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Metal-free C(aryl)–P bond cleavage: Experimental and computational studies

Carbon–phosphorus (C–P) bond cleavage reactions are one of the most important transformations because organophosphorus compounds are widely utilized as pharmaceuticals, phosphine ligands, organocatalysts, and functional materials. Therefore, C–P bond cleavage reactions have been developed using various approaches such as radicals produced using photolysis or peroxides, reduction using transition metal catalysts and alkali metals, and via P(V) intermediates (Scheme 1A). However, these synthetic methodologies require relatively harsh conditions, leading to low functional group tolerance. In addition, they require the use of precious transition metals and the formation of highly polarized C–P bonds in activated species.

Recently, the group of Prof. Shinobu Takizawa and Mohamed S. H. Salem as a collaborator from SANKEN, Osaka University have developed a metal-free C(aryl)–P bond cleavage reaction starting via the reaction of triarylphosphines and alkynyl esters using water as a nucleophile and electrophile to yield propanoic acid/phosphine oxide derivatives (Scheme 1B), which have applications in pharmaceuticals and catalysis.

Scheme 1: Methods of C(aryl)–P bond cleavage.

The reaction proceeded under mild and neutral conditions (10 °C, 24 h, H2O as a nucleophile) without using any metal catalyst, which is consistent with the concepts of green chemistry. In addition, they have carried out the full optimization of the reaction system to obtain high yields (up to 98%). The scopes of phosphine reagents and activated alkynes were investigated under the optimal conditions to disclose a broad spectrum with high yields in most of the cases.

Takizawa, Salem and coworkers have complemented their experimental work with computational calculations to understand and verify their proposed reaction mechanism. DFT calculations and some control experiments using (allenic esters, or vinyl ketone instead of propiolate esters), and (D2O, or H218O instead of water) indicated that the rapid formation of hydroxy-λ5-phosphane as a key intermediate plays a crucial role in smooth C(aryl)–P bond cleavage (Scheme 2).

Scheme 2: The proposed reaction mechanism of rapid C(aryl)–P bond cleavage and 1,2-aryl migration to the Michael acceptor via a hydroxyl-λ5-phosphane intermediate.

The development of this new synthetic method using metal-free conditions is crucial for the development of greener chemical practices. Further, the understanding of the mechanism of these synthetic reactions has a key value in expanding their applications, as well as the synthesis of industrially important phosphorus-containing molecules.

Author:

Mohamed S. H. SALEM
Osaka University

Mohamed Salem is a Ph.D. student in the SANKEN at Osaka University (Japan). He received his M.Sc. in Medicinal Chemistry at the Faculty of Pharmacy, Suez Canal University in 2017. Subsequently, he received a Japanese Government Scholarship (MEXT) to study for a Ph.D. in 2019 with Professor Hiroaki SASAI and Shinobu TAKIZAWA. The research field of Mohamed Salem is asymmetric catalysis using first-row organometallic complexes such as Cobalt and Vanadium and the study and development of new green and cutting edge electrochemical transformations.

https://orcid.org/0000-0002-8919-095X
https://www.researchgate.net/profile/Mohamed-Salem-39

Corresponding Author:

Shinobu TAKIZAWA 滝澤 忍
Osaka University

Shinobu TAKIZAWA is an associate professor in the Institute of Scientific and Industrial Research (SANKEN) and AI Research Center at Osaka University (Japan). He received his Ph.D. in chemistry at the Graduate School of Pharmaceutical Science, Osaka University in 2000. From 2006 to 2008 he did postdoctoral studies at The Scripps Research Institute (USA) with Professor Dale L. Boger. The research field of Professor Shinobu TAKIZAWA is asymmetric catalysis using either organo-or organometallic catalysts and the study and development of new green and cutting edge chemical transformations either electrochemically or photochemically guided by AI and ML. He is the author of more than 118 articles indexed by SCI and cited more than 4000 times with an index H = 38.

https://orcid.org/0000-0002-9668-1888

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Tuning the rotational properties of oxindole-based molecular motors

Moving from single molecules to dynamic molecular systems and responsive materials requires control of molecules that can induce motion and enable machine-like functions. Light-driven rotary molecular motors are compounds that can undergo unidirectional rotational motion, using light as a power source. Their 360° rotation cycle is driven by the successive interconversion of four unique isomers of the motor, undergoing two energetically uphill photochemical E-Z isomerisation (PEZ) steps and two downhill thermal helix inversion (THI) steps. Thanks to this unidirectional rotational behaviour, molecular motors can be used to produce useful physical work on the nanoscale – finding a multitude of applications in fields of catalysis, smart materials, and nanotechnology. 

The physical characteristics governing the rotational motion of molecular motors include their rotational speed, the wavelength of light which the motors can consume to power their motion, and their photochemical efficiency (or quantum yield). Investigating these characteristics will allow us to understand the dynamic behaviour of molecular motors – and ultimately how to tune this behaviour – will allow molecular motors to be used as tuneable actuators and  molecular machines. 

Figure 1: A) Oxindole-based molecular motors functionalised on the upper half or lower half of the motor scaffold, with either cyano or methoxy groups; B) Unidirectional rotation cycle of the molecular motors, consisting of two photochemical E-Z isomersations (PEZ) and two thermal helix inversions (THI).

