Asymmetric total synthesis of dendrobatid alkaloids: preparation of indolizidine 251F and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.     

Synthesis of Natural Products by C−H Functionalization of Heterocycless

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C−H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.     

A protecting-group-free synthesis of arbusculone,andirolactone, pinnatolide,ipomolactone, cyclocapitelline and isocyclocapitelline

A general approach for a collective synthesis of natural products containing substituted THF ring is described. In this paper, Arbusculone, a small molecule natural product accomplished using a short route, is used as the key intermediate to achieve the total synthesis of Andirolactone, Pinnatolide, Ipomolactone, Cyclocapitelline, Isocyclocapitelline and their two isomers in less than ten steps. The present effort highlights protecting-group-free total syntheses and the shortest route to access these natural products from commercially available cheap starting materials.     

Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (−)‐Chaetominine and Its Biosynthetic Implications

The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (?)‐chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio‐inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.     

Synthetic approaches to neorogiolanes: enantiospecific synthesis of 12-methoxyneorogiola-1,3,5,7(17),8-pentaene

Enantiospecific synthesis of 12-methoxyneorogiola-1,3,5,7(17),8-pentaene, containing the complete carbon framework of the natural diquinane diterpenes neorogioldiols, starting from (S)-campholenaldehyde is described.     

Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).     

Asymmetric Synthesis of β, γ-β-Hydroxyl-γ-butyrolactones

Chiral β-hydroxyl-γ-butyrolactones have attracted substantial interest in recent years due to their presence inmany strongly active natural products having antitumor, fungicidal, anti-inflammatory activity, and their use as important precursors in natural product synthesis. [1] In the course of the total synthesis of the natural product Tuxpano lide ,[2] we found a concise and efficient strategy on the stereocontrolled synthesis of β-hydroxyl-γ-butyrolactonederivatives from cheap and achiral starting material.     

Enantiospecific total synthesis of the putative structure of cryptopyranmoscatone B2

Total synthesis of THP tethered pyrone containing natural product cryptopyranmoscatone B2 was accomplished from commercially available 2-deoxyribose. The key THP unit was assembled by FeCl₃ catalyzed cyclization of an allyl alcohol. Brown allylation and RCM reactions were employed to construct the lactone unit. The synthesis represents the first total synthesis of the putative structure of the natural product.     

Dearomatization strategies in the synthesis of complex natural products

Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three-dimensional molecular architectures.     

Sesquiterpene Cyclizations inside the Hexameric Resorcinarene Capsule: Total Synthesis of δ‐Selinene and Mechanistic Studies

The synthesis of terpene natural products remains a challenging task due to the enormous structural diversity in this class of compounds. Synthetic catalysts are unable to reproduce the tail‐to‐head terpene cyclization of cyclase enzymes, which create this diversity from just a few simple linear terpene substrates. Recently, supramolecular structures have emerged as promising enzyme mimetics. In the present study, the hexameric resorcinarene capsule was utilized as an artificial cyclase to catalyze the cyclization of sesquiterpenes. With the cyclization reaction as the key step, the first total synthesis of the sesquiterpene natural product δ‐selinene was achieved. This represents the first total synthesis of a sesquiterpene natural product that is based on the cyclization of a linear terpene precursor inside a supramolecular catalyst. To elucidate the reaction mechanism, detailed kinetic studies and kinetic isotope measurements were performed. Surprisingly, the obtained kinetic data indicated that a rate‐limiting encapsulation step is operational in the cyclization of sesquiterpenes.     

The Total Synthesis of Isodon Diterpenes

Families of structurally related molecules often provide stimulating targets for organic chemists that are engaged in the development of new methods and strategies for natural product synthesis. While typically focused on specific molecules, these synthetic investigations often lead to generalizable concepts and significant opportunities for learning in a greater sense. Historically well‐investigated families of natural products, such as the prostanoids, indole alkaloids, and macrolide antibiotics, provide ample evidence for the enduring value of these collective activities. In this Minireview, we turn our attention to the polycyclic family of diterpenes isolated from the Isodon genus of plants and provide an account of the recent methods and strategies utilized for their total synthesis.     

Recent advances of intermolecular Diels–Alder reaction in bio-inspired synthesis of natural products

The Diels–Alder(D–A)reaction is one of the most powerful reactions in organic synthesis.The intermolecular D–A reaction attracts much less attentions than its intramolecular counterpart in natural product synthesis,possibly due to the issues of reactivity and selectivity.In the past decade,the intermolecular D–A reaction has been increasingly utilized in the total synthesis of structurally complex natural products.In this article,we present a few examples for the elegant applications of the intermolecular D–A reaction that are inspired by biosynthetic hypotheses of the target natural products.These examples demonstrate that D–A reaction is not only useful for preparing building blocks but also powerful for coupling structurally complicated and sterically demanding segments in a highly chemo-and stereo-controlled fashion,which may inspire further developments of intermolecular D–A reaction from both strategy and methodology perspectives.     

Synthesis of Substituted γ-Butyrolactones: β-Hydroxymethyl-, β-Methylene and Cyclopropane Derivatives

A β-hydroxymethyl-γ-butyrolactone, which is a useful intermediate for the synthesis of several natural products with biological activity, was synthesized with good yield and a reduced number of steps from simple commercially available starting materials. Model compounds of natural products containing the unsaturated γ-butyrolactone unit, such as butenolides and β-methylene-γ-butyrolactones, were also conveniently synthesized from this hydroxymethyl-lactone.     

Total synthesis of spiruchostatin B aided by an automated synthesizer

The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.     

Total Synthesis of Millingtonine

Millingtonine is a glycosidic alkaloid that exists as a pair of pseudo‐enantiomeric diastereomers. Consideration of the likely biosynthetic origins of this unusual natural product has resulted in the development of a seven‐step total synthesis. Results from this synthetic work provide evidence in support of a proposed network of biosynthetic pathways that can account for the formation of several phenylethanoid natural products.     

Synthetic studies on polymaxenolides: synthesis and structure elucidation of nominal epoxyafricanane and other africane-type sesquiterpenoids

A racemic total synthesis of the sesquiterpenoid unit of the hybrid marine natural product polymaxenolide has been achieved based on a three-component assembly followed by ring-closing metathesis as the key steps. However, the spectral data of our product synthesized from Δ(9(15))-africanene by epoxidation were not identical with those of the natural product named epoxyafricanane. The structure confirmation of the synthetic nominal epoxyafricanane is described.     

"Common synthetic scaffolds" in the synthesis of structurally diverse natural products

Selected natural products have long been considered as desirable targets for total synthesis due to their unique biological properties and their challenging structural complexity. Laboratory synthesis of natural compounds usually relies on target-oriented synthesis, involving the production, isolation and purification of successive intermediates, requiring multiple steps to arrive to the final product. A far more economical approach using common synthetic scaffolds that can be readily transformed through biomimetic-like pathways to a range of structurally diverse natural products has been evolved in the last decade, leading synthesis to new directions. This tutorial review critically presents the hallmarks in this field.     

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor

Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.     

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.