Synthesis Of Natural Products Research Articles

(+)-Nootkatone, the flavor of grapefruit

Nootkatone is one of the most valuable citrus flavors. Originally isolated from the heartwood of the Nootka cypress (Callitropsis nootkatensis), it was probably the identification of nootkatone as a minor component of grapefruit oil that catapulted this sesquiterpene into the focus of flavor research and made it a highly sought-after citrus aroma in recent decades. The odors of ( +)-nootkatone and (−)-nootkatone are perceptible in the air at threshold concentrations of 30 ppm and 66,000 ppm of saturated vapor, respectively. While ( +)-nootkatone embodies a strong grapefruit scent and has a bitter taste, (−)-nootkatone has a faint woody vetiver note and is virtually tasteless. In 2020, nootkatone was registered by the US Environmental Protection Agency as an insect repellent and natural insecticide that may repel and kill mosquitoes, fleas, ticks, mites, lice, and termites. Moreover, numerous pharmacological activities of nootkatone have been thoroughly investigated. As expected, a wealth of synthetic approaches, which are essentially based on the oxidation of valencene and on total syntheses, have been published in the last 60 years since its discovery. However, in addition to extraction from natural sources (e.g., grapefruit peel), the enzymatic oxidation of valencene and fermentative processes are the preferred production technologies today. The market is expected to grow considerably over the next 10 years, not least owing to the wide range of potential applications in the pharmaceutical, personal, and home care sector.How the reader may benefit: learn more about the total synthesis of natural products, allylic oxidation, and Robinson annulation, gain deeper insights into the biosynthesis of sesquiterpenes and finally discover how enantiopure compounds, such as ( +)-nootkatone, are produced at an industrial scale.Graphical

Bioinspired Total Synthesis of Natural Products.

ConspectusCurrently, the frontier challenges in total synthesis pertain to increasing the synthetic efficiency and enabling the divergent synthesis of a number of natural products. Bioinspired synthesis has been well recognized as an effective approach to increasing synthetic efficiency. Especially, when bioinspired synthesis was applied at late-stage skeletal diversification to generate various natural products with distinct carbon skeletons, it held special promise for achieving both goals. In our laboratory, bioinspired synthesis has served as one of two long-standing principles for facilitating the efficient synthesis of natural products. In this Account, we summarize our endeavors and journeys in the bioinspired synthesis of natural products. We categorize our work into three parts based on the imitation of biosynthetic reactions and processes.(1) To mimic the key cyclization steps. Inspired by the biosynthetic process that formed the core skeleton, we developed new synthetic methods to enable the rapid and efficient construction of the core skeletons of the targeted molecules, ultimately leading to their concise total synthesis, for example, seven-step total synthesis of lamellarins D and H featuring three bioinspired oxidative coupling reactions, seven-step total synthesis of clavicipitic acid highlighted by a C-H activation/aminocyclization cascade reaction, eight-step total synthesis of phalarine via a bioinspired oxidative coupling, seven-step total synthesis of α-cyclopiazonic acid, and ten-step total synthesis of speradine C through a bioinspired cascade cyclization reaction initiated by the benzylic carbocation of indole. (2) To mimic the revised biosynthetic pathway proposed by us. In some cases, the proposed biosynthetic processes may be flawed, as they contradict some basic principles of chemistry. Thus, an alternative biosynthetic process must be proposed and investigated. We showcase the total synthesis of euphorikanin A through a bioinspired benzilic acid-type rearrangement and bipolarolides A and B via a bioinspired Prins reaction/ether formation cascade cyclization. (3) To mimic the skeletal diversification process. Nature usually synthesizes a multitude of products from a key common intermediate in a divergent manner. Biogenic skeletal diversification to generate various natural products with distinct carbon skeletons has also drawn our attention. Compared with single-target-oriented synthesis, skeletal-diversity-oriented synthesis of natural products remains underexplored due to its high synthetic challenges. We showcased the divergent total syntheses of ten pallavicinia diterpenoids with three distinct skeletons and six grayanane diterpenoids with three distinct skeletons, which were achieved with unprecedented ease and high efficiency by imitation of the proposed biogenic skeletal diversification process. These two successful projects can serve as inspiration for the application of the bioinspired skeletal diversification strategy to other skeletally diverse natural products.

