Applications In Natural Product Synthesis Research Articles

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.

Anodic Oxidation as an Enabling Tool for the Synthesis of Natural Products

Electrochemistry provides a valuable toolbox for organic synthesis and offers an appealing, environmentally benign alternative to the use of stoichiometric quantities of chemical oxidants or reductants. Its potential to control current efficiency along with providing alternative reaction conditions in a classical sense makes electrochemistry a suitable method for large-scale industrial transformations as well as for laboratory applications in the synthesis of complex molecular architectures. Even though research in this field has intensified over the recent decades, many synthetic chemists still hesitate to add electroorganic reactions to their standard repertoire, and hence, the full potential of preparative organic electrochemistry has not yet been unleashed. This short review highlights the versatility of anodic transformations by summarizing their application in natural product synthesis.1 Introduction2 Shono-Type Oxidation3 C–N/N–N Bond Formation4 Aryl–Alkene/Aryl–Aryl Coupling5 Cycloadditions Triggered by Oxidation of Electron-Rich Arenes6 Spirocycles7 Miscellaneous Transformations8 Future Prospects

Chagosensine: A Riddle Wrapped in a Mystery Inside an Enigma.

The marine macrolide chagosensine is supposedly distinguished by a (Z,Z)-configured 1,3-chlorodiene contained within a highly strained 16-membered lactone ring, which also incorporates two trans-2,5-disubstituted tetrahydrofuran (THF) rings; this array is unique. After our initial synthesis campaign had shown that the originally proposed structure is incorrect, the published data set was critically revisited to identify potential mis-assignments. The “northern” THF ring and the anti-configured diol in the “southern” sector both seemed to be sites of concern, thus making it plausible that a panel of eight diastereomeric chagosensine-like compounds would allow the puzzle to be solved. To meet the challenge, the preparation of the required building blocks was optimized, and a convergent strategy for their assembly was developed. A key role was played by the cobalt-catalyzed oxidative cyclization of alken-5-ol derivatives (“Mukaiyama cyclization”), which is shown to be exquisitely chemoselective for terminal alkenes, leaving even terminal alkynes (and other sites of unsaturation) untouched. Likewise, a palladium-catalyzed alkyne alkoxycarbonylation reaction with formation of an α-methylene-γ-lactone proved instrumental, which had not found application in natural product synthesis before. Further enabling steps were a nickel-catalyzed “Tamaru-type” homocrotylation, stereodivergent aldehyde homologations, radical hydroindation, and palladium-catalyzed alkyne-1,2-bis-stannation. The different building blocks were assembled in a serial fashion to give the idiosyncratic chlorodienes by an unprecedented site-selective Stille coupling followed by copper-mediated tin/chlorine exchange. The macrolactones were closed under forcing Yamaguchi conditions, and the resulting products were elaborated into the targeted compound library. Yet, only one of the eight diastereomers turned out to be stable in the solvent mixture that had been used to analyze the natural product; all other isomers were prone to ring opening and/or ring expansion. In addition to this stability issue, our self-consistent data set suggests that chagosensine has almost certainly little to do with the structure originally proposed by the isolation team.

Recent Advances and Prospects in the Tishchenko Reaction

AbstractTishchenko reaction is the dimerization of two molecules of an aldehyde to produce symmetrical esters. These esters find wide applications in many reactions in organic synthesis. A variant of this reaction, the Evans‐Tishchenko reaction, catalyzed by SmI2 affords 1,3‐anti‐diol monoesters. This chemistry has found wide applications in natural product synthesis as it offers a mild and efficient methodology for the formation of 1,3‐diols stereoselectively. In this review, we mainly focus on recent advancements in the transition metal catalyzed and lanthanide‐actinide catalyzed Tishchenko reactions and their applications in organic synthesis covering literature from 2014 to 2019.

Construction of all-carbon quaternary stereocenters by catalytic asymmetric conjugate addition to cyclic enones in natural product synthesis

This review discusses the construction of all-carbon quaternary stereocenters using catalytic asymmetric conjugate addition and its application in natural product synthesis.

The scientific legacy of Frieder W. Lichtenthaler.

