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Novel route to the [7-5-5] tricyclic core of Daphniphyllum alkaloids

To date, more than 320 new alkaloids have been isolated from the evergreen plants of the Daphniphyllum genus. In ancient times, extracts of the bark and leaves of Daphniphyllum plants were used in Chinese herbal medicines to cure minor ailments and treat pain. Recent studies have discerned that the Daphniphyllum class of alkaloid displays significant and varying biological activity, including anticancer, antioxidant and vasorelaxant activities. However, their unique polycyclic architectures containing multiple quaternary stereocenters render these alkaloids synthetically challenging.

A recent OBC publication by Tohru Fukuyama and Satoshi Yokoshima of Nagoya University reports on the synthesis of a common structural core prevalent among the Daphniphyllum alkaloids. The common [7-5-5] tricyclic core features a quaternary carbon centre, two contiguous stereogenic centres and a tetrasubstituted C-C double bond.

The study began with the synthesis of the adjacent stereogenic centres, which was ultimately achieved through a Claisen-Ireland rearrangement with a 73% isolated yield (1 step) and dr = 6.3:1.

The challenging tetrasubstituted C-C double bond was tackled next. Limited procedures for the installation of the tetrasubstituted C-C alkene have been reported for the [7-5-5] tricyclic core. The highly congested nature of such substituted double bonds results in destabilizing eclipsing interactions, which are mirrored in the transition states leading to them. The tetrasubstituted C-C double bond of the [7-5-5] tricyclic core was therefore carried out using an E1cB-elimination of intermediate 28 to generate the a,b-unsaturated ketone 29 with a 78% isolated yield.
Extensive investigations revealed that the quaternary carbon centre could be accessed through a 2,3-Wittig rearrangement, which occurred stereoselectively on the less hindered face of the bicyclic intermediate. Quite efficiently, this transformation yielded intermediate 36 which contained a vinyl group that was to be used in the construction of the 7-membered ring. Final steps included a ring-closing metathesis and an intramolecular carbonyl ene reaction to complete the [7-5-5] ring system.

This creative study provides an excellent platform for the total synthesis of Daphniphyllum alkaloids that have the [7-5-5] tricyclic core.

To find out more see:

Synthesis of the [7-5-5] tricyclic core of Daphniphyllum alkaloids
Yusuke Kitabayashi, Tohru Fukuyama and Satoshi Yokoshima
DOI: 10.1039/C8OB00859K


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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New class of synthetic antibody mimics for improved therapeutics

Molecules capable of mimicking the binding and/or functional sites of proteins represent a promising avenue for the development of potential drug candidates. This strategy allows for the incorporation of key structural features into simpler scaffolds and opens a wide range of opportunities for developing molecules with enhanced and modular biological activities.

A recent OBC publication by Professor Rob Liskamp of Glasgow University addresses a current challenge in the development and application of complementarity determining region (CDR) mimics, which have recently been shown to successfully behave as synthetic antibody mimics.

 

The concept of simplifying large proteins into simpler structures requires the synthesis of preorganized molecular scaffolds, which function as the core structural unit for attaching the biologically active CDR component. Such analogues have been shown to possess increased bioavailability, proteolytic stability and exhibit reduced immunogenic responses.

The group had previously reported the synthesis of a CTV-derived scaffold (Figure, compound 2), onto which different peptide segments could be incorporated, essentially generating synthetic CDRs with novel and tuneable physico-chemical properties. Poor solubulity however, has limited the progress of this class of compound in the drug discovery process.

Their current study focuses on the development of a scalable, one-pot synthesis of water soluble CTV-derived scaffolds (Figure, compounds 3, 4), which incorporate mono or diethylene glycol spacers. Late-stage diversification of the CTV-derived scaffolds is ammenable through Cu(I)-catalyzed azide-alkyne cycloaddition. This allows for the generation of a diverse series of synthetic antibodies, which were shown to mimic the antigen binding site of monoclonal antibody (mAb) infliximab (Remicade)—used for the treatment of human tumour necrosis factor alpha (hTNFa) mediated autoimmune diseases. SPR binding studies against the hTNFa receptor identified 5 leads with KD’s measured between 11 and 66 mM. While further modifications are required to improve solubility for evaluation in vitro, this study demonstrates the potential of this work to extend beyond antibody mimics. As any azide handle can be linked to the CTV-derived scaffold, one can envision the application of this methodology toward alternative protein mimics.