Regioselective Palladaelectro‐catalyzed Chlorination of Arenes in an Undivided Cell

Chloroarenes constitute fundamental building blocks in organic synthesis and are widely applied in the synthesis of bioactive compounds, fine chemicals, materials, natural products and pharmaceuticals. Electrochemical chlorination has been recognized as a promising synthetic method for accessing chloroarenes, but it has proved challenging to achieve in practice as shown by the limited number of existing protocols. Herein, we report on a highly general electrocatalytic strategy for the regioselective chlorination of various substituted heteroaryl scaffolds in an undivided cell setup, using ethyl chloroformate as the chlorine source. This strategy offers several practical advantages over existing methodologies, including an operationally simple experimental setup, exceptional functional group tolerance, and the possibility to form either the mono‐ or bis‐chlorinated products in high selectivity depending on the choice of catalyst loading, electric current and ethyl chloroformate equivalents. The practicality and selectivity of the protocol were demonstrated by the successful chlorination of an array of densely‐substituted arene frameworks as well as by the synthesis of chlorinated bioactive molecules.

Recent Advances and Challenges in the Production of Hydroxylated Natural Products Using Microorganisms

Hydroxylation reaction is a significant source of structural diversity in natural products (NPs), playing a crucial role in improving the bioactivity, solubility, and stability of natural product molecules. This review summarizes the latest research progress in the field of natural product hydroxylation, focusing on several key hydroxylases involved in the biosynthesis of NPs, including cytochrome P450 monooxygenases, α-ketoglutarate-dependent hydroxylases, and flavin-dependent monooxygenases. These enzymes achieve selective hydroxylation modification of various NPs, such as terpenoids, flavonoids, and steroids, through different catalytic mechanisms. This review systematically summarizes the recent advances on the hydroxylation of NPs, such as amino acids, steroids, terpenoids, lipids, and phenylpropanoids, demonstrating the potential of synthetic biology strategies in constructing artificial biosynthetic pathways and producing hydroxylated natural product derivatives. Through metabolic engineering, enzyme engineering, genetic engineering, and synthetic biology combined with artificial intelligence-assisted technologies, a series of engineered strains have been successfully constructed for the efficient production of hydroxylated NPs and their derivatives, achieving efficient synthesis of hydroxylated NPs. This has provided new avenues for drug development, functional food, and biomaterial production and has also offered new ideas for the industrial production of these compounds. In the future, integrating artificial synthetic pathway design, enzyme directed evolution, dynamic regulation, and artificial intelligence technology is expected to further expand the application of enzyme-catalyzed hydroxylation reactions in the green synthesis of complex NPs, promoting research on natural product hydroxylation to new heights.

Spiro[bicyclo[3.2.0]heptane-2,2'-[1,3]dioxolan]-6-one - a versatile intermediate for the synthesis of cyclopentane-derived natural products

Spiro[bicyclo[3.2.0]heptane-2,2'-[1,3]dioxolan]-6-one - a versatile intermediate for the synthesis of cyclopentane-derived natural products

Recent Developments in the Metal-Catalyzed Synthesis of Nitrogenous Heterocyclic Compounds.

Metal-catalyzed cyclization reactions have become a powerful and efficient approach for the stereoselective construction of both carbocyclic and heterocyclic ring systems. Transition metal complexes, with their ability to activate and selectively functionalize organic substrates, have revolutionized various areas of synthetic chemistry. This review highlights recent advancements in metal-catalyzed cyclization reactions, especially in the synthesis of nitrogen-containing heterocycles like imidazoles, pyridines, pyrimidines, and indoles. These advancements have significantly impacted fields such as natural product synthesis, pharmaceuticals, functional materials, and organic electronics. Novel catalytic systems, ligand designs, and reaction conditions continue to expand the capabilities of these reactions, driving further the progress made in synthetic organic chemistry. This review provides a comprehensive overview of recent research.

