Synthesis of Asebogenin and Balsacone A Precursor by a Novel Synthetic Strategy: Recent Opportunities for and Challenges of Total Synthesis of Balsacone A

One of the main areas of interest of synthetic organic chemistry is the rapid construction of small molecules with proven diverse biological activities for the development of new strategies to cure human health. In particular, the development of novel synthetic strategies is the most important option for reaching the molecular scaffolds of active molecules of natural origin. Balsacone A and asebogenin are compounds that exhibit a wide variety of important biological activities. In this respect, it has become very important to develop new strategies for the construction of biologically active natural and synthetic balsacone analogues. In particular, balsacone derivatives with hydroxy-substituted dihydrochalcone skeletons can be isolated from plant sources or obtained by hemi-syntheses using bio-sourced precursors. An efficient synthetic strategy to synthetically obtain balsacone A is the aim of the present study that considers the limited natural availability of these molecules as well as other factors, such as cost and time. Starting with phloroglucinol, a nine-step synthesis of the precursor of balsacone A was achieved at a 10% overall yield. Furthermore, asebogenin, which has a dihydrochalcone structure and plays a key role in the synthesis of balsacone A, was synthesised with a good yield.     

Recent topics in total syntheses of natural dimeric naphthoquinone derivatives

This digest overviews successful synthetic approaches to natural dimeric 1,4-naphthoquinones. Several natural dimeric 1,4-naphthoquinone derivatives have been isolated from natural sources including plants, bacteria, and fungi. They have diverse structures and attractive biological activities. However, it is difficult to construct the dimeric scaffolds efficiently and selectively, because 1,4-naphthoquinones and their derivatives are highly reactive. Efficient and attractive synthetic methodologies to construct unique dimeric 1,4-naphthoquinone skeletons are reviewed.     

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.     

Mangicols: structures and biosynthesis of A new class of sesterterpene polyols from a marine fungus of the genus Fusarium

A marine fungal isolate, tentatively identified as Fusarium heterosporum, has been found to produce a series of structurally novel sesterterpene polyols, the mangicols A-G (4-10). The structures of the new compounds, including the stereochemistry of mangicol A, were assigned by interpretation of spectral data derived from both natural products and synthetic derivatives. The mangicols, which possess unprecedented spirotricyclic skeletal components, show only weak to modest cytotoxicities toward a variety of cancer cell lines in in vitro testing. Mangicols A and B, however, showed significant antiinflammatory activity in the PMA (phorbol myristate acetate)-induced mouse ear edema model. A biosynthetic pathway for the neomangicol and mangicol carbon skeletons is proposed on the basis of the incorporation of appropriate radiolabeled precursors.     

Microwave-assisted syntheses of N-heterocycles using alkenone-, alkynone- and aryl-carbonyl O-phenyl oximes: formal synthesis of neocryptolepine

This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.     

A ligand-free Pd-catalyzed cascade reaction: an access to the highly diverse isoquinolin-1(2H)-one derivatives via isocyanide and Ugi-MCR synthesized amide precursors

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.     

Synthesis of Heterocycles through Denitrogenative Cyclization of Triazoles and Benzotriazoles

During the past few decades, there has been considerable growth in the development of denitrogenative reactions of triazole skeletons to construct valuable cyclic compounds, particularly heterocycles. Despite the inherent difficulty of the ring-opening of triazole derivatives, many novel and efficient approaches have arisen in this area mainly with the use of transition metal (such as rhodium, palladium, silver, copper) catalysis, photolysis, or free radical mediated reactions. Generally, these procedures begin with the ring-opening of 1,2,3-triazoles or benzotriazoles followed by N₂ extrusion and subsequent diverse transformations, which enable the rapid synthesis of various heterocycles in a single step. To avoid overlap with other related reviews, this minireview covers the recent advances in the denitrogenative cyclization of 1,2,3-triazoles since 2016 and the denitrogenative cyclization of benzotriazoles since 2012.     

Generating Skeletal Diversity from the C19‐Diterpenoid Alkaloid Deltaline: A Ring‐Distortion Approach

The development of new drugs calls for large collections of diverse molecules with considerable complexity. Ring distortion of natural products provides an efficient and facile approach to access new architectures with intriguing biological activities, by harnessing their inherent complexity. In this study, such a strategy has been explored on an abundant C₁₉‐diterpenoid alkaloid, deltaline, enabling the synthesis of 32 new derivatives bearing a broad spectrum of unique scaffolds. Extensive spectroscopic studies including X‐ray crystallographic analyses strongly supported the structures of the obtained novel skeletons, which present comparable opportunities with the great contributions made by nature for discovery of new lead compounds.     

