The Diels–Alder Reaction in Total Synthesis

The Diels–Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels–Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.     

Biocatalytic Total Synthesis of Ikarugamycin

Nature provides an inexhaustible diversity of small organic molecules with beautiful molecular architectures that have strong and selective inhibitory activities. However, this tremendous biomedical potential often remains inaccessible, as the structural complexity of natural products can render their synthetic preparation extremely challenging. This problem is addressable by harnessing the biocatalytic procedures evolved by nature. In this work, we present an enzymatic total synthesis of ikarugamycin. The use of an iterative PKS/NRPS machinery and two reductases has allowed the construction of 15 carbon–carbon and 2 carbon–nitrogen bonds in a biocatalytic one‐pot reaction. By scaling‐up this method we demonstrate the applicability of biocatalytic approaches for the ex vivo synthesis of complex natural products.     

Biosynthesis and Chemical Synthesis of Presilphiperfolanol Natural Products

Presilphiperfolanols constitute a family of biosynthetically important sesquiterpenes which can rearrange to diverse sesquiterpenoid skeletons. While the origin of these natural products can be traced to simple linear terpene precursors, the details of the enzymatic cyclization mechanism that forms the stereochemically dense tricyclic skeleton has required extensive biochemical, computational, and synthetic investigation. Parallel efforts to prepare the unique and intriguing structures of these compounds by total synthesis have also inspired novel strategies, thus resulting in four synthetic approaches and two completed syntheses. While the biosynthesis and chemical synthesis studies performed to date have provided much insight into the role and properties of these molecules, emerging questions regarding the biosynthesis of newer members of the family and subtle details of rearrangement mechanisms have yet to be explored.     

Julia–Kocienski olefination: a key reaction for the synthesis of macrolides

The unification of carbonyl compounds and heteroaryl sulfones provides one of the best methods for the construction of C–C double bond for synthetic chemists in designing synthetic routes to natural and non-natural products. For the C–C double bond formation, olefination, particularly the Julia–Kocienski olefination (JK-olefination) has emerged as a powerful key reaction in the synthesis of natural products that contain macrocycles. Molecules of interest include macrolides, whose biological importance, lack of natural resources, and interesting structure placed a challenge among the scientific community for their total synthesis. Thus, for systematic documentation we have summarized the synthetic approaches toward several important macrolides highlighting the Julia–Kocienski olefination as one of the key steps. This review is intended to show the utility of the Julia–Kocienski olefination in the synthesis of biologically important macrocyclic natural products.     

Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis

The akuammiline alkaloids are a family of intricate natural products which have received considerable attention from scientists worldwide. Despite the fact that many members of this alkaloid class were discovered over 50 years ago, synthetic chemistry has been unable to address their architectures until recently. This minireview provides a brief overview of the rich history of the akuammiline alkaloids, including their isolation, structural features, biological activity, and proposed biosyntheses. Furthermore, several recently completed total syntheses are discussed in detail. These examples not only serve to highlight modern achievements in alkaloid total synthesis, but also demonstrate how the molecular scaffolds of the akuammilines have provided inspiration for the discovery and implementation of innovative cascade reactions for the rapid assembly of complex structures.     

Recent developments in the synthesis of zoanthamine alkaloids

This review provides a compilation of the most recent synthetic approaches and total syntheses of zoanthamine alkaloids, which are structurally unique heptacyclic marine natural products that display a range of interesting biological activities. This review is focused on synthetic methodologies for the construction of the three adjacent quaternary asymmetric carbon atoms on the cyclohexane ring (C-ring) of these compounds. The literature covered in this review dates from 2008 to the end of 2013.     

Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids

Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.     

Syntheses of Fumagillin and Ovalicin

This review focuses on the synthetic strategies used for the construction of fumagillin, ovalicin, and other natural products of this family that are known angiogenesis inhibitors. These compounds are comprised of a cyclohexane framework, two epoxides, and five or six contiguous stereogenic centers. The first total syntheses of fumagillin and ovalicin were reported by Corey in 1972 and 1985, respectively. There were numerous studies directed at these natural products in the decades that followed with many reports appearing in the year 2000 or later. Despite the relatively small size of these molecules, their syntheses highlight the efficient construction of stereogenic centers in organic synthesis.     

Total synthesis and biosynthesis of the paraherquamides: an intriguing story of the biological Diels-Alder construction

The syntheses and biosyntheses of the paraherquamide and brevianamide families of prenylated indole-derived alkaloids are reviewed. It has been proposed that the unique bicyclo[2.2.2]diazaoctan ring system that is common to this family of natural products, arises by a biological intramolecular Diels-Alder cycloaddition reaction. Both synthetic approaches and total syntheses of several members of this family of natural products are reviewed. The biosynthesis of these alkaloids has also constituted an active area of research and the current state of knowledge on the biosynthesis of these natural products are reviewed.     

