Spatially resolved whole-transcriptomic and proteomic profiling of lung cancer and its immune-microenvironment according to PD-L1 expression.

The expression of PD-L1 on tumor cells (TCs) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. Using a Digital Spatial Profiling, we performed proteomic and whole-transcriptomic analyses of TCs and immune cells (ICs) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. Our findings were validated using immunohistochemistry, The Cancer Genome Atlas, and immunotherapy cohorts. ICs in areas with high PD-L1 expression on TCs showed more features indicative of immunosuppression and exhaustion than ICs in areas with low PD-L1 expression on TCs. TCs highly expressing PD-L1 within immune-inflamed (IF) areas show up-regulation of pro-inflammatory processes, whereas TCs highly expressing PD-L1 within immune-deficient (ID) areas show up-regulation of various metabolic processes. Using differentially expressed genes of TCs between the IF and ID areas, we identified a novel prognostic gene signature for lung cancer. In addition, a high ratio of CD8+ cells to M2 macrophages was found to predict favorable outcomes in patients with PD-L1-expressing lung cancer after immune checkpoint inhibitor therapy. This study demonstrates that TCs and ICs have distinct spatial features within the tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.

Versatile Light-Mediated Synthesis of Degradable Bottlebrush Polymers Using α-Lipoic Acid.

Bottlebrush polymers have a variety of useful properties including a high entanglement molecular weight, low Young's modulus, and rapid kinetics for self-assembly. However, the translation of bottlebrushes to real-world applications is limited by complex, multi-step synthetic pathways and polymerization reactions that rely on air-sensitive catalysts. Additionally, most bottlebrushes are non-degradable. Herein, we report an inexpensive, versatile, and simple approach to synthesize degradable bottlebrush polymers under mild reaction conditions. Our approach relies on the "grafting-through" polymerization of α-lipoic acid (LA)-functionalized macromonomers. These macromonomers can be polymerized under mild, catalyst-free conditions, and due to reversibility of the disulfide bond in LA, the resulting bottlebrush polymers can be depolymerized by cleaving disulfide backbone bonds. Bottlebrushes with various side-chain chemistries can be prepared through the atom transfer radical polymerization (ATRP) of LA-functionalized macromonomers, and the backbone length is governed by the macromonomer molecular weight and solvent polarity. We also demonstrate that LA-functionalized macromonomers can be copolymerized with acrylates to form degradable bottlebrush networks. This work demonstrates the preparation of degradable bottlebrush polymers with a variety of side-chain chemistries and provides insight into the light-mediated grafting-through polymerization of dithiolane-functionalized macromonomers.

Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment.

BACKGROUND: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear. METHODS: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses. RESULTS: Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction. CONCLUSIONS: This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX's immunomodulatory role in TNBC but also underscore the potential of targeting TAMs' antigen presentation capabilities in immunotherapy approaches.

Stereoselective total synthesis of (3Z)- and (3E)-elatenynes.

We describe here the highly stereoselective total synthesis of the Laurencia C15 acetogenins (3Z)- and (3E)-elatenynes having a 7,12-dibromo-6,9-cis-10,13-cis adjacent bis-tetrahydrofuran (THF) core. The present synthesis features a highly stereoselective, protecting group-dependent, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 7-hydroxy-6,7-cis-6,9-cis-THF intermediate 10, deployment of the sequential ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for the stereoselective introduction of the C(10)-C(15) unit, a sequential Sharpless asymmetric dihydroxylation (SAD)/intramolecular Williamson etherification for the construction of the 10,13-cis-THF ring, and a modified Nakata chloromethanesulfonate-mediated SN2 displacement for the 7,12-dibromo functionality. Furthermore, our strategy based on chelate-controlled IAEA methodology would provide access to any member of the C15 adjacent bis-THF acetogenin class.

Sleep time on back as a predictor of adherence to positive airway pressure therapy.

