Synthesis Of Natural Products Research Articles

Recent progress in the synthesis of natural product inspired bioactive glycohybrids

Carbohydrates are a basic structural component that are indispensable to all cellular processes. In addition to being employed as chiral starting materials in the synthesis of a variety of natural products, carbohydrates are recognized as naturally occurring molecules having an enormous variety of functional, stereochemical, and structural properties. The understanding and biological roles of carbohydrate derived molecules can be greatly improved by selectively synthesizing functional carbohydrates through incorporating them with privileged scaffolds. For a deeper understanding of their roles and the development of functional materials based on sugar, it is crucial to develop new techniques for efficiently synthesizing, functionalizing, and modifying carbohydrates. Glycohybrids have a wide range of structural and functional characteristics along with protein-carbohydrate interactions that are crucial to mammalian biology and a number of disease states. This review, consisting the literature from January 2017 to July 2023 and provide an overview of recent developments in the chemical synthesis of glycohybrids based on natural product scaffolds of coumarin, quinolone, naphthalene diimide, indole, isatin, naphthoquinone, imidazole and pyrimidine. The biological activity of active glycohybrids are discussed in this review.

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

AbstractIncorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional‐group interconversions, the use of enzymatic C−C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel–Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure–activity relationship studies of [7.7]paracyclophane natural products.

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D.

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C-C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel-Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure-activity relationship studies of [7.7]paracyclophane natural products.

P450Rdb: A manually curated database of reactions catalyzed by cytochrome P450 enzymes

IntroductionCytochrome P450 enzymes (P450s) are recognized as the most versatile catalysts worldwide, playing vital roles in numerous biological metabolism and biosynthesis processes across all kingdoms of life. Despite the vast number of P450 genes available in databases (over 300,000), only a small fraction of them (less than 0.2 %) have undergone functional characterization. ObjectivesTo provide a convenient platform with abundant information on P450s and their corresponding reactions, we introduce the P450Rdb database, a manually curated resource compiles literature-supported reactions catalyzed by P450s. MethodsAll the P450s and Reactions were manually curated from the literature and known databases. Subsequently, the P450 reactions organized and categorized according to their chemical reaction type and site. The website was developed using HTML and PHP languages, with the MySQL server utilized for data storage. ResultsThe current version of P450Rdb catalogs over 1,600 reactions, involving more than 590 P450s across a diverse range of over 200 species. Additionally, it offers a user-friendly interface with comprehensive information, enabling easy querying, browsing, and analysis of P450s and their corresponding reactions. P450Rdb is free available at http://www.cellknowledge.com.cn/p450rdb/. ConclusionsWe believe that this database will significantly promote structural and functional research on P450s, thereby fostering advancements in the fields of natural product synthesis, pharmaceutical engineering, biotechnological applications, agricultural and crop improvement, and the chemical industry.

Stereocontrolled Aldol-like Reactions Involving Oxocarbenium Intermediates

Oxocarbenium cations are key intermediates for the stereocontrolled construction of carbon–carbon bonds. Particularly, we have developed a wide range of stereoselective aldol–like processes that take advantage of the high reactivity of the oxocarbenium species arising from acetals, glycals, and orthoesters with metal enolates. This Account describes the development and optimization of such processes, together with other significant contributions, with a particular emphasis on their application to the synthesis of natural products.

Recent Advances in Application of Alkoxy Radical in Organic Synthesis

Alkoxy radicals have been identified as versatile intermediates in synthetic chemistry in the last few decades. Over the last decade, various catalytic processes for the in situ generation of alkoxy radicals have been explored, leading to the development of new synthetic methodologies based on alkoxy radicals. In this review, we provided a comprehensive review of recent developments in the utilization of alkoxy radicals in diverse organic transformations, natural product synthesis, and the late-stage modification of bioactive molecules through the implementation of the photoredox methodology.

Dehalogenative Arylation of Unactivated Alkyl Halides via Electroreduction.