This article presents a selection of topics from Professor Frieder W. Lichtenthaler's scientific lifework. It describes his contributions to, and further development of, the nitromethane cyclization of dialdehydes leading to amino sugars and amino nucleosides, as well as a new coupling methodology for purine nucleosides. A number of chiral building blocks derived from sugars like the "sugar enolones," enollactones, hydroxyhexenals, and their synthetic applications in natural product syntheses are covered. The article further describes the chemistry of "ulosyl bromides" and their glycosidation reactions, including those with bifunctional acceptors, which led to the synthesis of spectinomycin and gomphoside. Lichtenthaler's work on the preparation of synthetically useful building blocks from disaccharides that are readily available in bulk quantities, and his studies on the reactivity, as well as the selective O-functionalization of sucrose, higher oligosaccharides, and cyclodextrins based on computer simulations, are highlighted. The article also presents his research on the syntheses of chiral building blocks from readily available ketoses and their synthetic applications. Finally the chapter concludes with his significant contributions in the field of the history of carbohydrate chemistry.

Acid‐Catalyzed Regiodivergent Annulation of 4‐Hydroxycoumarins with Isoprene: Entry to Pyranocoumarins and Pyranochromones

An acid‐catalyzed regiodivergent formal [3+3] annulation of 4‐hydroxycoumarins with isoprene is developed. A variety of pyranocoumarins were obtained exclusively in the presence of strong Brønsted acid, while varying to Lewis acid delivered pyranochromones as main products. The protocol also features high atom‐economy, wide substrate scope, easy scale‐up, and good applications in natural product synthesis.

Highly Diastereoselective Synthesis of Syn-1,3-Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates.

Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one-pot process with no loss of overall yield or diastereoselectivity.

Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

AbstractSyn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity.

Development, Scope, and Applications of Titanium(III)-Catalyzed Cyclizations to Aminated N-Heterocycles.

The exceptionally mild conditions of a titanium(III)-catalyzed cyclization reaction paired with a convenient acid/base extraction have enabled the straightforward synthesis, isolation, and direct N-functionalization of amino heterocycles such as 3-aminoindoles and -pyrroles. The unprotected heterocycles are ideal building blocks for the installation of aminated indoles and pyrroles into target molecules, but their sensitivity has previously impeded their synthesis by modern catalytic methods. This full paper presents the development and extended scope of the new cyclization methodology. The transformation of the products into fused bis-indoles is also demonstrated along with the discovery of an unusual palladium-catalyzed reductive biphenyl coupling reaction. The titanium(III)-catalyzed cyclization has also been applied to the synthesis of substituted 3-iminoindolines, which are of potential interest for applications in natural product synthesis and exhibit tunable blue-to-green fluorescence properties.

Alkyne-Forming Furan Fragmentation: A General Method to Convert Furans into Alkynoic Acids

Furans are readily available and highly reactive heterocycles that serve as versatile four-carbon synthons in organic synthesis. Recently, we discovered that furans, upon oxidation with singlet oxygen, can be transformed into alkynes via dual C–C double-bond cleavage. This Synpacts article presents an overview of the historical context and the development of this furan fragmentation reaction. We also discuss its application in natural product synthesis and a plausible reaction mechanism.1 Introduction2 Background of Alkyne-Forming Furan Fragmentation3 Reaction Development4 Conclusion

Recent development on the [5+2] cycloadditions and their application in natural product synthesis.

The [5+2] cycloaddition is one kind of fascinating and powerful reaction to access seven-membered ring systems existing in complex natural products and pharmaceuticals. In this review, recent developments on the [5+2] cycloadditions and their application in the synthesis of complex natural products are discussed. A focus is given to the way in which the [5+2] cycloadditions have influenced the logical process of the synthesis. This article is organized by reaction types, aiming to provide a clear clue to the latest research trends.

Well-Defined Alkyne Metathesis Catalysts: Developments and Recent Applications.

Although alkyne metathesis has been known for 50 years, rapid progress in this field has mostly occurred during the last two decades. In this article, the development of several highly efficient and thoroughly studied alkyne metathesis catalysts is reviewed, which includes novel well-defined, in situ formed and heterogeneous systems. Various alkyne metathesis methodologies, including alkyne cross-metathesis (ACM), ring-closing alkyne metathesis (RCAM), cyclooligomerization, acyclic diyne metathesis polymerization (ADIMET), and ring-opening alkyne metathesis polymerization (ROAMP), are presented, and their application in natural product synthesis, materials science as well as supramolecular and polymer chemistry is discussed. Recent progress in the metathesis of diynes is also summarized, which gave rise to new methods such as ring-closing diyne metathesis (RCDM) and diyne cross-metathesis (DYCM).

