Photo-induced tungsten-catalyzed cascade synthesis of pyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate and its reaction mechanism.

A pyrrolo[2,1-a]isoquinoline core structure is prevalent in marine and other natural products. This article describes a tungsten-catalyzed [3+2] cycloaddition aromatization of dihydroisoquinoline ester and maleic anhydride or an acrylate. The photochemical reaction tolerates a range of functional groups such as ester, cyano, ketone, bromide, and alkene. It is shown that the cycloaddition-aromatization of 2-substitued acrylate catalyzed by a tungsten photocatalyst can be used to evaluate the leaving ability of the leaving group. Experiments done to determine the reaction mechanism revealed that the formation of an ion-pair intermediate generated in situ from dihydroisoquinoline ester and (Z)-4-methoxy-4-oxobut-2-enoic acid via the solvolysis of maleic anhydride with methanol is crucial for the cascade process to occur. The key cycloadduct acid intermediate derived from [3+2] cycloaddition was isolated and determined by X-ray crystallography.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

MFN2 suppresses the accumulation of lipid droplets and the progression of clear cell renal cell carcinoma.

Dissolving the lipid droplets in tissue section with alcohol during a hematoxylin and eosin (H&E) stain causes the tumor cells to appear like clear soap bubbles under a microscope, which is a key pathological feature of clear cell renal cell carcinoma (ccRCC). Mitochondrial dynamics have been reported to be closely associated with lipid metabolism and tumor development. However, the relationship between mitochondrial dynamics and lipid metabolism reprogramming in ccRCC remains to be further explored. We conducted bioinformatics analysis to identify key genes regulating mitochondrial dynamics differentially expressed between tumor and normal tissues and immunohistochemistry and Western blot to confirm. After the target was identified, we created stable ccRCC cell lines to test the impact of the target gene on mitochondrial morphology, tumorigenesis in culture cells and xenograft models, and profiles of lipid metabolism. It was found that mitofusin 2 (MFN2) was downregulated in ccRCC tissues and associated with poor prognosis in patients with ccRCC. MFN2 suppressed mitochondrial fragmentation, proliferation, migration, and invasion of ccRCC cells and growth of xenograft tumors. Furthermore, MFN2 impacted lipid metabolism and reduced the accumulation of lipid droplets in ccRCC cells. MFN2 suppressed disease progression and improved prognosis for patients with ccRCC possibly by interrupting cellular lipid metabolism and reducing accumulation of lipid droplets.

Difluoromethylated Difunctionalization of Alkenes under Visible Light.

Difluoromethylated compounds usually act as bioisosteres for alcohol functional groups and show unique physicochemical and biological properties. The cyano-difluoromethylation of alkenes using 5-((difluoromethyl)sulfonyl)-1-phenyl-1H-tetrazole as a CF2H radical difluoromethyl precursor was developed to afford nitriles including a CF2H group. A low-cost, stable, easily handled 5-((difluoromethyl)sulfonyl)-1-methyl-1H-tetrazole (DFSMT) was synthesized and applied as the radical CF2H reagent. Using DFSMT as the radical CF2H precursor, the oxyl-difluoromethylation of alkenes was developed to obtain difluoromethylated ether products. All of the reactions showed good functional group tolerability. Initial mechanistic experiments indicated that the CF2H radical was involved as the key active intermediate.

Visible Light Mediated Chemoselective Hydroxylation of Benzylic Methylenes.

We have developed a metal-free photocatalytic selective hydroxylation of benzylic methylenes to secondary alcohols. This approach utilizes low-cost eosin Y as photocatalyst, O2 as green oxidant, and inexpensive triethylamine as inhibitor for overoxidation. The mild reaction conditions enable the production of secondary alcohols with 56-95% yields, making it a promising and environmental-friendly method for the synthesis of secondary alcohols from benzylic methylenes.

Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.

Mitochondrial dynamics and autophagy play essential roles in normal cellular physiological activities, while abnormal mitochondrial dynamics and mitochondrial autophagy can cause cancer and related disorders. Abnormal mitochondrial dynamics usually occur in parallel with mitochondrial autophagy. Both have been reported to have a synergistic effect and can therefore complement or inhibit each other. Progress has been made in understanding the classical mitochondrial PINK1/Parkin pathway and mitochondrial dynamical abnormalities. Still, the mechanisms and regulatory pathways underlying the interaction between mitophagy and mitochondrial dynamics remain unexplored. Like other existing reviews, we review the molecular structure of proteins involved in mitochondrial dynamics and mitochondrial autophagy, and how their abnormalities can lead to the development of related diseases. We will also review the individual or synergistic effects of abnormal mitochondrial dynamics and mitophagy leading to cellular proliferation, differentiation and invasion. In addition, we explore the mechanisms underlying mitochondrial dynamics and mitochondrial autophagy to contribute to targeted and precise regulation of mitochondrial function. Through the study of abnormal mitochondrial dynamics and mitochondrial autophagy regulation mechanisms, as well as the role of early disease development, effective targets for mitochondrial function regulation can be proposed to enable accurate diagnosis and treatment of the associated disorders.

