Organic Chemistry Frontiers Blog

Recent advances in chemistry, synthetic biology, and material science have enabled the development of cell membrane-based drug delivery systems (DDSs), often referred to as “artificial cells” or protocells. In particular, the use of these cellular mimics for directed delivery and controlled release of therapies has burgeoned with advances in molecular biology, proteomics, nanotechnology, biotechnology, and polymer chemistry. Our paper focuses on a discussion on the concept of building simple functional units that recapitulate living cells, protocells, that can respond to and deliver targeted therapies. Artificial cells can be made by removing functions from natural systems in a top-down manner, or assembly from synthetic, organic, or inorganic materials, through a bottom-up approach where simple units are integrated to form more complex structures.

Fig. 1 Schematic illustration representing a human-made artificial cell comprising of nucleic acids, cytoskeleton, small biomolecules, and cytoplasmic organelles in a giant unilamellar vesicle.

Artificial cells that use liposomes, polymersomes, or dendrimersomes to create a membrane component have been developed as advanced DDSs for cancer treatments, gene therapies, and vaccines. Surface modification of these carriers can improve payload delivery, through increasing circulation times and preventing degradation, and enable systems with active-targeting and stimulus-responsive capabilities. Overall, artificial cells can be fabricated with various sizes, deformability, sustained/controlled payload release profiles, and versatile targeting functions. There are still remarkable differences between the living cellular membranes and their artificial compartments, and studies to develop new materials as well as basic experiments to better understand how a membrane’s composition contributes to its physical properties and biological functions are important to bridge this gap. Therefore, the development of alternative and new smart and improved properties such as nanoscale efficiency, self-organization, and adaptability for therapeutic and diagnostic applications is needed. Ultimately, creating artificial cells with properties and functions of living cells and have broad clinical utility will require extensive cross-disciplinary cooperation among the fields of biophysics, biochemistry, medicine, biomedical engineering, materials science, and molecular/cellular biology.

Corresponding author: Nureddin Ashammakhi

Nureddin Ashammakhi is focusing on translational tissue regenerative therapy. Currently, he is working on 3D bioprinting and organ-on-a-chip models for regenerative and personalized medicine. He is an expert in bioabsorbable, nanofibrous, and drug release implants. He was previously a professor of biomaterials technology in the Tampere University of Technology, Finland, Chair of regenerative medicine, Keele University, UK, and Adjunct Professor in Oulu University, Finland before he joined UCLA as a visiting professor, then as Associate Director of the Center for Minimally Invasive Therapeutics and Adjunct Professor after which he joined Michigan State University.

Contact information:

Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, Engineering V, Los Angeles CA 90095, USA, Email: n.ashammakhi@ucla.edu, n.ashammakhi@gmail.com

Helical structures are ubiquitous in nature. DNA or right-handed α-helix of proteins exemplify the sophistication of natural, helical structures whose chirality stems from an efficient transfer of asymmetry from the constitutive L-amino acids or D-carbohydrates. Inspired by these functional, helical structures, a plethora of examples of man-made helical architectures by using macromolecules or small molecules have been reported in literature. The helical structures constituted by small molecules are especially interesting since the generation of such helices involves an organized arrangement of assembled or self-assembled monomeric units that, very often, possess inherent elements of asymmetry. On the other hand, supramolecular polymers, macromolecular species constituted by the non-covalent interaction of monomeric units, have emerged as very useful benchmark to construct and investigate helical structures. The decoration of these monomeric units with elements of asymmetry usually provokes the efficient transfer of asymmetry from the molecular to the supramolecular level, thus, generating helical supramolecular polymers.  

However, to the best of our knowledge, there are no studies on the optimal distance for point chirality to afford an efficient transfer of asymmetry that results in the formation of helical supramolecular polymers. Recently, the group of Prof. Luis Sánchez, at the Department of Organic Chemistry (Universidad Complutense de Madrid, Spain) has reported on the synthesis of a series of self-assembling N-annulated perylenes 1-4 (Figure 1a) endowed with chiral, peripheral side chains located at increasing distance from the aromatic moiety. The p-surface of the N-annulated perylene and the presence of the amide functional groups favour the self-assembly of 1-4 by π -stacking of the aromatic units and the formation of an array of H-bonding interactions, respectively. The presence of the trialkoxybenzamide moiety bridged to the N-annulated perylene unit by a linear spacer of variable number of methylene units allows the formation of an intramolecularly H-bonded pseudocycle (Figure 1b) that, in the case of compounds 1-3, retards their cooperative supramolecular polymerization. This is not the case of compound 4 in which the separation between these two structural units makes difficult the efficient formation of the 10-membered H-bonded pseudocycle.  

