Chemo-enzymatic syntheses of drimane-type sesquiterpenes and the fundamental core of hongoquercin meroterpenoid by recombinant squalene-hopene cyclase

Squalene-hopene cyclase (SHC) converts squalene (C(30)) into pentacyclic triterpenes of hopene and hopanol. A linear sesquiterpene, (6E,10E)-2,6,10-trimethyldodeca-2,6,10-triene, underwent cyclization catalyzed by SHC, affording the following six bicyclic sesquiterpenes (drimane skeleton) in relatively high yield (68%): drim-7(8)-ene, drim-8(12)-ene, drim-8(9)-ene, driman-8α-ol, driman-8β-ol, and the novel sesquiterpene, named quasiclerodane, the skeleton of which is analogous to that of clerodane diterpene. To extend the scope of the enzymatic syntheses, acyclic sesquiterpenes to which a phenol moiety was appended were subjected to the enzymatic reaction catalyzed by SHC. The cyclic meroterpene core present in hongoquercins A and B was successfully prepared. The formation mechanisms of drimane-type sesquiterpenes and the cyclic meroterpene core of hongoquercins A and B are discussed.     

Distribution of drimane sesquiterpenoids and tocopherols in liverworts, ferns and higher plants: Polygonaceae, Canellaceae and Winteraceae species

The liverwort, Porella vernicosa complex produces a very hot tasting polygodial, a drimane-type sesquiterpene dialdehyde. The same compound has been isolated from two ferns, Thelypteris hispidula and Blechnum fluviatile, as well as from the higher plants Polygonum hydropiper, P. hydropiper f. purpurascens (Polygonaceae), Cinnamosma, Caspicodendron, Canella and Warburgia species (Canellaceae), and Pseudowintera colorata, Tasmannia lanceolata, Drimys and Zygogynum species (Winteraceae). In addition, the liverworts and higher plants which elaborate polygodial and its related pungent drimane dials contain a small amount of alpha-tocopherol, gamma-tocopherol or delta-tocotrienol. The present paper gives the results of a comparative study on the drimane-type sesquiterpenoids in some liverworts, ferns and higher plants, and the role of tocopherols in these plant groups.     

Sesquiterpenes produced by Pestalotiopsis microspora HF 12440 isolated from Artocarpus heterophyllus

Abstract

A drimane-type sesquiterpene, (+)-dendocarbin L (1) together with two bisabolane-type sesquiterpenes, (+)-sydonic acid (2) and (+)-sydowic acid (3) were isolated from the mycelium of Pestalotiopsis microspora HF 12440, an endophytic fungus from the stem of Artocarpus heterophyllus. The structures of all compounds were elucidated using spectroscopic methods and by comparison with the literature. Compound 1 was isolated from the fungi for the first time, compounds 2 and 3 were firstly obtained from this endophytic fungus. Compound 3 showed cytotoxicity (IC₅₀ 2.56?μg/mL) against murine leukemia P-388 cells.     

Unusual sesquiterpene glucosides from Amaranthus retroflexus

Implementing the phytochemical study of the weed Amaranthus retroflexus, four new sesquiterpene glucosides were isolated from the methanolic extract of the plant. The structures of these metabolites are determined on the basis of the mass spectrometry, and 1D and 2D NMR spectroscopies (DQ-COSY, TOCSY, HSQC, HSQC-TOCSY, HMBC, and NOESY). Two compounds are characterized by a new aglycone and differed from the site of glucosylation. The other two compounds are dimeric diastereoisomers.All the glucoside sesquiterpenes were tested on the wild species Taraxacum officinale to evaluate the role of this weed in the habitat and on the seed of A. retroflexus to verify the potential autotoxic effect of the plant.     

Drimenol: A versatile synthon for compounds with trans-drimane skeleton

Several reviews have been published on sesquiterpenes, and on drimane-type sesquiterpenes, going through drimenol and related compounds among others. However, to our knowledge, this is the first review exclusively on drimenol. Although, the main focus is on drimenol as a synthon for other drimane-type compounds, synthetic routes to obtain racemic and (-)-drimenol are summarized, as well as its isolation and determination of its configuration, in the early fifties. The reviewed synthetic routes start from natural (-)-drimenol as chiral synthon in most of cases, nevertheless total syntheses are considered as well. The strategies where racemic drimenol is involved begin with biomimetic cyclization of trans-farnesol. Microbiological procedures to functionalize the A ring of drimenol are also commented. The revision is classified according to the chemical structure of the final product, which mainly correspond to structures of natural occurrence, although other related derivatives are also analyzed.     