Herein, a facile and efficient dehalogenative arylation of unactivated alkyl halides enabled by electrochemical reductive coupling is developed, affording a series of C(sp2)-C(sp3) products in moderate to good yields. This protocol proceeds in the absence of transition metal catalysts and redox mediators. The reaction features mild conditions, broad substrate scope, and high tolerance of functional groups and is demonstrated to be applicable for gram-scale synthesis and late-stage functionalization of natural products.

High-Efficiency Multiplexed Cytosine Base Editors for Natural Product Synthesis in Yarrowia lipolytica.

Yarrowia lipolytica is an industrial host with a high fatty acid flux. Even though CRISPR-based tools have accelerated its metabolic engineering, there remains a need to develop tools for rapid multiplexed strain engineering to accelerate the design-build-test-learn cycle. Base editors have the potential to perform high-efficiency multiplexed gene editing because they do not depend upon double-stranded DNA breaks. Here, we identified that base editors are less toxic than CRISPR-Cas9 for multiplexed gene editing. We increased the editing efficiency by removing the extra nucleotides between tRNA and gRNA and increasing the base editor and gRNA copy number in a Ku70 deficient strain. We achieved five multiplexed gene editing in the ΔKu70 strain at 42% efficiency. Initially, we were unsuccessful at performing multiplexed base editing in NHEJ competent strain; however, we increased the editing efficiency by using a co-selection approach to enrich base editing events. Base editor-mediated canavanine gene (CAN1) knockout provided resistance to the import of canavanine, which enriched the base editing in other unrelated genetic loci. We performed multiplexed editing of up to three genes at 40% efficiency in the Po1f strain through the CAN1 co-selection approach. Finally, we demonstrated the application of multiplexed cytosine base editor for rapid multigene knockout to increase naringenin production by 2-fold from glucose or glycerol as a carbon source.

Strategic application of C-H oxidation in natural product total synthesis.

The oxidation of unactivated C-H bonds has emerged as an effective tactic in natural product synthesis and has altered how chemists approach the synthesis of complex molecules. The use of C-H oxidation methods has simplified the process of synthesis planning by expanding the choice of starting materials, limiting functional group interconversion and protecting group manipulations, and enabling late-stage diversification. In this Review, we propose classifications for C-H oxidations on the basis of their strategic purpose: type 1, which installs functionality that is used to establish the carbon skeleton of the target; type 2, which is used to construct a heterocyclic ring; and type 3, which installs peripheral functional groups. The reactions are further divided based on whether they are directed or undirected. For each classification, examples from recent literature are analysed. Finally, we provide two case studies of syntheses from our laboratory that were streamlined by the judicious use of C-H oxidation reactions.

Road Map Toward Computer-Guided Total Synthesis of Natural Products. The Dysiherbol A Case Study: What if Serendipity Hadn't Intervened?

We present a computational study inspired by the story of dysiherbol A, a natural product whose putative structure was found incorrect through synthesis by a completely fortuitous event. While the carbon connectivity and chemical environment between both structures remain similar, the real dysiherbol A has a different molecular weight than that reported for the natural product. Had the synthesis groups not been favored by fortune, it could be speculated that a substantial amount of time and effort would have been required to solve the structural puzzle. Within the realm of computer-guided total synthesis of natural products, the question arose whether a synthesis group could have in silico reassigned the structure before embarking on the experimental adventure. To address this query, we evaluated some state-of-the-art computational procedures based on their computational demand and ease of implementation for nonexpert users with basic skills in computational chemistry (including HOSE, CASCADE, ANN-PRA, ML-J-DP4, DP4, and DP4+). While discussing the strengths and limitations of these methods, this case study provides a roadmap of what could be done before venturing into complex and time-demanding total synthesis projects.

The isocyanide SN2 reaction

The SN2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in SN2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in SN2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.

Total synthesis of natural products containing the tetralone subunit

Total synthesis of natural products containing the tetralone subunit

Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products.

