Search

Herein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a "local-desymmetrization" approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.

The field of organic synthesis is facing an exciting yet challenging time in its own history, and in the history of science and humanity. In this essay, personal perspectives in response to the five questions posed by the Editors of this Special Issue covering the history, contribution, perception, predictability, and future of organic synthesis, are presented. Through this collection of historical facts, personal viewpoints, encounters, and speculations, the scientific community and beyond may rejuvenate an appreciation for organic synthesis as both a powerful central science and an indispensable enabling technology, and collectively strive towards the next bright chapter in the human history.

The total synthesis of the flagship Strychnos indole alkaloid, strychnine, has been accomplished. The developed synthetic sequence features a novel vinylogous 1,4-addition, a challenging iodinium salt mediated silyl enol ether arylation, a palladium-catalyzed Heck reaction, and a streamlined late-stage conversion to strychnine. Furthermore, an application of asymmetric counterion-directed catalysis (ACDC) in the context of target-oriented organic synthesis has been rendered access to an optically active material. The synthetic sequence described herein represents the most concise entry to optically active strychnine to date.

Here we report asymmetric total syntheses of communesin F and a putative member of the communesin family of bis-aminal alkaloid natural products. The successful strategy featured the invention of an asymmetric organocatalytic reaction to unify two oxindole subunits, a Ti(OiPr)4-mediated dehydrative skeletal rearrangement, and a late-stage Pd(OAc)2-catalyzed directed CH-alkenylation reaction. Collectively, the synthetic technologies disclosed herein enabled the preparation of a late-stage polycyclic intermediate catered for the synthesis of both naturally occurring and designed communesins. More importantly, speculated and yet to be discovered member(s) of the communesin family can now be accessed to facilitate a better understanding of the communesin biosynthetic network.

An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one-pot, sequential palladium-catalyzed enyne cycloisomerization and rhodium-catalyzed diene-assisted pyrrolidine formation by allylic CH activation. The developed transition-metal-catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late-stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.

A putative virus-induced disorder showing mottling and deformation on leaves and fruits of sweet pepper was observed in Taiwan in 2009. Crude sap of symptomatic sweet pepper leaves reacted positively in enzyme-linked immunosorbent assay (ELISA) with antisera to tospoviruses in the Watermelon silver mottle virus (WSMoV) serogroup. A virus culture, TwPep3, isolated from the symptomatic sweet pepper revealed isometric virions measuring about 80–100 nm in diameter via electron microscopy. Seedlings of sweet pepper inoculated with TwPep3 showed similar symptoms as those observed in the field. A 0.9-kb viral genome of isolate TwPep3 could be amplified using degenerate primers for L RNA conserved region of tospoviruses but not using those of tobamoviruses, potyviruses and Cucumber mosaic virus. The partial L RNA sequence of isolate TwPep3 (KF383955) shared 75.1% and 82.4% nucleotide identities with those of WSMoV and Tomato necrotic ringspot virus (TNRV), respectively. To determine the taxonomic relationship of isolate TwPep3, the full length of S RNA (KF383956) was sequenced. Sequence analyses showed that the nucleocapsid (N) gene of TwPep3 shared 82–83% and 87.9–89% nucleotide and amino acid sequence identities, respectively, with those of five isolates of TNRV, the most closely related tospovirus. Moreover, the NSs proteins and S RNAs of TwPep3 and TNRV shared only 78.7% and 77.6% amino acid and nucleotide sequence identities, respectively. Based on our results, isolate TwPep3 should be considered as a new tospovirus and we propose the name Pepper chlorotic spot virus (PCSV). A specific primer pair designed in the N gene was successfully used in reverse transcription-polymerase chain reaction for PCSV diagnostic work.

