Derivatization Of Natural Products Research Articles

Copper(II)/Rhodium(III)‐Catalyzed Three‐Component Sequential Annulation‐Olefination of 2‐Arylquinoxalines

AbstractThe quinoxaline scaffold occurs in many pharmaceuticals, natural products and organic materials. In this study, a Cu(II)/Rh(III)‐catalyzed regioselective annulation‐olefination sequence for the formation and modification of quinoxalines was developed using ethanol and water as the solvent, with relatively broad substrate scope and functional group tolerance. This protocol has been successfully applied to the derivatization of natural products and pharmaceuticals. Additionally, the derivatives exhibited enhanced antiproliferative activities against A‐2780 and HCT‐116 cell lines, underscoring their potential as promising lead compounds for ovarian cancer and colon cancer treatment.

Visible‐Light‐Induced Desulfurative Coupling of Alkyl Benzothiazolyl Sulfides with Electron‐Deficient Alkenes/Alkynes: Dual Role of Base‐Activated Hantzsch Esters

Hantzsch ester (HEH) is a bench‐stable compound used in hydrogenation and photo‐induced reactions, where it acts as a photoreductant and an electron donor. In this study, we describe a new use of this classical reductant in the visible‐light‐induced desulfurative coupling of alkyl benzothiazolyl sulfides with electron‐deficient alkenes/alkynes via activation with base additives. C(sp3)–S scission is achieved through catalyst‐free HEH anion‐mediated reactions and organo‐photocatalysis. The synthetic utility is illustrated with several examples of derivatization of natural products, including monosaccharides. In addition, mechanistic investigations reveal that the HEH anion acts as a photoreductant in catalyst‐free reactions and as a sacrificial reductant in the organo‐photocatalysis.

Function-Oriented Synthesis of Pentacyclic Triterpenoids and Discovery of an ent-Estrane as a Natural Product-Inspired Androgen Receptor Antagonist.

While pentacyclic triterpenoids have a rich history in chemistry and biology, the challenges associated with their asymmetric synthesis contribute to the current reality that medicinal exploration in the area is largely constrained to natural product derivatization. To address this deficiency, a function-oriented synthesis of pentacyclic triterpenoids was pursued. Overall, we report a divergent synthesis of 26-norgermanicol and 26-norlupeol and we have identified a new class of androgen receptor antagonist that is ∼6× more potent than lupeol.

Automated silylation of flavonoids using 3D printed microfluidics prior to chromatographic analysis: system development.

Flavonoids are a class of secondary plant metabolites with low molecular weights. Most flavonoids are highly polar and unsuitable for gas chromatographic analyses. Derivatization is commonly used to make them amenable to gas chromatography by altering their physicochemical properties. Although highly effective, derivatization techniques introduce extra preparation steps and often use hazardous chemicals. The aim of this study was to automate derivatization (specifically, silylation) by developing 3D printed microfluidic devices in which derivatization of flavonoids can occur. A microfluidic device was designed and 3D printed using clear polypropylene. Quercetin and other flavonoids (TED 13 and ZTF 1016) isolated from plant extracts were silylated with N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) at room temperature both in batch and in continuous flow. All the samples were analyzed using Fourier transform infrared (FTIR) spectroscopy, gas chromatography combined with mass spectrometry (GC-MS), and high-resolution accurate mass spectrometry (HR-MS). Interestingly, the HR-MS results showed that the flow method was about 25 times more efficient than the batch method for quercetin samples. The TED 13 flavonoid was completely derivatized in the flow method compared to the batch method where the reaction was incomplete. Similar results were observed for ZTF 1016, where the flow method resulted in a four times derivatized compound, while the compound was only derivatized once in batch. In conclusion, 3D printed microfluidic devices have been developed and used to demonstrate a semi-automated, inexpensive, and more efficient natural product derivatization method based on continuous flow chemistry as an alternative to the traditional batch method.

PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders

IntroductionNatural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. ObjectivesInspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. MethodsTaking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. ResultsIn this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo, leading to potent antitumor activities and reduced toxic side effects. ConclusionIn summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development.

