Assembly of Terpenoid Cores by a Simple,Tunable Strategy

Oxygenated, polycyclic terpenoid natural products have important biological activities. Although total synthesis of such terpenes is widely studied, synthetic strategies that allow for controlled placement of oxygen atoms and other functionality remains a challenge. Herein, we present a simple, scalable, and tunable synthetic strategy to assemble terpenoid‐like polycycloalkanes from cycloalkanones, malononitrile, and allylic electrophiles, abundantly available reagent classes.     

Zirconium mediated total synthesis of crinitol, 9-hydroxyfarnesoic acid, 9-hydroxyfarnesol, 9-hydroxysargaquinone and the selectively-protected aglycone of moritoside and euplexide A

Tandem formation of an unsaturated zirconacycle, insertion of methallyl carbenoid, and addition of an aldehyde provides a rapid synthetic route to several linear terpenoid and terpene-polyketide natural products.     

Recent advances in terpenoid syntheses from China

Total syntheses of terpenoids play an essential role in the development of synthetic organic chemistry and medicinal science. Chinese synthetic community has made more and more profound contribution to this field and has gradually grown into a major force in the world over the past years. In this review, we shall celebrate the achievement by surveying the recent terpenoid syntheses from China since 2010.     

Biosynthesis of Cosmosporasides Reveals the Assembly Line for Fungal Hybrid Terpenoid Saccharides

Fungal hybrid terpenoid saccharides constitute a new and growing family of natural products with significant biomedical and agricultural activities. One representative family is the cosmosporasides, which feature oxidized terpenoid units and saccharide moieties; however, the assembly line of these building blocks has been elusive. Herein, a cos cluster from Fusarium orthoceras was discovered for the synthesis of cosmosporaside C ( 1 ) by genome mining. A UbiA family intramembrane prenyltransferase (UbiA-type PT), a multifunctional cytochrome P450, an α,β-hydrolase, an acetyltransferase, a dimethylallyl transferase (DMAT-type PT) and a glycosyltransferase function cooperatively in the assembly of the scaffold of 1 using primary central metabolites. The absolute configuration at C4, C6 and C7 of 1 was also established. Our work clarifies the unexpected functions of UbiA-type and DMAT-type PTs and provides an example for understanding the synthetic logic of hybrid terpenoid saccharides in fungi.     

Synthesis of (-)-callicarpenal, a potent arthropod-repellent

Callicarpenal (1), a natural terpenoid isolated from American beautyberry (Callicarpa americana), has shown significant repellent activities against mosquitoes, ticks, and imported fire ants. Here we report our efficient synthetic approach to this natural product, and preliminary results of the mosquito biting-deterrent effects of callicarpenal as well as its synthetic precursors and related C₈-epimers. The synthetic strategy allows rapid access to various epimers and analogues of the natural product that can be used to explore its structure-activity relationship and optimize its biological properties.     

The Wittig Reaction in Industrial Practice

The effects of a scientific discovery on industrial practice are illustrated with reference to the Wittig reaction. The aim of utilizing the Wittig reaction of linking terpenoid building blocks to give vitamin A and carotenoids on an industrial scale prompted extensive research and development work of a synthetic and chemical engineering nature. The importance of the Wittig reaction and its variants in the synthesis of active compounds and fine chemicals in industrial research is demonstrated in the present article.     

Iterative Nucleophilic and Electrophilic Additions to Coordinated Cyclooctatetraene: An Efficient Route to cis-5,7-Disubstituted 1,3-Cyclooctadienes

A great synthetic potential is shown by cis-5,7-disubstituted 1,3-cyclooctadienes 1 with regard to terpenoid cyclo-C₈ compounds. Starting from the complexed cyclooctatetraene ligand, such compounds are readily available in good yields with the following procedure: nucleophilic addition, protonation, second nucleophilic addition, second protonation, and cleavage.     

Development of a Terpenoid Alkaloid‐like Compound Library Based on the Humulene Skeleton

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp³‐rich terpenoid scaffolds and nitrogen‐containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid‐like compounds based on Lewis‐acid‐catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid‐like compound library has a high level of three‐dimensional‐shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid‐like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid‐like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.     