Background Numerous studies focus on intramuscular (i.m.) injection of hypertonic saline-induced muscle pain and nociception. The spatio-temporal characteristics and dynamic variation of spinal neuronal activities elicited by i.m. hypertonic saline remain unknown. Methods The spatio-temporal variations of c-Fos expression in the lumbar spinal cord exposed to i.m. injection of 5.8% saline were investigated in male rats. Results After a unilateral i.m. 5.8% saline injection, c-Fos expression in dorsal horn of spinal L4-6 segments was significantly enhanced bilaterally (p

With their fascinating biological profiles and stunningly complex molecular architectures, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have long provided a fertile playing field for synthetic organic chemists. In particular, the recent advent of innovative synthetic methods and strategies together with C-C bond-forming reactions and asymmetric catalysis have revitalized this field tremendously. Consequently, PPAP targets which once seemed beyond reach have now been synthesized. This Review aims to highlight the recent achievements in the total synthesis of PPAPs, as well as notable methods developed for the construction of the bicyclo[3.3.1] core of these chemically and biologically intriguing molecules.

Mit ihren faszinierenden biologischen Profilen und erstaunlich komplexen Architekturen waren die polycyclischen polyprenylierten Acylphloroglucine (PPAPs) seit langem ein ertragreiches Gebiet fur Organiker. Besonders das jungste Aufkommen innovativer Synthesemethoden und -strategien, in Verbindung mit C-C-Bindungsbildungsreaktionen und der asymmetrischen Katalyse, hat dieses Gebiet stark wiederbelebt. Infolgedessen konnte nun Synthesen von PPAP-Zielstrukturen realisiert werden, die fruher unmoglich erschienen. Ziel dieses Aufsatzes ist die Darstellung kurzlich komplettierter Totalsynthesen von PPAPs und der bemerkenswerten Methoden, die fur die Konstruktion des Bicyclo[3.3.1]-Kernes dieser chemisch und biologisch faszinierenden Molekule entwickelt wurden.

Asymmetric entry to the bicyclic core structure of (+)-hyperforin is presented. The developed synthetic strategy features a carefully orchestrated stereochemical relay from the single chiral center residing within (–)-Wieland–Miescher ketone and an intramolecular aldol reaction to cast the [3.3.1] bicyclic scaffold found in a diverse array of polycyclic polyprenylated acylphloroglucinols.

In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients' well-being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.

In this article, a Lewis acid mediated 1,4-addition/formal [3+2] cycloaddition reaction engaging functionalized β-carboline and 1,4-benzoquinone has been demonstrated. Application of this developed technology facilitated the construction of the challenging C-9′–C-15 quaternary center linkage in the dimeric indole alkaloid, haplophytine, and enabled the preparation of an advanced key intermediate en route to the total synthesis of this historical natural product.

In this communication, second-generation analogues of palmerolide A, a recently reported cytotoxic agent against melanoma cancer cells, were rationally designed, synthesized, and biologically evaluated. Structural variations of the enamide side chain and the C1-C8 segment of palmerolide A revealed a narrow structure-activity relationship window of the newly synthesized compounds. In addition, mechanistic and pharmacological studies were performed to assess the therapeutic potential of palmerolide A.

In this article, application of the masked o-benzoquinone intramolecular Diels-Alder reaction in the total synthesis of platencin (2), a recently reported Fab inhibitory antibiotic, is described. Through intelligence gathering, the evolving strategies ultimately culminated in three syntheses of the tricyclic core structure 11 of platencin (2). The influence of the remote stereocenter(s) in the diastereoselectivity of the intramolecular Diels-Alder reaction was investigated, together with a remarkable additive effect in drastically improving the diastereoselectivity of the intramolecular Diels-Alder reaction of the dienone 17. The synthetic technology developed was further applied to the preparation of rationally designed analogues, based on the hypothesized FabF/FabH selectivity model. Antibacterial studies of platencin (2) and of the synthesized analogues 3-9 against a panel of normal and resistant strains are also reported.

Similar, but different: Possessing almost the same but not identical structures, the recently discovered natural products hopeahainol A (1) and hopeanol (2) exhibit important but differing biological properties (see structures). Their first total synthesis has now been achieved through a series of novel cascade reactions and skeletal rearrangements.

