategies have also emerged, particularly through the engineering of G-quadruplex (G4) motifs and G-G mismatches. These methods exploit the structural propensities of engineered gRNAs, employing small-molecule ligands to induce specific conformational changes that modulate the CRISPR activity. Whether stabilizing G4 formation or promoting G-G mismatches, these strategies demonstrate the precision and sophistication required for the molecular-level control of gene editing.Further enhancing these innovations, techniques like host-guest chemistry and conditional diacylation cross-linking have been developed to directly alter gRNA structure and function. These approaches provide nuanced, reversible, and safe control over CRISPR systems, advancing both the precision and reliability of gene editing technologies. In conclusion, this body of work highlights the convergence of chemistry, materials science, and molecular biology to create integrative solutions for gene editing. By combination of bioorthogonal chemistry, RNA engineering, and advanced materials, these advancements offer unprecedented accuracy and control for both fundamental research and therapeutic applications. These innovations not only advance genetic research but also contribute to developing safer and mo","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aromatic Metamorphosis: Skeletal Editing of Aromatic Rings.","authors":"Hideki Yorimitsu","doi":"10.1021/acs.accounts.5c00091","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00091","url":null,"abstract":"<p><p>ConspectusAromatic rings are fundamental structural motifs found in natural products, synthetic intermediates, pharmaceuticals, agrochemicals, and functional materials. While transformations at the periphery of these rings are well-established, modifying their core frameworks has remained an underexplored frontier. Our group has pioneered the concept, termed \"aromatic metamorphosis\", enabling skeletal transformations of aromatic rings by replacing an endocyclic atom with a different atom or inserting an atom into aromatic rings, which leads to novel synthetic strategies and diverse molecular architectures.The concept of aromatic metamorphosis was first demonstrated in the stepwise conversion of dibenzothiophenes and dibenzofurans into triphenylenes. These transformations, facilitated by palladium and nickel catalysts, involve the strategic activation of robust C-S and C-O bonds as the key steps. Next, the approach was extended to the two-step conversions of dibenzothiophenes into carbazoles, dibenzophospholes, fluorenes, etc., which involve oxidation into the corresponding sulfones and subsequent sequential inter- and intramolecular nucleophilic aromatic substitution reactions. These new synthetic routes have provided efficient access to optoelectronic materials. Especially, the S<sub>N</sub>Ar-based aromatic metamorphosis facilitated the construction of a heterohelicene library with systematic variation in endocyclic atoms. This strategy has revolutionized the way molecular libraries are constructed and enables the rapid discovery of functional molecules.In addition to the endocyclic substitutions, ring-expanding aromatic metamorphosis through atom insertion has also been explored. We developed nickel-catalyzed boron insertion into benzofurans, generating benzoxaborins, which are important scaffolds for medicinal chemistry. This novel catalytic transformation has been successfully scaled to industrial synthesis by companies, which demonstrates the practical utility of aromatic metamorphosis. Furthermore, manganese-catalyzed and lithium-metal-promoted methodologies have expanded the ranges of heteroatoms inserted and aromatic frameworks cleaved, providing methods to access heterocycles with a diversity in element compositions.Reductive dilithiation of thiophenes efficiently yields 1,4-dilithiobutadienes, which react with a variety of electrophiles to produce a series of nonbiogenic heteroles, such as boroles, phospholes, and siloles. In principle, this method should allow the sulfur atom in readily available thiophenes to be replaced with any atom and is therefore considered an ideal example of aromatic metamorphosis in terms of rapid construction of diverse chemical spaces with a variety of elements.Aromatic metamorphosis proposes many new synthons and retrosynthetic disconnections that defy the conventional wisdom of organic synthesis. By making full use of metamorphosing the aromatic skeleton, a library with skeletal diversity can be con","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple Disadvantage and Social Networks: Toward an Integrated Theory of Health Care Use During Reentry From Criminal Justice Settings.","authors":"Anastasiia Timmer, Oshea D Johnson, Kathryn M Nowotny","doi":"10.1177/0306624X221132989","DOIUrl":"10.1177/0306624X221132989","url":null,"abstract":"<p><p>Research consistently finds the disproportionate negative health impact of the criminal justice system on racial and ethnic minorities. Yet less is known about the underlying mechanisms of health care utilization during community reintegration. We contribute to the literature theoretically by integrating two perspectives: network theory of social capital and multiple disadvantage hypothesis and providing a more nuanced explanation of health service use during reentry. We identify incarceration history as a unique disadvantaged status that precludes people from accessing social networks and social capital. We further elaborate on the phenomenon of racialized reentry and illustrate how multiple disadvantaged statuses are linked to social networks and health care.