Nickel-Catalyzed Highly Selective Reductive Carbonylation Using Oxalyl Chloride as the Carbonyl Source

Nickel-catalyzed carbonylative cross-electrophile coupling which emerges as a powerful, efficient, and low-cost method for constructing challenging carbonyl derivatives has attracted increasing attention of organic chemists. To avoid the generation of a poisonous, volatile, and inert nickel carbonyl complex, it is critical to develop an efficient, cheap, and easily available CO surrogate. Oxalyl chloride, a cheap commercially available chemical, is one of the most versatile organic reagents used in chemical reactions. In this work, high chemoselectivity can be achieved with a 1:1:1 ratio of Ar–I to alkyl-I to oxalyl chloride. A wide range of alkyl aryl ketones which present an important class of molecules in synthetic and medicinal chemistry are accessed from alkyl halides, aryl iodides, under mild conditions. Primary and secondary alkyl iodides were suitable substrates. Various functional groups were well tolerated, affording up to 90% yields. This protocol was also used in the derivatization of natural products and drug molecules. Mechanistic investigation indicates that the reaction of Zn and oxalyl chloride under mild reaction conditions could release CO slowly. This knowledge should be useful for the further development of multicomponent carbonylative cross-coupling reactions.

Directed Biosynthesis of New to Nature Alkaloids in a Heterologous Nicotiana benthamiana Expression Host.

Plants produce a wide variety of pharmacologically active molecules classified as natural products. Derivatization of these natural products can modulate or improve the bioactivity of the parent compound. Unfortunately, chemical derivatization of natural products is often difficult or impractical. Here we use the newly discovered biosynthetic genes for two monoterpene indole alkaloids, alstonine and stemmadenine acetate, to generate analogs of these compounds. We reconstitute these biosynthetic genes in the heterologous host Nicotiana benthamiana along with an unnatural starting substrate to produce the corresponding new-to-nature alkaloid product.

Research Advances on Anti-Cancer Natural Products.

Malignant tumors seriously threaten people’s health and life worldwide. Natural products, with definite pharmacological effects and known chemical structures, present dual advantages of Chinese herbs and chemotherapeutic drug. Some of them exhibit favorable anti-cancer activity. Natural products were categorized into eight classes according to their chemical structures, including alkaloids, terpenoids and volatile oils, inorganic salts, phenylpropanoids, flavonoids and isoflavones, quinone, saponins and polysaccharides. The review focused on the latest advances in anti-cancer activity of representative natural products for every class. Additionally, anti-cancer molecular mechanism and derivatization of natural products were summarized in detail, which would provide new core structures and new insights for anti-cancer new drug development.

Photocatalytic C-H Trifluoromethylthiolation by the Decatungstate Anion.

A broadly applicable method for the trifluoromethylthiolation of methylene C(sp3)-H, methine C(sp3)-H, α-oxygen C(sp3)-H, and formyl C(sp2)-H bonds is presented using the decatungstate anion as the sole catalyst. By adjusting the substrate ratio and reaction concentration, this method was applied to 40 examples in good regioselectivities, including the derivatization of natural products. Furthermore, SCF3-drug analogues were synthesized by subsequent functionalization of the SCF3 products, highlighting the importance of this photocatalyzed C-H functionalization.

Synthesis of N-Arylcytisine Derivatives Using the Copper-Catalyzed Chan-Lam Coupling.

N-Arylcytisine derivatives are quite rare. We report here a practical methodology to obtain these compounds. Using the copper-catalyzed Chan-Lam coupling, we synthesized new N-arylcytisine derivatives at room temperature, in air and using inexpensive phenylboronic acids. Cytisine and 3,5-dihalocytisines can act as substrates, and among the products, the p-Br-derivative 2r was used as a substrate to obtain biaryl derivatives under Pd-coupling conditions; ester 2j was converted into its acid and amide derivatives using classical carbodiimide conditions. This shows that the Chan-Lam cross-coupling reaction can be included as a versatile synthetic tool in the derivatization of natural products.

Glycorandomization: A promising diversification strategy for the drug development.