Upper airway collapse can be effectively dealt with positive airway pressure (PAP), and patient adherence is considered as a major determining factor for success of PAP therapy. This study was performed to determine the potential factors affecting the adherence to PAP in patients with OSA by using polysomnography (PSG) parameters recorded for diagnosis of OSA. The data of 158 patients between December 2018 and July 2021 were collected. They were prescribed with PAP and used the device during the adaptation period for 90 days. They were categorized into adherent and non-adherent group according to the criteria of good adherence as use of PAP ≥ 4 h per night on 70% of nights. Demographic, clinical characteristics, and PSG results were reviewed. Among 158 patients engaged in PAP therapy, 121 patients (76.6%) met the criteria of good adherence. No significant differences were found in good adherence rate regarding demographic and clinical characteristics. None of the polysomnographic factors showed significant differences between adherent and non-adherent groups. However, the percentage of sleep time on back in the adherent group was significantly higher than non-adherent group (p = 0.041). The cut-off value was determined to be 41.45% (95% confidence interval 0.43 to 0.79) by receiver operating characteristic curve analysis and the odds ratio was calculated as 2.97. Only the percentage of sleep time on back appeared to be polysomnographic predictor for identifying good adherence to PAP therapy in OSA patients. However, the conclusions may be limited in generalization due to the small sample size.

Concise Stereoselective Total Synthesis of (-)-Hedycoropyran A.

A concise and stereoselective total synthesis of (-)-hedycoropyran A was accomplished in a substrate-controlled manner from a readily available alkene. Highlights of the synthesis include a highly diastereoselective dehydrogenative cycloetherification to construct the trans-2-aryl-6-alkyl-3,6-dihydro-2H-pyran framework and late-stage substrate-controlled trans-dihydroxylation at C(3,4).

Total Synthesis and Structure Confirmation of (-)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core.

The total synthesis and structure confirmation of the potent cytotoxic agent (-)-asimitrin (1), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/l-Selectride reduction protocol for stereoselective introduction of the C(21)-C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring.

Quantitative proteomics identifies TUBB6 as a biomarker of muscle-invasion and poor prognosis in bladder cancer.

Muscle-invasive urothelial carcinoma (MIUC) of the bladder shows highly aggressive tumor behavior, which has prompted the quest for robust biomarkers predicting invasion. To discover such biomarkers, we first employed high-throughput proteomic method and analyzed tissue biopsy cohorts from patients with bladder urothelial carcinoma (BUC), stratifying them according to their pT stage. Candidate biomarkers were selected through bioinformatic analysis, followed by validation. The latter comprised 2D and 3D invasion and migration assays, also a selection of external public datasets to evaluate mRNA expression and an in-house patient-derived tissue microarray (TMA) cohort to evaluate protein expression with immunohistochemistry (IHC). Our multilayered platform-based analysis identified tubulin beta 6 class V (TUBB6) as a promising prognostic biomarker predicting MIUC of the bladder. The in vitro 2D and 3D migration and invasion assays consistently showed that inhibition of TUBB6 mRNA significantly reduced cell migration and invasion ability in two BUC cell lines with aggressive phenotype (TUBB6 migration, P = .0509 and P < .0001; invasion, P = .0002 and P = .0044; TGFBI migration, P = .0214 and P = .0026; invasion, P < .0001 and P = .0001; T24 and J82, respectively). Validation through multiple public datasets, including The Cancer Genome Atlas (TCGA) and selected GSE (Genomic Spatial Event) databases, confirmed TUBB6 as a potential biomarker predicting MIUC. Further protein-based validation with our TMA cohort revealed concordant results, highlighting the clinical implication of TUBB6 expression in BUC patients (overall survival: P < .001). We propose TUBB6 as a novel IHC biomarker to predict invasion and poor prognosis, also select the optimal treatment in BUC patients.

New Insight into Rubber Composites Based on Graphene Nanoplatelets, Electrolyte Iron Particles, and Their Hybrid for Stretchable Magnetic Materials.

