CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.

Anti-inflammatory bicyclic polyprenylated acylphloroglucinols with diverse architectures including an unprecedented 6/6/6 tricyclic core from Garcinia yunnanensis.

Garciyunnanol A (1), an unprecedented 1,2-seco-bicyclic polyprenylated acylphloroglucinol (BPAP) possessing a unique 6/6/6 tricyclic core, was characterized from Garcinia yunnanensis together with 16 BPAPs, including eight new compounds (garciyunnanols B-I, 2-9). Biogenetically, the bicyclo[3.3.1]nonane-2,4,9-trione moiety of 12 reconstructed the bicyclic δ-lactone core of 2 through Norrish type Ⅰ cleavage and cyclization, followed by a cyclization of two side chains to form an intriguing 6/6/6 tricyclic core of 1. Their structures were elucidated through analysis of spectroscopic data, calculation and comparison of ECD spectra. Bioactivity evaluation manifested that compounds 1, 2, 5, 6 and 14 demonstrated superior inhibition of NO production compared to the positive control dexamethasone. Notably, compound 5 exhibited a dose-dependent inhibitory effect on NO production, with an IC50 value of 0.25 ± 0.87 µM. Furthermore, experiments involving ELISA, Western blotting, and immunofluorescence staining revealed that 5 effectively reduced the secretion of interleukin-1ß in LPS plus nigericin-stimulated THP-1 macrophages by inhibiting the activation of the NLRP3 inflammasome.

Penetration enhancers strengthen tough hydrogel bioadhesion and modulate locoregional drug delivery.

The human body possesses natural barriers, such as skin and mucosa, which limit the effective delivery of therapeutics and integration of medical devices to target tissues. Various strategies have been deployed to breach these barriers mechanically, chemically, or electronically. The development of various penetration enhancers (PEs) offers a promising solution due to their ability to increase tissue permeability using readily available reagents. However, existing PE-mediated delivery methods often rely on weak gel or liquid drug formulations, which are not ideal for sustained local delivery. Hydrogel adhesives that can seamlessly interface biological tissues with controlled drug delivery could potentially resolve these issues. Here, we demonstrate that tough adhesion between drug-laden hydrogels and biological tissue (e.g. skin and tumours) can lead to effective local delivery of drugs deep into targeted tissues by leveraging the enhanced tissue penetration mediated by PEs. The drug release profile of the hydrogel adhesives can be fine-tuned by further engineering the nanocomposite hydrogel matrix to elute chemotherapeutics from 2 weeks to 2 months. Using a 3D tumour spheroid model, we demonstrated that PEs increased the cancer-killing effectiveness of doxorubicin by facilitating its delivery into tumour microtissues. Therefore, the proposed tough bioadhesion and drug delivery strategy modulated by PEs holds promise as a platform technique to develop next-generation wearable and implantable devices for cancer management and regenerative medicine.

The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.

Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate.

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

Preparation and Characterization of Lutein Co-Amorphous Formulation with Enhanced Solubility and Dissolution.

Lutein is an oxygenated fat-soluble carotenoid and a functional compound with proven health benefits for the human body. Nevertheless, the poor water solubility and low oral bioavailability of lutein greatly limit its application. To address this, we developed an effective approach to enhance the water solubility of lutein through co-amorphous formulation. Specifically, the lutein-sucralose co-amorphous mixture was prepared at a molar ratio of 1:1 using ethanol and water as solvents by employing the solvent evaporation method, followed by solid-state characterization and dissolution testing conducted to assess the properties of the formulation. The X-ray diffraction pattern with an amorphous halo and the differential scanning calorimetry thermogram with no sharp melting peaks confirmed the formation of a binary co-amorphous system. Changes in peak shape, position, and intensity observed in the Fourier transform infrared spectroscopy spectrum revealed intermolecular interactions between lutein and sucralose molecules, while molecular dynamics simulations identified interaction sites between their hydroxyl groups. Additionally, dissolution testing demonstrated better dissolution performance of lutein in the co-amorphous form compared to pure lutein and physical mixture counterparts. Our findings present a novel strategy for improving the water solubility of lutein to make better use of it.

Hourly effect of atmospheric reactive nitrogen species on the onset of acute ischemic stroke: Insight from the Shanghai Stroke Service System Database.