Polyketide natural products have significant promise as pharmaceutical targets for human health and as molecular tools to probe disease and complex biological systems. While the biosynthetic logic of polyketide synthases (PKS) is well-understood, biosynthesis of designer polyketides remains challenging due to several bottlenecks, including substrate specificity constraints, disrupted protein-protein interactions, and protein solubility and folding issues. Focusing on substrate specificity, PKSs are typically interrogated using synthetic thioesters. PKS assembly lines and their products offer a wealth of information when studied in a chemoenzymatic fashion. This review provides an overview of the past two decades of polyketide chemoenzymatic synthesis and their contributions to the field of chemical biology. These synthetic strategies have successfully yielded natural product derivatives while providing critical insights into enzymatic promiscuity and mechanistic activity.

Synthetic Study on the Lycoricidine Alkaloids

AbstractA stereoselective synthesis of isolycoricidine, a natural product belonging to the Amaryllidaceae alkaloids family was produced. In addition, a synthetic study on the main core of lycoricidine led to the formation of analogues and a diastereomer of dihydrolycoricidine. Our strategy was based on an oxidative phenol dearomatization, a stereoselective Heck process, a selective dihydroxylation on a dienone system, several stereoselective reductions, and an oxidative retro‐Michael procedure as an amine‐deprotecting group strategy. Furthermore, two steps highlight the usefulness of hypervalent iodines in total synthesis of natural products.

Engaging Isatins and Amino Acids in Multicomponent One-Pot 1,3-Dipolar Cycloaddition Reactions-Easy Access to Structural Diversity.

Multicomponent reactions (MCRs) have undoubtedly emerged as the most indispensable tool for organic chemists worldwide, finding extensive utility in the synthesis of intricate natural products, heterocyclic molecules with significant bioactivity, and pharmaceutical agents. The multicomponent one-pot 1,3-dipolar cycloaddition reactions, which were initially conceptualized by Rolf Huisgen in 1960, find extensive application in contemporary heterocyclic chemistry. In terms of green synthesis, the multicomponent 1,3-dipolar cycloaddition is highly favored owing to its numerous advantages, including high step- and atom-economies, remarkable product diversity, as well as excellent efficiency and diastereoselectivity. Among the numerous pieces of research, the most fascinating reaction involves the utilization of azomethine ylides generated from isatins and amino acids that can be captured by various dipolarophiles. This approach offers a highly efficient and convenient method for constructing spiro-pyrrolidine oxindole scaffolds, which are crucial building blocks in biologically active molecules. Consequently, this review delves deeper into the dipolarophiles utilized in the 1,3-dipolar cycloaddition of isatins and amino acids over the past six years.

Advances in Isocyanide‐Based Multicomponent Synthesis of Quinoxaline Scaffolds

AbstractThe present review article includes recent advances in the synthesis of structurally and functionally diversified quinoxalines‐drug‐like small molecules with molecular complexity. We have extended our efforts to include the research work concerning the isocyanide‐based multicomponent reactions. The synthetic methods included in the present review article will provide an access for a diverse range of natural product mimetic scaffolds with the use of isocyanide‐.based combinatorial synthesis. These isocyanide based reactions will be significant for the synthesis of complex bioactive natural products and potential synthetic pharmaceuticals. The present review will contribute considerably to the organic syntheses and particularly drug discovery research including pharmaceutical and medicinal chemistry. Academically, the present review article will be interesting for the researchers engaged in design and development of isocyanide‐based organic transformations. Moreover, we hope that the isocyanide‐based multicomponent reactions will find major applications in industrially significant organic transformations and to develop new synthetic routes to facilitate the incorporation of heterocyclic substructures into pharmaceutically active molecules.