Figure 1. Chemical structure of the N-annulated perylenetetracarboxamides 1–4 showing the open arms (a) and the metastable 7–10-membered pseudocycles (b); (c) Schematic representation of the cooperative supramolecular polymerization of 1-4 that yields M-type helical aggregates for 1-3 but achiral aggregates for 4.

The increasing separation between the peripheral side chains in compounds 1-4 provokes a clear depletion of the dichroic response that indicates the reduction on the ability for transferring asymmetry from compound 1 to compound 4, in which no dichroic response is registered (Figure 2a and 2b). However, the strong trend of compound 4 to bundle results in a clear anisotropic organization of the supramolecular fibers formed upon its self-assembly that affords a strong linear dichroism effect (Figure 2c) 

Figure 2. a) CD spectra of compounds 2-4 in MCH at 25 ºC; CD (b) and LD (c) spectra of 4 in MCH at different concentrations.

The results presented herein contribute to establish a structure-function relationship in the generation of helical supramolecular structures and to shed light on the intricated process of the origin of natural homochirality. 

Org. Chem. Front., 2021, Advance Article 
https://doi.org/10.1039/D1QO00837D 

Luis Sánchez
Universidad Complutense de Madrid

Luis Sánchez Martín (ORCID: 0000-0001-7867-8522) is Full Professor in the Department of Organic Chemistry at the Universidad Complutense de Madrid (Spain). He received his PhD in Chemistry at the Faculty of Chemical Sciences in 1997. From 1999 to 2000 he did a postdoctoral stay at Rijksuniversiteit Groningen (The Netherlands). The research interest of Prof. Luis Sánchez is the investigation of the supramolecular polymerization of electroactive monomeric units and the studies of transfer and amplification of asymmetry from the molecular to the supramolecular level to yield helical structures. He is coauthor of more than 135 articles indexed by SCI, cited more than 10000 times and with an index h = 48.

https://www.ucm.es/supramolecular

Mechanically interlocked molecules (MIMs) have received an increasing attention from the scientific community during the last decades. Among their potential applications in numerous fields, the design of molecular machinery based on MIM is one of the most prominent. The presence of at least two mechanically bonded components in the MIM´s backbone allows these systems to undergo a variety of large-amplitude internal dynamics, making them ideal candidates to be included in artificial machines.  

Lately, mechanized systems, mainly [2]rotaxanes, have been found as interesting molecules to be used as ligands in metal-mediated transformations or as organocatalysts, both in achiral and chiral processes. Due to the internal translational motions, remarkable examples of switchable catalysts have been described. The catalytically active site present on the thread can be exposed or concealed by the bulky macrocycle by action of an external stimulus, altering the catalytic activity of the systems (Catalysis ON or OFF, Figure 1). Moreover, the orthogonal disposition of the two components, creating dynamic enzyme-like 3D cavities, can be advantageous for the control of the reaction outcomes, highly important in asymmetric processes. Consequently, catalytically active threads are generally more reactive (and less selective) than their corresponding rotaxanes, in which the active site is hindered by the ring.  

Figure 1. Schematic representation of a switchable interlocked catalyst.

Recently, the researchers Alberto Martinez-Cuezva, Jose Berna and members of the Synthetic Organic Chemistry Lab of the University of Murcia and the group of Marcos A. P. Martins(NUQUIMHE) from the Universidade Federal de Santa María (Brazil) have found that interlocked organocatalysts can be more active than their corresponding threads (Figure 2a). The authors synthesized a series of one- and two binding-site threads 1 and their corresponding hydrogen-bonded rotaxanes 2 by following a clipping methodology. These systems have succinamides as binding sites and a secondary amine as the active site, able to catalyze iminium-type transformations. All the systems were evaluated as catalysts in the Michael addition of acetylacetone to crotonaldehyde, following the conversion over time towards the formation of the Michael adduct (Figure 2b). Remarkably, the two binding-site systems were more active to the one binding-site analogs, and more importantly, the interlocked catalysts were more efficient than the corresponding free threads. The presence of the bulky polyamide macrocycle is able to activate the electrophile (aldehyde) towards a nucleophilic attack of the amine. Moreover, the iminium intermediate is stabilized by the polyamide ring.   