New and soft composites with good mechanical stretchability are constantly addressed in the literature due to their use in various industrial applications such as soft robotics. The stretchable magnetic materials presented in this work show a promising magnetic effect of up to 28% and improved magnetic sensitivity. The composites are soft in nature and possess hardness below 65. These composites were prepared by mixing silicone rubber with fillers such as graphene nanoplatelets (GNP), electrolyte-iron particles (EIP), and their hybrid via solution mixing. The final composites were cured at room temperature for 24 h and their isotropic and anisotropic properties were studied and presented. The mechanical properties under compressive and tensile strain were studied in detail. The results show that the compressive modulus was 1.73 MPa (control) and increased to 3.7 MPa (GNP) at 15 per hundred parts of rubber (phr), 3.2 MPa (EIP), and 4.3 MPa (hybrid) at 80 phr. Similarly, the mechanical stretchability was 112% (control) and increased to 186% (GNP) at 15 phr, 134% (EIP), and 136% (hybrid) at 60 phr. Thus, GNP emerges as a superior reinforcing filler with high stiffness, a high compressive modulus, and high mechanical stretchability. However, the GNP did not show mechanical sensitivity under a magnetic field. Therefore, the hybrids containing GNP and EIP were considered and an improved mechanical performance with magnetic sensitivity was noticed and reported. The mechanism involves the orientation of EIP under a magnetic field causing a magnetic effect, which is 28% for EIP and 5% for hybrid.

Causes and management of persistent septal deviation after septoplasty.

Septoplasty is one of the most common otolaryngological surgical procedures. The causes of persistent septal deviation after primary septoplasty vary. The purpose of this study was to identify factors associated with failure of primary septoplasty, operative techniques that correct residual septal deviation, and surgical outcomes. Seventy-four adults who underwent revision septoplasty to treat persistent septal deviations were enrolled. The level of hospital in which primary septoplasty was performed, type of septal deviation, septal portion exhibiting persistent deviation, and techniques used to correct the deviation were evaluated. Outcomes were measured subjectively using a visual analog scale (VAS), and objectively using acoustic rhinometry. The first septoplasties were usually performed in primary and secondary hospitals. C-shaped deviations were more common than S-shaped ones in both the anteroposterior and cephalocaudal dimensions. The most common region of persistent septal deviation was the caudal septum (44.6%), followed by multiple sites (20.3%). The corrective techniques included excision of the remnant deviated portion (70.3%), septal cartilage traction suturing (27.0%), spreader grafting (13.5%), and cross-suturing (6.8%). The VAS score improved significantly 6 months after surgery. The minimal cross-sectional area and nasal cavity volume of the convex side increased significantly after revision septoplasty. Patients who underwent septoplasty in primary and secondary hospitals were more likely to require revision septoplasty. The caudal septum was the most common site of persistent septal deviation. Careful preoperative evaluation of the caudal septal deviation and selection of an appropriate surgical technique may reduce the need for revision septoplasty.

Highly Stereodivergent Construction of a C2-Symmetric cis,cis- and trans,trans-2,6-Dioxabicyclo[3.3.0]octane Framework by Double Intramolecular Amide Enolate Alkylation: Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene.

The highly stereoselective construction of C2-symmetric cis,cis- and trans,trans-2,6-dioxabicyclo[3.3.0]octane (fused bis-tetrahydrofuran) skeletons 4a and 4b has been accomplished via a novel stereodivergent double intramolecular amide enolate alkylation of common cyclization substrate 5 through the judicious choice of "chelate" versus crown ether-promoted "nonchelate" control. Application of this methodology has provided access to substrate-controlled concise total syntheses of (+)-laurenidificin (3) and (+)-aplysiallene (ent-2), which possess cis/cis- and trans/trans-fused bis-tetrahydrofuran cores, respectively.

Synthesis of 7,2'-Dihydroxy-4',5'-Dimethoxyisoflavanone, a Phytoestrogen with Derma Papilla Cell Proliferative Activity.