DDQ-Promoted Mild and Efficient Metal-Free Oxidative α-Cyanation of N-Acyl/Sulfonyl 1,2,3,4-Tetrahydroisoquinolines.

A mild and highly efficient metal-free oxidative α-cyanation of N-acyl/sulfonyl 1,2,3,4-tetrahydroisoquinolines (THIQs) has been accomplished at an ambient temperature via DDQ oxidation and subsequent trapping of N-acyl/sulfonyl iminium ions with (n-Bu)3SnCN. Employing readily removable N-acyl/sulfonyl groups as protecting groups rather than N-aryl ones enables a wide range of applications in natural product synthesis. The synthetic utility of the method was illustrated using a short and efficient formal total synthesis of (±)-calycotomine in three steps.

Recent Developments in Polyene Cyclizations and Their Applications in Natural Product Synthesis

Cascade polyene cyclization reactions are highly efficient and elegant bioinspired transformations that involve simultaneous multiple bond constructions to rapidly generate complex polycyclic molecules. This review summarizes the most prominent work on a variety of cationic and radical cascade cyclizations and their applications in natural product synthesis published between 2014 and 2018.1 Introduction2 Cationic Polyene Cyclizations2.1 Lewis Acid Mediated Polyene Cyclizations2.2 Brønsted Acid Mediated Polyene Cyclizations2.3 Halogen Electrophile Initiated Polyene Cyclizations2.4 Sulfur Electrophile Initiated Polyene Cyclizations2.5 Transition-Metal-Mediated Cationic Polyene Cyclizations3 Radical Polyene Cyclizations3.1 Transition-Metal-Mediated Radical Polyene Cyclizations3.2 Photocatalyst-Mediated Polyene Cyclizations4 Origin of Stereocontrol in Polyene Cyclizations5 Conclusion

A General Copper-based Photoredox Catalyst for Organic Synthesis: Scope, Application in Natural Product Synthesis and Mechanistic Insights.

Organic transformations can broadly be classified into four categories including cationic, anionic, pericyclic and radical reactions. While the last category has been known for decades to provide remarkably efficient synthetic pathways, it has long been hampered by the need for toxic reagents, which considerably limited its impact on chemical synthesis. This situation has come to an end with the introduction of new concepts for the generation of radical species, photoredox catalysis - which simply relies on the use of a catalyst that can be activated upon visible light irradiation - certainly being the most efficient one. The state-of-the-art catalysts mostly rely on the use of ruthenium and iridium complexes and organic dyes, which still considerably limits their broad implementation in chemical processes: alternative readily available catalysts based on inexpensive, environmentally benign base metals are therefore strongly needed. Furthermore, expanding the toolbox of methods based on photoredox catalysis will facilitate the discovery of new light-mediated transformations. This article details the use of a simple copper complex which, upon activation with blue light, can initiate a broad range of radical reactions.

Formation of tetrasubstituted C–C double bondsviaolefin metathesis: challenges, catalysts, and applications in natural product synthesis

Among the many types of transition-metal-catalysed C–C bond forming reactions, olefin metathesis is without a doubt one of the most thriving fields in modern organic synthetic chemistry.

Cycloaddition/annulation strategies for the construction of multisubstituted pyrrolidines and their applications in natural product synthesis

Pyrrolidines are privileged substructures of numerous bioactive natural products and drugs.

The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses.

The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivatives including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivatives. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomolecules. In this review, we present mechanistic studies, chemical methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivatives, and their applications in the synthesis of bioactive natural products and their congeners.

Beyond olefins: new metathesis directions for synthesis.

The olefin-olefin metathesis reaction has emerged as one of the most important carbon-carbon bond-forming reactions, as illustrated by its wide use in the synthesis of complex molecules, natural products and pharmaceuticals. The corresponding metathesis reaction between carbonyls and olefins or alkynes similarly allows for the formation of carbon-carbon bonds. Although these variants are far less developed and utilized in organic synthesis, they possess attractive qualities that have prompted chemists to incorporate and explore these modes of reactivity in complex molecule synthesis. This review highlights selected examples of carbonyl-olefin and carbonyl-alkyne metathesis reactions in organic synthesis, in particular in the total synthesis of natural products and complex molecules, and provides an overview of current advantages and limitations.