Organic & Biomolecular Chemistry Blog

Amino acids form the fundamental building blocks of proteins and peptides and largely control the biochemical and biophysical properties of a living organism. Incorporation of fluorine in amino acids has been an area of wide interest, because replacement of a hydrogen atom with a fluorine atom leads to a significant change in the electronic properties of a substrate and could potentially lead to a wide variation in its biological activity. The most common functional group introduced in this regard is the trifluoromethyl (-CF₃) group, which provides an alternative to the -CH₃ group in terms of its electronic properties. One very commonly available source of the -CF₃ group is ethyl 3,3,3-trifluoromethyl pyruvate, which was utilized very elegantly by Professor Mario Waser and his group in their recent report published from the Johannes Kepler University, Linz to form α-trifluoromethylated proline derivatives, which are potentially very interesting surrogates for naturally occurring proline.

Scheme 1: Diastereoselective formal (3+2) cyclization to form α-CF₃ proline derivatives

Benzyl imine derived from ethyl 3,3,3-trifluoromethyl pyruvate was treated with benzylidene indanedione (1) in the presence of LiOH to form the spirocyclic α-trifluoromethyl proline derivative 3 as the sole diastereomer (Scheme 1). It was observed that simple ammonium salts used as phase transfer catalysts could improve the conversion drastically and benzyl triethylammonium bromide (TEBAB) was found to be the best reagent for the same. This transformation exhibits a wide substrate scope with different acceptors and donors alike, while maintaining very good diastereoselectivities.

Mechanistically, the transformation is driven by the formation of the stable 2-azaallyl carbanions (4 and 4’), which by virtue of its two resonating forms could form the two different spirocyclic regioisomers 3 and 5 (Scheme 2). It was observed that the α-nucleophilic attack on the Michael acceptor 1 proceeded exclusively and there was no trace of the γ-adduct for any of the substrates. The remarkable levels of diastereoselectivity of the α-adducts adds to the ingenuity of the method.

Scheme 2: Formal (3+2) cyclization modes leading to α-CF₃ proline derivatives

This is indeed a very useful and efficient method for the construction of an unprecedented class of α-trifluoromethylated proline derivatives which can easily be incorporated in peptide chains for biological studies. There is however, room for improvement in this methodology, as the efforts towards enantioselective formation of the trifluoromethylated proline derivatives were unfortunately met with failures. The authors used cinchona alkaloid derived chiral phase transfer catalysts, which resulted in unsatisfactory enantioselectivities. A successful enantioselective protocol towards the formation of fluorinated amino acids would drive this field of research even further in future.

About the blog writer: Satrajit Indu is a recent PhD graduate from Indian Institute of Technology Bombay. His doctoral work in the group of Prof. Krishna P. Kaliappan was mainly focused on the total synthesis of complex natural products and development of new catalytic methods aimed for achieving interesting chemical transformations. A keen interest in organic chemistry coupled with an urge to communicate with the scientific community has driven him to take up blog writing.

Polycyclic aromatic hydrocarbons (PAHs) containing heteroatoms have recently been grabbing the attention of scientists as they exhibit intriguing photophysical properties and can be widely used as building blocks for π-conjugated materials due to the effect of heteroatoms on the electronic properties of the system.

PAHs are often employed in OLEDs. Over the last few years, these PAHs have been synthesized in several different ways. Kawashima et.al synthesized different acene-like π-extended dibenzoborines such as compound B which show fascinating photophysical properties. More recently, Hatakeyama et.al have reported the synthesis of various PAHs that contain multiple 1,4-azaborine rings, such as compound C, which show excellent thermally activated delayed fluorescence. By investigating these types of molecules in more detail, their electronic properties can be improved to make better OLEDs.

a) Representative examples of previously reported dibenzoazaborine-based pi-conjugated compounds and b) planarized B,N-phenylated dibenzoazaborine 1 together with reference compounds 2-4

a) UV-vis absorption and b) fluorescence spectra of 1 (red), 2 (blue), 3 (green) and 4 (orange) in THF.