Figure 2. a) Organocatalysts evaluated in this study; b) Conversion of the Michael addition of acetylacetone to crotonaldehyde over time catalyzed by the threads and their corresponding [2]rotaxanes.

Symbiotic Actinomycetes are known to produce a plethora of natural products of pharmacological importance and global genome sequencing efforts unraveled their unique and still mostly untapped biosynthetic potential. To activate natural product biosynthesis in Actinobacteria and to harvest the wealth of natural products, cultivation conditions mimicking the natural environment turned out to be amongst the most promising approach next to molecular biotechnological tools. We have recently applied ecology-driven interaction studies between bacterial symbionts of fungus-farming termites and their natural antagonists to activate the biosynthetic repertoire of actinomycetous symbionts. In light of these studies, we revisited the bacterial symbiont Streptomyces sp. M56 (from now on named M56), which showed very strong antagonistic effect against parasitic co-isolated fungi and was found to produce, not only the ansamycin-derived natural products natalamycin and geldanamycin, but also elaiophylins and the structurally related efomycins.  

Our group thoroughly investigated culture extracts obtained from strain M56 by liquid chromatography/high resolution tandem mass spectrometry (LC-HRMS²) and Global Natural Product Social Molecular Networking (GNPS) analysis. Indeed, dereplication of the acquired MS² data based on available databases resulted in the detection of several polyhydroxylated macrolides identified as the antifungal azalomycins (Figure 1). Although the planar structures of azalomycins were reported as early as 1959 and the first skeletal structure assigned already in 1982, reports on their absolute structures remained inconclusive with varying structural assignments across the literature (Figure 2). 

Figure. 1. A) HRMS²-based GNPS analysis depicting molecular ion cluster putatively assigned as an azalomycin cluster with putative structural features assigned to m/z 1096.69, 1082.67 and 1068.66 (diol moiety C-18 and C-19); m/z 1080.69 and 1066.68 (C-19 alcohol); m/z 1062.68 and 1048.67 (enoyl derivatives); m/z 1078.68 (C-19/C-18 epoxy). Data obtained from HRMS² measurements of EtOAc extract (7 d, ISP2 liquid broth) in positive mode ESI-HRMS. B) Stereochemical assignment of isolated azalomycins (1–4) from Streptomyces sp. M56.

Figure 2. A) Structure of azalomycin (1) with key COSY (bold) and HMBC (pink arrow) and NOE (blue double-headed arrow) correlations and coupling constant analysis. B) Stereochemical assignment of azalomycins substructures isolated from different producer strains based on a) NMR analysis and b) in silico PKS domain predictions. C) Chemical structures of azalomycins reported from Streptomyces sp. 211726,^22,29 and Streptomyces malaysiensis DSM 4137²³ and Streptomyces hygroscopicus. Stereocenters that differ from herein proposed structure or have been newly assigned based on analytical experiments are colour-coded in red.

Due to their strong antimicrobial activity, but inconclusive structural assignments, we re-evaluated the analytical and bioactivity data of azalomycins. Here, we provide a conclusive analysis of their stereochemical assignment based on comparative NMR and gene clusters studies and propose to partially revise the absolute structures and names of azalomycins from previous reports (Figure 3).

Figure 3. A) Graphical comparison of azalomycins biosynthesis gene cluster (azu) from Streptomyces sp. M56 and azalomycin F_3a biosynthesis gene cluster (azl) from Streptomyces sp. 211726, and niphimycin C biosynthesis gene cluster (npm) from Streptomyces sp. IMB7-145. B) Schematic representation of important biosynthetic transformations yielding the azalomycin core structure. The ER domain of module 1 is assumed to be non-functional; dash-circulated domain represents the missing module required for chain elongation. Ata (blue): malonyl-CoA selective AT domain (acetate unit); ATp (light red): methylmalonyl-CoA selective AT domain (propionate unit); ACP (dark red): acyl carrier protein; DH (light orange): dehydratase; ER (brown-black): enoylreductase; KR: ketoreductase (A1 or B1); TE (purple): thioesterase.

