Synthesis Of Bioactive Natural Products Research Articles

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization.

Chemoenzymatic strategies that combine synthetic and enzymatic transformations offer efficient approaches to yield target molecules, which have been increasingly employed in the synthesis of bioactive natural products. In the biosynthesis of macrocyclic nonribosomal peptides, polyketides, and their hybrids, thioesterase (TE) domains play a significant role in late-stage macrocyclization. These domains can accept mimics of native substrates in vitro and exhibit potential for use in total synthesis. This review summarizes the recent advances of TE domains in the chemoenzymatic synthesis for these natural products that aim to address the common issues in classical synthetic approaches and increase synthetic efficiencies, which have the potential to facilitate further pharmaceutical research.

Catalytic asymmetric carbenoid α-C-H insertion of ether.

Significant advancements have been made in catalytic asymmetric α-C-H bond functionalization of ethers via carbenoid insertion over the past decade. Effective asymmetric catalytic systems, featuring a range of chiral metal catalysts, have been established for the enantioselective synthesis of diverse ether substrates. This has led to the generation of various enantioenriched, highly functionalized oxygen-containing structural motifs, facilitating their application in the asymmetric synthesis of bioactive natural products.

Deconstructive and Divergent Synthesis of Bioactive Natural Products.

Natural products play a key role in innovative drug discovery. To explore the potential application of natural products and their analogues in pharmacology, total synthesis is a key tool that provides natural product candidates and synthetic analogues for drug development and potential clinical trials. Deconstructive synthesis, namely building new, challenging structures through bond cleavage of easily accessible moieties, has emerged as a useful design principle in synthesizing bioactive natural products. Divergent synthesis, namely synthesizing many natural products from a common intermediate, can improve the efficiency of chemical synthesis and generate libraries of molecules with unprecedented structural diversity. In this review, we will firstly introduce five recent and excellent examples of deconstructive and divergent syntheses of natural products (2021-2023). Then, we will summarize our previous work on the deconstructive and divergent synthesis of natural products to demonstrate the high efficiency and simplicity of these two strategies in the field of total synthesis.

A Historical Review of the Total Synthesis of Natural Products Developed in Portugal

AbstractTotal synthesis of natural products is an important discipline of organic chemistry that has enabled the development of new synthetic methods and strategies for the preparation and study of the structure and reactivity of complex naturally occurring products. In this review we summarize the synthetic strategies developed in Portugal by several research groups for the synthesis of bioactive natural products including alkaloids, cyclitols, fatty alcohols, phenylpropanoic acids, γ‐butyrolactones, xanthones and nucleosides.

Recent Advances in the Synthesis and Applications of m-Aryloxy Phenols.

Since phenol derivatives have high potential as building blocks for the synthesis of bioactive natural products and conducting polymers, many synthesis methods have been invented. In recent years, innovative synthetic methods have been developed for the preparation of m-aryloxy phenols, which has allowed for the preparation of complex m-aryloxy phenols with functional groups, such as esters, nitriles, and halogens, that impart specific properties of these compounds. This review provides an overview of recent advances in synthetic strategies for m-aryloxy phenols and their potential biological activities. This paper highlights the importance of m-aryloxy phenols in various industries, including plastics, adhesives, and coatings, and it discusses their applications as antioxidants, ultraviolet absorbers, and flame retardants.

[Bridge between Total Synthesis of Bioactive Natural Products and Development of Drug Leads].

Although natural products are rich sources for drug discovery, only a small percentage of natural products themselves have been approved for clinical use, thus it is necessary to modulate various properties, such as efficacy, toxicity, and metabolic stability. A question in natural product drug discovery is how to logically design natural product derivatives with desired biological properties. This review describes our recent studies regarding the medicinal chemistry of tunicamycin. Tunicamycin inhibits bacterial phospho-N-acetylmuramic acid (MurNAc)-pentapeptide translocase (MraY), which is an essential enzyme in bacteria and a good target for antibacterial drug discovery. The usefulness of tunicamycin as antibacterial agents is limited by off-target inhibition of human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). We positioned the total synthesis of tunicamycin as a starting point for the research and have accomplished the synthesis of tunicamycin V by using the Achmatowicz reaction, [3,3] sigmatropic rearrangement of allyl cyanate, and stereoselective glycosylation as key reactions. Next, the minimum structural requirements for tunicamycin V for MraY inhibition were established by systematic structure-activity relationship studies with truncated analogs of tunicamycin V. Our collaborative study elucidated a crystal structure of human GPT in complex with tunicamycin. This structural information was then exploited to rationally design an MraY-specific inhibitor of tunicamycin V in which the GlcNAc moiety was modified to a MurNAc amide. The analog was identified as a highly selective MraYAA inhibitor.