This paper reports a concise and scalable method for the synthesis of the phytoestrogen 7,2'-dihydroxy-4',5'-dimethoxyisoflavanone 1 via an optimized synthetic route. Compound 1 was readily obtained in 11 steps and 11% overall yield on a gram scale from commercially available 3,4-dimethoxyphenol. The key features of the synthesis include the construction of the deoxybenzoin unit through a sequence of Claisen rearrangement, oxidative cleavage, and aryllithium addition and the efficient synthesis of the isoflavanone architecture from highly functionalized 2-hydroxyketone.

Efficacy of TnR Nasal Mesh for prevention of septal perforation during septoplasty.

OBJECTIVE: Septoplasty has been reported as the most common cause of the septal perforation. The interposition of the graft materials between the flaps at the site of the tear may be helpful to decrease the likelihood of septal perforation. The purpose of this study was to investigate the efficacy of TnR Nasal Mesh on the prevention of septal perforation following septoplasty. METHODS: Among 46 patients had septal perforation after septoplasty, 35 patients were treated with TnR Nasal Mesh and 11 with autologous septal cartilage for bilateral mucosal tears at the corresponding area of the nasal septum. TnR Nasal Mesh or septal cartilage was placed between the injured mucoperichondrial flaps and confirmed in its original position at both sides under nasal endoscope. Objective endoscopic examination for septal mucosa status was evaluated between the patients who were treated with TnR Nasal Mesh or septal cartilage. RESULTS: Twenty patients (57.1%) showed complete bilateral mucosa healing and nine (25.7%) had unilateral healing after TnR Nasal Mesh insertion. However, complete bilateral and unilateral mucosa healing was observed in 4 (36.4%) and 1 patients (9.1%) treated with septal cartilage, respectively. Complete healing rate for septal perforation was significantly higher in TnR Nasal Mesh than in septal cartilage insertion (p=0.022). None of the patients showed complications or adverse reactions after TnR Nasal Mesh or septal cartilage treatment. CONCLUSION: TnR Nasal Mesh insertion after bilateral septal mucosal tear during septoplasty reduces permanent septal perforation without an apparent adverse effect. Therefore, TnR Nasal Mesh may be a safe and effective graft material for the prevention of septal perforation following septoplasty.

Understanding interfacial segregation in polymer blend films with random and mixed side chain bottlebrush copolymer additives.

Bottlebrush polymers are complex macromolecules with tunable physical properties dependent on the chemistry and architecture of both the side chains and the backbone. Prior work has demonstrated that bottlebrush polymer additives can be used to control the interfacial properties of blends with linear polymers but has not specifically addressed the effects of bottlebrush side chain microstructures. Here, using a combination of experiments and self-consistent field theory (SCFT) simulations, we investigated the effects of side chain microstructures by comparing the segregation of bottlebrush additives having random copolymer side chains with bottlebrush additives having a mixture of two different homopolymer side chain chemistries. Specifically, we synthesized bottlebrush polymers with either poly(styrene-ran-methyl methacrylate) side chains or with a mixture of polystyrene (PS) and poly(methyl methacrylate) (PMMA) side chains. The bottlebrush additives were matched in terms of PS and PMMA compositions, and they were blended with linear PS or PMMA chains that ranged in length from shorter to longer than the bottlebrush side chains. Experiments revealed similar behaviors of the two types of bottlebrushes, with a slight preference for mixed side-chain bottlebrushes at the film surface. SCFT simulations were qualitatively consistent with experimental observations, predicting only slight differences in the segregation of bottlebrush additives driven by side chain microstructures. Specifically, these slight differences were driven by the chemistries of the bottlebrush polymer joints and side chain end-groups, which were entropically repelled and attracted to interfaces, respectively. Using SCFT, we also demonstrated that the interfacial behaviors were dominated by entropic effects with high molecular weight linear polymers, leading to enrichment of bottlebrush near interfaces. Surprisingly, the SCFT simulations showed that the chemistry of the joints connecting the bottlebrush backbones and side chains played a more significant role compared with the side chain end groups in affecting differences in surface excess of bottlebrushes with random and mixed side chains. This work provides new insights into the effects of side chain microstructure on segregation of bottlebrush polymer additives.

