Short Synthesis Research Articles

A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.

Predictive factors for the outcome of emotional and/or behavioural disorders in 18- to 48-month-old children after parent-child psychotherapy: Protocol of a European prospective cohort study

ObjectivesSeveral studies have shown that in young children, behavioural and/or emotional disorders are more difficult to manage than regulatory disorders. Moreover, data are lacking on outcome predictive factors. This article presents a short synthesis of previous research about outcome predictive factors in child psychiatry. It also describes the protocol of a longitudinal observational European multicentre study the main objective of which was to identify predictive factors of behavioural and emotional disorder outcome in toddlers after parent-child psychotherapy. The secondary objectives were to study predictive factors of the outcome in parents (anxiety/depression symptoms) and parent-child relationship. MethodIn order to highlight medium-effect size, 255 toddlers (age: 18 to 48 months) needed to be included. Outcomes will be assessed by comparing the pre- and post-therapy scores of a battery of questionnaires that assess the child's symptoms, the parents’ anxiety/depression, and the parent-child relationship. Multivariate linear regression analysis will be used to identify predictive factors of the outcome among the studied variables (child age and sex, socio-economic status, life events, disorder type, intensity and duration, social support, parents’ psychopathology, parents’ attachment, parent-child relationships, therapy length and frequency, father's involvement in the therapy, and therapeutic alliance). Expected results and conclusionThis study should allow identifying some of the factors that contribute to the outcome of externalizing and internalizing disorders, and distinguishing between pre-existing and treatment-related variables. It should also help to identify children at higher risk of poor outcome who require special vigilance on the part of the therapist. It should confirm the importance of therapeutic alliance. Trial registrationID-RCB 2008-A01088-47.

Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane.

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

A short total synthesis of (±)-mersicarpine via visible light-induced cascade photooxygenation.

A short total synthesis of the Kopsia alkaloid (±)-mersicarpine is presented. As the key step, a visible light-induced catalytic cascade photooxygenation was utilized, to convert a 3,3-disubstituted tetrahydrocarbazole intermediate, in one step, into a perhydropyrido[1,2-a]indole dione as the immediate precursor to the natural product. The synthesis of mersicarpine was achieved with an overall yield of 12% over 13 steps.

Measuring the contributions of helicases to break-induced replication.

Break-Induced Replication (BIR) is a homologous recombination (HR) pathway that differentiates itself from all other HR pathways by involving extensive DNA synthesis of up to hundreds of kilobases. This DNA synthesis occurs in G2/M arrested cells by a mechanism distinct from regular DNA replication. BIR initiates by strand invasion of a single end of a DNA double-strand break (DSB) followed by extensive D-loop migration. The main replicative helicase Mcm2-7 is dispensable for BIR, however, Pif1 helicase and its PCNA interaction domain are required. Pif1 helicase was shown to be important for extensive repair-specific DNA synthesis at DSB in budding and fission yeasts, flies, and human cells, implicating conservation of the mechanism. Additionally, Mph1 helicase negatively regulates BIR by unwinding migrating D-loops, and Srs2 promotes BIR by eliminating the toxic joint molecules. Here, we describe the methods that address the following questions in studying BIR: (i) how to distinguish enzymes needed specifically for BIR from enzymes needed for other HR mechanisms that require short patch DNA synthesis, (ii) what are the phenotypes expected for mutants deficient in extensive synthesis during BIR, (iii) how to follow extensive DNA synthesis during BIR? Methods are described using yeast model organism and wild-type cells are compared side-by-side with Pif1 deficient cells.

Synthesis of 4-Aryl-1,2-naphthoquinones via a conjugate addition-oxidation reaction catalyzed by p-toluenesulfonic acid

A catalytic conjugate addition-oxidation reaction of 1,2-naphthoquinones has been investigated. p-Toluenesulfnoic acid was found to be the most effective catalyst for the reaction. This developed method provides a short, simple, convenient, and low-cost synthesis of 4-aryl-1,2-naphthoquinones.

A Novel Approach for the Synthesis of (<i>R</i>) and (<i>S</i>)-Nicotine

Nicotine is an alkaloid mainly found in leaves of tobacco and is used therapeutically for patients seeking relief from tobacco dependence in the form of products such as gums, patches, lozenges etc. In these products, majorly nicotine derived from tobacco is used which is inherently contaminated with undesirable nicotine related substances as impurities at low levels and is difficult to remove. Hence, use of synthetic nicotine is considered as an option which will be devoid of such impurities. In this work, a short and efficient synthesis of (R) and (S) nicotine was achieved by leveraging a key esterification between racemic homoallylic alcohol intermediate (2) and (S)-Ibuprofen (3) to produce diastereomers (5a) and (5b) which were easily separable under standard column chromatography conditions. Use of (S)-Ibuprofen (3) as a chiral resolving agent constitutes a novel approach which was not reported earlier. A subsequent hydrolysis of the diastereomers furnished the homoallylic alcohol intermediates (S)-6a and (R)-6a with high enantiopurity, which was effectively translated to the corresponding (R)-nicotine and (S)-nicotine respectively.