A potential role of human esophageal cancer-related gene-4 in cardiovascular homeostasis.

Human esophageal cancer related gene-4 (ECRG-4) encodes a 148-aminoacid pre-pro-peptide that can be processed tissue-dependently into multiple small peptides possessing multiple functions distinct from, similar to, or opposite to the tumor suppressor function of the full-length Ecrg4. Ecrg-4 is covalently bound to the cell surface through its signal peptide, colocalized with the innate immunity complex (TLR4-CD14-MD2), and functions as a 'sentinel' molecule in the maintenance of epithelium and leukocyte homeostasis, meaning that the presence of Ecrg-4 on the cell surface signals the maintained homeostasis, whereas the loss of Ecrg-4 due to tissue injury activates pro-inflammatory and tissue proliferative responses, and the level of Ecrg-4 gradually returns to its pre-injury level upon wound healing. Interestingly, Ecrg-4 is also highly expressed in the heart and its conduction system, endothelial cells, and vascular smooth muscle cells. Accumulating evidence has shown that Ecrg-4 is involved in cardiac rate/rhythm control, the development of atrial fibrillation, doxorubicin-induced cardiotoxicity, the ischemic response of the heart and hypoxic response in the carotid body, the pathogenesis of atherosclerosis, and likely the endemic incidence of idiopathic dilated cardiomyopathy. These preliminary discoveries suggest that Ecrg-4 may function as a 'sentinel' molecule in cardiovascular system as well. Here, we briefly review the basic characteristics of ECRG-4 as a tumor suppressor gene and its regulatory functions on inflammation and apoptosis; summarize the discoveries about its distribution in cardiovascular system and involvement in the development of CVDs, and discuss its potential as a novel therapeutic target for the maintenance of cardiovascular system homeostasis.

MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood-brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood-brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood-brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.

Identification of SRSF10 as a promising prognostic biomarker with functional significance among SRSFs for glioma.

AIMS: The serine/arginine-rich splicing factor (SRSF) protein family members are essential mediators of the alternative splicing (AS) regulatory network, which is tightly implicated in cancer progression. However, the expression, clinical correlation, immune infiltration, and prognostic value of SRSFs in gliomas remain unclear. MATERIALS AND METHODS: Glioma samples were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Several databases, such as HPA, DAVID, UALCAN were used to comprehensively explore the roles of SRSFs. In addition, experimental validation of SRSF10 was also conducted. KEY FINDINGS: Here, we found the expression alterations of the SRSF family in glioma samples using data from the TCGA and CGGA_325 datasets. Among the 12 genes, most were found to be closely associated with glioma clinical features, which linked to poor prognosis in glioma patients. Interestingly, survival analysis identified only SRSF10 as a potential independent risk prognostic biomarker for glioma patients. Immune analysis indicated that glioma patients with high SRSF10 expression may respond well to immunotherapies targeting immune checkpoint (ICP) genes. Finally, knocking down SRSF10 reduced glioma cell viability, induced G1 cell cycle arrest, and induced the exclusion of bcl-2-associated transcription factor 1 (BCLAF1) exon 5a. SIGNIFICANCE: Overall, this study uncovers the oncogenic roles of most SRSF family members in glioma, with the exception of SRSF5, while highlighting SRSF10 as a potential novel independent prognostic biomarker for glioma.

Synthesis of Bench-stable Polycyclic Organophosphorus Heterocycles via Staudinger-type Annulations of ortho-Azidophenols.