To find out more see:

Synthetic antibody protein mimics of infliximab by molecular scaffolding on novel CycloTriVeratrilene (CTV) derivatives
Ondřej Longin, 
DOI:10.1039/C8OB01104D


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Reactivity Caging Strategy for Controlling Bioorthogonal Reactivity

Bioorthogonal reactions offer a unique and highly effective means of studying biological molecules in their native environment. Classical examples include native chemical ligations, Staudinger ligation, and click chemistry though numerous examples have been reported in the literature over the past several decades.

The majority of studies centred around the development of bioorthogonal reagents have focused on improving kinetics and selectivity in vivo. However, less explored are reagents in which their reactivity in biological settings is modulated through controlled activation by light or a specific enzyme.

In their recent OBC publication, Professor Scott Laughlin and coworkers describe the modular control of novel cyclopropane-tetrazine ligation. Previous reports have demonstrated the poor reactivity of C3 disubstituted cyclopropene in these types of reactions due to unfavourable steric interactions between the C3 substituents and the tetrazine during the transition state (Figure A). To this end, 3-N-substituted spirocyclopropenes were designed to control ligation through a “reactivity caging strategy” in which the introduction of a removable bulky N-protecting group sterically inhibits premature reaction with the tetrazine partner (Figure B and C).

The novel cyclopropene scaffold was synthesized from commercially available starting materials in good overall yields and applied successfully to the labelling of a tetrazine-modified protein. Given the widespread use of light-removable nitrogen protecting groups, the group predicts their activatable cyclopropene scaffold will be amenable to control at multiple wavelengths. While optimization of reaction kinetics is still required, this study provides interesting opportunities for the application of diverse caging groups in modulating reactivity for specific biological systems and applications.

To find out more see:

Caged cyclopropenes for controlling bioorthogonal reactivity
Pratik Kumar, 
DOI:10.1039/C8OB01076E


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Novel bis-urea anionophores facilitate ion transport in live cell environments

The development of synthetic molecules capable of facilitating the transport of ions across cell membranes has become a prominent and active field of research. These compounds mimic the activity of natural ionophores and have found broad application in materials sciences, chemical biology and medicine.

The majority of known synthetic ionophores facilitate the transport of cations. However, there is mounting evidence to support the ability of anion selective ionophores (anionophores) to act as anticancer agents and novel leads in the treatment of channelopathies—diseases, such as cystic fibrosis, caused by dysfunctional ion channels or related regulatory proteins. The ultimate hope is that they can be used to restore ion channel function in such cases.

An important step toward practical application is to demonstrate the activity of anionophores not only in synthetic vesicle assays but in live cell environments. In a collaborative study between Prof. Phillip Gale of the University of Sydney, Prof. Anthony Davis and Prof. David Sheppard of the University of Bristol, the biological activity of a series of ortho-phenylene bis-urea (OPBU) anionophores was explored using a biological anion transport assay employing Fischer rat thyroid cells. This family of anionophores is readily prepared from commercially available starting materials using simple chemistry which allows for facile structural variation and the study of structure-activity relationships.

It was shown that activity was dependent on both the electronic nature and lipophilicity of the bis-urea anionophore. Interestingly, while lipophilicity was shown to promote intrinsic activity it also had a contrary effect on deliverability which hampered the anionophore’s effectiveness in living cells. Bis-urea 4a (Figure) was shown to be the most effective in all assays and is based on a difluorinated central scaffold.

This study provides interesting insight into the biological activity of this class of anionophores and is a promising first step toward their potential application in medicine.