Biography

Ki Hyun Kim is associate professor in the School of Pharmacy at the Sungkyunkwan University (Republic of Korea). He earned his pharmacist’s license in 2005 and he received his PhD in the School of Pharmacy at the Sungkyunkwan University in 2011. From 2011 to 2012 he did postdoctoral studies at the School of Pharmacy at the Sungkyunkwan University, and from 2012 to 2013 at Harvard University and Harvard Medical School. He started his faculty in the School of Pharmacy at the Sungkyunkwan University in 2014. The main research field of Professor Kim is the discovery of the secondary metabolites from diverse natural resources including wild mushrooms, insect-associated bacteria, marine natural sources and medicinal plants and his group has substantial experience and expertise in natural product isolation and structural elucidation using mainly NMR-based analysis as well as biological activity evaluations. He is the author of 7 patents and more than 300 articles indexed by SCIE and cited more than 1500 times with an index H = 20.

π-Conjugated macrocycles are molecules with unique properties that are increasingly exploited for applications. Their study began in the early 1960s and many π-conjugated macrocycles have been synthesized since. However, only recently the field has moved towards making use of the unique properties of these cyclic molecules for applications. π-Conjugated macrocycles are now being investigated in organic solar cells, photodetectors, field-effect transistors, light-emitting diodes, and battery electrodes. They can also be used in bioimaging, as templates for the growth of carbon nanotubes, and as molecular nanoreactors.

Figure 1. (a) Reversible two-electron reduction of a π-conjugated macrocycle for charge storage in organic battery electrodes. (b) Visualization of chemical shielding tensors (VIST) helping to rationalize the optoelectronic properties.

Despite this recent interest in π-conjugated macrocycles, there are only a small number of experimental studies that investigate how the properties of π-conjugated macrocycles evolve with systematic structural changes. Recently, a team around Florian Glöcklhofer has reported such a systematic experimental study and combined it with an in-depth computational analysis. The study reveals the central role of local and global aromaticity for rationalizing the optoelectronic properties of the macrocycles. A recently developed computational method for the visualization of chemical shielding tensors (VIST) was applied to provide unique insight into local and global ring currents occurring in different planes along the macrocycles.

Figure 2. Functional group introduction and aromatic unit variation in a set of π-conjugated macrocycles.

The study makes a significant contribution to the development of structure–property relationships and molecular design guidelines and will help to understand, rationalize, and predict the properties of other π-conjugated macrocycles. Furthermore, it shows that cyclophanetetraenes, the investigated class of macrocycles, provide versatile scaffolds for applications due to their unusual properties along with their high tunability. Their remarkable optoelectronic properties, in particular their large Stokes shifts and the accessibility of a variety of charged states, were traced back to their formal ground state antiaromaticity along with high structural flexibility.

Rimmele, M.;  Nogala, W.;  Seif-Eddine, M.;  Roessler, M. M.;  Heeney, M.;  Plasser, F.; Glöcklhofer, F., Functional group introduction and aromatic unit variation in a set of π-conjugated macrocycles: revealing the central role of local and global aromaticity, Organic Chemistry Frontiers 2021, Advance Article. https://doi.org/10.1039/D1QO00901J

Author’s Biography

Florian Glöcklhofer is an Erwin Schrödinger Fellow in the Department of Chemistry at Imperial College London. He received his PhD in 2017 at TU Wien (Vienna) for developing a reaction for the conversion of quinones into cyanated aromatic compounds. His research in the field of π-conjugated organic compounds focuses on the design and synthesis of π-conjugated macrocycles for battery electrodes and organic electronics and on the development of new synthetic approaches to aromatic organic compounds.

https://www.gloecklhofer-research.com/

Organofluorine compounds play an important role in pharmaceuticals, agrochemicals, and functional materials, due to their special chemical, physical and biological properties, such as increased electronegativity, hydrophobicity, bioavailability and metabolic stability. Therefore, great efforts have recently been devoted to the development of new methods for the synthesis of fluorinated compounds. Conventional strategies mainly focus on the selective introduction of fluorine atom or fluorine-containing moiety into organic molecules. Alternatively, the development of novel synthetic methodologies via the selective activation of C-F bond is of vital importance, which could allow for the synthesis of partially fluorinated synthetic intermediates from readily available polyfluorinated starting materials. The research of C-F bond activation is the most challenging task in organic synthesis, which has recently drawn increasing attention from chemists. In this review, we mainly focus on the C-F bond activation of CF₃ groups for the synthesis of fluorinated compounds as well as discussion of their mechanisms(Scheme 1).

Scheme 1 The C-F bond functionalization of trifluoromethyl-containing compounds.