The formation of a five- or six-membered ring is known to stabilize unstable molecular structures such as hemiacetals. This idea can also be extended to stabilize other high-coordinated p-block element species. Herein, we synthesized two novel polycyclic organophosphorus heterocycles via Staudinger-type annulations. Reactions of either ortho-phosphinoarenesulfonyl fluorides 1 or ortho-phosphinobenzoic acid methyl esters 4 with ortho-azidophenols 2 gave rise to penta-coordinated P(V) heterocycles, benzo-benzo-1,2,3-thiazaphospholo-1,3,2-oxazaphosphole (B-B-TAP-OAP) 3 and benzo-benzo-1,2-azaphospholo-1,3,2-oxazaphosphol-12-one (B-B-AP-OAP) 5 in satisfactory yields. It is remarkable that heterocycles 3 and 5 are both bench-stable and exhibit considerable stability in a 10 % aqueous tetrahydrofuran solution. Preliminary computational studies disclosed that the formation of nitrogen gas is the key driving force for the annulations. In addition, the formation of a strong Si-F bond is another contributor to the annulation of 1 and 2.

Potential window alignment regulating ion transfer in faradaic junctions for efficient photoelectrocatalysis.

In the past decades, a band alignment theory has become a basis for designing different high-performance semiconductor devices, such as photocatalysis, photoelectrocatalysis, photoelectrostorage and third-generation photovoltaics. Recently, a faradaic junction model (coupled electron and ion transfer) has been proposed to explain charge transfer phenomena in these semiconductor heterojunctions. However, the classic band alignment theory cannot explain coupled electron and ion transfer processes because it only regulates electron transfer. Therefore, it is very significant to explore a suitable design concept for regulating coupled electron and ion transfer in order to improve the performance of semiconductor heterojunctions. Herein, we propose a potential window alignment theory for regulating ion transfer and remarkably improving the photoelectrocatalytic performance of a MoS2/Cd-Cu2ZnSnS4 heterojunction photocathode. Moreover, we find that a faradaic potential window, rather than the band position of the intermediate layer, is a criterion for identifying interface charge transfer direction. This finding can offer different perspectives for designing high-performance semiconductor heterojunctions with suitable potential windows for solar energy conversion and storage.

Synthesis of functionalized tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones through base-promoted annulation of quinoline-derived dipolarophiles and cyclic enaminones.

An eco-friendly and metal-free method for the synthesis of tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones was established. Quinoline-derived dipolarophiles and cyclic enaminones as starting materials undergo a 1,4-Michael addition/SNAr tandem annulation reaction affording the target products. This approach features transition metal-free conditions, good functional group tolerance and operational simplicity.

Supratentorial Collision Tumor of Hemangioblastoma and Metastatic Clear Cell Renal Cell Carcinoma in a Patient with von Hippel-Lindau Disease.

Collision tumors are rarely reported in patients with von Hippel-Lindau (VHL) disease, even though VHL patients often present with multi-organ tumor syndromes, like hemangioblastoma and renal cell carcinoma (RCC). Hemangioblastoma is rarely located in a supratentorial location, and intracranial lateral ventricular is also not a common site of metastasis for RCC. It is extremely rare for the two tumors to collide in the supratentorial area. We report a 64-year-old man with a history of clear cell RCC who presented with a sudden headache. The brain magnetic resonance imaging revealed that there was a cystic-solid mass in the intracranial lateral ventricular trigone. Histopathologically, the tumor consisted of two distinct components, most of which showed the typical morphology of hemangioblastoma. However, there were a few acinar structures composed of clear cells scattered in hemangioblastoma, and these acinar structures were subsequently confirmed as clear cell RCC. The genetic testing confirmed that the patient had VHL disease with de novo somatic mutation. Based on our case report, we systematically reviewed the characteristics of collision tumor composed of hemangioblastoma and metastatic RCC in VHL patients. The special growth site of our case is the first report of this kind of collision tumor, and can also help enrich our understanding of VHL disease and collision tumor.

Benzannulation with Et3N as 1,3-Diene Variants.

With triethylamine as a 1,3-diene variant, a simple and practical process for the synthesis of phthalimides has been developed from readily available maleimide. The transformation can be performed in the absence of a metal catalyst with high levels of functional group tolerance. Various phthalimide compounds were constructed in moderate to good yields under mild conditions. Mechanism research indicates that oxygen and acid also play crucial roles in this reaction.

AQP4 is an Emerging Regulator of Pathological Pain: A Narrative Review.