Rapid and scalable synthesis of chiral bromolactones as precursors to α-exo-methylene-γ-butyrolactone-containing sesquiterpene lactones

The sesquiterpene lactones cover a diverse and pharmacologically important diversity space. In particular, the electrophilic α-exo-methylene-γ-butyrolactone moiety that is preponderant in this natural product family has been shown to readily engage in covalent inhibition via conjugate addition of cysteine residues in target proteins. However, the synthetic accessibility of sesquiterpenes or related probes to investigate their mode of action remains laborious. Herein, we present a rapid and scalable route to chiral bromolactones as enabling precursors in the synthesis of sesquiterpene lactones.     

Pseudoguaiane-type sesquiterpenes and inhibitors on nitric oxide production from Dichrocephala integrifolia

Three new pseudoguaiane-type sesquiterpenes, dichrocepholides A-C, and two new pseudoguaiane-type sesquiterpene dimers, dichrocepholides D and E, were isolated from the aerial part of Dichrocephala integrifolia. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, the extract and its principal sesquiterpene constituent, parthenin, showed an inhibitory activity on nitric oxide (NO) production and on induction of inducible NO synthase.     

Biologically active constituents of Centipeda minima: sesquiterpenes of potential anti-allergy activity.

Ether, methanol and aqueous extracts of Centipeda minima (Compositae) herbs were found to have significant anti-allergy activities in passive cutaneous anaphylaxis (PCA) test. Three flavonoids, two sesquiterpene lactones and an amide were isolated from this plant material as inhibitors to induced histamine release from mast cells. The sesquiterpenes were identified as isobutyroylplenolin and senecioylplenolin by spectral investigations. The flavonoids and sesquiterpenes exhibited significant anti-allergy activity in PCA test with p.o. administration.     

Structure revision of HM-3, an aromatic sesquiterpene isolated from the phytopathogenic fungus Helicobasidium mompa. First total syntheses of HM-3 and HM-4

The first total syntheses of HM-3 and HM-4, aromatic sesquiterpenes isolated from the phytopathogenic fungus Helicobasidium mompa, have been accomplished. The structure assigned to the sesquiterpene HM-3 was found to be incorrect by total synthesis. A Claisen rearrangement-RCM reaction based strategy was employed for the total synthesis of the aromatic sesquiterpene HM-4 (cuparene-1,2-diol), which on selective monoacetylation established the structure of HM-3, a cuparene derivative.     

Taxonomic Insights and Its Type Cyclization Correlation of Volatile Sesquiterpenes in Vitex Species and Potential Source Insecticidal Compounds: A Review

Sesquiterpenes (SS) are secondary metabolites formed by the bonding of 3 isoprene (C5) units. They play an important role in the defense and signaling of plants to adapt to the environment, face stress, and communicate with the outside world, and their evolutionary history is closely related to their physiological functions. This review considers their presence and extensively summarizes the 156 sesquiterpenes identified in Vitex taxa, emphasizing those with higher concentrations and frequency among species and correlating with the insecticidal activities and defensive responses reported in the literature. In addition, we classify the SS based on their chemical structures and addresses cyclization in biosynthetic origin. Most relevant sesquiterpenes of the Vitex genus are derived from the germacredienyl cation mainly via bicyclogermacrene and germacrene C, giving rise to aromadrendanes, a skeleton with the highest number of representative compounds in this genus, and 6,9-guaiadiene, respectively, indicating the production of 1.10-cyclizing sesquiterpene synthases. These enzymes can play an important role in the chemosystematics of the genus from their corresponding routes and cyclizations, constituting a new approach to chemotaxonomy. In conclusion, this review is a compilation of detailed information on the profile of sesquiterpene in the Vitex genus and, thus, points to new unexplored horizons for future research.     

The Biosynthetic Gene Cluster of Mushroom-Derived Antrocin Encodes Two Dual-Functional Haloacid Dehalogenase-like Terpene Cyclases

(−)-Antrocin ( 1 ), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol ( 2 ) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2 . Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2 . Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold.     

