6’-Amino-5,7-Dibromo-2-Oxo-3’-(Trifluoromethyl)-1’H-Spiro[Indoline-3,4’-Pyrano[2,3-c]Pyrazole]-5’-Carbonitrile

The multicomponent reactions are environmentally benign synthetic methods of building-up of complex molecules and several levels of structural diversity for diverse applications. Spirooxindoles are an important synthetic target possessing extended biological activity and drug discovery applications. In this communication, the multicomponent transformation of 5,7-dibromoisatin, malononitrile, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one in EtOH at reflux in the presence of sodium acetate was carefully investigated to give 6’-amino-5,7-dibromo-2-oxo-3’-(trifluoromethyl)-1’H-spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile in excellent yield. The structure of the new compound was established by means of elemental analysis, mass and nuclear magnetic resonance, and infrared spectroscopy.

Synthesis of Antimycobacterial Agents that Harness Mycothiol and Cysteine conjugate β-lyase Metabolic Pathways

<p>Mycobacterium tuberculosis kills approximately two million people each year and is second only to HIV/AIDs in terms of death from infectious disease. The most pertinent problem in regards to Mycobacterium tuberculosis today is the increasing prevalence of drug resistant strains. Thus, there is a great need for the development of new drugs with novel targets. This thesis aimed to address this problem by synthesizing a compound that could exploit the mycothiol detoxification pathway, unique to Mycobacterium, in order to cause cell death, through the release of a harmful halothioketene. The research described herein involved the successful synthesis of the desired mycothiol analogue, along with three other related compounds. The target compounds were synthesised via protection of N-acetyl glucosamine, followed by thioglycosidation with cyclohexane thiol. Subsequent deprotection and coupling to Boc protected Strichlorovinyl cysteine provided access to the synthetic target and its β-anomer, as well as their Boc protected precursors. The original synthetic target demonstrated weak antimycobacterial activity against Mycobacterium smegmatis and an encouraging sub 100 μM MIC against Mycobacterium bovis derived Bacillus Calmette–Guérin. Unexpectedly the beta anomer of the synthetic target also displayed antimycobacterial activity against Bacillus Calmette–Guérin (MIC 125 - 250 μM). All compounds proved to be active against HL60 cells (16-114 μM). Whilst further work is required to improve efficacy, the work presented here demonstrates the potential of these compounds as leads for the generation of new antimycobacterial agents.</p>

Synthesis of Antimycobacterial Agents that Harness Mycothiol and Cysteine conjugate β-lyase Metabolic Pathways

<p>Mycobacterium tuberculosis kills approximately two million people each year and is second only to HIV/AIDs in terms of death from infectious disease. The most pertinent problem in regards to Mycobacterium tuberculosis today is the increasing prevalence of drug resistant strains. Thus, there is a great need for the development of new drugs with novel targets. This thesis aimed to address this problem by synthesizing a compound that could exploit the mycothiol detoxification pathway, unique to Mycobacterium, in order to cause cell death, through the release of a harmful halothioketene. The research described herein involved the successful synthesis of the desired mycothiol analogue, along with three other related compounds. The target compounds were synthesised via protection of N-acetyl glucosamine, followed by thioglycosidation with cyclohexane thiol. Subsequent deprotection and coupling to Boc protected Strichlorovinyl cysteine provided access to the synthetic target and its β-anomer, as well as their Boc protected precursors. The original synthetic target demonstrated weak antimycobacterial activity against Mycobacterium smegmatis and an encouraging sub 100 μM MIC against Mycobacterium bovis derived Bacillus Calmette–Guérin. Unexpectedly the beta anomer of the synthetic target also displayed antimycobacterial activity against Bacillus Calmette–Guérin (MIC 125 - 250 μM). All compounds proved to be active against HL60 cells (16-114 μM). Whilst further work is required to improve efficacy, the work presented here demonstrates the potential of these compounds as leads for the generation of new antimycobacterial agents.</p>

Driving Aspirational Process Mass Intensity Using SMART-PMI and Innovative Chemistry

