Applications In Natural Product Synthesis Research Articles

Recent Advances in the Nickel-Catalyzed Alkylation of C-H Bonds.

Functionalization of C-H bonds has emerged as a powerful strategy for converting inert, nonfunctional C-H bonds into their reactive counterparts. A wide range of C-H bond functionalization reactions has become possible by the catalysis of metals, typically from the second row of transition metals. First-row transition metals can also catalyze C-H functionalization, and they have the merits of greater earth-abundance, lower cost and better environmental friendliness in comparison to their second-row counterparts. C-H bond alkylation is a particularly important C-H functionalization reaction due to its chemical significance and its applications in natural product synthesis. This review covers Ni-catalyzed C-H bond alkylation reactions using alkyl halides and olefins as alkyl sources.

Skeletal Editing of (Hetero)Arenes Using Carbenes.

(Hetero)arenes continue to prove their indispensability in pharmaceutical engineering, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more-potent complex molecular scaffolds through peripheral and skeletal editing has been considered a challenging goal in synthetic organic chemistry. Despite many excellent reviews that have discussed peripheral editing (i.e., C-H functionalization) of (hetero)arenes, their skeletal editing via single atom insertion, deletion, or transmutations has so far been less discussed. In this review, we tried to summarize and depict the state-of-the-art skeletal editing reactions on heteroarenes using carbenes, with a focus on general mechanistic considerations and the potential application of this transformation for the synthesis of natural products. The potential opportunities and inherent challenges encountered while developing these strategies have also been highlighted.

Homogeneous Gold Catalysis for Regioselective Carbocyclization of Alkynyl Precursors.

π-Activation of alkynyl precursors possessing an endogenous carbon nucleophile is one of the imperative topics in homogeneous gold catalysis as it offers Csp3-Csp2 and Csp2-Csp2 linked carbocycles. However, the exo-dig and endo-dig cyclization modes unlocks the possibility of both small and large rings respectively, thereby losing regioselectivity. Nevertheless, several gold-catalyzed carbocyclizations which permits one isomer by controlling or avoiding the formation of other went largely unnoticed.Hence, this review is an attempt to summarize such approaches reported from early 2000's to till date along with our viewpoint on contributing parameters for regioselectivity. This review covers only unimolecular reactions with classifications primarily based on the type of endogenous nucleophiles such as silyloxyenols, enamides/enamines, benzenoids, heteroaromatics and alkyls/alkenyls. From an application perspective, these reactions are significant in total synthesis and materials science. Therefore, those reactions that finds application in natural product synthesis and π-functional materials are highlighted in appropriate places.

Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis.

ConspectusBenzo-fused skeletons are ubiquitous in agrochemicals, medicines, natural products, catalysts, and other organic function materials. The assembly of these skeletons in an efficient manner is an actively explored field in organic synthesis. Palladium/norbornene (Pd/NBE) cooperative catalysis is a powerful tool for the expeditious assembly of polysubstituted arenes through bis-functionalization of the ortho and ipso positions of aryl iodides in one operation. Owing to the efforts of Lautens, Catellani, and others, an array of Pd/NBE-promoted annulations for the syntheses of diversified benzo-fused rings have been developed. However, these methods have not been broadly applied in total synthesis yet.Our group is interested in efficient and practical total synthesis of biologically active molecules. In the past 7 years, we have been devoted to the development of new annulation strategies for the assembly of common benzo-fused skeletons through Pd/NBE-promoted reactions of aryl iodides with novel bifunctional reagents. In this Account, we summarize our laboratory's systematic efforts in this direction. First, readily available epoxides and aziridines were exploited as versatile bifunctional alkylating reagents, which enables quick assembly of a series of valuable benzo-fused heterocycles, including isochromans, dihydrobenzofurans, 1,3-cis-tetrahydroisoquinolines (THIQs), 1,3-trans-THIQs, etc. Second, a convergent access to 5-7-membered benzo-fused carbocycles (including indanes and tetrahydronaphthalenes) was developed by Pd/NBE-promoted annulation of aryl iodides with simple olefinic alcohol-containing alkylating reagents. Third, a Pd/NBE-promoted annulation between aryl iodides and cyclohexanone-containing amination reagents was developed for the construction of benzo-fused N-containing bridged scaffolds. Thus, we have established a practical and versatile toolbox for the quick assembly of diversified benzo-fused skeletons. These new annulation reactions are of high chemo-, regio-, and stereoselectivities with good step and atom economy. Moreover, they are able to rapidly increase molecular complexity from simple building blocks. Finally, their synthetic value has been demonstrated by immediate adoption in several efficient total syntheses of medicines and complex natural products. Compared to conventional synthetic logics, the Pd/NBE-promoted annulation toolbox allows the development of highly convergent strategies, which significantly improves the overall synthetic efficiency.We believe the results presented in this Account will have significant implications beyond our research. It can be envisaged that new Pd/NBE-promoted annulations as well as new applications in complex total synthesis will be revealed in the near future.