The Total Synthesis of Diquinane-Containing Natural Products

Diquinane or bicyclo[3.3.0]octane is a conspicuous structural unit existing in the carbo-frameworks of a wide range of natural products such as alkaloids and terpenoids. These diquinane-containing molecules not merely exhibit intriguing architectures, but also showcase a broad spectrum of significant bioactivities, which draw widespread attention from the global synthetic community. During the past decade, with an aim to accomplish the total syntheses of such specified cornucopias of natural products, a variety of elegant strategies for construction of the diquinane ring system have been disclosed. In this Minireview, the achievements on this subject in the timeline from 2010 to June 2020 are demonstrated and it is discussed how the diquinane unit is strategically forged in the context of the specific target structure. In addition, impacts of the selected works to the field of natural product total synthesis is highlighted and the particular outlook of diquinane-containing natural product synthesis is provided.     

Recent progress toward synthesis of chlorosulfolipids: total synthesis and methodology

Chlorosulfolipids (CSLs) are an intriguing family of natural products featuring highly chlorinated linear hydrocarbon skeletons. Although CSLs were first isolated in 1962, chemical synthesis of CSLs was hampered because relevant methods for stereoselective construction of the polychlorinated motifs of CSLs were scarce. Since Carreira’s first total synthesis of the CSL mytilipin A in 2009, several groups, including our own, have reported total syntheses of CSLs. As a result of these total syntheses, important progress has been made in the development of reliable synthetic methods for stereoselective polychlorination. In this digest, we summarize the total syntheses of CSLs by focusing on synthetic methods for stereoselective polychlorination of the organic frameworks of CSLs.     

Total synthesis of potent antifungal marine bisoxazole natural products bengazoles A and B

The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazoles. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation.     

Synthesis of Cytotoxic Palmerolides

The chemical synthesis of the palmerolides is the subject of this review. The palmerolides are a family of Antarctic marine natural products, many of which display potent and selective cytotoxicity against melanoma cells. The confluence of promising bioactivities, limited natural supplies, and complex structures makes the palmerolides exciting targets for chemical synthesis. To date, several approaches have been reported, and a consensus strategy based on convergent fragment assembly has emerged. Collective wisdom from myriad approaches reviewed here may enable hybrid strategies capable of delivering larger amounts of synthetic palmerolides to support continued biological studies. Considering the relative lack of options for melanoma chemotherapy and the intriguing activity profile of the palmerolides, efforts aimed at developing an efficient, gram‐scale synthesis of palmerolide A and congeneric structures should be given a high priority.     

Recent advances in the synthesis of new glycopeptide antibiotics

The vancomycin family of glycopeptide antibiotics has been inspiring research in the field of synthetic chemistry since the 1980s. Recent studies have moved away from the focus of total synthesis into new territory: the design and evaluation of novel compounds based on the natural products which exhibit improved antibacterial activity. Modern approaches to drug synthesis draw together investigations into the nature of the binding environment, and innovative synthetic methodologies which provide solutions to the challenging structural features and stereochemistry associated with this intriguing class of compounds. New analogues, derivatives and dimers of the natural products, as well as recent successes in the total synthesis of the complestatins are described in this tutorial review, covering literature from the last decade.     

Total Synthesis of (+/−)‐Frondosin B and (+/−)‐5‐epi‐Liphagal by Using a Concise (4+3) Cycloaddition Approach

A recently developed (4+3) cycloaddition between dienes and furfuryl alcohols, as precursors of oxyallyl‐type cations, has been used as a key step in the racemic syntheses of two natural products: frondosin B and liphagal. This work demonstrates the synthetic potential of this cycloaddition reaction, and offers a short synthetic route to an interesting family of natural products. A full account of these synthetic studies is presented, further illustrating the mechanism, scope, and limitations of this straightforward synthetic method for seven‐membered rings.     

Divergent Total Synthesis of Atisane‐Type Diterpenoids

Atisane‐type diterpenoids are the principal constituent of tetracyclic C₂₀‐diterpenoids, widely isolated from the plant kingdom with varying degrees of structural complexity and pharmacological activity. The tetracarbocyclic system with the unique bicyclo[2.2.2]octane skeleton of this natural product family has generated interest within the synthetic community. Divergent total synthesis is an effective tactic to synthesize several atisane‐type diterpenoids using structural interconversion from a common intermediate. This account summarizes the divergent total synthesis of atisane‐type diterpenoids.     

Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid,perophoramidine

The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ether-containing precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred.     

Modern aldol methods for the total synthesis of polyketides

The aldol reaction is one of the most important methods for the stereoselective construction of polyketide natural products, not only for nature but also for synthetic chemistry. The tremendous development in the field of aldol additions during the last 30 years has led to more and more total syntheses of complicated natural products. This Review illustrates by means of selected syntheses of natural products the new variants of the aldol addition. This includes aldol additions with various metal enolates, as well as metal-complex-catalyzed, organocatalytic, and biocatalytic methods.     

Construction of fused polycyclic ethers by strategies involving ring-closing metathesis

Large fused polycyclic ether natural products of marine origin are some of the most complex and formidable synthetic targets found in Nature, and they continue to fascinate and inspire those engaged in target-directed synthesis and the development of new synthetic methods. Novel strategies for the rapid and stereoselective assembly of fused polyethers have been devised in which ring-closing metathesis reactions are used to accomplish cyclic ether construction. Two-directional and iterative ring construction approaches involving ring-closing metathesis are being employed to assemble polyether sequences found in marine natural products such as the ciguatoxins and gambieric acids.