Isopropenyl Group Research Articles

Asymmetric Total Synthesis of (-)-Lemnalemnane A.

The asymmetric total synthesis of lemnalemnane A, a rare rearranged sesquiterpenoid, has been accomplished in 13 steps from (S)-carvone. The key features of the synthesis are the removal of the isopropenyl group derived from (S)-carvone via a radical intermediate, the formation of the bicyclo[3.3.1]nonane skeleton using the Dieckmann condensation, the stereocontrolled construction of five continuous chiral centers by chemo- and stereoselective reduction and stereoselective introduction of the alkyne group, and the formation of the spirolactone moiety via a hemiacetal intermediate.

Total Synthesis of Azulene Derivative, a Blue Pigment Isolated from Lactarius indigo, and Colorant Application of Its Aqueous Dispersion.

Safety concerns in the food industry have increased the demand for natural food colorants. However, the application ranges of natural blue colorants are insufficient because they are scarce in nature, and the currently available natural blue dyes are limited to water-soluble products. In this study, we investigated a fat-soluble azulene derivative isolated from the mushroom Lactarius indigo as a potential candidate for a natural blue colorant. We developed its first total synthesis, where the azulene skeleton was constructed from a pyridine derivative and an ethynyl group was converted into an isopropenyl group using zirconium complexes. Moreover, nanoparticles of the azulene derivative were prepared via reprecipitation method, and their colorant ability was investigated in aqueous solutions. The new candidate food colorant exhibited a deep-blue color in an organic solvent and aqueous dispersion.

Enantioselective Total Synthesis of 10-Desoxy Analogue of a Previously Reported Natural Peroxyguaidiol

Described herein is an enantioselective synthesis of an analogue of a previously reported guaiane endoperoxide isolated from aerial parts of Croton arboreous. The polycyclic framework of the target structure was constructed with the C-7 stereogenic center derived from L-(-)-carvone and other stereogenic centers installed via substrate chirality-induced asymmetric reactions, starting with the synthesis of the seven-membered ring through regioselective enolization of carvone, ring-expansion, and installation of a conjugated C═C bond. Further functionalization was then achieved through regioselective enolization, triflation, and installation of an isopropenyl group. During the synthesis, some exceptions to the well-known rules of "thermodynamic control" and "kinetic control" in enolization of asymmetric cyclic ketones were observed. In construction of the bridged five-membered and endoperoxy rings, a peroxycarbenium [3 + 2] cycloaddition reaction with alkenes was carried out with several alkenes-silyl-gem-dihydroperoxides of different relative configurations. However, no expected [3 + 2] products were observed. Finally, the five-membered ring was smoothly installed through an intramolecular Darzens reaction, and the peroxy functionality was introduced via a carbon-centered radical-mediated reaction with triplet oxygen, followed by an intramolecular etherification under acidic conditions. Comparison of the 1H and 13C NMR spectra of the synthetic analogue and the natural product revealed that the latter was definitely not an endoperoxide.

Model Synthetic Study of Tutin, a Picrotoxane-Type Sesquiterpene: Stereoselective Construction of a cis-Fused 5,6-Ring Skeleton.

Picrotoxinin, coriamyrtin, and tutin are representative natural products classified as picrotoxane-type sesquiterpenes and they function as strong neurotoxins. Because they possess a cis-fused 5,6-ring skeleton with a highly congested functionalization, organic chemistry researchers have pursued the development of a stereoselective synthesis method for such skeleton. This study aims to stereoselectively synthesize the cis-fused 5,6-ring skeleton with two tetrasubstituted carbons at both angular positions using a model compound. The results revealed that the desymmetrization of the 2-methyl-1,3-cyclopentanedione moiety via the DL-proline-mediated intramolecular aldol reaction of a pentanal derivative bearing an isopropenyl group and the five-membered ring at the 3- and 5-position, respectively, provided the desired cis-fused skeleton. This reaction can construct four contiguous stereogenic centers of the bicyclic skeleton with the two angular positions in good yield with high stereoselectivity. Further, this reaction was applied to the kinetic resolution of the racemate using L-proline, providing the enantiomeric pure aldol product with the desired skeleton. This method can be utilized for total synthesis of picrotoxane-type sesquiterpenes.

Triflic Imide‐Catalyzed Glycosylation of Disarmed Glycosyl ortho‐Isopropenylphenylacetates and ortho‐Isopropenylbenzyl Thioglycosides

AbstractGlycosylation reaction involving the coupling of a glycosyl donor with a glycosyl acceptor is one of the cornerstones of chemical preparation of pure glycans and glycoconjugates of biological relevance. Catalytic glycosylation of glycosyl ester donors and thioglycosides is an attractive but underexplored topic in carbohydrate chemistry. Herein, triflic imide (Tf2NH)‐catalyzed glycosylation of various O‐, S‐, and C‐nucleophiles has been achieved using disarmed glycosyl ortho‐isopropenylphenylacetates (GIPPAs) and ortho‐isopropenylbenzyl thioglycosides as glycosylating agents. The reactions proceed under mild conditions to give the desired glycosides in good‐to‐excellent yields. Of particular note, the comparable reactivity for the α‐isomers and the β‐ones of GIPPAs is observed. The mechanistic investigation demonstrates that the isopropenyl group is essential for the reaction and its preferential protonation triggers the reaction. This work provides another member to the arsenals of glycosyl ester and thioglycoside donors suitable for acid‐catalyzed glycosylation to create various glycosidic bonds.