To find out more see:

Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes
Christopher M. Dias, Hongyu Li, Hennie Valkenier, Louise E. Karagiannidis,  
DOI:
10.1039/C7OB02787G


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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New rigid spin-labels for enhanced EPR studies of RNA

Electron paramagnetic resonance (EPR) is powerful technique for studying chemical species containing unpaired electrons. It has far reaching applications in a number of fields as it can be used to elucidate structural, electronic and conformational dynamic features in a given system. 

In biological settings, paramagnetic probes have been developed to ‘spin-label’ desired biomolecules using a technique called site-directed spin labelling (SDSL). In combination with other methods, EPR has emerged as an efficient means of studying proteins close to their native physiological states and can be used to glean information regarding the immediate environment of the spin-labeled side-chain as well as measure intra- and intermolecular distances within the protein. A challenge has been in developing rigid spin-labels to improve the accuracy of distance measurements as the most reliable information is attained if the distance between spin-labels is unchanged by conformational flexibility.

In their most recent OBC publication, Prof. Snorri Sigurdsson of the University of Iceland and Prof. Thomas Prisner of Goethe University describe the development of an enhanced isoindoline-nitroxide derivative of uridine (ImUm), the first example of a conformationally constrained spin label for RNA.

Limited mobility of ImUM is a result of the nitroxide N-O bond lying in the same axis as the bond used to link it to the uridine base. As a result, bond rotation does not drastically alter the position of the nitroxide. Additionally, ImUm was shown to bind specifically and with high affinity to abasic sites in duplex RNAs. Here, rigidity is further enhanced through intramolecular hydrogen bonding between the nitroxide probe and the orphaned uracil base. ImUm is a promising label for EPR studies of RNA, providing highly useful and dynamic structural information unbiased by conformational flexibility.

To find out more see:

A semi-rigid isoindoline-derived nitroxide spin label for RNA
Dnyaneshwar B. Gophane,  
DOI: 10.1039/C7OB02870A


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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In silico screening as an effective tool in drug discovery

According to statistics published by the World Health Organization (WHO), tuberculosis (TB) is globally one of the leading causes of death from a curable infectious disease. While antibiotics represent a major breakthrough for modern medicine, the spread of multi-drug resistant (MDR) bacterial strains, such as Mycobacterium tuberculosis, have become a major threat to healthcare.

Encouragingly, renewed efforts in antibiotic research have resulted in the identification of new leads, some of which are currently in clinical trials. Even in light of these promising efforts, Dr. Ehmke Pohl of Durham University and collaborators from the Cambridge Crystallographic Data Centre and Institut Pasteur de Lille are emphasizing the need to optimize existing TB treatments as well as develop an efficient means of identifying novel therapeutics.

Structure-based drug discovery is an integral part of most industrial drug discovery programs and as a result, there is an ever-growing number of protein X-ray crystal structures available in databases such as the Protein Data Bank (PDB). Pohl and collaborators outline a robust and versatile strategy for an in silico screening protocol based on compounds in the ZINC database (a free resource of commercially available chemical compounds) and crystal structures in the PDB.

Their current OBC study focuses on the transcriptional regulator EthR which is involved in M. tuberculosis resistance. EthR has been shown to limit the efficacy of ethionamide-based drugs by downregulating the EthA enzyme involved in activation of ethionamide prodrugs. EthR has therefore been validated as a suitable target as its inhibition boosts ethionamide action.

Using tailored chemical and physicochemical descriptors (for example: compound volume) and a detailed knowledge of the EthR binding pocket, approximately 6 million compounds were evaluated for compatibility using KNIME pipeline software. 409 201 diverse compounds were identified for docking studies and surprisingly, only 6 compounds failed to produce feasible binding interactions. After a careful post-docking filter, 284 chemically diverse compounds were obtained and a visual analysis of all binding poses and ligand geometries in combination with computational analysis narrowed the screen down to 85 substrates. These in silico hits were then evaluated for their capability to bind to EthR using thermal protein stability studies which resulted in 20 new potential candidates for lead optimization with reasonable EC50 values.