Backbround The relationship between Helicobacter pylori (Hp) infection and oesophageal squamous-cell carcinoma (ESCC) risk is still inconclusive. Our previous study found an inverse association between the two, but its mechanism is still unknown. Thus, we conducted in vitro studies to clarify the issue. Materials and methods One ESCC (CE 81T/VGH) cell line was co-cultured with Hp, using one gastric adenocarcinoma (AGS) cell line as the control. Hp–induced cell apoptosis was determined by flow cytometry, terminal transferase-mediated dUTP nick end labelling (TUNEL) assay and staining; caspase-3 protein expressions in cell lysates were detected by Western immunoblot. Results Increased apoptosis was found in CE 81T/VGH, but not in AGS cells, by flow cytometry and TUNEL assay after being co-cultured with Hp at the multiplicity of infection of 1/100 (but not at 1/400) for 36 h. The amount of activated caspase-3 (17/19 kDa) also increased in CE 81T/VGH, but not in AGS cells, after co-culturing with Hp at MOI of 1/100 for 36 h. The results were confirmed by triplicate experiments in which the different apoptotic assays remained consistent. Conclusions Our study provides indirect evidence of the inverse association between Hp infection and ESCC risk, which is possibly due to Hp-induced apoptosis in ESCC cells. A further in vivo study is necessary to confirm our findings.

Hexacyclic framework: The total synthesis of the complex C18 -norditerpenoid alkaloid neofinaconitine has been achieved by a convergent approach. This remarkable synthesis featured two Diels-Alder cycloadditions and subsequent Mannich-type N-acyliminium and radical cyclizations to establish the unique hexacyclic core structure of the target molecule.

Aim To present a case of adenoid cystic carcinoma (ACC) in the mandible, and manifesting as a periapical lesion. Summary A 56-year-old male suffered from pain around the right mandibular first molar for approximately 1 week. Oral examination revealed that the involved tooth was restored by a full coverage crown with no obvious abnormalities. A periapical radiograph revealed two ill-defined radiolucencies associated with the tooth, one over the mesial and another over the distal roots of the tooth; incomplete root filling and furcation involvement also being noted. The affected tooth was extracted based on the clinical impression of apical periodontitis. The surrounding tissue of the root apex was curetted and sent for histopathological examination, which revealed ACC. Key learning points • Adenoid cystic carcinoma affecting the mandible may mimic a periapical lesion. Proper diagnosis of such a lesion is dependent on thorough clinical, radiographic and microscopic examinations. • Such a case highlights the benefits of biopsy and histological examination of collected tissues. • Diagnosis of lesions in the mandible should include salivary gland tumours.

Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego. All solvents were purified according to the method of Grubbs. Non-aqueous reagents were transferred under nitrogen or argon via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Buchi rotary evaporator using a water bath. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still. Thin-layer chromatography (TLC) was performed on Silicycle 0.25 mm silica gel F-254 plates. Visualization of the developed chromatogram was performed by fluorescence quenching or by anisaldehyde, ceric ammonium molybdate, or potassium permanganate stain. H and C NMR spectra were recorded on a Bruker 500 (500 MHz and 125 MHz) unless otherwise noted. Chemical shifts (δ) are reported from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 7.26, C6D6: δ 7.15

The aim of the present study was to investigate the sequential expression of placental glutathione S-transferase (GST-P) during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch squamous cell carcinogenesis. Both immunohistochemical and immunoblot analyses were employed to detect the epithelial GST-P in hamster buccal pouch mucosa over a 15-week treatment regimen. No GST-P positivity was demonstrated in the pouches of the control group. GST-P positive cells were first noted as early as 1 week after DMBA applications. A gradual increase in both the mean number and size of GST-P-positive foci was noted in the first 12 experimental weeks, but a plateau level was approached thereafter. The early GST-P-positive-area were located in the basal layer, or occasionally in the middle layer, of DMBA-treated hamster buccal pouch mucosa. Later, the stained sites became enlarged and were scattered randomly in different layers or in the whole thickness of the dysplastic and non-dysplastic epithelium. The keratin layer was only occasionally involved during the first 12 weeks of DMBA treatment but positive staining was more noticeable in the final stage of the experiment. Both exophytic (8-12 weeks) and invasive (13-15 weeks) squamous cell carcinomas showed GST-P positivity, in both cytoplasmic and nuclear components. Immunoblot analysis revealed no band in the crude tissue extracts of the control pouches whereas GST-P polypeptide of molecular weight approximately 26 kD was demonstrated in DMBA-treated pouches over the whole 15-week treatment regimen. Results of the present work indicate that GST-P is a stable and persistent label for almost all of the carcinogen-altered cells during DMBA-induced hamster buccal pouch carcinogenesis. Immunohistochemically detectable GST-P may be a potential marker throughout oral chemical carcinogenesis.