On the Halogenation of Tyrosine N‐Oxime Methyl Ester

Efficient syntheses of mono‐, di‐, and heterodihalogenated derivatives of tyrosine N‐oxime methyl ester are reported. Monohalogenation with N‐bromosuccinimide (NBS), N‐chlorosuccinimide (NCS) or N‐iodosuccinimide (NIS) was optimized by addition of acid to suppress dihalogenation, affording bromo, chloro, and iodo derivatives in 71%, 50‐53%, and 78‐80% yields, respectively. Homodihalogenation utilized a two‐step, one‐flask process via a spirocyclic intermediate, yielding dibromo, dichloro, and diiodo analogues, respectively (75‐76%, 54‐56%, 79‐80%). This strategy was extended to synthesize heterodihalogenated bromochloro, bromoiodo, and chloroiodo derivatives from monohalogenated analogues (50‐77%). Key to this approach was the formation of an oxidized spirocyclic intermediate using excess N‐halosuccinimide, followed by Na₂S₂O₄ reduction. This method ensures complete conversion and simplifies purification. Nine halogenated building blocks were prepared. These methods provide practical access to versatile precursors for natural product synthesis and derivatization, offering potential for diverse synthetic applications including regioselective palladium‐catalyzed couplings.

Yeast metabolism adaptation for efficient terpenoids synthesis via isopentenol utilization

Microbial biosynthesis has become the leading commercial approach for large-scale production of terpenoids, a valuable class of natural products. Enhancing terpenoid production, however, requires complex modifications on the host organism. Recently, a two-step isopentenol utilization (IU) pathway relying solely on ATP as the cofactor has been proposed as an alternative to the mevalonate (MVA) pathway, streamlining the synthesis of the common terpenoid precursors. Herein, we find that isopentenol inhibits energy metabolism, leading to reduced efficiency of the IU pathway in Saccharomyces cerevisiae. To overcome this, we engineer an IU pathway-dependent (IUPD) strain, designed for growth-coupled production. The IUPD strain is compelled to enhance the ATP supply, essential for the IU pathway, and incorporates a high-throughput screening method for enzyme evolution. The refined IU pathway surpasses the MVA pathway in synthesizing complex terpenoids. Our work offers valuable insights into developing growth-coupled strains adapted to efficient natural product synthesis.

One‐Pot Synthesis of Ortho‐Halogen‐Substituted Aryl(Alkynyl)Phosphinates Via Aryne‐Phosphite‐Haloalkyne Coupling

AbstractThe one‐pot formation of two C−P bonds and one C−halogen bond was achieved through a mild three‐component coupling reaction utilizing arynes, phosphites, and haloalkynes. In this reaction, the aryl anion, generated from the nucleophilic addition of phosphite to aryne, directly attacked the halogen of the haloalkyne. The reaction proceeded smoothly with a wide substrate scope and good functional group tolerance. This operationally simple method enables direct access to ortho‐halogen‐substituted aryl(alkynyl)phosphinates. The synthetic utility of ortho‐halogen‐substituted aryl(alkynyl)phosphinates with prospective applications in natural product synthesis, medicinal chemistry, and materials chemistry has also been demonstrated.

Whole-Cell Biotransformation for the Preparation of Chromopyrrolic Acid and 5,5'-dichloro-Chromopyrrolic Acid in Escherichia coli.