An important metric for gauging the impact a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step PMI for a given synthesis from a process description is more and more common across the industry. Our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with seven EPA Green Chemistry Challenge Awards in the last 15 years. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what ‘good’ looks like for any given molecule. Predicting aspirational PMI for a synthetic target is not yet possible from chemical structure alone. The only tool chemists have at their disposal to predict PMI requires the synthetic route to be available, which is inherently retrospective. We have developed SMART-PMI (in-Silico MSD Aspiration-al Research Tool) to fill this glaring gap. Using only a 2D chemical structure, which enables a measure of molecular complexity, we can generate a predicted SMART-PMI using historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges for Successful, World Class, and Aspirational PMI. Using this model, chemists can develop powerful synthetic strategies that make the biggest impact on PMI and, in turn, drive improvements to the model. The potential of SMART-PMI to set industry-wide aspirational PMI targets is discussed.

Synthesis of Indoloquinolines: An Intramolecular Cyclization Leading to Advanced Perophoramidine-Relevant Intermediates

The bioactive natural product perophoramidine has proved a challenging synthetic target. An alternative route to its indolo[2,3-b]quinolone core structure involving a N-chlorosuccinimde-mediated intramolecular cyclization reaction is reported. Attempts to progress towards the natural product are also discussed with an unexpected deep-seated rearrangement of the core structure occurring during an attempted iodoetherification reaction. X-ray crystallographic analysis provides important analytical confirmation of assigned structures.

Evaluating the Performance of a Magnetic Nanoparticle-Based Detection Method Using Circle-to-Circle Amplification

This work explores several issues of importance for the development of a diagnostic method based on circle-to-circle amplification (C2CA) and oligonucleotide-functionalized magnetic nanoparticles. Firstly, the performance of the detection method was evaluated in terms of sensitivity and speed. Synthetic target sequences for Newcastle disease virus and Salmonella were used as model sequences. The sensitivity of the C2CA assay resulted in detection of 1 amol of starting DNA target with a total amplification time of 40 min for both target sequences. Secondly, the functionalization of the nanoparticles was evaluated in terms of robustness and stability. The functionalization was shown to be very robust, and the stability test showed that 92% of the oligos were still attached on the particle surface after three months of storage at 4 °C. Altogether, the results obtained in this study provide a strong foundation for the development of a quick and sensitive diagnostic assay.

Biomimetic Approaches to the Synthesis of Natural Disesquiterpenoids: An Update

Natural disesquiterpenoids represent a small group of secondary metabolites characterized by complex molecular scaffolds and interesting pharmacological profiles. In the last decade, more than 400 new disesquiterpenoids have been discovered and fully characterized, pointing out once more the “magic touch” of nature in the design of new compounds. The perfect blend of complex and unique architectures and biological activity has made sesquiterpene dimers an attractive and challenging synthetic target, inspiring organic chemists to find new and biomimetic approaches to replicate the efficiency and the selectivity of natural processes under laboratory conditions. In this work, we present a review covering the literature from 2010 to 2020 reporting all the efforts made in the total synthesis of complex natural disesquiterpenoids.

ESTRATÉGIAS PARA A SÍNTESE DO ÁCIDO LISÉRGICO

STRATEGIES FOR THE SYNTHESIS OF LYSERGIC ACID. (+)-Lysergic acid [(+)-1] is a precursor of several substances with well-established pharmacological properties, including some drugs approved and commercialized around the world. Thus, the importance of (+)-1 as a synthetic target becomes undoubted and various strategies for the synthesis of its tetracyclic core have been reported in the literature. Therefore, in this review article we will address in chronological order the total and formal syntheses of lysergic acid (1), separating them into racemic and chiral/asymmetric syntheses. Until now, there are 24 syntheses described in the literature, namely, 11 total and 13 formal syntheses. Considering all the syntheses accomplished, 15 were planned to produce (±)-lysergic acid [(±)-1] and 9 presented routes to eventually provide (+)-lysergic acid [(+)-1]. A significant evolution regarding approaches and efficiency may be observed since the first synthesis of (±)-1 until the last asymmetric synthesis of (+)-1.

Efficient Construction of the Hexacyclic Ring Core of Palau’amine: The pKa Concept for Proceeding with Unfavorable Equilibrium Reactions

Palau’amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in...