Total Synthesis Of Natural Products Research Articles

Recent advances in palladium‐catalyzed α‐arylation reactions

The indispensable role of α‐arylated compounds in chemistry can be accounted from its presence in various pharmaceuticals we use in our daily life. Chemists are establishing diverse methods for the synthesis of various α‐arylated compounds by considering their applications in different fields including biology, medicine, agrochemicals, material science, etc. Diverse pharmacologically active compounds, natural products, and drugs contain α‐arylated carbonyl groups in their structure. The impact of transition metal catalysis in chemistry is overwhelming, among which palladium is the predominant due to its high reactivity as well as catalytic potential. α‐Arylation reactions with palladium catalysts have been successful in producing a variety of desired chemicals. The formation of active pharmaceutical ingredients and total synthesis of natural products can now be achieved by the development of novel pathways through the α‐arylation of carbonyl compounds, catalyzed by palladium. Wide variety of simple arylating agents could be used under the condition of palladium catalysis. Syntheses that utilize α‐arylation methods often offer advanced ways that improve overall yields, expand the scope of the synthesis, and reduce the steps. One of the synthetic achievements is the increased selectivity obtained with lower amounts of the catalyst. Gentle reaction conditions were employed, and broad substrate scope was accomplished. Recent advances in the α‐arylation reactions of various compounds, catalyzed by palladium, is discussed in this review covering literature from 2016 to 2022.

Relevant Developments in the Use of Three-Component Reactions for the Total Synthesis of Natural Products. The last 15 Years.

Multicomponent reactions (MCRs) offer a highly useful and valuable strategy that can fulfill an important role in synthesizing complex polysubstituted compounds, by simplifying otherwise long sequences and increasing their efficiency. The total synthesis of selected natural products employing three-component reactions as their common strategic MCR approach, is reviewed on a case-by-case basis with selected targets conquered during the last 15 years. The revision includes detailed descriptions of the selected successful sequences; relevant information on the isolation, and bioactivity of the different natural targets is also briefly provided.

Strategies for the Construction of Benzobicyclo[3.2.1]octane in Natural Product Synthesis.

Benzobicyclo[3.2.1]octane is a cage-like unique motif containing a bicyclo[3.2.1]octane structure fused with at least one benzene ring. It is found in various natural products that exhibit structural complexities and important biological activities. The total synthesis of natural products possessing this challenging structure has received considerable attention, and great advances have been made in this field during the past 15 years. This review summarizes thus far achieved chemical syntheses and synthetic studies of natural compounds featuring the benzobicyclo[3.2.1]octane core. It focuses on strategic approaches constructing the bridged structure, aiming to provide a useful reference for inspiring further advancements in strategies and total syntheses of natural products with such a framework.

Cluster Preface: Biomimetic Synthesis

Jun Deng (left) received his B.Sc. from Lanzhou University and his Ph.D. from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (2014) with Professor Ang Li. After a short period of postdoctoral research in the lab of Professor Andrew Myers at Harvard University (2014–2016), he was appointed a Pioneer ‘Hundred Talents Program’ Researcher at Kunming Institute of Botany, Chinese Academy of Sciences in 2017. In December 2020, he moved to Nankai University where he is a professor at the College of Chemistry. He received the Thieme Journals Award (2020). His research focuses on natural product total synthesis and medicinal chemistry. Yefeng Tang (right) earned his B.S. from Lanzhou University (1995–1999) and his M.S. from the Institute of Materia Medica, Chinese Academy of Medical Science (1999–2002). From 2003 to 2006, he pursued his Ph.D. under the guidance of Professor Zhen Yang and Professor Jiahua Chen at Peking University. Subsequently, he conducted postdoctoral research with Prof. K. C. Nicolaou at The Scripps Research Institute between 2006 and 2009. In 2010, he commenced his independent career at the School of Pharmaceutical Sciences, Tsinghua University, where he is now a tenured professor. His primary research interests encompass the total synthesis of natural products, the development of synthetic methodologies, and the discovery of antiviral and anti-aging drugs.