Synthesis of bioactive natural products and their analogs at room temperature – an update

Abstract Sustainability is a concept that is employed to distinguish methods and procedures that can ensure the long-term productivity of the environment as it includes environmental, social, and economic dimensions. New generations can live on this planet with less hazardous substances and minimum requirement of energy for chemical transformations as green chemistry is related to creativity and the development of innovative research. Among the 12 principles of this clean chemistry, the sixth principle is devoted to the “design of energy efficiency” which discloses that less or the minimum amount of energy is required to conduct a specific reaction with optimum productivity. The most successful way to save energy is to construct strategies/methodologies that are capable enough to carry out the chemical transformations at ambient temperature and standard pressure. Hence, the present review wishes to cover the synthesis of bioactive natural products and their derivatives at room temperature. Bioactive secondary metabolites play a crucial role in the drug discovery together with drug development process; chiefly anticancer along with antibiotic molecules is noticeably enriched with molecules of natural origin. Natural sources, structures, and biological activities of natural products are highlighted in this review and it is also aimed to offer an overview of the design and synthesis of bioactive natural products and their analogs at room temperature for the first time efficiently.

Laccase-mediated synthesis of bioactive natural products and their analogues.

Laccases are a class of multicopper oxidases that catalyse the one-electron oxidation of four equivalents of a reducing substrate, with the concomitant four-electron reduction of dioxygen to water. Typically, they catalyse many anabolic reactions, in which mostly phenolic metabolites were subjected to oxidative coupling. Alternatively, laccases catalyse the degradation or modification of biopolymers like lignin in catabolic processes. In recent years, laccases have proved valuable and green biocatalysts for synthesising compounds with therapeutic value, including antitumor, antibiotic, antimicrobial, and antioxidant agents. Further up to date applications include oxidative depolymerisation of lignin to gain new biomaterials and bioremediation processes of industrial waste. This review summarizes selected examples from the last decade's literature about the laccase-mediated synthesis of biologically active natural products and their analogues; these will include lignans and neolignans, dimeric stilbenoids, biflavonoids, biaryls and other compounds of potential interest for the pharmaceutical industry. In addition, a short section about applications of laccases in natural polymer modification has been included.

Recent Achievements in the Synthesis of Oxazoles

Oxazole-containing compounds have diverse biological activities, such as antimicrobial, anticancer, antitubercular, anti­inflammatory, antidiabetic, antiobesity, antimalarial, and antiviral activities, and some of them have been used as drugs for treating diseases. They also play important roles in the synthesis of bioactive natural products, pharmaceuticals and synthetic transformations as well as in materials, catalyst and agriculture fields. Thus, the development of more efficient and facile synthetic approaches to access oxazole compounds has attracted the intensive interest of chemists, and diverse methods for their synthesis have been investigated. Various established methods have been improved and modified, while numerous novel methods have been discovered. This article will summarize considerable studies on the construction of the oxazole skeleton which date back to 2014.

[Studies on the Syntheses of Bioactive Natural Products Having a Fused Ring System Based on Novel Skeletal Construction Methods].

Here, I describe a part of our efforts to develop synthetic strategies to construct bioactive natural products having a fused ring system. We have designed four chiral building blocks bearing contiguous quaternary stereocenters for the syntheses of bioactive C17-oxygenated steroids/triterpenoids and C9-oxygenated labdane diterpenoids. The compounds were stereoselectively synthesized from α-substituted glycolic acid (R)-3-methylcyclohex-2-enyl esters through Ireland-Claisen rearrangement to construct the stereocenters simultaneously. Synthetic utility of a β-type building block is highlighted by total syntheses of marrubiin (11 steps, 22%) and related seven labdane diterpene lactones, cyllenine C (12 steps, 29%), marrulactone (13 steps, 11%), marrulanic acid (14 steps, 10%), marrubasch F (12 steps, 14%), marrulibacetal (14 steps, 4%), marrulibacetal A (14 steps, 2%), and desertine (15 steps, 0.5%). These syntheses feature the construction of the [6.6.5]-tricyclic ring portion via a Pauson-Khand reaction, cleavage of the resultant cyclopentenone ring and an elongation of the C9 side chain by an epoxide opening reaction. The relative stereochemistry of desertine was determined to be 13R, 14S, 15S, 16R by some chemical conversions and NMR analysis. Further efforts toward total syntheses of oxygenated terpenoids using three other chiral building blocks and structure-activity relationship study of synthesized labdane diterpene lactones are currently underway in our laboratory and will be reported in due course.