Enantioselective synthesis of structurally diverse aryl γ-/δ- lactones using an engineered carbonyl reductase

Optically pure aryl γ-/δ-lactones are valuable building blocks in the organic synthesis of natural products and pharmaceutical compounds. The asymmetric reduction of aryl keto acids or esters using carbonyl reductase provides a green and atom-economic synthetic route to these molecules. However, this method is still challenging due to the substantial steric hindrance of substrates, which has limited its practical application. Herein, we report the engineering of a carbonyl reductase SmCRV4, which showed excellent enantioselectivity (99% (S)) for methyl 3-benzoyl propionate (1a), to obtain the mutant SmCRW6 by directed evolution. The specific activity and catalytic efficiency of SmCRW6 towards 1a were 4.9-fold and 3.2-fold higher than those of the parent SmCRV4, respectively. The mutant SmCRW6 showed a broad substrate scope (26 examples) with improvement in specific activity and enantioselectivity for most substrates. Finally, 7 chiral aryl lactones and 10 aliphatic lactones were prepared using lyophilized enzyme powder. In scaled-up synthesis, three aryl γ-/δ-lactones were prepared with > 97% conversions, 76 − 88% yields and ee up to > 99%, and the highest space-time yield (STY) of 28.2 g L−1 h−1 reported so far for (S)-γ-phenyl-γ-butyrolactone was obtained through biocatalysis.

Comparative metabolomic and transcriptomic analysis of Saccharomyces cerevisiae W303a and CEN.PK2-1C.

Saccharomyces cerevisiae is a health microorganism closely related to human life, especially in food and pharmaceutical industries. S. cerevisiae W303a and CEN.PK2-1C are two commonly used strains for synthetic biology-based natural product production. Yet, the metabolomic and transcriptomic differences between these two strains have not been compared. In this study, metabolomics and transcriptomics were applied to analyze the differential metabolites and differential expression genes (DEGs) between W303a and CEN.PK2-1C cultured in YPD and SD media. The growth rate of W303a in YPD medium was the lowest compared with other groups. When cultured in YPD medium, CEN.PK2-1C produced more phenylalanine than W303a; when cultured in SD medium, W303a produced more phospholipids than CEN.PK2-1C. Transcriptomic analysis revealed that 19 out of 22 genes in glycolysis pathway were expressed at higher levels in CEN.PK2-1C than that in W303a no matter which media were used, and three key genes related to phenylalanine biosynthesis including ARO9, ARO7 and PHA2 were up-regulated in CEN.PK2-1C compared with W303a when cultured in YPD medium, whereas seven DEGs associated with phospholipid biosynthesis were up-regulated in W303a compared with CEN.PK2-1C when cultured in SD medium. The high phenylalanine produced by CEN.PK2-1C and high phospholipids produced by W303a indicated that CEN.PK2-1C may be more suitable for synthesis of natural products with phenylalanine as precursor, whereas W303a may be more appropriate for synthesis of phospholipid metabolites. This finding provides primary information for strain selection between W303a and CEN.PK2-1C for synthetic biology-based natural product production.

Synthesis and Application of Immunomodulatory Natural Products

Synthesis and Application of Immunomodulatory Natural Products

Infusion of Magnetic Nanocatalyst to Microwave Propped Synthesis of Bioactive Azaheterocycles

Abstract: Microwave-assisted synthesis is a powerful tool in organic chemistry, providing a rapid and efficient method for the synthesis of bioactive heterocycles. The application of micro-waves significantly reduces reaction times and increases percentage yields with high purity of the final product. To make the synthetic protocol greener, the application of the magnetic nanocata-lyst is a rapidly growing area of interest nowadays. Magnetic nanocatalyst, with its unique fea-tures like magnetic separable facile recovery from the reaction media heterogeneously, makes the overall synthetic strategy cleaner, faster, and cost-effective. Aiming this, in the present review, we will focus on the infusion of Magnetic nanocatalyst to microwave-assisted synthesis of vari-ous classes of azaheterocyclic compounds, including pyridines, pyrimidines, quinolines, and ben-zimidazoles. The synthetic methodologies involved in the preparation of these heterocycles are highlighted, along with their biological activities. Furthermore, in this review, the most recent and advanced strategies to incorporate nanocatalysts in the microwave-assisted synthesis of nat-ural products containing azaheterocyclic moieties in drug discovery programs are elucidated in detail, along with the incoming future scope and challenges.