Organic Chemistry Frontiers Blog

Among small drugs and pharmaceutically relevant molecules, alkaloids have a leading role and those related to pyrrolidine and piperidine are the most common five- and six-membered aliphatic N-heterocycles. Differently from their aromatic counterparts, there are limited strategies to access substituted saturated N-heterocycles with ease and efficiency which fall into two main categories: the cyclization of suitable precursors and the modification of readily available pyrrolidines and piperidines.

Recently, many researchers have dedicated their attention to alternative conditions in order to lower the reaction temperature while keeping the efficiency high in term of both yield and selectivity. In 2010, the group of Köhler observed, for the first time, the acceleration of a Heck reaction under UV-visible light using both homogeneous or heterogeneous Pd(II) pre-catalysts. Few years later, Gevorgyan disclosed an original visible light-induced room temperature Heck reaction between functionalised alkyl halides and styrenes. That was the starting point for the employment of transition metal complexes, especially those containing Pd, as unconventional photocatalysts and remarkable results have been reported by the research groups of Gevorgyan, Fu, Königs, Glorius and Rueping.

Recently, Renzi et al. presented a synthetic strategy to obtain arylated vinyl pirrolidines and piperidines starting from N-tosylaminoallenes. Key to the process was the usage of the blue light which allowed the efficient exploitation of the simple catalytic system Pd(OAc)₂/2PPh₃ at room temperature. More than fifty Electron-donating, electron-withdrawing aryl and heteroaryl bromides were coupled with allenes in a Pd(0) catalysed cross coupling. A subsequent domino cyclisation is triggered by the tosylamino functionality. The mechanistic investigation, both experimental and computational, highlighted three main aspects: no radicals seems to be involved in this mechanism, the light is not needed in the oxidative addition of Pd(0) to the aryl bromide because of the associated low energy barrier. On the contrary, the light plays its main role in the carbo-palladation step, but its influence in making easier the formation of the active Pd(0) species cannot be excluded (figure 1).

Corresponding authors:

Annamaria Deagostino
Dept. of Chemistry – University of Torino

Annamaria Deagostino is associate professor of organic chemistry at the University of Torino. She graduated in chemistry at the University of Torino and after a fellowship at the University of Padova, in 1998 she received her Ph.D. in chemistry at the University of Torino, supervisor Prof. Paolo Venturello, and in the same year she obtained a postdoctoral fellowship at the University of Caen, under the supervision of Prof. Marie-Claire Lasne. In 1999, she became assistant professor of organic chemistry at the University of Torino. The main interests of her research group are in the field of synthetic organic chemistry, mainly focused on organopalladium chemistry, visible light photo-catalysis and the synthesis of BNCT (Boron Neutron Capture Therapy) theranostic agents.

Giovanni Ghigo
Dept. of Chemistry – University of Torino

Giovanni Ghigo is assistant professor of organic chemistry at the University of Torino since 2005. He graduated in chemistry 1994 and in 1999 received his Ph.D. in Chemistry at the University of Torino, supervisor Prof. Glauco Tonachini. He obtained postdoctoral fellowships at the University of Torino then at the University of Lund.

GG is a computational organic chemist interested in the study of the mechanisms of a large type of organic reactions spanning from the generation and oxidation of organic pollutants and, more recently, metal-free, copper or palladium catalyzed and photocatalyzed reactions with synthetic applications.