Sharpless Asymmetric Epoxidation: Applications in the Synthesis of Bioactive Natural Products

This review discusses an important synthetic tool proposed by K.B. Sharpless in 1980, known as the Sharpless asymmetric epoxidation of allylic alcohols, and examines its use in the total synthesis of representative exponents of biologically active natural products. Focus is given to the synthesis of simple to highly complex secondary metabolites, including lactones, amino acids, diterpenes, and macrolides. The Sharpless approach involves the use of a catalyst, titanium tetra isopropoxide [Ti(OiPr)4], dialkyl tartrate as a chiral ligand, and tert-butyl hydroperoxide (TBHP) as an oxidizing agent. The method allows converting allylic alcohols to epoxides, which are chiral building blocks and versatile intermediates in the synthesis of natural products. The biological and synthetic importance of epoxides lies in the susceptibility of the three-membered heterocyclic ring to stereoand regioselective opening by nucleophilic or acidic reagents, providing oxygen adducts.

The Art of Total Synthesis of Bioactive Natural Products via Microwaves

Natural products are the most effective source of potential drug leads. The total synthesis of bioactive natural products plays a crucial role in confirming the hypothetical complex structure of natural products in the laboratory. The total synthesis of rare bioactive natural products is one of the great challenges for the organic synthetic community due to their complex structures, biochemical specificity, and difficult stereochemistry. Subsequently, the total synthesis is a long process in several cases, and it requires a substantial amount of time. Microwave irradiation has emerged as a greener tool in organic methodologies to reduce reaction time from days and hours to minutes and seconds. Moreover, this non-classical methodology increases product yields and purities, improves reproducibility, modifications of selectivity, simplification of work-up methods, and reduces unwanted side reactions. Such beneficial qualities have stimulated this review to cover the application of microwave irradiation in the field of the total synthesis of bioactive natural products for the first time during the last decade. An overview of the use of microwave irradiation, natural sources, structures, and biological activities of secondary metabolites is presented elegantly, focusing on the involvement of at least one or more steps by microwave irradiation as a green technique.

Applications of Yamaguchi Method to Esterification and Macrolactonization in Total Synthesis of Bioactive Natural Products

AbstractYamaguchi protocol provides functionalized esters regioselectively from carboxylic acids and alcohols employing 2,4,6‐trichlorobenzoyl chloride as the condensation reagent in the presence of a stoichiometric amount of 4‐N,N‐dimethylaminopyridine. The key features of this method comprise a high yield of esters, short reaction time, mild conditions, macrocyclic lactone ring formation, and regioselective preparation of highly functionalized esters. Such beneficial quality of this method as a whole have motivated the organic chemist and biological community to explore the application of Yamaguchi protocol in more heights and as a result, the present overview is aimed to cover the application of this method as a key step in the area of the total synthesis of bioactive natural products. The present review tries to focus on the natural sources, structures, and biological activities of the promising natural products elegantly.

N‐Nitroso As A Novel Directing Group in Transition‐Metal‐Catalyzed C(sp2)−H Bond Functionalizations of N‐Nitrosoanilines

AbstractIn the last few decades, the syntheses of bioactive natural products and functional materials have been achieved via C−H bond functionalizations where the transition metals in coordination with the directing groups trigger the C−H bond activation. A wide variety of directing groups has been recognized for transition‐metal‐catalyzed ortho‐C−H bond functionalization of arenes. Recently, N‐nitroso group has been established as a new, efficient and sometimes as a traceless directing group in ortho‐C(sp2)−H bond functionalizations of N‐nitrosoanilines. During functioning as a traceless‐directing‐group, the N ‐O bond of N‐nitrosoaniline acts as an internal oxidant to recycle the employed catalyst. Pd, Rh, Co, Ru and Ir catalysts have been screened for the ortho C−H bond functionalizations of N‐nitrosoanilines constructing new C−C, C−O, C−N and C−X bonds. Herein, we have summarized all the recently developed N‐nitroso group directed ortho‐C(sp2)−H bond functionalization reactions of N‐nitrosoanilines.