Pathological pain presents significant challenges in clinical practice and research. Aquaporin-4 (AQP4), which is primarily found in astrocytes, is being considered as a prospective modulator of pathological pain. This review examines the association between AQP4 and pain-related diseases, including cancer pain, neuropathic pain, and inflammatory pain. In cancer pain, upregulated AQP4 expression in tumor cells is linked to increased pain severity, potentially through tumor-induced inflammation and edema. Targeting AQP4 may offer therapeutic strategies for managing cancer pain. AQP4 has also been found to play a role in nerve damage. Changes in AQP4 expression have been detected in pain-related regions of the brain and spinal cord; thus, modulating AQP4 expression or function may provide new avenues for treating neuropathic pain. Of note, AQP4-deficient mice exhibit reduced chronic pain responses, suggesting potential involvement of AQP4 in chronic pain modulation, and AQP4 is involved in pain modulation during inflammation, so understanding AQP4-mediated pain modulation may lead to novel anti-inflammatory and analgesic therapies. Recent advancements in magnetic resonance imaging (MRI) techniques enable assessment of AQP4 expression and localization, contributing to our understanding of its involvement in brain edema and clearance pathways related to pathological pain. Furthermore, targeting AQP4 through gene therapies and small-molecule modulators shows promise as a potential therapeutic intervention. Future research should focus on utilizing advanced MRI techniques to observe glymphatic system changes and the exchange of cerebrospinal fluid and interstitial fluid. Additionally, investigating the regulation of AQP4 by non-coding RNAs and exploring novel small-molecule medicines are important directions for future research. This review shed light on AQP4-based innovative therapeutic strategies for the treatment of pathological pain. Dark blue cells represent astrocytes, green cells represent microglia, and red ones represent brain microvasculature.

[Study on alleviating neuroinflammatory injury in ischemic stroke rats by electrical stimulation with scalp acupuncture based on IFN-γ mediated JAK/STAT1 signaling pathway].

OBJECTIVE: To explore the molecular mechanism of electrical stimulation with scalp acupuncture (ESA) in alleviating neuroinflammatory injury in ischemic stroke rats based on interferon γ (IFN-γ)-mediated Janus kinase/signal transduction and transcriptional activator 1 (JAK/STAT1) signaling pathway. METHODS: Fifty-six SD rats aged 7 weeks were randomly divided into normal, model, ESA and inhibitor groups, with 14 rats in each group. The middle cerebral artery embolization rat model was established by means of thread embolization. Rats in the inhibitor group were intraperitoneally injected with the inhibitor PJ34 (5 mg/mL, 25 mg/kg) once a day for 7 days. Rats in the ESA group were treated at bilateral anterior parietotemporal slash (MS6) with ESA (2 Hz/100 Hz, 1 mA), 30 min a day for 7 days. Before and after interventions, the neurological deficit score and neurobehavioral score were evaluated. The percentage of cerebral infarction volume was detected by TTC staining. The positive expressions of interleukin (IL)-6 and IL-10 in cerebral cortex were detected by immunohistochemistry. The protein expression levels of IFN-γ, JAK1, JAK2 and phosphorylated (p)-STAT1 in rats cerebral cortex were detected by Western blot. RESULTS: Compared with the normal group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the expression levels of IL-6, IFN-γ, JAK1, JAK2 and p-STAT1 in cerebral cortex were increased (P<0.01), while the expression level of IL-10 was decreased (P<0.01) in the model group. Compared with the model group, the neurological deficit score and neurobehavioral score after treatment were significantly decreased (P<0.01), the percentage of cerebral infarction volume was decreased (P<0.01), the expression levels of IL-6, IFN-γ, JAK1, JAK2 and p-STAT1 in cerebral cortex were decreased (P<0.01), while the expression level of IL-10 was increased (P<0.01) in the ESA and inhibitor groups. ESA was superior to inhibitors in improving neurological deficit score and down-regulating p-STAT1 expression (P<0.05, P<0.01), and was inferior to inhibitor in reducing the percentage of cerebral infarction volume as well as down-regulating IFN-γ and JAK1 (P<0.01, P<0.05). CONCLUSION: Down-regulating the expression of IFN-γ and inhibiting the activity of JAK/STAT1 signaling pathway may be one of the mechanisms by which ESA alleviates neuroinflammatory injury in ischemic stroke rats.

[Effects of electro-scalp acupuncture on inflammatory response and microglial polarization in the ischemic cortex of rats with ischemic stroke].