Glycorandomization is a natural product derivatization strategy in which different sugar moieties are linked to the aglycone part of the naturally existing glycosides to create glycorandomized libraries. Sugars attached to the natural products are responsible for affecting their solubility, mechanism of action, target recognition, and toxicity and thus, by changing the sugar part, these properties could be modified. Glycorandomization can be done via two approaches (i) a synthetic approach known as neoglycorandomization, and (ii) chemoenzymatic approach including in-vitro and in-vivo glycorandomization. Glycorandomization can be a promising technology for the drug discovery that has proved its potential to improve pharmacokinetic (solubility) and pharmacodynamic profile (mechanism of action, toxicity, and target recognition) of the parent compounds. The substrate flexibility of glycosyltransferases and other enzymes towards sugars and/or aglycone substrates has made this technique versatile. Further, the enzymes can be altered by genetic engineering to generate glycorandomized libraries of diverse natural product scaffolds. This technique has the potential to produce new compounds that can be helpful to the mankind by treating the threatening disease states. This review covers the different strategies for glycorandomization as a tool in drug discovery and development. The fundamentals of glycorandomization, different types, and further development of differentially glycorandomized libraries of natural products and small molecule based drugs have been discussed.

Chemical derivatization of natural products: Semisynthesis and pharmacological aspects- A decade update

Natural products and their semisynthetic derivatives continue to be an important source of potential drug leads. Natural products and their analogues structures possess the characteristics of high chemical diversity, zenith biochemical specificity, and other significant molecular activities as well as pharmacological properties that create them favorably as lead structures for new drug discovery and continue to motivate novel inventions in medicine, chemistry, and biology. Natural products were employed as very good starting materials for analogue design and synthesis as semisynthetic derivatives exhibit higher biological activities in several cases. Such beneficial quality of semisynthetic derivatives as a whole have motivated the organic chemist and biological community to explore the application of semisynthetic derivatives in more heights and as a result, the present review is aimed to offer an overview of natural sources of the starting natural compounds, semisynthesis and biological activities of semisynthetic derivatives during the last decade. • Semisynthesis and biological activities of semisynthetic derivatives have been explored during the last decade. • A semisynthesis is an essential tool for enhancing the biological property of parent natural products. • Inserting halogen atoms in natural products are excellent examples of chemical modifications. • The chemical derivatization represents the only practical means to study structure-activity relationships. • Natural products and their analogues continue to be the monumental source of potential drug leads.

A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings

The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. Since natural products are the most valuable source for the discovery of therapeutics, the derivatization of natural products has been extensively investigated to generate molecules for biological screenings. However, most previous approaches only modified a limited number of functional groups, which resulted in a limited number of skeleta. Here we show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry – the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings. This library occupies a unique chemical space compared to selected diverse reference compounds. The diversification strategy developed herein for steroids can also be expanded to other types of natural products.

Natural product derivatization with β-lactones, β-lactams and epoxides toward ‘infinite’ binders

β-Lactones, β-lactams and epoxides are privileged structural motifs found in both therapeutics and natural products. Herein we report several strategies for annulation of these motifs onto natural products that are not known to covalently modify their cellular targets. These strategies can facilitate identification of previously unidentified cellular targets or identify novel cellular targets of these natural products. The reported strategies include telescoped synthesis of β-lactones from allylic alcohols, nucleophile-catalyzed Michael aldol-β-lactonizations, and [2 + 2] β-lactam annulations with complex, commercially available alkene-containing natural products as substrates. A novel method for the tagging of phenolic natural products with epoxides is also reported.

Unprecedented derivatization of ferulic acid through selective methoxylation by Aspergillus brasiliensis ATCC 16404

Ferulic acid (FA) is a natural hydroxycinnamic acid widely found in medicinal and edible plants. Several experts have reported the biological potential of FA, including antioxidant and antimicrobial activities. The use of microorganisms in the derivatization of natural products is a useful and advantageous approach to the achievement of high value-added compounds. In order to access chemical derivatives, we conducted the biotransformation of FA by Aspergillus brasiliensis ATCC 16404 for 5 d. In the second day of fermentation, the FA was converted into the new (E)-3-(4-hydroxy-3-methoxyphenyl)-2-methoxyacrylic acid. This is the first time that the extended π-conjugation remained in the chemical structure after the biotransformation of FA. The cytotoxicities of FA and its derivative were evaluated. The biotransformation yielded a derivative less toxic than the parent compound.

(Poly)cationic λ3-Iodane Mediated Oxidative Ring Expansion of Secondary Alcohols.