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"495-514"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40436558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are Most Published Criminological Research Findings Wrong? Taking Stock of Criminological Research Using a Bayesian Simulation Approach.","authors":"Richard E Niemeyer, K Ryan Proctor, Joseph A Schwartz, Robert G Niemeyer","doi":"10.1177/0306624X221132997","DOIUrl":"10.1177/0306624X221132997","url":null,"abstract":"<p><p>This study uses Bayesian simulations to estimate the probability that published criminological research findings are wrong. Toward this end, we employ two equations originally popularized in John P.A. Ioannidis' (in)famous article, \"Why Most Published Research Findings are False.\" Values for relevant parameters were determined using recent estimates for the field's average level of statistical power, level of research bias, level of factionalization, and quality of theory. According to our simulations, there is a very high probability that most published criminological research findings are false-positives, and therefore wrong. Further, we demonstrate that the primary factor contributing to this problem is the poor quality of theory. Stated differently, even when the overall level of research bias is extremely low and overall statistical power is extremely high, we find that poor theory still results in a high rate of false positives. We conclude with suggestions for improving the validity of criminological research claims.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"475-494"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40467077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noncanonical Amino Acids Dictate Peptide Assembly in Living Cells.","authors":"Xin Liu, Binbin Hu, Zhilin Yu","doi":"10.1021/acs.accounts.4c00796","DOIUrl":"10.1021/acs.accounts.4c00796","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusEmulating the structural features or functions of natural systems has been demonstrated as a state-of-the-art strategy to create artificial functional materials. Inspired by the assembly and bioactivity of proteins, the self-assembly of peptides into nanostructures represents a promising approach for creating biomaterials. Conventional assembled peptide biomaterials are typically formulated in solution and delivered to pathological sites for implementing theranostic objectives. However, this translocation entails a switch from formulation conditions to the physiological environment and raises concerns about material performance. In addition, the precise and efficient accumulation of administered biomaterials at target sites remains a significant challenge, leading to potential biosafety issues associated with off-target effects. These limitations significantly hinder the progress of advanced biomaterials. To address these concerns, the past few years have witnessed the development of in situ assembly of peptides in living systems as a new endeavor for optimizing biomaterial performance benefiting from the advances of stimuli-responsive reactions regulating noncovalent interactions. In situ assembly of peptides refers to the processes of regulating assembly via stimuli-responsive reactions at target sites. Due to the advantages of precisely forming well-defined nanostructures at pathological lesions, in situ-formed assemblies with integrated bioactivity are interesting for the development of next-generation biomedical agents.Despite the great potential of in situ assembly of peptides for developing biomedical agents, this research area still suffers from a limited toolkit for operating peptide assembly under complicated physiological conditions. Considering the advantages of amino acids in being incorporated into peptide backbones and modified with stimuli-responsive units, development of an amino acid toolkit is promising to address this concern. Therefore, our laboratory has been intensively engaged in designing and discovering stimuli-responsive noncanonical amino acids (ncAAs) to expand the toolkit for manipulating peptide assembly under various biological conditions. Thus far, we have synthesized peptides containing ncAAs 4-aminoproline, 2-nitroimidazole alanine, Se-methionine, sulfated tyrosine, and glycosylated serine, which allow us to develop acid-responsive, redox-responsive, and enzyme-responsive assembly systems. Based on these stimuli-responsive ncAAs, we have established complex self-sorting assembly, self-amplified assembly, and dissipative assembly systems in living cells to optimize the bioactivity of peptides. The resulting in situ assembly systems exhibit morphological adaptability to the biological microenvironment, which contributes to overcoming delivery barriers and improvement of targeting accumulation. Therefore, by utilizing the developed toolkit, we have further created supramolecular PROTACs, supramolecu","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1081-1093"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Pragmatic American Revisited: A Direct Replication of Pickett and Baker (2014).","authors":"Angela M Jones, Sean Patrick Roche","doi":"10.1177/0306624X221133007","DOIUrl":"10.1177/0306624X221133007","url":null,"abstract":"<p><p>In 2014, Pickett and Baker cast doubt on the scholarly consensus that Americans are pragmatic about criminal justice. Previous research suggested this pragmaticism was evidenced by either null or positive relationships between seemingly opposite items (i.e., between dispositional and situational crime attributions and between punitiveness