Synthesis of triterpene acids conjugates with α-tocopherol synthetic analogs

Heterodimers were synthesized of pharmacologically important α-tocopherol synthetic analogs with triterpene acids(betulonic, betulinic), potential polyfunctionsl drugs possessing antioxidant activity. The combination of the fragments of biologically active substances was performed through linkers (residues of succinic acid, hydrazine, glycine, tetramethylenediamine) binding the side chain of the antioxidant molecule with atoms C³ or C²⁸ of the terpenoid.     

Selective preparation of benzyltitanium compounds by the metalative Reppe reaction. Its application to the first synthesis of alcyopterosin A

Dialkoxytitanacyclopentadienes, prepared from two different acetylenes and a divalent titanium alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl, reacted with propargyl bromide to give directly benzyltitanium compounds. The resultant benzyltitanium compounds underwent deuteriolysis, iodinolysis (with I2), or oxygenation (with O2 gas) to give the corresponding deuterium-labeled compounds, iodides, or alcohols, illustrating their synthetic versatility. The first synthesis of alcyopterosin A, a bicyclic aromatic sesquiterpenoid recently isolated and characterized, has been achieved by this method, starting with an appropriate combination of an acetylene and a diyne.     

Trinuclear Metal Clusters in Catalysis by Terpenoid Synthases

Terpenoid synthases are ubiquitous enzymes that catalyze the formation of structurally and stereochemically diverse isoprenoid natural products. Many isoprenoid coupling enzymes and terpenoid cyclases from bacteria, fungi, protists, plants, and animals share the class I terpenoid synthase fold. Despite generally low amino acid sequence identity among these examples, class I terpenoid synthases contain conserved metal binding motifs that coordinate to a trinuclear metal cluster. This cluster not only serves to bind and orient the flexible isoprenoid substrate in the precatalytic Michaelis complex, but it also triggers the departure of the diphosphate leaving group to generate a carbocation that initiates catalysis. Additional conserved hydrogen bond donors assist the metal cluster in this function. Crystal structure analysis reveals that the constellation of three metal ions required for terpenoid synthase catalysis is generally identical among all class I terpenoid synthases of known structure.     

Enantioselective syntheses of (+)-xylarenal A and ent-xylarenal A

[reaction: see text] The total synthesis of the sesquiterpenoid xylarenal A is reported. This first synthetic entry to an eremophilane terpenoid with an exocyclic vinyl aldehyde unit involves the use of the bicyclic enone (+)-3, which after a gamma-oxidation and alpha'-allylation leads to the formation of the ketone (+)-8. After its acylation, an oxidative cleavage of the allyl side chain followed by alpha-methylenation of the resulting aldehyde gives (+)-xylarenal A (1). The synthesis of (-)-xylarenal A from (-)-3 is also reported. Moreover, the first total synthesis of the trinoreremophilane (+)-1alpha-hydroxyisoondetianone (5) is described.     

Geographical traceability of West Liguria extravirgin olive oils by the analysis of volatile terpenoid hydrocarbons

This study aimed at evaluating if the volatile terpenoid hydrocarbons of extravirgin olive oils from West Liguria, a North Italy region, could trace their geographical origin. If terpenoid hydrocarbons were individually considered, three compounds, i.e. alpha-copaene, alpha-muurolene and alpha-farnesene, allowed building a simple decision tree and discriminating oils produced in West Liguria from oils produced in other Mediterranean regions. Moreover, the multivariate analysis allowed building West Liguria class-models with high predictive ability, confirming the fundamental role of the volatile terpenoid hydrocarbons for the geographical characterisation of West Liguria oils.     

Terpenoid Biosynthesis Off the Beaten Track: Unconventional Cyclases and Their Impact on Biomimetic Synthesis

Terpene and terpenoid cyclizations are counted among the most complex chemical reactions occurring in nature and contribute crucially to the tremendous structural diversity of this largest family of natural products. Many studies were conducted at the chemical, genetic, and biochemical levels to gain mechanistic insights into these intriguing reactions that are catalyzed by terpene and terpenoid cyclases. A myriad of these enzymes have been characterized. Classical textbook knowledge divides terpene/terpenoid cyclases into two major classes according to their structure and reaction mechanism. However, recent discoveries of novel types of terpenoid cyclases illustrate that nature’s enzymatic repertoire is far more diverse than initially thought. This Review outlines novel terpenoid cyclases that are out of the ordinary.     