In their recent OBC publication, Professor Shigehiro Yamaguchi of the Institute of Transformative Bio- Molecules, Nagoya University et al. explored in detail the relation between the structure of materials and their electronic structures. They mainly focused on the correlation between the ring-fusion mode, where two cyclic rings fused in a planar manner, and the degree of structural constraint within the dibenzoazaborine skeleton. As constraining molecules into a planar fashion can extend π-conjugation and increase chemical stability, Shigehiro planarized the B-, N- phenyl groups in dibenzoazaborine to synthesize a new family of planarized triarylboranes with a carbazole substructure, confirming this structure by single-crystal X-ray diffraction analysis. They studied the photophysical properties of 1 and compared it with compunds 2-4. Compound 1 showed an intense absorption band at λ_abs= 402 nm unlike compounds 2-4 which showed λ_abs at 389 and 371, 400, 404 and 387 nm respectively. The fluorescence spectra of compound 1 showed an intense deep blue emission with a full width at half maximum (FWHM) of 27 nm which is due to its rigid structure. The optimized structure of 1 with respect to DFT calculations matched with the experimentally determined crystal structure. They report the time dependent DFT calculations which prove compound 1 to have the highest oscillator strength (f) amongst compounds 1-4, resulting in the largest molar absorption coefficient (ε). This clearly represents that it absorbs light strongly at the given wavelength. They also studied the electrochemical properties of 1-4 using cyclic voltammetry which resulted in one reversible reduction wave irrespective of the structural constraint showing that there are no electronic effects imposed on the structural constraint.

In conclusion, Shigehiro et al. succeeded in synthesizing structurally constrained, planarized dibenzoazaborines and investigating their photophysical and electronic effects.

Read their full article at https://rsc.li/2Xw8uoA.

Blog writer description: I am A. Vamshi Krishna, pursuing a PhD in organic chemistry with Prof. D. B. Ramachary at the University of Hyderabad. My research mainly focuses on asymmetric supramolecular-organocatalysis where we synthesise highly functionalized biologically active novel scaffolds with excellent selectivity and yields. I am passionate about scientific writing.

Developing efficient crop fertilisation has become an ever-growing concern given the increasing demand for global food production. Slow-release fertilisers have been developed as a strategy to increase the efficiency of crop production while minimizing nutrient waste, reducing negative environmental impacts and enhancing crop yield. Mechanisms for controlled nutrient diffusion include semi-soluble or complex forms of the nutrient, slow hydrolysis of water-soluble compounds, and encapsulation of the nutrient within semipermeable or permeable coatings for controlled solubility/release (among many others). While slow-release strategies are promising, technical limitations such as the brittle nature of inorganic coatings and composites or the imperishable nature of synthetic polymer coatings hinder their industrial utility.

In a collaborative study published by Professor Justin Chalker of Flinders University, the group sought to develop an efficient and durable slow-release fertiliser derived from canola oil and elemental sulfur. Sulfur is highly appealing given its low cost, abundance, and that it is a secondary plant nutrient and fungicide. Numerous studies and years of research, however, have demonstrated that a persistent limitation of sulfur-coated fertilizers is their brittle nature. The present study, therefore, focused on converting sulfur to a more durable polymer form to be used as a composite with or encapsulate NPK (nitrogen, phosphorous, and potassium) nutrients.

Inverse vulcanisation was used to prepare the sulfur polymer. In this process, elemental sulfur is heated to promote the production of thiyl radicals which can react with an unsaturated small-molecule cross-linker. In this case, canola oil was used as the cross-linker to form a polysulfide polymer capable of encapsulating NPK nutrients.

Elution studies in which fertiliser is placed in a soil column and conductivity of the outflow is measured demonstrated the superior capabilities of the sulfur-encapsulated NPK fertiliser in controlling NPK nutrient release relative to free NPK. A small-scale plant growth study also found that plants treated with the composites were significantly healthier and produced more fruit relative to other groups. What’s even more exciting is the fact that the canola oil polysulfide can be made from recycled cooking oil, converting food waste into valuable fertilisers.

With the rising challenge of feeding a rapidly growing population while also mitigating damaging environmental impacts, studies such as this that make significant strides toward efficient and sustainable agricultural practices are more important than ever.

To find out more see:

Sulfur polymer composites as controlled-release fertilisers 
Maximilian Mann, Jessica E. Kruger, Firas Andari, Joshua McErlean, Jason R. Gascooke, Jessica A. Smith, Max J. H. Worthington, Cheylan C. C. McKinley, Jonathan A. Campbell, David A. Lewis, Tom Hasell, Michael V. Perkins and Justin M. Chalker
DOI:10.1039/C8OB02130A

Victoria Corless has recently completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centered 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. She is passionate about communicating new discoveries to enhance science literacy.