Acute ischemic stroke (AIS) is one of the most predominant causes of mortality and disability in China. Significant uncertainties in stroke diagnosis and time of onset have resulted in inconsistent evidence on the association between ambient air pollution and the risk of AIS. The present study aimed to evaluate the impact of air pollution on AIS onset based on high time-resolution air pollution data and a stroke-specific registry across the past five years. Hourly concentrations of PM2.5, PM10, O3, SO2, CO, NO2 and nitrous acid (HONO) were monitored from 2017 to 2021, with which a distributed lag non-linear model and conditional logistic regression models coupled with a time-stratified case-crossover design were applied to 106,623 AIS cases recorded in the Shanghai Stroke Service (4S) database during the study period. Results from the conditional logistic regression models indicate that acute exposure to PM2.5, PM10, SO2, NO2 and HONO was found to be associated with AIS onset, respectively. The corresponding cumulative excessive risks of AIS onset were 0.8 %, 1 %, 2.4 %, 2.1 % and 1.8 % for each interquartile range increase in the respective concentration. The longest lag-effect (up to 13 h) was observed for reactive nitrogen species (RNS), such as NO2 and HONO, which remained robust in two-pollutant models. Similar important role of RNS in AIS onset were confirmed by the distributed lag non-linear model. By demonstrating the transient effect of ambient air pollution on AIS, especially the relationships between RNS and AIS for the first time, our study provides stringent evidence for future mitigation strategies for pollution emission and public health.

Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential.

Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.

G9a in Cancer: Mechanisms, Therapeutic Advancements, and Clinical Implications.

G9a, also named EHMT2, is a histone 3 lysine 9 (H3K9) methyltransferase responsible for catalyzing H3K9 mono- and dimethylation (H3K9me1 and H3K9me2). G9a contributes to various aspects of embryonic development and tissue differentiation through epigenetic regulation. Furthermore, the aberrant expression of G9a is frequently observed in various tumors, particularly in prostate cancer, where it contributes to cancer pathogenesis and progression. This review highlights the critical role of G9a in multiple cancer-related processes, such as epigenetic dysregulation, tumor suppressor gene silencing, cancer lineage plasticity, hypoxia adaption, and cancer progression. Despite the increased research on G9a in prostate cancer, there are still significant gaps, particularly in understanding its interactions within the tumor microenvironment and its broader epigenetic effects. Furthermore, this review discusses the recent advancements in G9a inhibitors, including the development of dual-target inhibitors that target G9a along with other epigenetic factors such as EZH2 and HDAC. It aims to bring together the existing knowledge, identify gaps in the current research, and suggest future directions for research and treatment strategies.

Nucleophilic Organocatalyst for Photochemical Carbon Radical Generation via SN2 Substitution.

Photochemical generation of radicals is a powerful way to construct various molecules. But most of these methods rely on initiators or the redox properties of radical precursors. Herein, we report a photochemical organic catalyst that reacts with benzyl halide to generate carbon radical via an SN2 pathway. This nucleophilic catalyst can be easily prepared and is bench-stable. The SN2 process does not rely on the redox properties of halides, showing potential synthetic utility. Control experiments and UV-vis spectroscopic analysis indicate that the SN2 substitution adduct is the key intermediate.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models.

INTRODUCTION: Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes. METHODS: Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described. RESULTS: Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation. CONCLUSIONS: Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy.

Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation-akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

Clinically-observed FOXA1 mutations upregulate SEMA3C through transcriptional derepression in prostate cancer.

FOXA1 is a pioneer transcription factor that is frequently mutated in prostate, breast, bladder, and salivary gland malignancies. Indeed, metastatic castration-resistant prostate cancer (mCRPC) commonly harbour FOXA1 mutations with a prevalence of 35%. However, despite the frequent recurrence of FOXA1 mutations in prostate cancer, the mechanisms by which FOXA1 variants drive its oncogenic effects are still unclear. Semaphorin 3C (SEMA3C) is a secreted autocrine growth factor that drives growth and treatment resistance of prostate and other cancers and is known to be regulated by both AR and FOXA1. In the present study, we characterize FOXA1 alterations with respect to its regulation of SEMA3C. Our findings reveal that FOXA1 alterations lead to elevated levels of SEMA3C both in prostate cancer specimens and in vitro. We further show that FOXA1 negatively regulates SEMA3C via intronic cis elements, and that mutations in FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting DNA binding of FOXA1. Our findings underscore the key role of FOXA1 in prostate cancer progression and treatment resistance by regulating SEMA3C expression and suggest that SEMA3C may be a driver of growth and tumor vulnerability of mCRPC harboring FOXA1 alterations.

Autophagy-driven regulation of cisplatin response in human cancers: Exploring molecular and cell death dynamics.