Among various oxidation reactions, olefin epoxidation is undoubtedly one of the most studied organic conversion reactions. The target product epoxide is amongst extensively used chemicals and has important applications in the synthesis of polymers, food additives and drugs. Therefore, efficient synthesis of epoxides holds a significant place for academic and industrial research perspectives. Traditional olefin epoxidation methods generally require toxic and harmful, high-priced oxidants with harsh reaction conditions and difficult separation. The most commonly used process for the industrial synthesis of epoxides is the halogenated alcohol (Br, Cl) method (HALCON process). However, this process produces a large amount of chlorine (bromine) wastewater during the production process, causing serious pollution to the environment. The epoxidation of olefins by electrochemical oxidation of bromide ions is an emerging and promising strategy (Scheme 1). The choice of the electrode is very important for electro-epoxidation process. The common electrodes currently being used in the scientific community are platinum electrodes and carbon electrodes, however they all have certain limitations. Although the platinum electrode has good catalytic activity for the oxidation of bromide ions, but it can be easily corroded by bromide ions, which affect its catalytic activity and causes the waste of precious metal. In addition, carbon electrodes are also known to possess low catalytic activity. Therefore, the development of an economical and efficient electrode that could promote the oxidation of bromide ions for the facile epoxidation of olefins still needs to be endeavoured.

Scheme 1 a Classical protocols for epoxidation, b Our proposed electrosynthesis for epoxidation.

Recently, Zai’s group has reported a strategy for the electrochemical, efficient and green synthesis of styrene epoxide. First, the team synthesized a series of metal sulfide electrodes by solvothermal method, and analysed the catalytic activity of metal sulfide electrodes for bromide ion oxidation via linear sweep voltammetry (LSV). The team noticed that cobalt-based sulfides, especially heterostructure CoS₂/CoS, can effectively promote the oxidation of bromide ions on the anode. Subsequently, the electrochemical epoxidation of styrene was carried out with metal sulfides as the anode and carbon rod as the cathode, and a series of optimizations were carried out for the optimal reaction solvent, time and temperature. Under the optimal reaction conditions, the platinum electrode (Pt) displayed a selectivity of 55% for styrene epoxide. This may be due to the surface corrosion of platinum electrode by bromide ions during the reaction and the other reason could be the smaller electrochemical surface area (ECSA) of the platinum electrode. Moreover, the metal sulfide electrodes Cu₇S₄, CdS, MnS, FeS₂, NiS₂ have 73%, 76%, 78%, 80%, and 81% selectivity to Styrene epoxide, respectively. It is worth noting that the selectivity of CoS and CoS electrodes towards styrene epoxide reached 88% and 90%, respectively. When CoS and CoS₂ were combined to form heterojunction CoS₂/CoS, Highly selective synthesis of styrene epoxide (97%) was attained with GF-CoS₂/CoS as anode and carbon rod as cathode. The applied voltage was reduced to 4-5 V at 30 mA cm^-2 compared to 7.8-9.3 V on Pt cathode, which effectively reduces the energy consumption of the reaction. Subsequently, the team conducted in-depth studies on the mechanism (Scheme 2) involved in the electrochemical epoxidation of styrene by conducting experiments in different electrolytes, different atmospheres, different reaction cells (single, H-type), and different free radical quenchers (Figure 1).

Scheme 2 Reaction mechanism involved in electro-epoxidation.

Figure 1 Optimization of electrode systems. Blue zone: Metal sulfide-based electrodes as anode. Yellow zone: Pt used as anode or cathode.

The mechanistic investigations inferred the generation of oxygen redox species (such as OH•, H₂O₂, O₂•^¯) besides the olefin-based radicals and bromine radical, facilitating the epoxide formation. The synergistic cooperation between the bromine redox species and oxygen redox species (generated on graphite rod cathode) can establish a benign electro-epoxidation system for olefin substrates in an ambient environment (Scheme 3). The group demonstrated that the proposed strategy could also be applied to other olefins. As this strategy is simple, sustainable, and economical so, it could be of great significance for technical aspects.

Corresponding author:

Jiantao Zai Associate Professor
Shanghai Jiaotong University

Jiantao Zai is associate professor in the school of chemistry and chemical engineering in Shanghai Jiaotong University. He is engaged in the design, synthesis and performance research of inorganic solid materials, especially micro-nano, multi-component functional materials. He has published 106 papers in journals such as Nat Commun, Adv Energy Mater, Nano Energy, etc. The papers have been cited 4559 times, and the H index is 40. In 2015, he won the first prize of Shanghai Natural Science (No.5), and was selected as Shanghai in 2018. Youth Science and Technology Venus (Class A).