2-BENZAZEPINES III1, 2 IMPROVED SYNTHESIS OF 2, 3, 4, 5-TETRAHYDRO-2-BENZAZEPIN-1-ONE

3-Methylfuran is an important building block of terpenoid compounds¹⁾ and some of these compounds are biologically active, for example as a defence substance of animal.²⁾ Though many methods have been developed for the syntheses of 3-substituted furan derivatives,³⁾ most of them lack the generality as a synthetic method of (3-furanyl) methyl derivative. Tannis has recently reported the construction of 3-substituted furan derivative by using 3-(lithiomethyl) furan or 3-(chloromagnesium methyl) furan, and demonstrated the generality of his method.⁴⁾     

Supramolecular Capsule Catalysis Enables the Exploration of Terpenoid Chemical Space Untapped by Nature

Terpenes represent the largest and the most diverse class of natural compounds. This is remarkable as the whole variety is accessed from just a handful of highly conserved linear precursors. Modification of the cyclization precursors would enable a dramatic expansion of the accessible chemical space. However, natural enzymes do not enable us to tap into this potential, as they do not tolerate larger deviations from the prototypical substrate structure. Herein we report that supramolecular capsule catalysis enables facile access to diverse and novel terpenoid skeletons that formally can be traced back to C3-phenyl, benzyl, and homoprenyl derivatives of farnesol. Novel skeletons related to the presilphiperfolane core structure, as well as novel neoclovene derivatives were accessed efficiently in only four synthetic steps. Importantly, the products obtained carry functional groups that may be readily derivatized further.     

One-pot multi-component synthesis and cytotoxic activity of terpenoid dimers containing azapolycyclic spacers

Novel terpenoid dimers linked through the E–E rings were synthesized by catalytic multicomponent condensation of amino derivatives of methyl maleopimarate with form-aldehyde and dimethyl-tetraazadecalin or tetraazaperhydro- tetracene. Primary screening of the synthesized terpenoid dimers for cytotoxic activity was performed.     

Synthesis of the Bicyclic Lactone Core of Leonuketal,Enabled by a Telescoped Diels–Alder Reaction Sequence

The Diels–Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels–Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]‐bicyclic lactone ring system and its [3.2.1] isomer. Our four‐step, protecting‐group‐free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels–Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.     

Combinatorial biosynthesis in plants: a (p)review on its potential and future exploitation

Combinatorial biochemistry, also called combinatorial biosynthesis, comprises a series of methods that establish novel enzyme-substrate combinations in vivo and, in turn, lead to the biosynthesis of new, natural product-derived compounds that can be used in drug discovery programs. Plants are an extremely rich source of bioactive natural products and continue to possess a huge potential for drug discovery. In this review, we discuss the state-of-the-art in combinatorial biosynthesis methods to generate novel molecules from plants. We debate on the progress and potential in biotransformation, mutasynthesis, combinatorial metabolism in hybrids, activation of silent plant metabolism and synthetic biology in plants to create opportunities for the combinatorial biosynthesis of plant-derived natural products, and, ultimately, for drug discovery. The therapeutic value of two classes of natural products, the terpenoid indole alkaloids and the triterpene saponins, is particularly highlighted.     

Discovery of new biocatalysts for the glycosylation of terpenoid scaffolds

The synthesis of terpenoid glycosides typically uses a chemical strategy since few biocatalysts have been identified that recognise these scaffolds. In this study, a platform of 107 recombinant glycosyltransferases (GTs), comprising the multigene family of small molecule GTs of Arabidopsis thaliana have been screened against a range of model terpenoid acceptors to identify those enzymes with high activity. Twenty-seven GTs are shown to glycosylate a diversity of mono-, sesqui- and diterpenes, such as geraniol, perillyl alcohol, artemisinic acid and retinoic acid. Certain enzymes showing substantial sequence similarity recognise terpenoids containing a primary alcohol, irrespective of the linear or cyclical structure of the scaffold; other GTs glycosylate scaffolds containing secondary and tertiary alcohols; the carboxyl group of other terpenoids also represents a feature that is recognized by GTs previously known to form glucose esters with many different compounds. These data underpin the rapid prediction of potential biocatalysts from GT sequence information. To explore the potential of GTs as biocatalysts, their use for the production of terpenoid glycosides was investigated by using a microbial-based whole-cell biotransformation system capable of regenerating the cofactor, UDP-glucose. A high cell density fermentation system was shown to produce several hundred milligrams of a model terpenoid, geranyl-glucoside. The activities of the GTs are discussed in relation to their substrate recognition and their utility in biotransformations as a complement or alternative to chemical synthesis.