Estimation of Number of Graphene Layers Using Different Methods: A Focused Review.

Graphene, a two-dimensional nanosheet, is composed of carbon species (sp2 hybridized carbon atoms) and is the center of attention for researchers due to its extraordinary physicochemical (e.g., optical transparency, electrical, thermal conductivity, and mechanical) properties. Graphene can be synthesized using top-down or bottom-up approaches and is used in the electronics and medical (e.g., drug delivery, tissue engineering, biosensors) fields as well as in photovoltaic systems. However, the mass production of graphene and the means of transferring monolayer graphene for commercial purposes are still under investigation. When graphene layers are stacked as flakes, they have substantial impacts on the properties of graphene-based materials, and the layering of graphene obtained using different approaches varies. The determination of number of graphene layers is very important since the properties exhibited by monolayer graphene decrease as the number of graphene layer per flake increases to 5 as few-layer graphene, 10 as multilayer graphene, and more than 10 layers, when it behaves like bulk graphite. Thus, this review summarizes graphene developments and production. In addition, the efficacies of determining the number of graphene layers using various characterization methods (e.g., transmission electron microscopy (TEM), atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectra and mapping, and spin hall effect-based methods) are compared. Among these methods, TEM and Raman spectra were found to be most promising to determine number of graphene layers and their stacking order.

Silicone Rubber Composites Reinforced by Carbon Nanofillers and Their Hybrids for Various Applications: A Review.

Without fillers, rubber types such as silicone rubber exhibit poor mechanical, thermal, and electrical properties. Carbon black (CB) is traditionally used as a filler in the rubber matrix to improve its properties, but a high content (nearly 60 per hundred parts of rubber (phr)) is required. However, this high content of CB often alters the viscoelastic properties of the rubber composite. Thus, nowadays, nanofillers such as graphene (GE) and carbon nanotubes (CNTs) are used, which provide significant improvements to the properties of composites at as low as 2-3 phr. Nanofillers are classified as those fillers consisting of at least one dimension below 100 nanometers (nm). In the present review paper, nanofillers based on carbon nanomaterials such as GE, CNT, and CB are explored in terms of how they improve the properties of rubber composites. These nanofillers can significantly improve the properties of silicone rubber (SR) nanocomposites and have been useful for a wide range of applications, such as strain sensing. Therefore, carbon-nanofiller-reinforced SRs are reviewed here, along with advancements in this research area. The microstructures, defect densities, and crystal structures of different carbon nanofillers for SR nanocomposites are characterized, and their processing and dispersion are described. The dispersion of the rubber composites was reported through atomic force microscopy (AFM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The effect of these nanofillers on the mechanical (compressive modulus, tensile strength, fracture strain, Young's modulus, glass transition), thermal (thermal conductivity), and electrical properties (electrical conductivity) of SR nanocomposites is also discussed. Finally, the application of the improved SR nanocomposites as strain sensors according to their filler structure and concentration is discussed. This detailed review clearly shows the dependency of SR nanocomposite properties on the characteristics of the carbon nanofillers.

Properties of Silicone Rubber-Based Composites Reinforced with Few-Layer Graphene and Iron Oxide or Titanium Dioxide.