Given the ever-growing number of high resolution crystal structures in the PDB, in silico screening approaches can be tailored to any well-characterized protein structure and utilized as an efficient tool for identifying new active molecules.

To find out more see:

New active leads for tuberculosis booster drugs by structure-based drug discovery
Natalie J. Tatum, 
DOI:10.1039/C7OB00910K


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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An unusual hydride source for reductive aminations

The reductive amination reaction between amines and carbonyls is a highly useful and versatile means of forming C-N bonds. Given the accessibility of starting materials and its modular nature, reductive aminations have found extensive application not only in organic synthesis but medicinal chemistry and the production of agro- and industrial chemicals.

Developing efficient and economical processes to access valuable materials is a priority in industry. One of the most fundamental ways of doing this is to adhere to the principle of atom economy which moves to minimize waste generated by a chemical reaction at the molecular level. While traditionally, chemists have focused on improving yield or minimizing the number of steps in a reaction sequence, atom economy aims to design reactions in which all atoms involved in a chemical process are present in the desired products.

An international team of researchers have recently published a novel iridium-catalyzed reductive amination using carbon monoxide (CO) as an alternative reductant. This process does not require an external hydrogen source as the hydride is abstracted by the catalyst/carbon monoxide complex from the hemiaminal intermediate, forming an iridium-hydride species. Essentially, the hydride is derived internally (from the amine) as a result of the deoxygenative potential of carbon monoxide. The reaction is also tolerant to a number of functional groups that are incompatible with other commonly employed reducing reagents.

This is a very interesting twist on the reductive amination reaction for which external sources of hydrogen are often required. While it could be called atomic economic from this standpoint, the fact that carbon dioxide is a major by product of the reaction detracts from this claim and could be problematic on an industrial level. Regardless, this work is a significant first step and demonstrates the importance of optimizing the efficiency of well-established protocols in organic synthesis for large scale purposes.

To find out more see:

Reductive amination catalyzed by iridium complexes using carbon monoxide as a reducing agent

DOI:10.1039/C7OB01005B


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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The effect of polymer architecture on the self-assembly and stability of complex coacervation

Complex coacervation refers to a liquid-liquid phase separation that arises from the association of oppositely charged polyelectrolytes in water. It is a widely used laboratory technique and coacervate-based materials have extensive application in the food and cosmetic industries as well as drug delivery and the development of biomedical adhesives.

Under favourable conditions, the coalescence of coacervate droplets leads to a separation of a system into two liquid layers: a polymer-rich coacervate phase in equilibrium with a polymer poor supernatant. Coacervation is entropically driven and occurs through an initial electrostatic attraction between oppositely charged molecules followed by the release of counterions and rearrangement of water molecules. However, our understanding of factors that control self-assembly and stability at the molecular level remains limited.

In the past, many studies have focused on how the chemical nature of a polymer affects coacervation without considering the effect of polymer architecture. In a collaborative study recently published in OBC, Prof. Sarah Perry and Prof. Todd Emerick et al., of the University of Massachusetts Amherst investigate the effect of branching in polypeptide-based comb polymers on the self-assembly and stability of complex coacervates.

In comparison to branched copolymers, the interaction of oppositely charged linear copolymers to form charge-neutral coacervate complexes is understandably straightforward. However, the extent to which a mismatched polymer architecture would alter coalescence is relatively unclear and a question that Perry and Emerick sought to answer.

The self-assembly and stability of complex coacervates resulting from oppositely charged linear polymers, linear and comb polymer and two comb polymers (see Figure) were determined/compared through turbidity measurements, optical microscopy and Monte Carlo simulations. Ultimately, it was observed that the comb structure did not form coacervates as the branched structure prevents cooperative interactions between oppositely charged polymer pairs and releases fewer counterions, leading to a weaker driving force for coacervation.

This study provides insight to the role that polymer architecture plays on complex coacervation and highlights the need to develop a detailed and predictable understanding of molecular level effects of polymer chemistry and architecture in coacervate formation.