Despite the challenges posed by drug resistance and side effects, chemotherapy remains a pivotal strategy in cancer treatment. A key issue in this context is macroautophagy (commonly known as autophagy), a dysregulated cell death mechanism often observed during chemotherapy. Autophagy plays a cytoprotective role by maintaining cellular homeostasis and recycling organelles, and emerging evidence points to its significant role in promoting cancer progression. Cisplatin, a DNA-intercalating agent known for inducing cell death and cell cycle arrest, often encounters resistance in chemotherapy treatments. Recent studies have shown that autophagy can contribute to cisplatin resistance or insensitivity in tumor cells through various mechanisms. This resistance can be mediated by protective autophagy, which suppresses apoptosis. Additionally, autophagy-related changes in tumor cell metastasis, particularly the induction of Epithelial-Mesenchymal Transition (EMT), can also lead to cisplatin resistance. Nevertheless, pharmacological strategies targeting the regulation of autophagy and apoptosis offer promising avenues to enhance cisplatin sensitivity in cancer therapy. Notably, numerous non-coding RNAs have been identified as regulators of autophagy in the context of cisplatin chemotherapy. Thus, therapeutic targeting of autophagy or its associated pathways holds potential for restoring cisplatin sensitivity, highlighting an important direction for future clinical research.

DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression.

Transcriptome analysis of the Bactrian camel (Camelus bactrianus) reveals candidate genes affecting milk production traits.

BACKGROUND: Milk production traits are complex traits with vital economic importance in the camel industry. However, the genetic mechanisms regulating milk production traits in camels remain poorly understood. Therefore, we aimed to identify candidate genes and metabolic pathways that affect milk production traits in Bactrian camels. METHODS: We classified camels (fourth parity) as low- or high-yield, examined pregnant camels using B-mode ultrasonography, observed the microscopic changes in the mammary gland using hematoxylin and eosin (HE) staining, and used RNA sequencing to identify differentially expressed genes (DEGs) and pathways. RESULTS: The average standard milk yield over the 300 days during parity was recorded as 470.18 ± 9.75 and 978.34 ± 3.80 kg in low- and high-performance camels, respectively. Nine female Junggar Bactrian camels were subjected to transcriptome sequencing, and 609 and 393 DEGs were identified in the low-yield vs. high-yield (WDL vs. WGH) and pregnancy versus colostrum period (RSQ vs. CRQ) comparison groups, respectively. The DEGs were compared with genes associated with milk production traits in the Animal Quantitative Trait Loci database and in Alashan Bactrian camels, and 65 and 46 overlapping candidate genes were obtained, respectively. Functional enrichment and protein-protein interaction network analyses of the DEGs and candidate genes were conducted. After comparing our results with those of other livestock studies, we identified 16 signaling pathways and 27 core candidate genes associated with maternal parturition, estrogen regulation, initiation of lactation, and milk production traits. The pathways suggest that emerged milk production involves the regulation of multiple complex metabolic and cellular developmental processes in camels. Finally, the RNA sequencing results were validated using quantitative real-time PCR; the 15 selected genes exhibited consistent expression changes. CONCLUSIONS: This study identified DEGs and metabolic pathways affecting maternal parturition and milk production traits. The results provides a theoretical foundation for further research on the molecular mechanism of genes related to milk production traits in camels. Furthermore, these findings will help improve breeding strategies to achieve the desired milk yield in camels.

Mechanistic study on the side arm effect in a palladium/Xu-Phos-catalyzed enantioselective alkoxyalkenylation of γ-hydroxyalkenes.

Recently, the asymmetric bifunctionalization of alkenes has received much attention. However, the development of enantioselective alkoxyalkenylation has posed a considerable challenge and has lagged largely behind. Herein, we report a new palladium-catalyzed enantioselective alkoxyalkenylation reaction, using a range of primary, secondary, and tertiary γ-hydroxy-alkenes with alkenyl halides. By employing newly identified Xu-Phos (Xu8 and Xu9) with a suitable side-arm adjacent to the PCy2 motif, a series of allyl-substituted tetrahydrofurans were obtained in good yields with up to 95% ee. Besides (E)-alkenyl halides, (Z)-alkenyl halide was also examined and provided the corresponding (Z)-product as a single diastereomer, supporting a stereospecific oxidative addition and reductive elimination step. Moreover, deuterium labeling and VCD experiments were employed to determine a cis-oxypalladation mechanism. DFT calculations helped us gain deeper insight into the side-arm effect on the chiral ligand. Finally, the practicability of this method is further demonstrated through a gram-scale synthesis and versatile transformations of the products.