Chromopyrrolic acid (CPA) and its congeners are important intermediates for the biosynthesis and synthesis of various dimeric tryptophan natural products. We have constructed two E. coli strains (CPA001/CPA002) harboring a single plasmid carrying genes coding for a combination of two enzymes (LaStaO/LzrO and VioB) that are able to convert L-tryptophan (L-Trp)/5-chloro-L-tryotophan (5-Cl-L-Trp) to chromopyrrolic acid (CPA)/5,5'-dichloro-chromopyrrolic acid (5,5'-diCl-CPA). Effect on the production of CPA were evaluated by varying the parameters of strain cultivation and biotransformation process. Under the optimized conditions, up to 325 mg/L of CPA and 275 mg/L of 5,5'-diCl-CPA could be obtained by supplementing L-Trp and 5-Cl-L-Trp, respectively, to a working culture of CPA001, or to a phosphate buffer-resuspended culture of CPA002. The practicability of this whole-cell biotransformation system could also be served as a potential platform for the preparation of CPA congeners.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr‐Catalyzed Dimerization

AbstractA concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr‐catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2‐bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr‐catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization.

A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C-H Functionalization of Anilines.

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

AbstractTryptophan and its non‐canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long‐standing challenge. Here, we report a regioselective synthesis of non‐canonical tryptophans bearing C4−C7 substituents via Rh‐catalyzed annulation between structurally diverse tert‐butyloxycarbonyl (Boc)‐protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc‐directed C−H metalation and demetalation to afford a wide range of C2‐unsubstituted indole products in a redox‐neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non‐canonical tryptophan residues in a highly regioselective manner.

Theoretical Analysis of Multi-conformational Transition States and Diastereo/Regio-selective Reactions in Natural Product Synthesis

Theoretical Analysis of Multi-conformational Transition States and Diastereo/Regio-selective Reactions in Natural Product Synthesis

Tandem Acylation and Aromatization of Vinylogous Esters: A Regiospecific Approach to Resorcinyl Ketones.

This study demonstrates the direct conversion of vinylogous esters into selectively protected 6-acyl resorcinols (4-alkoxy/aryloxy-2-hydroxy arylketones) in a regiospecific manner. Resorcinyl ketones are first-time synthesized, diverging from their traditional roots, originating from non-benzenoid pool materials. Converting cyclohexenones into phenol- or resorcinol-based arylketones remains challenging due to the stability and reactivity issues of intermediate products. Addressing this critical gap, we introduce a novel strategy: sequential one-pot acylation and oxidative aromatization of vinylogous esters. This innovative approach aims to surmount the long-standing barrier, facilitating the synthesis of diverse resorcinyl ketones. Furthermore, this method proves valuable for the synthesis of functionalized diaryl ethers and in the total synthesis of bioactive natural products and drug molecules such as angolensin, isoliquiritigenin, demethylsorbicillin, ponganone VII, and ipriflavone. It is also useful for modifying bioactive acids and alcohols by introducing a resorcinol functionality in the late stage of synthesis. Synthetic analogues of oxybenzone demonstrated superior ultraviolet (UV) absorption properties, effectively covering the entire UV-A and UV-B regions, spanning from 230 to 410 nm.

Total Syntheses of Cyclomarin and Metamarin Natural Products.

The first total synthesis of the heptapeptide Cyclomarin A (CymA) was achieved via new routes to chiral amino acid building blocks (highlighted) and solid-phase peptide synthesis. A structurally misassigned epimer of CymA (CymA'), Cyclomarin C, and Metamarin were also synthesized. Affirmation of the syntheses was corroborated by observations that the synthetic molecules have antimicrobial activities mirroring those of the natural products. Interestingly, CymA' is more potent than CymA.

Study of Electron Beam Irradiated Palladium on Carbon Catalysts for Transfer Hydrogenation Reactions of Nitroarenes Compounds