Concise Total Syntheses of Bioactive Alkaloids Enabled by Development or Application of Cascade Reactions: A Personnel Adventure

AbstractDesign and development of new tactics and strategies to improve synthetic efficiency is a hot topic and main concern in nowadays’ chemical synthesis of bioactive natural products. Cascade reactions, which construct several bonds in one step via an orchestrated sequence, have been regarded as an important tactic to rapidly increase the molecular complexity, therefor to improve the synthetic efficiency. In this perspective account, we demonstrated and highlighted the significance of cascade reaction developments and applications in concise syntheses of bioactive alkaloids based on our own recent adventure in this research field. What is the most favorite and original chemistry developed in your research group?Total synthesis of bioactive natural products is the most favorite chemistry in my research group and development or application of new strategies to improve the synthetic efficiency is the most original chemistry developed in my research group.How do you get into this specific field? Could you please share some experiences with our readers?My PhD project was total synthesis of bioactive natural lignans and I devoted myself into synthetic methodology development during my postdoctoral research period. In my opinion, a highly efficient synthetic method will greatly shorten the synthetic route and improve its efficiency for a target‐oriented total synthesis. On the other hand, target‐oriented total synthesis is the best platform to evaluate the practical value of a synthetic method. So I choose total synthesis of natural products and target‐oriented synthetic methodology development as my research fields when I began my independent research.How do you supervise your students?When the students start their projects, I discuss the research subjects with them once a month. Every Saturday night we hold a group meeting to learn and discuss the most recent published literatures related to our research. I give more encouragement when the students meet difficulties in their research. Then we try to solve the difficulties together.What is the most important personality for scientific research?In my view, diligence and persistence are the most important personalities for scientific research.What's your hobby? What's your favorite book(s)?Reading. My favorite book is Sapiens‐a brief history of humankind.How do you keep balance between research and family?I usually spend six days (from Monday to Saturday) on research work. On Sunday I will cook some delicious food and enjoy it with my family. My wife understands and supports my work very well. She has done a lot for our family.

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates.

Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor.

Pyroglutamic Acid and its Derivatives: The Privileged Precursors for the Asymmetric Synthesis of Bioactive Natural Products

Pyroglutamic acid is one of the privileged asymmetric precursors for the synthesis of a variety of molecules such as Angiotensin-Converting Enzyme (ACE) inhibitors, angiotensin II receptor subtypes (AT-1 receptor antagonists), as well as bioactive natural products. Starting with primary reports in 1980’s, last almost four decades has witnessed a rapid overgrowth of publications using pyroglutamic acid as a preferred asymmetric precursor and these have been well documented. Pyroglutamic acid has two differential carbonyl groups a lactam carbonyl and a carboxylic functionality along with an NH group, and all of these functionalities can be further derivatized/ transformed and in turn opened avenues for the synthesis of variety of molecules. Derived easily from glutamic acid by internal cyclization, pyroglutamic acid offers a cheap and very good source of chirality and has provided an important tool for the synthesis of natural products/intermediates to natural products. Herein, we wish to describe the exploitation of the chemistry of pyroglutamic acid and its derivatives in the asymmetric synthesis of natural products establishing its versatility as a privileged asymmetric precursor.

CpTiCl2 -Catalyzed Cross-Coupling between Internal Alkynes and Ketones: A Novel Concept in the Synthesis of Halogenated, Conjugated Dienes.

A novel concept for the synthesis of halogenated, conjugated dienes is disclosed: the CpTiCl2 -catalyzed coupling of keto-alkynes, in the presence of Me3 SiBr/Et3 N⋅HBr. This reaction provided five-, six-, and seven-membered carbocycles, nitrogenated heterocycles, as well as six-membered oxygenated heterocycles leading to a brominated conjugate diene. These products showed high reactivity in the Diels-Alder, Suzuki, and Sonogashira reactions, giving complex chemical structures in only three steps from the corresponding acyclic keto-alkyne. Hopefully, this strategy will pave the way towards the synthesis of bioactive natural products and new materials.

New Synthetic Method for Efficient Synthesis of Bioactive Natural Products —Biomimetic Synthesis of Chaxines—

New Synthetic Method for Efficient Synthesis of Bioactive Natural Products —Biomimetic Synthesis of Chaxines—

Direct synthesis of secondary amides from ketones through Beckmann rearrangement using O-(mesitylsulfonyl)hydroxylamine

The Beckmann rearrangement is a versatile method for the preparation of secondary amides from ketones via oxime intermediates and has been widely used in the synthesis of bioactive natural products and pharmaceuticals. Herein, we have developed a highly efficient direct method for the preparation of secondary amides and lactams from ketones using O-(mesitylsulfonyl)hydroxylamine (MSH). The reactions proceed rapidly at room temperature under mild condition without requiring any additive, and tolerate multiple functional groups. A simple aqueous work-up often furnished the products in excellent yield with high purity.