Short and efficient synthesis of alkylresorcinols: a route for the preparation of cannabinoids

In this work, we describe a general and efficient method for the preparation of alkylresorcinols (ARs), also in deuterated form.

Knoevenagel Condensation between 2-Methyl-thiazolo[4,5-b]pyrazines and Aldehydes.

Knoevenagel condensation, an olefin-forming reaction from active methyl/methylene-containing compounds and aldehydes, is a fundamental and useful synthetic method. Benzothiazoles are, however, out of the scope of Knoevenagel condensation. Here, we report that Knoevenagel condensation between aldehydes and 2-methyl-thiazolo[4,5-b]pyrazines (MeTPy), a fused ring structure comprising pyrazine and thiazole, proceeded smoothly, despite minor structural differences from benzothiazoles. This finding will be useful for short synthesis of MeTPy-containing functional molecules, such as a tau probe analog 1.

A new short synthesis route for favipiravir and its analogue: Their tautomerization behaviour

Halogen substitution in a pyrazine ring is achieved in an efficient manner. The solid state data revealed the formation of two types of halogen bonding in the structures.

Short electrochemical asymmetric synthesis of (+)-N-acetylcolchinol

A short synthesis of N-acetylcolchinol using a greener pathway is reported where all the redox steps, except for the asymmetric reduction, were carried out electrochemically, replacing protocols that employ stoichiometric hazardous reagents.

Pd-Catalyzed Umpolung Chemistry of Glycal Acetates and Their [2,3]-Dehydrosugar Isomers.

Glycals and their [2,3]-dehydrosugar derivatives have commonly been used in synthetic chemistry as electrophiles. Here we report a Pd-catalyzed polar inversion (umpolung) of this reaction, where the glycals and isomers can be used as nucleophiles. The reaction showed high regio- and stereoselectivity in the presence of numerous aromatic and aliphatic aldehydes. The synthetic utility of this reaction was demonstrated by the short synthesis of the tetrahydropyran fragment of the anticancer natural product mucocin.

Recent Progress and Development Trend of Self-Sweeping Fiber Laser

Since 2011, when Kir’yanov et al. first reported a new wavelength self-sweeping ytterbium-doped fiber laser that does not rely on any tuning element but only on the dynamic induced grating generated in the gain fiber by the standing wave resonator structure, the self-sweeping effect based on fiber waveguides has been extensively studied, leading to great progress in fundamental physics and other applications of self-sweeping fiber lasers. Different doped fiber lasers have not only achieved the self-sweeping effect, but also observed new phenomena such as anomalous self-sweeping and continuous pulses. Due to their remarkable spectral and pulsed characteristics, self-sweeping fiber lasers have been widely used in spectral detection, fiber sensing and short pulse synthesis. In this paper, we will introduce the classification of different doped self-sweeping fiber lasers, summarize their different implementations, and introduce their self-sweeping laws, pulse characteristics, recent progress of applications and future development prospects.

Synthesis of defected UIO‐66 with boosting the catalytic performance via rapid crystallization

AbstractDue to environmental and health concerns, it is very important to develop high activity oxidative desulfurization (ODS) catalyst for petroleum purification. Recently, defect engineering of metal organic frameworks (MOFs) to generate a large number of unsaturated catalytic active sites is a very promising approach. Defective MOF has good research value as ODS catalyst. Here, UIO‐66 with lots of defects can be prepared by rapid crystallization using concentrated hydrochloric acid as a modulator. The prepared UIO‐66 material has good industrial applicability due to its low synthesis temperature (100°C), short synthesis time (20–30 min), large‐scale preparation, and excellent catalytic performance (dibenzothiophene can be entirely removed in 6 min under the optimal catalytic conditions [25‐mg catalyst, 60°C, O/S 7.5]). The obtained material exhibits not only extraordinary ODS activity of 37.6 mmol h−1 g−1 but also good cycle stability for the removal of DBT (in 7 cycles without significant loss of activity, greater than 90.2%). And for large space volume 4,6‐DMDBT, it also shows excellent catalytic performance. The ODS mechanism of defect UIO‐66 for DBT is explored, and it proves that hydroxyl radicals and superoxide radicals are generated and play a critical role in ODS reaction. The excellent catalytic performance of defect UIO‐66 gives mainly the credit to the abundant defect sites, large specific surface area, and pore volume.