Selective C-H aromatization of aromatic compounds has long been a challenging issue. Directing group strategies can only make the ortho- or meta-sites of the aromatic compounds activate in past years. Recently, an elegant approach was reported to successfully achieved the para-arylation of arene by means of a cooperative action of directing group with norbornene relay (Scheme 1). This strategy first implements meta-C-H activation through directing group guidance, subsequently, the transient mediator norbornene relay Pd to the para-position to achieve precise siteselectivity. Understanding this novel relay mechanism is of great significance for achieving more extensive and accurate site selection. 

Scheme 1. Siteselective C-H functionalization.

Dezhan Chen and collaborators explored in detail the mechanism of the arylation of arenes by means of norbornene relay palladation through meta- to para-selectivity using DFT calculations. The results revealed that the reaction was initiated by a [mono N-protected amino acid ligand-Pd] complex to activate firstly the meta-C-H guided by the directing group. The para-arylation was subsequently achieved by NBE relay palladation from meta- to para-position (Figure 1). Significantly, the palladium/norbornene cooperative relay was realized by a bimetallic Pd-Ag complex. The authors demonstrated that the Pd-Ag bimetallic complex play a significant stabilization role in secondary para-C-H activation rather than the intuitive tether length (Figure 2).

Figure 1. Structure conversion of NBE relay Pd from meta- to para-position

Figure 2. Free energy profiles for the para-C-H activation catalyzed by monomeric Pd and heterodimeric Pd-Ag.

The calculated energy profiles of the NBE relay Pd through meta- to para-position to produce para-arylated product is summarized in Figure 3a (black pathway). The author further optimized the energy profiles of NBE relay palladation through para- to meta-position (blue pathway), while this pathway was kinetically unfavorable. The calculation results shown that directing group assisted primary C-H activation was the rate-determining step for the overall catalytic cycle, also the key step of determining siteselectivity. The primary meta-activation was favorable in energy due to less ring strain in the cyclic nitrile-coordinated C-H transition states in meta-position. As illustrated by the Gibbs energy profile in Figure 3b, norbornene insertion, as the key step to achieve the expected Pd relay, can take place spontaneously with exothermic of 7.1 kcal/mol, which can compensates for the energy needed to cross the barrier. It follows that the palladium relay process is driven thermodynamically to achieve the activation from meta- to para-position.

Figure 3. (a) Free energy profiles of the full catalytic cycle of two pathways. (b) Free energy profiles for the major and minor pathway based on Curtin-Hammett scenario.

The perfect cooperation of a remote directing group and a transient mediator NBE through the alternating association with the Pd center achieved the active site relay through meta- to para-position. The present results provided a reasonable insight into the para-C-H arylation by Pd/MPAA/NBE cooperative catalysis in conjunction with a precise directing group and Ag(Ⅰ) additive and would have implications for understanding C-H functionalization chemistry by norbornene relay palladation.

Dezhan Chen is professor in College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University (China). He received his master’s degree in Department of Chemistry of Shandong University in 1989. He studied in UCLA at Houk group as a visiting scholar in 1996-1997. The research interest of Professor Chen is the exploration of theoretical mechanism of chemical reaction and its thermodynamic and kinetic processes.

Tasmania is a well-known touristic destination in Australia. During 1993-1995, Blackman and coworkers reported eleven new alkaloids named Cylindricines A – K (Figure 1) isolated from ascidian Clovelina cylindrical, which were collected from different locations of the East Coast of Tasmania. This group of alkaloids possess new tricyclic ring systems containing an a-tert-alkylamine motif, which are structurally related to lepadiformine and fasicularin.