Palladium-catalyzed hydrogenation is considered a crucial stage in the entire synthesis of difficult natural products as well as a crucial step in the manufacturing of fine compounds used in pharmaceuticals. When it comes to the reaction rate and simplicity of work-up, using Pd/C as heterogeneous catalyst is one of the best choice for process efficiency. In this study, nitroarenes compounds viz. 3-bromo nitrobenzene, 4-fluoro nitrobenzene, 3-methyl nitrobenzene, 4-hydroxy nitrobenzene reduced by using macro 10% Pd/C and micro 10% Pd/C to 3-bromo aniline, 4-fluoro aniline, 3-methyl aniline, 4-hydroxy aniline respectively and verified from 1H NMR studies. The reduction reactions were similar conditions using electron beam irradiated 250 kGy macro and micro 10% Pd/C catalyst. The effectiveness of commercial sources of palladium on carbon (Pd/C) varies widely, leading to the appreciable variations in the reaction times. The decrease in reaction time has been attributed to the higher dispersion of Pd particles upon irradiation. The physico-chemical characteristics of effective hydrogenation catalysts were determined to be: (i) small Pd particle size and (ii) homogeneous distribution of Pd on the carbon support. With no significant loss of catalytic activity, the electron beam-irradiated catalyst can be used again for five runs. These days, chemists can determine as well as forecast the effectiveness of catalysts before investing time and money in expensive synthetic materials.

Current Applications of Organocatalysis in Total Synthesis of Natural Products at Room Temperature

Current Applications of Organocatalysis in Total Synthesis of Natural Products at Room Temperature

Inoculation of Arthrobacter sp. improves the growth of Acanthocalycium sp. and the fruits nutraceutical quality and the flowers longevity

Research objective: The aim of this work is on the inoculation in the growing medium of Arthrobacter sp. and its effects on the growth, flower quality and longevity of cactus plants. To this end, the study of biometric parameters, i.e. plants and flowers (height, weight, number and duration), as well as root growth (weight), and the presence of disease were quantified as measures of plant productivity and compared with those obtained from non-inoculated plants. The use of alginate microspheres as a means of bacterial inoculation was also considered. Materials and Methods: Seedlings of Acanthocalycium (2 years old) Ferrarii, A. Glaucum and A. Violaceum were immediately planted in pots after purchase, in substrate containing (sand 20%, pumice 20% and peat 60%; pH 7; electrical conductivity 0.7 dS/m; total porosity 80% (v/v). A randomised complete block design was applied for the experiments: the pots were randomly divided into two series, one series was inoculated with the bacteria and the other non-inoculated was used as a control. Each month, plant growth was assessed according to (1) plant height, (2) vegetative and root weight, (3) number of flowers per plant (4) flower duration. In addition, the occurrence of possible diseases, in particular Fusarium sp. and Verticillium sp., was assessed. Total flavonoids, total phenols and antioxidant activity were also analysed. Results and Discussion: The experiment showed that the use of Arthrobacter sp. can indeed significantly improve the vegetative and root growth of Acanthocalycium sp. cacti. In addition, there was a significant improvement in the number and floral longevity as well as in the phenol, flavonoid and antioxidant content of the fruits of the inoculated plants compared to the untreated control. The experiment also showed that mortality due to the pathogens Fusarium sp. and Verticillium sp. was significantly reduced in the treated plant. In agreement with these authors, we found that PGPB treatments increased agronomic parameters and improved Fusarium and Verticillium resistance. In general, the application of biostimulants can increase the synthesis of bioactive compounds in plants by increasing resistance to phytopathologies. Inoculation with Arthrobacter sp. led to a significant reduction in the number of dead plants with respect to the diseases analysed. As a result of the stimulating action demonstrated in Acanthocalycium, bioproducts suitable for nutraceutical purposes may be developed in the future. Therefore, new microbe-assisted technologies can help plants to resist stress conditions, improving their tolerance and productivity. Conclusions: Due to its ‘multifunctionality’, the genus Acanthocalycium is considered as one of the species of the future, for ornamental use and medicinal aspects, and new results may help reveal its potential in the context of the bio-economy and circular economy. As natural resources and cultural practices are crucial in defining the quality of flowers when destined for food/nutraceutical applications, the inoculation of Acanthocalycium with Arthrobacter sp. can be envisaged to provide better plant growth under conditions of environmental stress, or as a soil fertiliser, but also to improve the synthesis of natural products used for therapeutic applications.