Recent development of allyl–allyl cross-coupling and its application in natural product synthesis

This review summarises the significant advancements of allyl–allyl cross-coupling reaction that have provided access to a wide variety of 1,5 dienes and its application in natural product synthesis.

Anthrol reductases: discovery, role in biosynthesis and applications in natural product syntheses.

Covering: up to 2023Short-chain dehydrogenase/reductases (SDR) are known to catalyze the regio- and stereoselective reduction of a variety of substrate types. Investigations of the deoxygenation of emodin to chrysophanol has led to the discovery of the anthrol reductase activity of an SDR, MdpC involved in monodictyphenone biosynthesis of Aspergillus nidulans and provided access to (R)-dihydroanthracenone, a putative biosynthetic intermediate. This facilitated the identification of several MdpC-related enzymes involved in the biosynthesis of aflatoxins B1, cladofulvin, neosartorin, agnestins and bisanthraquinones. Because of their ability to catalyze the reduction of hydroanthraquinone (anthrols) using NADPH, they were named anthrol reductases. This review provides a comprehensive summary of all the anthrol reductases that have been identified and characterized in the last decade along with their role in the biosynthesis of natural products. In addition, the applications of these enzymes towards the chemoenzymatic synthesis of flavoskyrins, modified bisanthraquinones, 3-deoxy anthraquinones, chiral cycloketones and β-halohydrins have been discussed.

Low-cost transition metal catalysed Negishi coupling: an update.

The Negishi coupling is a significant C-C bond-forming reaction to access synthetically valuable organic compounds. In recent years, researchers have developed sustainable first-row transition metal (Fe, Co, Ni and Cu) based complexes in place of the conventional Pd catalyst for this reaction. Several such low-cost metal-based catalysts showed high efficiency and potential application in natural product synthesis. This review focuses on the recent achievements in low-cost transition metal-based Negishi coupling reactions, covering reports from 2016.

Recent Applications and Trends in the Julia‐Kocienski Olefination

AbstractThe Julia‐Kocienski (J‐K) olefination is a modified version of Julia‐Lythgoe olefination. In this reaction, an aldehyde or ketone is coupled with heterocycle‐bearing sulfone in the presence of a strong base to yield alkene. It has shown wide application in the synthesis of olefinic fragments in natural product synthesis. The Julia‐ Kocienski olefination is one of the most efficient protocols for the synthesis of E‐alkenes. Nowadays, a variety of natural products were synthesised by using the Julia‐Kocienski olefination as the key step, and several developments and modifications were witnessed in this area. This review comprehends the recent developments and achievements in Julia‐Kocienski olefination along with its application in natural product synthesis covering literature from 2016 to 2021.

Properties and Mechanisms of Flavin-Dependent Monooxygenases and Their Applications in Natural Product Synthesis.

Natural products are usually highly complicated organic molecules with special scaffolds, and they are an important resource in medicine. Natural products with complicated structures are produced by enzymes, and this is still a challenging research field, its mechanisms requiring detailed methods for elucidation. Flavin adenine dinucleotide (FAD)-dependent monooxygenases (FMOs) catalyze many oxidation reactions with chemo-, regio-, and stereo-selectivity, and they are involved in the synthesis of many natural products. In this review, we introduce the mechanisms for different FMOs, with the classical FAD (C4a)-hydroperoxide as the major oxidant. We also summarize the difference between FMOs and cytochrome P450 (CYP450) monooxygenases emphasizing the advantages of FMOs and their specificity for substrates. Finally, we present examples of FMO-catalyzed synthesis of natural products. Based on these explanations, this review will expand our knowledge of FMOs as powerful enzymes, as well as implementation of the FMOs as effective tools for biosynthesis.

The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis.

In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (P-SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.

Synthesis of α-exo-Methylene-γ-butyrolactones: Recent Developments and Applications in Natural Product Synthesis

AbstractThe α-exo-methylene-γ-butyrolactone moiety is present in a vast array of structurally diverse natural products and is often central to their biological activity. In this short review, we summarize new approaches to α-exo-methylene-γ-butyrolactones developed over the past decade as well as their applications in total synthesis.1 Introduction2 Approaches to α-exo-Methylene-γ-butyrolactones2.1 Enantioselective Synthesis via Lactonization Approaches2.2 Enantioselective Halolactonizations2.3 Enantioselective Barbier-Type Allylation2.4 C–H Insertion/Olefination Sequences2.5 Alkene Cyclization2.6 Strain-Driven Dyotropic Rearrangement3 β-(Hydroxymethylalkyl)-α-exo-methylene-γ-butyrolactones4 Applications in Total Synthesis4.1 Sesquiterpene Lactones4.2 Lignans4.3 Other Monocyclic Natural Products4.4 Choice of Methodology in Recent Total Syntheses5 Summary and Outlook

Palladium-catalyzed cascade cyclizations involving C-C and C-X bond formation: strategic applications in natural product synthesis.