To find out more see:

The effect of comb architecture on complex coacervation
Brandon M. Johnston,  10.1039/C7OB01314K


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Unexpected divergent reactivity in Pt-catalyzed cyclizations of 1,5-bisallenes

As a result of their unique physical and chemical properties, allenes have become key building blocks in modern organic synthesis. The discovery and development of their varied reactivity have been extensively reported on in recent years, however, application to more challenging bisallene systems has been comparatively limited.

In her group’s recent OBC publication, Prof. María Paz Muñoz of the University of East Anglia sought to fill this gap in the bisallene literature. The study discusses the development of an unprecedented Pt-catalyzed cyclization of 1,5-bisallenes in the presence of oxygen nucleophiles to selectively access 6- and 7-membered rings.

After initial screening, it was observed that selectivity was highly sensitive to the reaction conditions and could, therefore, be tuned to yield the desired molecular scaffold. Interestingly, in the presence of nucleophilic alcohols, vinyltetrahydropyridines are formed preferentially while the formation of di- and tetrahydroazepines are favoured when water is used.

Exhaustive mechanistic studies provided insight into this divergent reactivity. It was determined that different mechanisms operate depending on the nucleophile and electronic nature of the bisallene (as a result of its nitrogen tether). It is proposed that, in the presence of nucleophilic alcohols, 6-membered vinyltetrahydropyridines are preferentially formed as a result of a platinum hydride active catalyst—which are known to form from platinum complexes and alcohols. Tetrahydroazepines, on the other hand, are favoured when water is used as the nucleophile, proceeding first through a nucleophilic attack followed by carbocylization to form the 7-membered ring.

Understanding this complex mechanistic behaviour provides important insight into bisallene reactivity and will no doubt enhance the scope of this work’s application in organic and medicinal chemistry.

This communication is part of the OBC themed collection, Mechanistic Aspects of Organic Synthesis. You can read the rest of the collection here.

 

To find out more see:

Nucleophile dependent formation of 6- and 7-membered N-heterocycles by platinum-catalysed cyclisation of 1,5-bisallenes
María Teresa Quirós,César Hurtado-Rodrigo and María Paz Muñoz
DOI:10.1039/C7OB01469D


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Inspired by nature: dynamic stimuli responsive catalysis based on molecular motors

Catalysis is a fundamental concept in chemistry, allowing chemists to effectively carry out difficult transformations to access valuable materials with precision and control. For the most part, research has focused on the development of new catalysts for optimized performance to achieve high conversion and selectivity. However, special attention is now being paid to engineering catalysts whose activity can be tuned through external stimuli. This concept is ubiquitous in nature and its implementation into artificial systems offers unique opportunities and promising future applications.

A recent OBC publication by Prof. Ben Feringa of the University of Groningen Nijenborgh discusses his group’s success in developing two novel bisthiourea catalysts which display dynamic control over activity and stereoselectivity in the Henry reaction using light and heat as external stimuli.

This catalyst design is based on a molecular motor previously reported by Feringa and inspired by nature where control over function, activity and selectivity can be attained through conformational changes within the catalyst’s active site induced by external stimuli.

In the current publication, upon irradiation of the catalyst in its stable trans state, (R,R)-(P,P)-trans (see Scheme), an unstable cis state is obtained, (R,R)-(M,M)-cis, in which the catalytic groups A and B are brought into proximity to carry out the desired enantioselective transformation. The catalyst can then be converted through heating to a stable cis state, the (R,R)-(M,M)-cis isomer, via a thermal helix inversion. In this conformation, the two active groups A and B remain within reaction proximity, however, as the helicity of the motor core is inverted, a pseudoenantiomeric catalytic environment is produced which results in the formation of the opposite enantiomer.

This is the first example of a tunable bisthiourea catalyst and represents an important advancement in the field of dynamic stimuli responsive catalysis. This new area of research offers great potential for advanced materials and solving long-standing challenges that have thus far been impossible to overcome using conventional methodologies.

To find out more see:
Dynamic control over catalytic function using responsive bisthiourea catalysts
M. Vlatković,  
DOI:10.1039/C7OB01851G


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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