Organic Chemistry Frontiers Blog

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