Indolyl‐Ynones: Building Blocks for Molecular Diversity

AbstractThis review centers on the synthetic strategies employed with indolyl‐ynones. Indolyl‐ynone, owing to its highly reactive ynone moiety, frequently partakes in dearomatizing spirocyclization reactions and subsequent rearrangement reactions when subjected to various reaction conditions. Hence, various heterocycles such as densely functionalized spiroindolenines, carbazoles, quinolines and carbo‐and hetero‐cycle substituted indoles are synthesized from indolyl‐ynones. In addition to this, the versatile spirocyclic indole scaffold exhibits the capability to produce tetracyclic and polyclic structures through intricate skeletal rearrangement processes. Moreover, the total synthesis of natural products using the indolyl‐ynone moiety was also compiled in this review.

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade.

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations.

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor.

A growing global health concern is metabolic syndrome, which is defined by low HDL, diabetes, hypertension, and abdominal obesity. Nuclear receptors are attractive targets for treatment of diseases associated with metabolic syndrome. Liver X receptors (LXRs) have become one of the most significant pharmacological targets among nuclear receptors. Multiple research studies emphasize the essential function of the liver X receptor (LXR) in the pathophysiology of metabolic syndrome. Puniceloid D, among natural products, demonstrated promising effects on LXRα. However, attempts at the total synthesis of natural products were faced with challenges, including long synthetic steps and low yields, requiring a more efficient approach. In this study, for the first time, we successfully synthesized puniceloid D through a seven-step process and conducted docking studies to gain a comprehensive understanding of the interactions involved in the binding of puniceloid D to LXR within different heterodimeric contexts. Our understanding of the pathophysiology of metabolic syndrome could be improved by these findings, which might assist with the development of novel treatment strategies.

Organocatalytic, Chemoselective, and Stereospecific House–Meinwald Rearrangement of Trisubstituted Epoxides

AbstractWe present a novel method for the chemoselective House–Meinwald rearrangement of trisubstituted epoxides under mild conditions with the use of simple perfluorinated disulfonimides as Brønsted acid catalysts. We isolated the α-quaternary aldehyde products in yields of 27–97% using catalyst loadings as low as 0.5 mol% on a scale of 1 mmol. In addition, we show the stereospecific rearrangement using an enantioenriched substrate, which makes this method suitable for applications in total synthesis of natural products.

Recent advances in oxidative phenol coupling for the total synthesis of natural products.

Covering: 2008 to 2023This review will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C-C and C-O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, etc.) will be surveyed. Future directions of this particular area of research will also be assessed.

Recent developments in the total synthesis of natural products using the Ugi multicomponent reactions as the key strategy.

The total syntheses of selected natural products using different versions of the Ugi multicomponent reaction is reviewed on a case-by-case basis. The revision covers the period 2008-2023 and includes detailed descriptions of the synthetic sequences, the use of state-of-the-art chemical reagents and strategies, as well as the advantages and limitations of the transformation and some remedial solutions. Relevant data on the isolation and bioactivity of the different natural targets are also briefly provided. The examples clearly evidence the strategic importance of this transformation and its key role in the modern natural products synthetic chemistry toolbox. This methodology proved to be a valuable means for easily building molecular complexity and efficiently delivering step-economic syntheses even of intricate structures, with a promising future.

Synthesis and applications of symmetric amino acid derivatives.

Symmetric α-amino acid derivatives can be used for the synthesis of intermolecularly linked peptides such as dimer-type peptides, and modified peptides in which two amino acids are intramolecularly linked. They are also synthetic intermediates for the total synthesis of natural products and functional molecules. These symmetric amino acid derivatives must be prepared based on organic synthesis. It is necessary to develop an optimal synthetic strategy for constructing the target symmetric amino acid derivative. In this review, we will introduce strategies for synthesizing symmetric amino acid derivatives. Additionally, selected applications of these amino acids in the life sciences will be described.

Gold-catalyzed cyclization and cycloaddition in natural product synthesis.