Herein, we report a simplified approach to the synthesis of medium-ring ethers through the electrophilic activation of secondary alcohols with (poly)cationic λ3-iodanes (N-HVI). Excellent levels of selectivity are achieved for C-O bond migration over established α-elimination pathways, enabled by the unique reactivity of a novel 2-OMe-pyridine-ligated N-HVI. The resulting HFIP-acetals are readily derivatized with a range of nucleophiles, providing a versatile functional handle for subsequent manipulations. The utility of this methodology for late-stage natural product derivatization was also demonstrated, providing a new tool for diversity-oriented synthesis and complexity-to-diversity (CTD) efforts. Preliminary mechanistic investigations reveal a strong effect of alcohol conformation on reactive pathway, thus providing a predictive power in the application of this approach to complex molecule synthesis.

Ferrocene derivatives of liquid chiral molecules allow assignment of absolute configuration by X-ray crystallography

The present study investigates a synthetically simple ferrocene derivatization of natural products and active pharmaceutical ingredients. Seven new crystal structures are analyzed together with 16 structures of ferrocene derivatives reported previously. In all cases, the unambiguous determination of the absolute structure was established from anomalous dispersion using the methods of Flack and Parsons. A comparison with other derivatization approaches shows the advantage of the described ferrocene derivatization for establishing the absolute configuration of novel compounds.

Andreas Herrmann

Angewandte Chemie International EditionVolume 56, Issue 8 p. 1956-1956 Author ProfileFree Access Andreas Herrmann First published: 19 January 2017 https://doi.org/10.1002/anie.201611742AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “I can never resist sweets. My favorite food is venison ...” This and more about Andreas Herrmann can be found on page 1956. Andreas Herrmann The author presented on this page has recently published his 10th article in Angewandte Chemie in the last 10 years: “High Affinity Recognition of a Selected Amino Acid Epitope within a Protein by Cucurbit[8]uril Complexation”: S. Sonzini, A. Marcozzi, R. J. Gubeli, C. F. van der Walle, P. Ravn, A. Herrmann, O. A. Scherman, Angew. Chem. Int. Ed. 2016, 55, 14000; Angew. Chem. 2016, 128, 14206. The work of A. Herrmann has been featured on the inside cover of Angewandte Chemie: “Light-Triggered Sequence-Specific Cargo Release from DNA Block Copolymer-Lipid Vesicles”: A. Rodríguez-Pulido, A. Kondratchuk, D. K. Prusty, J. Gao, M. Loi, A. Herrmann, Angew. Chem. Int. Ed. 2013, 52, 1008; Angew. Chem. 2013, 125, 1042. Date of birth: October 14, 1970 Position: Professor of Polymer Chemistry & Bioengieneering, Zernike Institute for Advanced Materials, University of Groningen E-mail: a.herrmann@rug.nl Homepage: http://www.rug.nl/research/zernike/polymer-chemistry-and-bioengineering/group-herrmann/polymer-chemistry-_-bioengineering-research ORCID: orcid.org/0000-0002-8886-0894 Education: 1997 Diploma in chemistry, University of Mainz 2001 PhD with Klaus Müllen, Max Planck Institute for Polymer Research, Mainz 2002–2003 Postdoctoral research with Donald Hilvert, ETH Zurich Awards: 2008 Reimund Stadler Prize, Gesellschaft Deutscher Chemiker (GDCh; German Chemical Society); 2009 ERC Starting Grant; 2009 Dr. Hermann Schnell Prize, GDCh; 2010 VICI Grant, Netherlands Organization for Scientific Research; 2013 EYEnovative Prize, Novartis; 2016 ERC Advanced Grant Current research interests: DNA hybrid materials; supercharged polypeptides; nanochemistry; biomacromolecular liquids and liquid crystals; supramolecular protecting groups Hobbies: Surfing, soccer, and skiing I can never resist sweets. My favorite food is venison. My favorite place on earth is the French Atlantic coast because it combines excellent waves and food. I chose chemistry as a career because I could not enter chemical engineering as I could not pursue the necessary practical training because of military service. Retrospectively, that was the best thing that ever happened. If I were not a scientist, I would be a cook developing new flavors with the help of chemistry. My worst nightmare is that all my PhD students and postdoctoral researchers follow my advice. The most exciting thing about my research is that the materials that we are fabricating on the nanometer scale execute functions in the macroscopic world. If I could go forward in time and do any experiment, it would be the fabrication of a cell from exclusively unnatural components that can grow and divide. The downside of my job is having too little time for my wife and three kids. When I'm frustrated, I bike home earlier and faster than usual. My best investment was in smart students. My 5 top papers: References 1“High-Density Noncovalent Functionalization of DNA by Electrostatic Interactions”: W. Chen, J. Y. Gerasimov, P. Zhao, K. Liu, A. Herrmann, J. Am. Chem. Soc. 2015, 137, 12884. (A general method for enveloping DNA with various amines in organic solvents.) 2“Thermotropic liquid crystals from biomacromolecules”: K. Liu et al., PNAS 2014, 111, 18596. (A simple method for liquifying and ordering DNA, RNA, and proteins in the absence of water.) 3“Selective Transformations of Complex Molecules are Enabled by Aptameric Protective Groups”: A. A. Bastian, A. Marcozzi, A. Herrmann, Nat. Chem. 2012, 4, 789. (Allows the regioselective one-step derivatization of natural products.) 4“DNA Block Copolymer Doing It All: From Selection to Self-Assembly of Semiconducting Carbon Nanotubes”: M. Kwak et al., Angew. Chem. Int. Ed. 2011, 50, 3206; Angew. Chem. 2011, 123, 3264. (A DNA polymer hybrid selectively disperses single-walled carbon nanotubes and guides their assembly in devices.) 5“DNA Block Copolymer Micelles—A Combinatorial Tool for Cancer Nanotechnology”: F. E. Alemdaroglu, N. C. Alemdaroglu, P. Langguth, A. Herrmann, Adv. Mat. 2008, 20, 899. (Fast and easy fabrication of drug carrier systems based on nucleic acid self-assembly.) Volume56, Issue8February 13, 2017Pages 1956-1956 ReferencesRelatedInformation