The risks associated with excessive exposure to ultraviolet (UV) radiation are well studied and many national healthcare initiatives have been pushing for large-scale sun protection programs. Despite this drive for a broader public awareness, recent studies have disclosed that skin cancers, such as melanoma, basal cell carcinoma, and squamous cell carcinoma, have become the most common form of cancer worldwide, with more new cases of skin cancer diagnosed in the U.S. than breast, prostate, lung and colon cancer combined.

In a recent OBC study by Professor Ronald Raines of MIT, the researchers identify that although the risk of skin cancer and visible signs of aging can be minimized by using sunscreen, there is still a need to develop more durable, non-greasy sunscreens that are not readily washed away with water or sweat.

Sunscreens typically form a protective barrier on the skin and protect against various types of UV radiation by either absorbing or reflecting UV light before it can reach DNA. Typical absorbing filters are small aromatic compounds, such as salicylates, cinnamates, benzophenones, or derivatives of p-aminobenzoic acid.

Previous studies have been carried out wherein small molecule UV filters have been attached to lipophilic moieties to minimize the amount of sunscreen washed away during physical activity. However, such compounds have not been shown to effectively withstand ‘washing’ and are often undesirably greasy, which according to the authors diminishes public compliance to use them.

Raines and coworkers propose that collagen mimic peptides (CMPs) could be used to effectively anchor pendent UV-filters to the skin. Natural collagen contains loops and interruptions in its overall 3D structure which provide numerous binding sites for CMPs (as demonstrated in the Raines group’s previous work). Since collagen is the primary component of skin, this would provide a means for efficiently tethering UV filters to the skin in order to create an effective, water-resistant sunscreen. Raines and coworkers showed the successful anchoring of a salicylic acid bound CMP and its retention on collagen-containing skin surrogates after repeated water washes. This strategy is highly modular and provides an excellent proof-of-concept for the development of more effective and durable sunscreens to address a worldwide concern.

To find out more see:

A pendant peptide endows a sunscreen with water-resistance
Aubrey J. Ellison and  Ronald T. Raines
DOI:10.1039/C8OB01773E

Victoria Corless has recently completed her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centered 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. She is passionate about communicating new discoveries to enhance science literacy.

The cyclobutane ring is a unique structural element found in a wide variety of biologically active natural products and synthetic molecules. Although cyclobutanes have been known for centuries, as a result of inherent ring strain, their application in synthesis has only become more popular in the last 40-50 years.

The photochemical [2+2] cycloaddition of alkenes represents a powerful strategy for the synthesis of cyclobutane rings. However, direct irradiation of cycloalkenes with UV light often leads to unwanted and difficult to control rearrangement pathways.

Professor Jimmie Weaver of Oklahoma State University proposes an alternative to direct irradiation of cycloalkenes by instead capturing energy in the form of ring strain. The Weaver group has applied their mild and efficient methodology toward the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework.

It is well known that thermal [2+2] cycloadditions are ‘forbidden’ processes due to unfavourable orbital overlap of the reaction partners during the transition state. However, a common exception to this is the [_π2_s+_π2_a] addition of alkenes and ketenes. The Weaver group proposes that a thermal [_π2_s+_π2_a] cycloaddition could take place for ground state alkenes by generating a high energy intermediate, which would result in a decreased relative energy barrier for the thermal cycloaddition.

This method uses an iridium-based photocatalyst to generate the highly strained trans-cycloheptene intermediate—which possesses 27-36 kcal/mol of ring strain—in order to drive the thermal [2+2] cycloaddition of cycloheptenes and various cycloalkene substrates. Interestingly, the reaction results in four new stereocenters which are generated with excellent stereoselectivity and regioselectivity. An added advantage of using light within the visible spectrum to activate the photocatalyst minimizes competitive photochemical [2+2] addition pathways.

This study is an excellent example of the application of basic principles to drive previously inaccessible mechanistic pathways. The authors hope that their study will encourage other applications of visible light energy to drive unfavourable endergonic reactions.

To find out more see:

An elusive thermal [2+2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings
Kamaljeet Singh,  Winston Trinh  and  Jimmie D. Weaver, III
DOI:10.1039/C8OB01273C 

Victoria Corless has recently completed 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. She is passionate about communicating new discoveries to enhance science literacy.

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.

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 K_D’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,  Mohammed Hezwani,  Helmus van de Langemheen and Rob M. J. Liskamp*
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.

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, Ting Jiang, Sining Li, Omar Zainul, and Scott T. Laughlin
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.

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,  Philip A. Gale, David N. Sheppard and Anthony P. Davis 
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.