Covering: 2016 to mid 2023Transition metal catalysis, known for its remarkable capacity to expedite the assembly of molecular complexity from readily available starting materials in a single operation, occupies a central position in contemporary chemical synthesis. Within this landscape, gold-catalyzed reactions present a novel and versatile paradigm, offering robust frameworks for accessing diverse structural motifs. In this review, we highlighted a curated selection of publications in the past 8 years, focusing on the deployment of homogeneous gold catalysis in the ring-forming step for the total synthesis of natural products. These investigations are categorized based on the specific ring formations they engender, accentuating the prevailing gold-catalyzed methodologies applied to surmount intricate challenges in natural products synthesis.

Recent advances in the synthesis and applications of fluoranthenes.

As an important subclass of polycyclic aromatic hydrocarbons (PAHs), fluoranthenes continue to attract significant attention in synthetic organic chemistry and materials science. In this article, an overview of recent advances in the synthesis of fluoranthene derivatives along with selected applications is provided. First, methods for fluoranthene synthesis with a classification based on strategic bond disconnections are discussed. Then, the total syntheses of natural products featuring the benzo[j]fluoranthene skeleton are covered. Finally, examples of important applications of a variety of fluoranthenes are summarized.

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives

The exploitation of natural products and their analogues in the field of pharmacology has been regarded as of great importance. It can be attributed to the fact that these scaffolds exhibit diverse chemical properties, distinct biological activities and zenith specificity in their biochemical processes, enabling them to act as favorable structures for lead compounds. The synthesis of natural products has been a crafty and hard-to-achieve task. Steglich esterification reaction has played a significant role in that area. It is a mild and efficient technique for constructing ester linkages. This technique involves the establishment of ester moiety via a carbodiimide-based condensation of a carboxylic acid with an alcohol, thiol or an amine catalyzed by dimethyl aminopyridine (DMAP). Specifically, labile reagents with multiple reactive sites are esterified efficiently with the classical and modified Steglich esterification conditions, which accounts for their synthetic utility. This review encloses the performance of the Steglich esterification reaction in forging the ester linkage for executing the total synthesis of natural products and their derivatives since 2018.

Chiral Hydroxamic Acid Ligands in the Asymmetric Synthesis of Natural Products

Chiral hydroxamic acid (HA) and bis-hydroxamic acid (BHA) ligands have made significant contributions to the field of asymmetric synthesis, particularly in the synthesis of natural products. These ligands possess unique molecular structures that allow for exceptional stereochemical control, leading to their widespread use in catalytic systems. This review highlights the advancements made in asymmetric synthesis using chiral hydroxamic acid and bis-hydroxamic acid ligands and their impact on the synthesis of complex natural products. This discussion encompasses their role in enantioselective C–C bond formation, the functionalization of C–H bonds, the asymmetric transformations involving heteroatoms, and their application in the total synthesis of natural products. The versatility and efficiency of chiral hydroxamic acid ligands and bis-hydroxamic acid ligands make them invaluable tools for synthetic chemists working towards the efficient and selective synthesis of natural products. This review provides a comprehensive overview of their contributions, showcasing their potential to expand the boundaries of chemical synthesis and access the diverse array of natural product scaffolds.

Recent Advances in Nucleophilic Lewis Base‐Catalyzed Cycloadditions for Synthesis of Spirooxindoles

AbstractSpirooxindoles are privileged scaffolds in diverse bioactive natural products and pharmaceuticals, significant achievements for the construction of these molecules have thus been made in the past years. Among them, organocatalysis, in particular, nucleophilic Lewis base catalysis, has recently emerged as an efficient and reliable method for the preparation of diverse and valuable functionalized spirooxindoles. According to different kinds of nucleophilic catalysts, we summarize and classify three catalytic strategies; these are tertiary amine‐catalyzed cycloadditions, NHC‐catalyzed cycloadditions, and tertiary phosphine‐catalyzed cycloadditions, respectively. Through these methods, potential bioactive spirooxindole skeletons owning various functional groups can be produced to enrich the small organic molecule library. In this review, we describe a comprehensive and updated advances of nucleophilic Lewis base catalytic cycloaddition reactions for the construction of spirooxindoles. Meanwhile, the related mechanism and the application of these annulation strategies in natural product total synthesis will be highlighted in detail.

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.

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.

Total synthesis of natural products containing the tetralone subunit

Total synthesis of natural products containing the tetralone subunit

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.