OBJECTIVE: To observe the effects of electro-scalp acupuncture （ESA） on the expression of microglial markers CD206 and CD32, as well as interleukin (IL)-6, IL-1ß, and IL-10 in the ischemic cortex of rats with ischemic stroke, and to explore the mechanisms of ESA on alleviating inflammatory damage of ischemic stroke. METHODS: Sixty 7-week-old male SD rats were randomly selected, with 15 rats assigned to a sham surgery group. The remaining rats were treated with suture method to establish rat model of middle cerebral artery occlusion (MCAO). The rats with successful model were randomly divided into a model group, a VitD3 group, and an ESA group, with 15 rats in each group. In the ESA group, ESA was performed bilaterally at the "top-temporal anterior oblique line" with disperse-dense wave, a frequency of 2 Hz/100 Hz, and an intensity of 1 mA. Each session lasted for 30 min, once daily, for a total of 7 days. The VitD3 group were treated with intragastric administration of 1,25-dihydroxyvitamin D3 (1,25-VitD3) solution (3 ng/100 g), once daily for 7 days. The neurological deficit scores and neurobehavioral scores were assessed before and after the intervention. After the intervention, the brain infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Immunofluorescence double staining was performed to detect the protein expression of CD32 and CD206 in the ischemic cortex. Western blot analysis was conducted to measure the protein expression of IL-6, IL-1ß, and IL-10 in the ischemic cortex. RESULTS: Compared with the sham surgery group, the model group showed increased neurological deficit scores and neurobehavioral scores (P<0.01), increased brain infarct volume (P<0.01), increased protein expression of CD32, IL-6, and IL-1ß in the ischemic cortex (P<0.01), and decreased protein expression of CD206 and IL-10 in the ischemic cortex (P<0.01). Compared with the model group, both the ESA group and the VitD3 group showed decreased neurological deficit scores and neurobehavioral scores (P<0.01), reduced brain infarct volume (P<0.01), decreased protein expression of CD32, IL-6, and IL-1ß in the ischemic cortex (P<0.01), and increased protein expression of CD206 and IL-10 in the ischemic cortex (P<0.01). Compared with the VitD3 group, the ESA group had lower neurological deficit score (P<0.05), larger brain infarct volume (P< 0.05), and lower protein expression of CD32, CD206, IL-1ß, and IL-10 in the ischemic cortex (P<0.01, P<0.05). CONCLUSION: ESA could improve neurological function in MCAO rats, and its mechanism may be related to promoting microglial M1-to-M2 polarization and alleviating inflammatory damage.

B cell metabolism in autoimmune diseases: signaling pathways and interventions.

Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

Local excision and radical excision for rectal gastrointestinal stromal tumors: a meta-analysis protocol.

Background: To date, several studies have compared the surgical and oncological outcomes of local excision (LE) and radical excision (RE) for rectal gastrointestinal stromal tumors (GISTs), but some have limited numbers of small series. This protocol outlines the planned scope and methods for a systematic review and meta-analysis that will compare the surgical and oncological outcomes of LE and RE in patients with rectal GISTs. Methods: This protocol is presented in accordance with the PRISMA-P guideline. PubMed, Embase, Web of Science, Cochrane Library and Wanfang database will be systematically searched. Furthermore, reference lists of all included articles will be screened manually to add other eligible studies. We will include randomized controlled trials (RCTs) and non-randomized studies (NRS) in this study. The primary outcomes evaluated will be R0 resection rate and disease-free survival, while the secondary outcomes will contain overall survival, length of stay, tumor rupture rate and complications. Two reviewers will independently screen and select studies, extract data from the included studies, and assess the risk of bias of the included studies. Preplanned subgroup analyses and sensitivity analyses are detailed within this protocol. The strength of the body of evidence will be assessed using GRADE. Discussion: This review and meta-analysis will provide a comprehensive evaluation of the current evidence concerning the application of LE and RE in patients with rectal GISTs. The findings from this review will serve as a foundation for future research and emphasize the implications for clinical practice. Systematic review registration: PROSPERO (CRD42017078338), https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=387409, PROSPERO CRD42017078338.

Chemodivergent Staudinger Reactions of Secondary Phosphine Oxides and Application to the Total Synthesis of LL-D05139ß Potassium Salt.

Unprecedented Staudinger reaction modes of secondary phosphine oxides (SPO) and organic azides are herein disclosed. By the application of various additives, selective nitrogen atom exclusion from the azide group has been achieved. Chlorotrimethylsilane mediates a stereoretentive Staudinger reaction with a 2-N exclusion which provides a valuable method for the synthesis of phosphinic amides and can be considered complementary to the stereoinvertive Atherton-Todd reaction. Alternatively, a 1-N exclusion pathway is promoted by acetic acid to provide the corresponding diazo compound. The effectiveness of this protocol has been further demonstrated by the total synthesis of the diazo-containing natural product LL-D05139ß, which was prepared as a potassium salt for the first time in 6 steps and 26.5 % overall yield.