Framework Of Natural Products Research Articles

Bioactive Extracts: Strategies to Generate Diversified Natural Product- Like Libraries

Abstract: Natural products have stimulated the interest of chemists owing to their abundant structural diversity and complexity. Indeed, natural products have performed an essential role, particularly in the cure of cancerous and infectious diseases, thereby providing medicinal researchers with several unexplored chemotypes for the innovation of new drugs. Fusion of chemical derivatization and combinatorial synthesis forms the basis of the concept of chemo diversification of plants. Diverse libraries of natural product analogs are constructed through existing biological and chemical approaches using unique schemes to expand natural product frameworks. This review aims to present several approaches employed to offer innovative opportunities to synthesize NP-inspired compound libraries. Reactive molecular fragments present in most natural products are chemically converted to chemically engineered extracts (CEEs) or semisynthetic compounds constituting distinct libraries. Bio-guided isolation for natural products required vital tools like reverse phase chromatography and bioautographic assays. Different established strategies from DTS, BIOS, CtD, FOS, FBDD to late-stage diversification facilitate the expansion of molecules with physicochemical properties. In particular, fragment-like natural products with novel skeletons may be used as preliminary points for chemical biology and medicinal chemistry programs with great capacity. In this review, we sum up how NPs have proven fruitful for the novel methodologies responsible for the diversification of complex natural products; therefore, it is worth going over the upcoming integration of natural products with combinatorial chemistry.

Late-Stage Diversification: A Motivating Force in Organic Synthesis.

Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need for a highly efficient and scalable synthetic route to a complex molecular scaffold for diversification frequently inspires new methodological development or unique application of existing methods on structurally intricate systems. Additionally, synthetic planning with an aim toward late-stage diversification can provide access to otherwise unavailable compounds or facilitate preparation of complex molecules with diverse patterns of substitution around a shared carbon framework. For these reasons among others, programs dedicated to the diversification of natural product frameworks and other complex molecular scaffolds have been increasing in popularity, a trend likely to continue given their fruitfulness and breadth of impact. In this Perspective, we discuss our experience using late-stage diversification as a guiding principle for the synthesis of natural product analogs and reflect on the impact such efforts have on the future of complex molecule synthesis.

Biomimetic Domino Knoevenagel/Cycloisomerization Strategy for the Synthesis of Citridone A and Derivatives.

Studies on Knoevenagel condensations between conjugated dienals and 4-hydroxy-2-pyridone/quinolone-type 1,3-dicarbonyl equivalents led to the development of a simple one-pot strategy to access citridone A and related synthetic cyclopenta[b]furopyridones/quinolones. The present work highlights the power of domino cascades in the synthesis of natural product frameworks and may help promote future studies on this promising new class of pyridone alkaloids.

Total Synthesis of Natural Products Containing Enamine or Enol Ether Derivatives.

Enamine and enol ethers are nucleophilic functional groups that are well known to most chemists. When enamine or enol ethers are present in natural products, they are nearly exclusively found as derivatives having a direct connection to electron-withdrawing groups for stabilization, and the resulting larger entities, such as enamides or enol acylates, can be further extended or modified in the framework of natural products. The restricted conformational space that is associated with even simple enamine and enol ether derivatives can be a strong determinant of the overall molecular structure, and the more polarized derivatives can endow some natural products with electrophilic properties and thus facilitate covalent interactions with biological targets.In this Account, I describe our efforts (published since 2016) to prepare natural products from several different classes that all feature enamine or enol ether derivatives as key functionalities. Our choice of targets has been guided by a desire to illuminate unknown biological mechanisms associated with the compounds or, alternatively, to improve upon known biological activities that appear to be promising from a biomedical perspective. In the present text, however, the exclusive focus will be on the syntheses.First, I will discuss the basic properties of the functional groups and briefly present a small collection of illustrative and inspirational examples from the literature for their construction in different complex settings. Next, I will provide an overview of our work on the macrocyclic APD-CLD natural products, rakicidin A and BE-43547A1, involving the development of an efficient macrocyclization strategy and the development of methods to construct the hallmark APD group: a modified enamide. The synthesis of the meroterpenoid strongylophorine-26 is discussed next, where we developed an oxidative quinone methoxylation to build a vinylogous ester group in the final step of the synthesis and employed FeCl3-mediated cascade reactions for the rapid assembly of the overall scaffold to enable a short semisynthesis from isocupressic acid. An efficient core scaffold assembly was also in focus in our synthesis of the alkaloid streptazone A with the signature enaminone system being assembled through a rhodium-catalyzed Pauson-Khand reaction. Sequential, site-selective redox manipulations were developed to arrive at strepatzone A and additional members of the natural product family. Finally, I discuss our work to prepare analogs of complex polyether ionophores featuring functionalized tetronic acids as cation-binding groups. A method for the construction of a suitably protected chloromethylidene-modified tetronate is presented which enabled its installation in the full structure through a C-acylation reaction. This work exemplifies how components of abundant polyether ionophores can be recycled and used to access new structures which may possess enhanced biological activities.