In recent years, combination therapy has received growing popularity as a powerful therapeutic tactic for the treatment of diseases. The justifications and benefits of combination therapy are far-reaching, including but not limited to addressing unmet medical needs such as cancer, malaria, and HIV/AIDS, improved clinical efficacy and safety with reduced dosage of a single medication, understanding the underlying science of the disease, alleviating pharmaco-economic impacts, and better drug life-cycle management. Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single-pill combination, Vytorin, is presented in this review. A cursory introduction to combination therapy and the rationale for the ezetimibe/simvastatin combination for the treatment of hyperlipidemia provides an instructive entry point. The discovery and mode of action of simvastatin and ezetimibe monotherapies set the scene for a detailed discussion on the discovery and development of Vytorin, with emphasis on bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single-pill combination therapy. Large-scale outcome clinical trials are also discussed to demonstrate the long-term effects of Vytorin.

The expression and localization of glutathione S-transferase (GST) isoenzymes in the epithelium of normal oral mucosa (n = 9), overlying reactive fibrous hyperplasia (n = 9), and of potentially malignant [leukoplakia (n = 25), submucous fibrosis (n = 12), verrucous hyperplasia (n = 16)] and malignant [squamous cell carcinoma (n = 36), verrucous carcinoma (n = 13)] oral lesions were examined immunohistochemically using polyclonal antibodies raised against GST isoenzymes (alpha, mu and pi) with the standard avidin-biotin-peroxidase complex (ABC) method. GST alpha, mu and pi were almost completely absent in the epithelium of normal oral mucosa and overlying benign fibrous tissues. GST alpha staining was cytoplasmic and focally positive, while GST mu staining was similar to but weaker than that seen for GST alpha. GST pi showed both cytoplasmic and nuclear staining and was expressed in 60% of leukoplakias with mild dysplasia (n = 15), 80% of leukoplakias with moderate to severe dysplasia (n = 10). 75% of submucous fibrosis samples (n = 12), 75% of verrucous hyperplasias (n = 16), 77% of verrucous carcinomas (n = 13), 81% of well-differentiated squamous cell carcinomas (n = 26) and 70% of moderate- to poorly-differentiated squamous cell carcinomas (n = 10). In addition, GST pi expression was independent of the state of differentiation of oral cancers. Since GST pi was significantly over-expressed in the oral premalignant and malignant lesions, the kinetics of GST pi-positive cells and the value of GST pi as a tumor marker in oral carcinogenesis need further investigation.

The recent advent of transition-metal mediated CH activation is revolutionizing the synthetic field and gradually infusing a “CH activation mind-set” in both students and practitioners of organic synthesis. As a powerful testament of this emerging synthetic tool, applications of CH activation in the context of total synthesis of complex natural products are beginning to blossom. Herein, recently completed total syntheses showcasing creative and ingenious incorporation of CH activation as a strategic manoeuver are compared with their “non-CH activation” counterparts, illuminating a new paradigm in strategic synthetic design.

In this tutorial review, recent advances in the synthesis of cyclopropane-containing natural products are discussed, highlighting the application of novel synthetic methodologies and innovative synthetic strategies in the construction of highly functionalized cyclopropanes. The examples showcased herein aim to inspire students and practitioners of organic synthesis to seek further advances in the chemical synthesis of cyclopropanes, both in the context of target-oriented syntheses and method developments.