Due to the electron-deficient property, α-trifluoromethylstyrenes exhibit unique reactivities in their C-F bonds activation, mainly including three kinds of reactions (S_N2′-type, S_NV and ipso-substitution reactions, Scheme 2).

Scheme 2 Allylic and vinylic C-F bond activation in SN2’-type, SNV and ipso-sunstitution reactions

The cleavage of C-F bond in trifluoromethylated aromatic (Scheme 3) and alkyl compounds (Scheme 4) could be achieved through using transition metal complexes, main-group Lewis acids and base-conditions. An alternative strategy mainly relied on the single-electron transfer (SET) via Low-valent metals, irradiation with visible light.

Scheme 3 Photoredox-catalyzed defluoroalkylation of ArCF3 with unactivated alkenes.

Scheme 4 Pd-catalyzed defluorination/arylation reaction of α-trifluoromethyl ketones with aryl boronic acids.

Trifluoromethyl ketones (Scheme 5) and their corresponding diazo compounds (Scheme 6) , N‑tosylhydrazones (Scheme 7) have been utilized as the coupling partners in modern synthetic organic chemistry. Recently, the C-F bond cleavage of these compounds has also been reported through transition-metal catalysts.

Scheme 5 Cu-catalyzed reaction of trifluoromethylketones with aldehydes.

Scheme 6 Cu-catalyzed gem-difluoroolefination of diazo compounds.

Scheme 7 Cu-catalyzed cross-coupling of N-tosylhydrazones with terminal alkynes.

Although great progress has been made in this rapidly developing area, these reactions still suffer from some issues of the limitation of substrates and poor regioselectivity. To overcome these central challenges, it is more important to extend the substrate scope of the existing methodologies, especial trifluoromethylated alkyl compounds. Furthermore, the robust catalytic systems will be developed for the selective activation of a single C-F bond in CF₃ groups.

 Guobing Yan

Zhejiang A&F University

Guobing Yan is a Professor in college of Jiyang at Zhejiang A&F University. He obtained B.Sc. degree from Jinggangshan Normal University, his M.Sc. degree from Suzhou University, and his Ph.D. degree from Tongji University in 2010. He spent two years in 2008 and 2009 as visiting student in professor Jianbo Wang’s laboratory at Peking University. In 2013, He joined Dr. Dong’s group at the University of Texas at Austin as a visiting professor. His current research interests focus on the transition-metal-catalyzed activation of inert chemical bonds and green synthetic chemistry. He is the author of 6 patents and more than 70 articles indexed by SCI.

Recent Advance in the C-F bond functionalization of trifluoromethyl-containing compounds

Guobing Yan, Kaiying Qiu and Ming Guo

https://doi.org/10.1039/D1QO00037C

Isocyanides have proven to be versatile building blocks in organic synthesis and medicinal chemistry due to their synthetic possibilities capable of reacting with electrophiles, nucleophiles and radicals. Multi-component reactions involving isocyanides have been well developed with the advantages of diverse skeletons of products, functional group compatibility, high chemo-, regio and stereoselectivities, and atom economy. With the continuous research on isocyanides, C(sp³)–H functionalization with isocyanides has made significant progresses with the advancement of mechanistic studies, new techniques and novel strategies in recent years. In this review, the group of Xu and coworkers of Shanghai University of China highlights the most recent advances of isocyanide chemistry in the C(sp³)–H functionalization since 2015 by elaborating the strategies of state-of-the-art synthetic routes. The synergistic combination of the isocyanide insertion and the C(sp³)–H bond activation offers a novel and efficient route to establish complicated reactions and provides an effective strategy for the synthesis of various nitrogen- and oxygen-containing compounds.

Figure 1.C(sp³)–H functionalization with isocyanides

Bin Xu received his bachelor’s degree from Shanghai University of Science and Technology in 1992. He conducted his PhD research with Professor Shengming Ma at Shanghai Institute of Organic Chemistry and completed his degree in 2000. After a two-year postdoctoral training at National Institutes of Health (NIH) as a Visiting Fellow (Mentor: Dr Kenneth A. Jacobson), he joined VivoQuest as a staff scientist (2002–2005). He began his independent academic career at Shanghai University in the end of 2005 as a Full Professor. His current research interests span the development of new methodology for nitrogen-containing heterocycles and their biological applications.

C(sp³)–H Functionalization with Isocyanides

Org. Chem. Front., 2021, Accepted Manuscript

https://pubs.rsc.org/en/content/articlelanding/2021/qo/d1qo00153a#!divAbstract