Recent Advances and Perspectives in the Synthesis and Applications of Tetrahydrocarbazol‐4‐ones†

Tetrahydrocarbazol‐4‐one represents a prevalent framework of numerous natural products and pharmaceuticals. This review summaries the recent synthetic progresses of this core structure, including Fischer indolization, oxidative and reductive coupling, α‐arylative cyclization by means of transition‐ metal catalysis or under metal‐free conditions, and other methods. The recently emerged enantioselective catalytic methods of tetrahydrocarbazol‐4‐ ones are also described. The mechanistic insights and applications of these strategies as a key step in the total (formal) synthesis of complex alkaloids are highlighted as well.

Diastereodivergent synthesis of enantioenriched α,β-disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene and Ir catalysis

The stereodivergent synthesis of natural product frameworks via a single transformation using simple starting materials is a significant challenge. The prevalence of γ-butyrolactones in biologically active natural products has long motivated the development of enantioselective strategies towards their synthesis. Herein, we report an enantio- and diastereodivergent [3 + 2] annulation reaction for the synthesis of α,β-disubstituted γ-butyrolactones through cooperative N-heterocyclic carbene organocatalysis and iridium catalysis. This method overcomes the challenges of merging N-heterocyclic carbene organocatalysis with iridium catalysis by the appropriate choice of ligands. The use of two chiral catalysts allowed control over the relative and absolute configuration of the two formed stereocentres, thereby providing selective access to all four possible stereoisomers of the γ-lactone products. The transformation could be extended to the synthesis of δ-lactams via [4 + 2] annulation. The synthetic utility of this methodology was illustrated in the concise synthesis of the naturally occurring lignan (−)-hinokinin. Methods to allow access to all isomers of a product are both valuable and challenging to achieve. Here the authors report a catalytic system comprised of an N-heterocyclic carbene and an iridium complex, and show that it can be used for the asymmetric, diastereodivergent synthesis of γ-butyrolactones.

The Application of Dioxygenase‐Based Chemoenzymatic Processes to the Total Synthesis of Natural Products

This Minireview describes the exploitation of certain enzymatically derived, readily accessible, and enantiomerically pure cis-1,2-dihydrocatechols as starting materials in the chemical synthesis of a range of biologically active natural products, most notably sesquiterpenoids and alkaloids.

Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a β-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C–C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016–2019.

Bifunctional oxindole-chromone 4C building block directed asymmetric synthesis of bispirocyclic hexahydroxanthones featuring five contiguous stereocenters and two side-by-side oxindoles

Optically active small molecules based on privileged natural product frameworks and rich in three-dimensional complexity are in high demand.

An Intramolecular Cycloaddition Approach to the Kauranoid Family of Diterpene Metabolites.

Synthetic studies toward the ent-kauranoid family of diterpene natural products are reported. An intramolecular (4 + 3) cycloaddition allows the direct elaboration of diverse natural product frameworks, encompassing a challenging bicyclo[3.2.1]octane core. The established routes comprise only a few synthetic operations (3-5 steps), transforming a range of simple starting materials into the tetracyclic scaffolds that are commonly found in many ent-kaurene metabolites.

Reactivity of 2-Nitropyrrole Systems: Development of Improved Synthetic Approaches to Nitropyrrole Natural Products.

Fundamental study of the reactivity of 2-nitropyrrole systems has enabled the identification of effective methods for incorporation of this unusual motif into advanced natural product frameworks. The presence of electron-rich pyrrole N-protecting groups (BOM, Boz) was demonstrated to enable a variety of previously unsuccessful palladium-mediated cross-couplings to be carried out in high yield. Based on this foundation, a series of regio- and stereoselective synthetic routes toward the nitropyrrolin and heronapyrrole families of natural products was developed by our group (G1-3). A full account of the strategic evolution of these approaches is reported here, highlighting the details of the setbacks encountered and eventual successes achieved en route, including the total synthesis of heronapyrrole B. The fundamental studies and completed total syntheses provide general access to the bioactive 2-nitropyrrole natural product manifold and also establish practical and efficient methods for preparation and elaboration of the medicinally relevant 2-nitropyrrole motif.