Chemical and biological integrity in natural products screening

Due to pressure from combinatorial chemistry and the streamlining of the drug discovery process through automated high-throughput screening technologies, pharmaceutically based natural products programs are under increasing scrutiny. However by taking advantages of technologies originally developed for high-throughput screening and combinatorial chemistry and applying them to processes considered as bottlenecks in classical natural products chemistry (purification, structure elucidation, sample availability) it is our opinion that natural products can still contribute to the effective discovery of novel bioactive and pharmaceutically relevant metabolites. We describe here several such strategies that if universally implemented, will demonstrate i) whether chemical diversity is truly being accessed, ii) that novel metabolites can be formatted in a manner appropriate for modern screening paradigms, and iii) that natural products can be rapidly identified not only for novelty and pharmaceutical relevance but to assess their true biological origin.     

A new and practical PIFA-promoted olefin amidohydroxylation: six- versus five-membered ring formation

A novel access to the isoindolinone and isoquinolin-2-one skeletons from adequately substituted aromatic precursors is described. The key intramolecular cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the corresponding vinyl or allyl substituted N-(p-methoxyphenyl)benzamide derivatives leading to the heterocyclic compounds through 5-exo-trig and 6-exo-trig processes, respectively.     

Asymmetric synthesis and cytotoxic activity of isomeric phytosphingosine derivatives

New phytosphingosine analogues have been conceived, synthesised and their cytotoxicity in B16 murine melanoma cells tested. These compounds embed an isomeric substitution pattern resulting from a formal permutation of the C-2 and C-4 substituents along the aliphatic skeleton of the original sphingoid base. Five different stereoisomers have been accessed through regio- and stereocontrolled opening of the oxirane of long chain epoxyamine precursors. The corresponding N-hexyl and N-octanoyl derivatives have also been prepared. In cell viability experiments all the primary amines were found to be more active than the natural phytosphingosine with IC(50) in the low μM range for the most potent compounds.     

A Local‐Desymmetrization‐Based Divergent Synthesis of Quinine and Quinidine

Herein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a “local‐desymmetrization” approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.     

A new, efficient and stereoselective synthesis of tricyclic and tetracyclic compounds by samarium diiodide induced cyclisations of naphthyl-substituted arylketones--an easy access to steroid-like skeletons

In this report, we present the application of samarium diiodide induced cyclisations of naphthyl-substituted ketones towards an easy and stereoselective access to tri- and tetracyclic-functionalised compounds. Typical naphthalene derivatives were studied to investigate the scope and limitations of this novel cyclisation process. The model substrates studied demonstrate that the samarium ketyl cyclisations are essentially restricted to the formation of six-membered rings. The diastereoselectivity of these reactions is strongly influenced by the connection of the alkyl side chain to the naphthalene core. Gamma-naphth-1-yl-substituted ketones furnished cyclisation products, such as 17 or 22-26, as single diastereomers, whereas gamma-naphth-2-yl-substituted precursors gave mixtures of diastereomers--as demonstrated by the conversion of model compound 10 into tricyclic products 18 a/18 b, or that of cyclohexanone derivative 33 into tetracyclic diastereomers 34 a/34 b. Cyclic ketones as ketyl precursors furnished steroid-like tetracyclic skeletons; however, due to the cis/cis fusion of rings B/C and C/D these products have an "unnatural" bowl-like shape. Several of the cyclisation products have been identified by X-ray analyses, which not only proved the constitutions, but also the relative configurations and the preferred conformations. Steroid analogue 23 was subjected to subsequent transformations, which demonstrate that the styrene-like double bond of such compounds can be used for further structural diversification. First attempts to synthesise related azasteroids by incorporating nitrogen atoms into the ketone moiety are also reported. Thus, pyrrolidine derivatives 44 and 47 as well as piperidine derivatives 50 and 52 were subjected to samarium diiodide induced cyclisations. The expected tetracyclic products 48, 49 a/49 b, 51 and 53 a/53 b were obtained in moderate to good yields. The stereoselectivities observed follow the rules already established for the all-carbon precursors. The resulting products, bearing a nitrogen atom in ring D, are interesting azasteroid analogues with "unnatural" configuration.     