Magnetothermally-responsive nanocarriers using confined phosphorylated halloysite nanoreactor for in situ iron oxide nanoparticle synthesis: A MW-assisted solvothermal approach

A family of easily recoverable magnetic and thermally responsive composite materials, with nanoscale dimensions, were synthesized by a rapid and simple solvothermal approach. The synthesis was thermally activated, accelerated, and controlled using a coaxial antenna to directly apply the microwave energy inside the solvothermal reactor. The composite materials were made up by a confined phosphorylated nanoreactor, namely halloysite nanotubes grafted on the inner lumen with phosphoric acid (HNTs-(H+-PO4)), that promoted the urea hydrolysis thus favoring the formation of a local alkaline environment to catalyze the homogeneous in situ precipitation of superparamagnetic iron oxide nanoparticles (IONs) selectively on their inner or outer surface. Two new MW-assisted solvothermal methodologies were used: 1) in the first the solvent is directly loaded into the MW-assisted reactor together with HNTs-(H+-PO4) mechanically preloaded with iron chloride and urea in the lumen 2) in the second the synthesis is preceded by a further pre-functionalization step of the iron salt with clove essential oil (EO) as a green functionalization agent. Structural, morphological, textural, and magnetic properties were assessed by TEM, N2 physisorption, TG-FTIR, ICP, XRD, magnetic and magnetic hyperthermia measurements. The MW-assisted solvothermal deposition of IONs was fully controlled using the phosphorylated nanoreactor, in short synthesis times, by a simple methodology following the principles of sustainable chemistry. IONs were selectively deposited on the outer surface or in the inner lumen of HNTs yielding easily recoverable superparamagnetic and thermally responsive nanocarriers suitable for applications like targeted hyperthermia therapy.

‘Maslow before Bloom’: Implementing a caring pedagogy during Covid-19

The speed at which the novel coronavirus, known as Covid-19, spread around the world in early 2020, has been well-documented. Countries closed their borders, cities and regions went into lockdown, schools and businesses closed and hospital geared up for an influx of patients (Cameron, 2020; OECD, 2021; UNESCO, 2020). On March 25, New Zealand went into Level 4 lockdown, the most restrictive of the government’s alert level system. The school holidays, due to start on April 9, were brought forward two weeks to give the Ministry of Education and schools a chance to prepare for school-led home learning. A survey of schools highlighted that only half the schools in the country felt they could deliver learning fully online, with lack of devices and limited Internet connectivity being the major problems (New Zealand Government, 2020). Most schools moved into home learning on April 15 and continued until after May 18, when the country moved down to Level 2. On return, schools needed to alter their approaches to comply with social distancing and hygiene requirements until the country returned to Level 1 in June. In August 2020, Auckland schools closed again and yet again several times in 2021 (Author, 2020; Cameron, 2020; Education Review Office [ERO], 2021; Henrickson, 2020; Ministry of Education, 2020). The arrival of the Delta variant in Auckland communities, in late August 2021, led to further regional lockdowns, some of which are still in place at the time of writing.
 This article draws on in-depth qualitative interviews with 20 teachers in either late 2020 or mid-2021, as part of a larger study of New Zealand schools’ responses to Covid-19. The article begins with a short synthesis of research literature on teachers’ responses to lockdowns overseas and in New Zealand. The methodology for our study is briefly outlined before describing the ‘caring pedagogy’ theoretical framework that underpins the approach to this article. The findings are presented in a semi-chronological order, from teachers’ preparation, to implementation, to returning to school. The findings are interspersed with ‘found poems’ created from verbatim transcripts to highlight teachers’ voices. The discussion section revisits the concepts in the article’s title, that is, ‘Maslow before Bloom.’ The overall purpose of our article is to portray the tension between teachers’ willingness to adopt a caring pedagogy and the toll that it took on them, personally and professionally.

Stereodivergent Attached‐Ring Synthesis via Non‐Covalent Interactions: A Short Formal Synthesis of Merrilactone A

AbstractA strategy to control the diastereoselectivity of bond formation at a prochiral attached‐ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non‐covalent interactions to control re‐ vs. si‐ facial selectivity en route to fully substituted attached‐rings. This divergency reflects differential engagement of one rotational isomer of the attached‐ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.

Stereodivergent Attached-Ring Synthesis via Non-Covalent Interactions: A Short Formal Synthesis of Merrilactone A.

A strategy to control the diastereoselectivity of bond formation at a prochiral attached-ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non-covalent interactions to control re- vs. si- facial selectivity en route to fully substituted attached-rings. This divergency reflects differential engagement of one rotational isomer of the attached-ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.

Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results.

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk factor. Proinflammatory signaling molecules in HF initiate vicious cycles altering mitochondrial function and perturbing calcium homeostasis, therefore affecting myocardial contractility. Specific anti-inflammatory treatment represents a novel approach to prevent and slow HF progression. This review provides an update on the putative roles of inflammatory mediators involved in heart failure (tumor necrosis factor-alpha; interleukin 1, 6, 17, 18, 33) and currently available biological and non-biological therapy options targeting the aforementioned mediators and signaling pathways. We also highlight new treatment approaches based on the latest clinical and experimental research.

Sequential Metal Catalysis towards 7‐Oxostaurosporine and Its Non‐Natural Septanose Analogue

AbstractWe report sequential metal catalysis towards indolocarbazole glycosides. The signature event is highlighted by i) Pd0‐catalyzed addition of indolocarbazole to alkoxyallene combined with ring‐closing‐metathesis; ii) Ru‐catalyzed chemoselective olefin migration; iii) PdII‐catalyzed oxidative cyclization to build the bicyclic core structure of the target compounds. This approach gave access to both natural pyranose‐ and non‐natural septanose glycosides. A short formal synthesis of 7‐oxostaurosporine was achieved via this strategy.