and rehabilitative policy support). Pickett and Baker argued that because these studies worded survey items in the same positive direction, respondents' susceptibility to acquiescence bias led to artificially inflated positive correlations. Using a simple split-ballot experiment, they manipulated the direction of survey items and demonstrated bidirectional survey items resulted in negative relationships between attributions and between support for punitive and rehabilitative policies. We replicated Pickett and Baker's methodology with a nationally representative sample of American respondents supplemented by a diverse student sample. Our results were generally consistent, and, in many cases, effect sizes were stronger than those observed in the original study. Americans appear much less pragmatic when survey items are bidirectional. Yet, we suggest the use of bidirectional over unidirectional survey items trades one set of problems for another. Instead, to reduce acquiescence bias and improve overall data quality, we encourage researchers to adopt item-specific questioning.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"454-474"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40684826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vinylcyclopropanes as Three-Carbon Synthons in Rhodium-Catalyzed Cycloadditions: Reaction Development, Mechanistic Studies, New Inspirations, and Synthetic Applications.","authors":"Pan Zhang, Zhi-Xiang Yu","doi":"10.1021/acs.accounts.4c00779","DOIUrl":"10.1021/acs.accounts.4c00779","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusCyclic structures are common in natural products and pharmaceuticals, but pose major synthetic challenges. Transition metal-catalyzed cycloadditions provide a direct and efficient route to complex ring systems in a single step. The demand for new transition metal-catalyzed cycloadditions remains high, as these methods enable access to diverse ring systems with unique substituents and stereochemistries that are often unattainable through existing cycloaddition techniques. Vinylcyclopropanes (VCPs) are widely recognized as versatile five-carbon (C&lt;sub&gt;5&lt;/sub&gt;) synthons in various transition metal-catalyzed cycloadditions, including [5 + 1], [5 + 2], and [5 + 2 + 1] reactions. In these reactions, VCP uses its vinyl group to facilitate C-C bond cleavage in the strained cyclopropane, aided by transition metals. In contrast, isolated cyclopropanes typically lack this reactivity. Building on these advantages, we discovered that by altering the connectivity between VCPs and other synthons, such as alkenes, alkynes, allenes, or dienes, VCPs can act as novel three-carbon (C&lt;sub&gt;3&lt;/sub&gt;) synthons, enabling previously unknown cycloadditions. This account outlines these discoveries.By connecting two-carbon (C&lt;sub&gt;2&lt;/sub&gt;) synthons to VCPs at positions 1, 2, or α, we created various substrates, including 2-&lt;i&gt;trans&lt;/i&gt;-ene/allene-VCPs, 1-ene/yne/allene-VCPs, and α-ene-VCPs. These substrates undergo [3 + 2] cycloadditions to construct fused bicyclic structures. Notably, 1-ene/yne/allene-VCPs enable the construction of 5/5 fused rings with bridgehead quaternary centers, representing a remarkable synthetic advancement. This reaction has also been extended to its asymmetric variant, marking the first asymmetric [3 + 2] reaction of its kind. Furthermore, 1-ene/yne-VCPs have been adapted for [3 + 2 + 1] cycloadditions, allowing the synthesis of 5/6 and 6/6 fused ring systems with bridged quaternary centers. The utility of this method is demonstrated through its application in the synthesis of several natural products. The success of the [3 + 2 + 1] cycloaddition further inspired the development of a novel [4 + 2] reaction using yne-vinylcyclobutanones (yne-VCBOs). While VCBO has traditionally been used as a six-carbon (C&lt;sub&gt;6&lt;/sub&gt;) synthon, we discovered that it functions as a four-carbon (C&lt;sub&gt;4&lt;/sub&gt;) synthon when alkynes are connected at the 1-position of VCBOs. This [4 + 2] reaction cocatalyzed by Rh and Zn yields 5/6 or 6/6 fused rings with bridgehead quaternary centers, which is the same motif formed via the [3 + 2 + 1] reaction of 1-yne-VCPs and CO.The synthesis of seven-membered rings remains a challenging endeavor. By connecting a diene to the 1-position of VCPs, we developed a Rh-catalyzed [4 + 3] cycloaddition, yielding 5/7 fused ring structures. Additionally, introducing CO into the reaction enabled a [4 + 3]/[4 + 1] cycloaddition, generating 5/7/5 triangular ring scaffolds. Both [4 + 3] and [4 + 3]/[4 + 1] reactions feature an unprece","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1065-1080"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.","authors":"H M O'Sullivan, M Conroy, D G Power, R M Bambury, D O'Mahony, D C Collins, M J O'Leary, S O'Reilly","doi":"10.1177/08258597221078391","DOIUrl":"10.1177/08258597221078391","url":null,"abstract":"<p><p><b>Background and Objectives:</b> Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. <b>Methods:</b> We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31^st of December 2018. A retrospective electronic chart review was performed. <b>Results:</b> The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, <i>P</i> = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (<i>P</i> = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, <i>P</i> = 0.02). <b>Conclusions:</b> ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"147-151"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39896200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}