Facile synthesis of a diverse library of mono-3-substituted β-cyclodextrin analogues

Substituted cyclodextrins (CDs) have many applications, but synthetic challenges have limited the derivatives that can routinely be accessed. In particular, although there is considerable interest in selective derivatization at the 2- and 3-hydroxyls on the secondary face, since bulky guest molecules are most likely to project through this larger aperture, syntheses of such derivatives have required arduous procedures that afford poor yields, limiting their accessibility and utility. We address this challenge via synthetic strategies that allow facile creation of diverse libraries of water-soluble mono-3-substituted-β-cyclodextrins, via the commercially available mono-3-amino-β-cyclodextrin. The power of these strategies is confirmed through synthesis of twenty water-soluble cyclodextrin analogues with amide, thioureas or urea linkers, using one-pot reactions producing ≥55% yields and purifications that do not require chromatography. This work opens new possibilities for the design of selective host molecules for use in supramolecular chemistry, chemical separations, pharmaceutical formulations, and calibration of molecular simulations.     

A Cascade Synthesis of Aminohydantoins Using In Situ‐Generated N‐Substituted Isocyanates

Nitrogen‐substituted isocyanates are rarely utilized but powerful building blocks for the development of cascade reactions in heterocyclic synthesis. These reactive amphoteric intermediates can be accessed in situ via an equilibrium that allows controlled reactivity in the presence of bifunctional partners such as α‐amino esters. A cascade reaction has been carried out that forms 3‐aminohydantoin derivatives using simple phenoxycarbonyl derivatives of hydrazides and hydrazones as precursors of N‐substituted‐isocyanates. This method allows rapid assembly of complex aminohydantoin derivatives, including analogues of medicinally‐relevant compounds, using simple reactants.     

Synthesis of Functionalized Aliphatic Acid Esters via the Generation of Alkyl Radicals from Silylperoxyacetals

We describe a catalytic method for the synthesis of a variety of functionalized aliphatic acid esters using silylperoxyacetals, which are versatile alkyl radical precursors with a terminal ester moiety. In the presence of an appropriate transition-metal catalyst, the in situ generation of alkyl radicals and the subsequent bond-forming process proceeds smoothly to afford synthetically valuable aliphatic acid derivatives. The present method can be applied to the efficient synthesis of a pharmaceutically important 1,1-diarylalkane motif. In addition, a novel strategy for the synthesis of structurally diverse hydroxy acid derivatives via a C−O bond formation process that utilizes TEMPO has been developed.     

Two Versatile and Parallel Approaches to Highly Symmetrical Open and Closed Natural Product‐Based Structures

Two parallel approaches for preparing diverse and highly symmetrical homohybrids derived from a series of mono‐ and diterpenes, steroids, and alkaloids are reported. Both procedures are based on the mono‐addition of bis(alkynyl) dilithium reagents to natural products having a carbonyl group to produce the corresponding alkynyl derivatives. The Glaser–Hay Cu‐promoted homocoupling of these alkynyl natural product mono‐adducts as well as the Huisgen Cu‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction resulted in the synthesis of steroid‐, terpene‐, and alkaloid‐based homohybrid derivatives incorporating diverse spacers to join the natural product scaffolds. Straightforward entries to novel closed highly symmetrical and complex estrone‐based macrocyclic and cage architectures by means of the Glaser–Eglinton homocoupling and the CuAAC reaction have been devised.     

Cephalotanins A–D,Four Norditerpenoids Represent Three Highly Rigid Carbon Skeletons from Cephalotaxus sinensis

Four polycyclic norditerpenoids, cephalotanins A–D ( 1 – 4 ) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis and structurally characterized by a combination of various methods. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Biosynthetic pathways for 1 – 4 were proposed by involving diverse and very fascinating chemical events with the coexisting cephalotane troponoids as the precursors. Compound 1 exhibited good NF‐κB inhibition with an IC₅₀ value of 4.12±0.61 μΜ.     

Basicity-Controlled [3+2] Cyclization of 3-Hydroxyquinolin-ones and β-Chlorinated Nitrostyrenes

The construction of novel skeletons through the recombination of natural products ring systems is attractive. Herein, a basicity-controlled synthesis of (dihydro)furo[2,3-c]quinolin-4(5H)-one derivatives through (3+2) cyclization between 3-hydroxyquinolin-2-ones and β-chlorinated nitrostyrenes was developed. In addition, preliminary study gave the chiral dihydrofuro[2,3-c]quinolin-4(5H)-one derivatives with up to 83 % ee.     

New conversion of Friendl(a)nder reaction of 3-amino-lH-benzo[f]chromene-2-carbonitriles with cyclohexanone

Two different skeletons of heterocyclic compounds, quinoline and quinazolinone analogs could be obtained by a novel one-potsynthesis from substituted 3-amino-lH-benzo[f]chromene-2-carbonitrile derivatives and cyclohexanone in DMF in the catalyst ofanhydrous zinc chloride under reflux. A plausible mechanism was proposed.