Small molecule drug development based on derivatization of natural products

Natural products in a general term refer to endogenous chemical substances or secondary metabolites produced by living organisms such as animals, plants or microorganisms. Historically, natural products have been indispensable resources as medication throughout human civilization worldwide. Crude or semi-purified extracts of these living organisms, especially terrestrial plants, have been described in a variety of ancient Chinese books and utilized to treat various human diseases. With the establishment of modern scientific system, research on individual active principles or secondary metabolites from these living organisms was expanded, initially focusing on the chemistry and pharmacological effects. The isolation, purification, pharmacological validation, and market of a naturally occurring natural product morphine as a painkiller directly led to the foundation of a modern pharmaceutical company Merck in 1893. Since then a number of natural products, such as quinine and penicillin, have been introduced as important medicines for the wellbeing of mankind. Novel natural products have been the gold mine as drug leads in the field of small molecule drug discovery and development to all pharmaceutical companies for over a century. With the great advancement in synthetic organic chemistry and medicinal chemistry large volume of structurally diversified small molecules can now be rapidly produced and screened in a high throughput manner, the role of natural products in modern drug discovery and development have been largely diminished. Very often intrinsic side effects with natural products such as toxicity, limited availability, and unfavorable potency and selectivity render it more and more difficult to utilize them directly as drug candidates. Practically, synthetic transformation or total synthesis of natural products is required due to above-mentioned suboptimal physicochemical and pharmacological properties or limited availability. 2015 Nobel Prize in Physiology or Medicine was awarded to the discoveries of two natural products based novel therapies: i.e. avermectin-based therapy against infections caused by roundworm parasites and artemisinin (Qinghaosu)-based therapy against Malaria. These two natural products technically possessed certain unfavorable properties and the clinically utilized medicines were indeed their synthetic derivatives. This review is intended to illustrate the importance and significance of structural determination and synthetic transformations on natural products in modern drug discovery and development.

Final-stage Site-selective Acylation for the Total Synthesis of Natural Glycosides.

The first total syntheses of multifidosides A-C are reported. The prominent feature is an unconventional retrosynthesis based on organocatalytic site-selective acylation of unprotected glycosides at the final stage of synthesis. A notable advantage of this strategy is that it avoids the risks of undesired side reactions during the removal of the protecting groups at the final stage of total synthesis. The proposed synthetic strategy has another advantage in terms of efficient late-stage derivatization of natural products. Due to the predictability and reliability of the catalytic site-selective introduction of various functionalized acyl groups, the present synthetic strategy could provide a general synthetic route to 4-O-acylglycosides, such as phenylethanoid glycosides and ellagitannins, which are of biological interest.