The increasing demand for polymer composites with novel or improved properties requires novel fillers. To meet the challenges posed, nanofillers such as graphene, carbon nanotubes, and titanium dioxide (TiO2) have been used. In the present work, few-layer graphene (FLG) and iron oxide (Fe3O4) or TiO2 were used as fillers in a room-temperature-vulcanized (RTV) silicone rubber (SR) matrix. Composites were prepared by mixing RTV-SR with nanofillers and then kept for vulcanization at room temperature for 24 h. The RTV-SR composites obtained were characterized with respect to their mechanical, actuation, and magnetic properties. Fourier-transform infrared spectroscopy (FTIR) analysis was performed to investigate the composite raw materials and finished composites, and X-ray photoelectron spectroscopy (XPS) analysis was used to study composite surface elemental compositions. Results showed that mechanical properties were improved by adding fillers, and actuation displacements were dependent on the type of nanofiller used and the applied voltage. Magnetic stress-relaxation also increased with filler amount and stress-relaxation rates decreased when a magnetic field was applied parallel to the deformation axes. Thus, this study showed that the inclusion of iron oxide (Fe3O4) or TiO2 fillers in RTV-SR improves mechanical, actuation, and magnetic properties.

Intraoperative botulinum toxin injection for superficial partial parotidectomy: A prospective pilot study.

OBJECTIVES: Sialocele and salivary fistula are not serious but troublesome complications after parotidectomy. Various modalities have been introduced to prevent postoperative saliva-related complications. However, clinical trials assessing the prophylactic use of botulinum toxin (BTX) for parotidectomy have not been conducted yet. Herein, we report a pilot study investigating the safety and efficacy of intraoperative BTX (iBTX) injection in partial superficial parotidectomy (PSP). PARTICIPANTS: Patients with benign parotid tumour were prospectively recruited for this clinical trial from 2017 to 2019. The study participants underwent PSP with iBTX injection. We retrospectively reviewed the clinical information of all the consecutive patients who underwent PSP without iBTX from 2013 to 2019. These patients were divided into two groups: the iBTX group (n = 36) and the control group (n = 54). RESULTS: Permanent facial palsy was not observed in either group. Two patients (3.7%) had transient marginal palsy in the control group but none had it in the iBTX group. The incidence of sialocele was significantly lower in the iBTX group than in the control group (2.8% vs. 20.4%, P < .05). Although the incidence of salivary fistula was lower in the iBTX group than in the control group (0% vs. 7.4%), no significant difference was determined between the two groups (P = .147). Total drainage volume was significantly lower in the iBTX group than in the control group (55.0 mL vs. 116.6 mL, P < .001). CONCLUSIONS: iBTX injection may be safe and effective in reducing sialocele and postoperative drainage in PSP. It might be a useful option to prevent saliva-related complications after PSP.

Asymmetric Total Synthesis and Determination of the Absolute Configuration of (+)-Srilankenyne via Sequence-Sensitive Halogenations Guided by Conformational Analysis.

This first asymmetric total synthesis of (+)-srilankenyne (1), a halogenated C15 tetrahydropyran acetogenin isolated from Aplysia oculifera, features a sequence-sensitive process guided by conformational analysis to solve the challenging problem of introducing halogens. A competing semipinacol rearrangement during the installation of C(12)-bromide was suppressed by our A1,3 strain-controlled bromination protocol with support from X-ray crystallographic and computational studies. The C(10)-chloride was then placed by the Nakata chloromesylate-mediated chlorination.

Diastereoselective Construction of trans-2-Alkyl-6-aryl-3,6-dihydro-2H-pyrans via Dehydrogenative Cycloetherification Promoted by DDQ.

A diastereoselective synthesis of trans-2-alkyl-6-aryl-3,6-dihydro-2H-pyrans has been described. Dehydrogenative cycloetherification of (E)-(±)-1-aryl-5-hydroxy-1-alkenes promoted by DDQ proceeded cleanly via 6-endo cyclization to afford trans-2-alkyl-6-aryl-3,6-dihydro-2H-pyrans (32 examples) in good yield (up to 89%) and with moderate to excellent diastereoselectivity (up to 99:1). The synthetic utility of the method was illustrated by the second total synthesis of (±)-(2R,6S)-3,4-dehydro-1,7-bis(4-hydroxy phenyl)-4'-de-O-methyl centrolobine and a total synthesis of (±)-centrolobine.