Figure 1. Structure of representative alkaloids of the cylindricine/fasicularin/lepadiformine family

The intriguing structures of cylindricines have attracted considerable attention from synthetic community. More than twenty research groups including those of Snider, Weinreb, Heathcock, Molander, Kibayashi, Trost, Ciufolini, Hsung, Shibasaki, Donohoe, Renaud, Pandey, and Chida/Sato have been engaged in their total syntheses, which resulted in many elegant approaches. However, efficient and flexible enantioselective synthetic approaches are still demanding.

Recently, the group of Huang and collaborators of the Xiamen University have disclosed a concise and versatile enantioselective total syntheses of (+)-cylindricines C, D, E and their diastereomers. Huang’s synthetic strategy to (+)-cylindricines C-E (1c-1e) stemmed from the identification of the a-tert-alkylamine motif-bearing prolinol moiety as the key structural feature and relied on the amides reductive bisalkylation, a versatile reaction originally developed by his group in 2010 and improved by replacing DTBMP with TTBP in 2021 (Scheme 1).

Scheme 1. Huang’s one-pot reductive bisalkylation of amides

According to the retrosynthetic analysis outlined in Scheme 2, Huang’s enantioselective total synthesis of (+)-cylindricine D (1d) is displayed in Scheme 3. Employing L-pyroglutamic acid derived lactam (S)-9 as the chiral pool, and Tf₂O/TTBP (2,4,6-tri-tert-butylpyrimidine) as an amide activation system, the reductive bisalkylation of lactam (S)-9 resulted in the formation of prolinol derivative 8 in 75% yield (dr = 7: 1). Another key feature of the reaction is the telescoping of four reactions [(1) partial reduction of ynone 5 to the presumed (Z)-enone 17; (2) N-deprotection; (3) O-deprotection; (4) intramolecular aza-conjugate addition] into one step, which rendered the synthesis highly efficient. On the other hand, following the same approach, they have synthesized (+)-cylindricines C and E (no shown) via 16.

Scheme 2. Huang’s retrosynthetic analysis of (+)-Cylindricine D

Scheme 3. Enantioselective total synthesis of (+)-cylindricine D (1d)

In summary, they have accomplished one of the shortest and the most efficient total syntheses of (+)-cylindricines C-E so far reported: cylindricine D (1d): 7 steps and 20.9% overall yield from (S)-9; (+)-cylindricine C (1c): 8 steps, 19.1% overall yield from (S)-12; O-Acetylation of (+)-cylindricine C afforded (+)-cylindricine E (1e).

Enantioselective Total Syntheses of Marine Natural Products (+)-Cylindricines C, D, E and Their Diastereomers

Ying-Hong Huang,† Zhan-Jiang Liu,† and Pei-Qiang Huang*

Pei-Qiang Huang obtained his B.Sc. (1982) from Xiamen University (China) and D. E. A. (1984) from Université de Montpellier II (France) under the direction of the late Professor B. Castro (INSERM-CNRS). After accomplishing the research work at the Institut de Chimie des Substances Naturelles (ICSN), CNRS under the supervision of Professor Dr. H.-P. Husson, his received his Ph D from Université de Paris-Sud (Orsay) (France) in 1987. He served as a postdoctoral fellow in the group of the late Professor W.-S. Zhou at Shanghai Institute of Organic Chemistry, CAS in 1988-1990. He was appointed as an associate Professor at Xiamen University in 1990, and was promoted to a full Professor in 1993. Professor Huang’s research team is interested in developing novel and efficient synthetic methodologies, total synthesis of natural products and medicinal relevant molecules, and chemical biology. He has co-editor several books, including: “Efficiency in natural product total synthesis” (Editors: Pei‐Qiang Huang, Zhu‐Jun Yao, Richard P. Hsung; Forwarded by Henry N. C. Wong), John Wiley & Sons, Inc., 2018. He is a fellow of RSC, and currently an associate editor of Org. Chem. Front.

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