Application of the Asymmetric Pictet-Spengler Reaction in the Total Synthesis of Natural Products and Relevant Biologically Active Compounds.

Tetrahydroisoquinolines are the framework of numerous natural products predominantly alkaloids, an important and one of the most wide spread families of naturally occurring compounds in the plant kingdom. Tetrahydroisoquinolines are commonly constructed through an old reaction, the so-called Pictet–Spengler Reaction (PSR). In this reaction, a β-aryl ethylamine undergoes an acid mediated condensation with a suitable aldehyde or ketone, followed by ring closure. In this review, we aim to highlight the applications of the asymmetric variant of this old name reaction in the total synthesis of natural products, chiefly, alkaloids, which exhibit significant biological properties.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

ChemInform Abstract: Synthesis of 3‐Hydroxyindanones via Potassium Salt of Amino Acid Catalyzed Regioselective Intramolecular Aldolization of ortho‐Diacylbenzenes.

Abstract First organocatalytic intramolecular aldolization of ortho -diacylbenzenes to construct highly functionalized 3-hydroxyindanones is described. In this transformation a high trans -selectivity is achieved by the use of metal salt of amino acid. This method allows an easy access to the strained spirocyclic 3-hydroxyindanones related to a number of natural product frameworks. Synthesis of a new class of indole skeleton substituted by 3-hydroxyindanones added an extra essence to this new protocol.

ChemInform Abstract: Gold versus Rhodium: Divergent Reactivity Enabled by the Catalyst

AbstractReview: application to the synthesis of important natural product frameworks; 16 refs.

Synthesis of many different types of organic small molecules using one automated process.

Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block-based synthesis platform to include even C(sp3)-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.

Synthesis of the Spirocyclic Framework of Sesterterpenoid Natural Products

A convergent synthetic route to the sesterterpenoid framework of the bioactive phorbaketal and alotaketal natural product families has been established. The synthetic approach hinges on a Hosomi-Sakurai coupling of complex acetal and allylsilane coupling partners, followed by DDQ-promoted oxidative cyclization of highly unsaturated advanced intermediates. This robust synthetic approach enables further investigations into the members of these natural product families and readily provides access to analogues for biological testing.

Synthesis of 3-hydroxyindanones via potassium salt of amino acid catalyzed regioselective intramolecular aldolization of ortho-diacylbenzenes

First organocatalytic intramolecular aldolization of ortho-diacylbenzenes to construct highly functionalized 3-hydroxyindanones is described. In this transformation a high trans-selectivity is achieved by the use of metal salt of amino acid. This method allows an easy access to the strained spirocyclic 3-hydroxyindanones related to a number of natural product frameworks. Synthesis of a new class of indole skeleton substituted by 3-hydroxyindanones added an extra essence to this new protocol.

Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

CdII-Mediated Efficient Synthesis and Complexation of Asymmetric Tetra-(2-pyridine)-Substituted Imidazolidine

One convenient CdII-mediated C–C/C–N bond-forming strategy toward asymmetric tetra-(2-pyridine)-substituted imidazolidine (L1), the basic framework of several natural products with bioactivity, has been found for the first time. In the reaction of tridentate N3-set neutral pyridine-type Schiff base ligand (L) possessing a [−HCNCH2−] linkage with CdCl2 at 70 °C for 3 days, one two-dimensional 44 topological layer [Cd3L1Cl6]n (1) could be obtained, in which ligand L1 resulted from [3 + 2] C–C/C–N asymmetric coupling dimerization of L. When equimolar amounts of NaSCN and NaNO3 were added to the reaction mixtures, one-dimensional chain [Cd2L1(SCN)Cl3]n (2) and zero-dimensional dinuclear Cd2L1(NO3)4(MeOH) (3) containing the same ligand L1 were also generated under the same reaction conditions, respectively. Obviously, the medium of the Cd2+ ion plays the key role in solvothermal in situ formation of ligand L1. Moreover, new ligand tetra-substituted imidazolidine (L1) could be obtained effectually from all three complexes 1–3 through the reactions of those compounds with Na2S.