Palladium-catalyzed cascade cyclizations (PCCs) are powerful synthetic tools that enable rapid assembly of polycyclic scaffolds. Palladium complexes can promote a variety of carbon-carbon and carbon-heteroatom bond-forming reactions with high chemo-, enantio-, and diastereoselectivity. The combination of multiple ring-forming elementary steps into a single cascade sequence can allow complex structures to be accessed with high step economy. This strategy has been employed to access natural products in several distinct classes, including the mitomycins, dragmacidins, isoryanodane diterpenes, and ergot alkaloids. In this tutorial review, we demonstrate how PCCs have expedited natural product synthesis by enabling the formation of both C-C and C-X (X = O, N) bonds in a single synthetic operation.

All-carbon [3 + 2] cycloaddition in natural product synthesis.

Many natural products possess interesting medicinal properties that arise from their intriguing chemical structures. The highly-substituted carbocycle is one of the most common structural features in many structurally complicated natural products. However, the construction of highly-substituted, stereo-congested, five-membered carbocycles containing all-carbon quaternary center(s) is, at present, a distinct challenge in modern synthetic chemistry, which can be accessed through the all-carbon [3 + 2] cycloaddition. More importantly, the all-carbon [3 + 2] cycloaddition can forge vicinal all-carbon quaternary centers in a single step and has been demonstrated in the synthesis of complex natural products. In this review, we present the development of all-carbon [3 + 2] cycloadditions and illustrate their application in natural product synthesis reported in the last decade covering 2011–2020 (inclusive).

Molecular Complexity from Aromatics: Recent Advances in the Chemistry of paraQuinol and Masked para‐Quinone Monoketal

AbstractSynthesis of complex organic molecules from simple, cheap, and readily available starting materials is one of the most challenging and desirable factors in organic synthesis. In the last two decades, various methods have been developed for the de‐aromatization reaction of planar aromatics compounds which lead to reactive intermediates like 2,5‐cyclohexadienone ketal and para‐quinol having a non‐planar framework. Recently, there is an upsurge of interest in the development of the chemistry of these intermediates due to their inherent dual electrophilic and nucleophilic character. The presence of diverse functionality makes them important scaffolds and thus these are intensively utilized for the development of methodologies towards the synthesis of the highly functionalized and diverse chemical framework. These synthons have also been used in the total synthesis of many natural products. Interestingly, these are also adaptable for asymmetric synthesis. This review is a summary of the recent development of methods for 2,5‐cyclohexadienone ketal and para‐quinol synthesis and their application in natural product synthesis.

Front Cover Picture: Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis (Adv. Synth. Catal. 24/2020)

Front Cover Picture: Stereoselective Construction of (<i>E,Z</i>)‐1,3‐Dienes and Its Application in Natural Product Synthesis (Adv. Synth. Catal. 24/2020)

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

AbstractThe E,Z‐configured 1,3‐diene unit is a common motif in numerous bioactive natural products. Although several powerful methods are available to produce these motifs with high levels of selectivity, their construction within a complex, polyfunctionalised structure, such as a natural product, requires well‐defined strategies to avoid undesirable reactions and low‐to‐moderate selectivities. The aim of this review is to provide a full account of the stereoselective strategies for building E,Z‐configured 1,3‐dienes, as well as to highlight selected total syntheses that employ them.magnified image

Transition Metal-Catalyzed Enantioselective C-H Functionalization via Chiral Transient Directing Group Strategies.

Transition metal-catalyzed enantioselective functionalization of C-H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the synthesis of complex chiral molecules. Despite significant progress, traditional directing group-enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C-H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.

Transition Metal‐Catalyzed Enantioselective C−H Functionalization via Chiral Transient Directing Group Strategies

AbstractTransition metal‐catalyzed enantioselective functionalization of C−H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the synthesis of complex chiral molecules. Despite significant progress, traditional directing group‐enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C−H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.

-Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis.

Due to their numerous reactivity modes, α-aminonitriles represent versatile and valuable building blocks in organic total synthesis. Since their discovery by Adolph Strecker in 1850, this compound class has seen a wide dissemination in synthetic applications from laboratory to million-ton industrial scale and was extensively used in the syntheses of various classes of natural products. As these compounds provide a multitude of reactivity options, we feel that a broad overview of their multiple reaction modes may reveal less familiar opportunities for successful total synthesis planning. This personal account article will thus focus on α-aminonitriles used as key intermediates in selected natural product synthesis sequences which have been reported in the two decades since Enders' and Shilvock's seminal review. Natural α-aminonitriles will also briefly be treated.

Bisketene Equivalents as Diels-Alder Dienes.

2,5-Bis(tert-butyldimethylsilyloxy)furans are established as vicinal bisketene equivalents for application as dienes in the Diels-Alder reaction. Cycloaddition with olefinic dienophiles, under exceptionally mild conditions, enables convergent access to highly substituted para-hydroquinones in unprotected form via a one-pot Diels-Alder/ring-opening/tautomerization sequence. The synthesis of para-benzoquinones from acetylenic dienophiles, including benzynes, is also demonstrated, and 2,5-bis(tert-butyldimethylsilyloxy)pyrroles are established as competent dienes for the synthesis of para-iminoquinones. Application in natural product synthesis enables gram-scale access to the neuroprotective agent (±)-indanostatin.