Sesquiterpene derivatives of the genusFerula

The review is devoted to a study of the sequiterpene derivatives of the plants of the genusFerula (Apiaceae). Information is given on the determination of the structure, stereochemistry, and characteristic reactions of 78 coumarins, 39 esters, and six sesquiterpene alcohols isolated from plants of the genusFerula. The possible biogenetic interrelationships and mutual transitions of the sesquiterpenes that are derivatives of aliphatic and of mono- and bicyclic hydrocarbons are discussed. Some information confirming the hypotheses made is given.     

Applications of artificial intelligence for chemical inference—XXI: Chemical studies of marine invertebrates—XVII. The computer-assisted identification of [+]-palustrol in the marine organism Cespitularia sp., aff. subviridis

In order to demonstrate the power utility of the interactive computer program CONGEN,⁵ an example describing its use in the identification of the tricyclic sesquiterpene alcohol, [+]-palustrol, in extracts of a marine Xeniid (Cespitularia sp., aff subviridis) is provided. The rotation of [+]-palustrol further supports the remarkable antipodal relationiship between sesquiterpenes from marine Coelenterates and their corresponding terrestrial forms.⁶     

Terpenoids—LXXVI: Precapnelladiene,a possible biosynthetic precursor of the capnellane skeleton

A new sesquiterpene hydrocarbon, precapnelladiene (I) which does not obey the isoprene rule, was isolated from the nonpolar fractions of the soft coral Capnella imbricata. Its structure was established by chemical as well as spectral evidence, with additional aid of the CONGEN computer program. Precapnelladiene has a fused 5- and 8-membered ring system and may be a biogenetic precursor of the unique tricyclic capnellane skeleton typical of sesquiterpenes isolated from the same marine animal.     

New Sesquiterpenes from Chloranthus japonicus

Chemical investigation of the roots of Chloranthus japonicus Sieb . has resulted in the isolation and characterization of four new eudesmane‐type sesquiterpenes including two new sesquiterpene cinnamates, along with one new and two known sesquiterpene dimers. Their structures were established by spectroscopic means and by comparison with the respective literature values.     

Chemical studies of marine invertebrates—XLIII: Novel sesquiterpenes from clavularia inflata and clavularia koellikeri (Coelenterata,Octocorallia,Stolonifera)

Two novel sesquiterpenes, 12-acetoxycyclosinularane (1) and 12-acetoxysinularene(2),have been isolated from Clavularia inftata. Their structures have been determined by X-ray diffraction analysis and chemical correlation respectively. Moreover, the new aromadendrane sesquiterpene(1R^*, 1aS^*, 4R^*, 7R^*, 7aS^*, 7bS^*, 5Z)-4,4a,7-trihydroxyaromadendr-5-en-8-oic acid methyl ester (19) has been isolated from the related species C. koellikeri. Its structure has been established by X-ray diffraction analysis. These compounds are the first sesquiterpenes isolated from Octocorallia of the order Stolonifera.     

A new sesquiterpene from the barks of Manglietia hookeri

A new sesquiterpene manghookerins A (1) was isolated from the barks of Manglietia hookeri (Magnoliaceae) together with five known eudesmane-type sesquiterpenes. The structure of manghookerins A (1) was elucidated by physical and spectroscopic data analysis, including 1D and 2D NMR, HR-ESI-MS and X-ray diffraction. The structures of known sesquiterpenes were established by comparing their spectroscopic data with those in literatures.     

Chemical Constituents from the Roots of Neolitsea hiiranensis

One triterpenoid, taraxerone ( 1 ); four germacrane-type sesquiterpene lactones, linderane ( 2 ), linderalactone ( 6 ), pseudoneolinderane ( 7 ), (+)-linderadine ( 8 ); one sesquiterpene dilactone, pseudoneoliacine ( 10 ); three elemane-type sesquiterpenes, isolinderalactone ( 3 ), compound 4 and sericealactone ( 9 ); one eudesmane type sesquiterpene, cryptomeridol ( 11 ); one glucoside, β-sitosterol-β-D-glucoside ( 12 ) along with β-sitosterol (5) were isolated from the roots of Neolitsea hiiranensis. The structures of these compounds were identified on the basis of spectral properties.     

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.