Molecular motors containing the heterocyclic oxindole moiety were discovered in 2019 and it was found that they have desirable rotational properties – they can be driven with benign visible light, and they can be synthesised easily and quickly, relative to traditional hydrocarbon-based molecular motors. Due to these advantages, more research into the functionalisation of oxindole-based motors could help to further improve these promising motors.

Recently, researchers in the group of Ben Feringa have carried out a systematic benchmark study on oxindole-based molecular motors; through functionalisation with cyano or methoxy groups at three different positions along the motor backbone, the rotational properties of oxindole-based molecular motors can be fine-tuned (Figure 1).

By functionalising the motors at these positions (Figure 1, R1, R2 and R3), the wavelength of light used to power the molecular motors can be further red-shifted into the visible region of the electromagnetic spectrum, which is a lower energy source of light. In some cases, the use of longer wavelengths even improved the photochemical efficiency of the motors. In addition, the photochemical quantum yields of the motors could be tuned, with electron withdrawing cyano groups improving the quantum yields of the photochemical isomerisation steps of the motor rotation cycle.

The favourable properties fulfilled by the oxindole-based molecular motors investigated in this work show the great potential of these molecules to be used as viable visible light-driven actuators, which can be fine-tuned to accurately control nanoscale motion in light responsive systems.

Corresponding author:

Professor Ben Feringa

Ben Feringa obtained his PhD degree in 1978 at the University of Groningen in the Netherlands under the guidance of Prof. Hans Wynberg. After working as a research scientist at Shell he was appointed full professor at the University of Groningen in 1988 and named the distinguished Jacobus H. van’t Hoff Professor of Molecular Sciences in 2004. He was elected foreign member of the American Academy of Arts and Sciences, and the Royal Society and is member of the Royal Netherlands Academy of Sciences. His research interests include stereochemistry, organic synthesis, asymmetric catalysis, molecular switches and motors, photopharmacology, self-assembly and nanosystems.

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Chemical transformation of Doubly N-Confused Porphodimethene to variants of (anti)Aromatic Doubly N-Confused Porphyrinoids and σ-aromatic Doubly N-Confused Isophlorinoid

Indian scientist, Dr Harapriya Rath and her collaborator Dr. Dandamudi Usharani experimentally isolated and theoretically supported the first ever s-aromatic doubly N-confused porphyrinoid. Unique π-reconstructions owing to sequential C-oxygenation of N-confused N-methyl pyrrole rings leading to the genesis of 18π aromatic doubly N-confused monooxo porphyrinoid, 16π antiaromatic doubly N-confused diioxo porphyrinoid and σ-aromatic doubly N-confused tetraoxo isophlorinoid via chemical transformation(s) of doubly N-confused porphodimethene.

Corresponding Author:

Harapriya Rath received her PhD degree from the Indian Institute of Technology, Kanpur, India on the Nonlinear Optical studies of Core-modified Aromatic Expanded porphyrinoids under the supervision of Prof. T. K. Chandrashekar in 2006. In 2007, she joined the group of Prof. Hiroshi Shinokubo at the Kyoto University, Japan as JSPS Postdoctoral fellow and focused on the subject of Möbius aromaticity (antiaromaticity) and excited state aromaticity of metallated all-aza expanded porphyrinoids. In 2009, she moved to Prof. Richard EP Winpenny’s lab at the University of Manchester, United Kingdom as a Royal Society Newton International postdoctoral fellow focusing on hybrid Organic-Inorganic Rotaxanes. In 2012, she started an independent academic career at Indian Association for the Cultivation of Science, Kolkata, India as an Assistant professor and Ramanujan Fellow. Since 2017, she is Associate Professor in the School of Chemical Sciences, IACS, Kolkata, India.

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Best Organic Chemistry Frontiers Covers of 2021

We are delighted to announce the Best Organic Chemistry Frontiers Covers of 2021!

Read below the scientific papers.

A solvent-free and efficient synthesis of bicyclic 2-pyridone derivatives for endoplasmic reticulum imaging

Org. Chem. Front., 2021, 8, 3631-3638

Issue 14 Volume 8 Outside Front Cover

Copper-catalyzed alkynylation/annulation cascades of N-allyl ynamides: regioselective access to medium-sized N-heterocycles

Org. Chem. Front., 2021, 8, 18-24

Issue 01 Volume 8 Inside Front Cover

Pd/LA-catalyzed decarboxylation enabled exclusive [5 + 2] annulation toward N-aryl azepanes and DFT insights

Org. Chem. Front., 2021, 8, 1902-1909

Issue 09 Volume 8 Outside Front Cover

Congratulations to the winners of Best Organic Chemistry Frontiers Covers of 2021!

We expressed our sincere appreciation for all the support and contributions from our authors, reviewers, and readers in the past 2021.

Looking forward to receiving your high-quality work in 2022.

Happy Chinese New Year!

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Piperidines and Pyrrolidines Obtained by Room Temperature Heck Reaction Thank to the Blue Light

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.

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Bromine and Oxygen Redox Species Mediated Highly Selective Electro-Epoxidation of Styrene

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).

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Insight into the Mechanism of the Arylation of Arenes via Norbornene Relay Palladation through meta- to para-Selectivity

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.

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Enantioselective total syntheses of marine natural products (+)-cylindricines C, D, E and their diastereomers

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.

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Use of artificial cells as drug carriers

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

 

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Unravelling the limits of the transfer of asymmetry in supramolecular polymers

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

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