Covalently Grafting Sulfur-Containing Polymers to Carbon Nanotubes Enhances the Electrochemical Performance of Sulfur Cathodes

Lithium–sulfur (Li–S) batteries have attracted extensive attention due to the high theoretical specific capacity of sulfur (1675 mA h g–1). Despite the advantage, the utility of Li–S batteries is limited by the low electrical conductivities of sulfur and its discharge products (i.e., Li2S2 and Li2S) as well as the “shuttle effect” of polysulfides. Herein, a strategy of covalently grafting sulfur-containing polymers to carbon nanotubes (CNTs) is proposed as a solution to the problems associated with sulfur cathodes. The sulfur-containing polymers are grafted to the CNTs using an “inverse vulcanization” method, wherein elemental sulfur is reacted with CNTs that are previously functionalized with isopropenyl groups. A morphological study of the resulting composite indicates that the material maintains the one-dimensional characteristic of CNTs and effectively establishes a porous network via overlap. Such structural features are found to facilitate electron transport in the composite and also suppress the shuttle effect of polysulfides. When compared to cells that are prepared from elemental sulfur, devices that contain the composite show improved specific capacity (i.e., 1368 mA h g–1 at 0.05 C) and a suppressed capacity fading rate (i.e., 0.074% per cycle at 1 C over 500 cycles). In a broader context, covalently attaching sulfur-containing polymers to CNTs provides design criteria for realizing cathode materials that may be employed in high-performance Li–S batteries.

Silica Gel-mediated Oxidation of Prenyl Motifs Generates Natural Product-Like Artifacts.

Prenyl moieties are commonly encountered in the natural products of terpenoid and mixed biosynthetic origin. The reactivity of unsaturated prenyl motifs is less recognized and shown here to affect the acyclic Rhodiola rosea monoterpene glycoside, kenposide A (8: ), which oxidizes readily on silica gel when exposed to air. The major degradation product mediated under these conditions was a new aldehyde, 9: . Exhibiting a shortened carbon skeleton formed through the breakdown of the terminal isopropenyl group, 9: is prone to acetalization in protic solvents. Further investigation of minor degradation products of both 8: and 8-prenylapigenin (8-PA, 12: ), a flavonoid with an ortho-prenyl substituent, revealed that the aldehyde formation was likely realized through epoxidation and subsequent cleavage at the prenyl olefinic bond. Employment of 1H NMR full spin analysis (HiFSA) achieved the assignment of all chemical shifts and coupling constants of the investigated terpenoids and facilitated the structural validation of the degradation product, 9: . This study indicates that prenylated compounds are generally susceptible to oxidative degradation, particularly in the presence of catalytic mediators, but also under physiological conditions. Such oxidative artifact/metabolite formation leads to a series of compounds with prenyl-derived (cyclic) partial structures that are analogous to species formed during PhaseI metabolism in vivo. Phytochemical and pharmacological studies should take precautions or at least consider the impact of (unavoidable) exposure of prenyl-containing compounds to catalytic and/or oxidative conditions.

Limonene-derived polycarbonates as biobased UV-curable (powder) coating resins

The evaluation of poly(limonene carbonate)s (PLCs), derived from orange oils and carbon dioxide, as UV-curable (powder) coating binders is described. PLCs with moderate molecular weight were prepared by copolymerization of limonene oxide with CO2 and a subsequent molecular weight reduction step by transcarbonation with 1,10-decanediol (1,10-DCD). These PLCs were cured with a trifunctional thiol monomer in the presence of a photoinitiator via thiol-ene chemistry to form poly(thioether-co-carbonate) networks. The UV curing of the resins following solvent casting was studied at 130 °C using ATR-FTIR, revealing a fast curing and a quick thiol-ene network (TEN) formation, realized by the addition reactions of thiol groups of the curing agent onto pendant isopropenyl groups of PLC. An ene addition enhanced by thiol-ene crosslinking was also observed, known as a ‘cage effect’, which was discovered for the first time in a UV-curable thiol-ene system. The efficient TEN formation was also evidenced by the high sol fractions in those UV-cured samples and their dynamic mechanical thermal analysis (DMTA). The DMTA results of these TENs showed high Tgs (up to 125.9 °C) and a wide range of thermomechanical properties, including rubbery moduli from 4.4–27.5 MPa. The UV-cured powder coating employing PLCs as binders showed outstanding properties such as high transparency, good acetone resistance, high pencil hardness (H-2 H) and high König hardness (174−199 s), suggesting their potential as very promising biobased alternatives to conventional powder coating resins.

Modification of Azepanobetulin at the Isopropenyl Group

Modification of the isopropenyl group of biologically active azepanobetulin via oxidation with ozone and selenium dioxide, allylic bromination, azidation, amination, reduction, 1,3-dipolar cycloaddition, and Claisen–Schmidt condensation afforded a series of C30-derivatives with oxygen- and nitrogen-containing aliphatic and heterocyclic substituents.

Standardised comparison of limonene-derived monoterpenes identifies structural determinants of anti-inflammatory activity

Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation. To identify the structural determinants of anti-inflammatory activity and potency which are required for chemical optimization towards development of new anti-inflammatory drugs, a selected group of monoterpenes especially abundant in mint species was screened by measuring bacterial lipopolysacharide (LPS)-induced nitric oxide (NO) production in murine macrophages. Nine compounds significantly decreased LPS-induced NO production by more than 30%. IC50 values were calculated showing that the order of potency is: (S)-(+)-carvone > (R)-(−)-carvone > (+)-dihydrocarveol > (S)-8-hydroxycarvotanacetone > (R)-8-hydroxycarvotanacetone > (+)-dihydrocarvone > (−)-carveol > (−)-dihydrocarveol > (S)-(-)-pulegone. Considering the carbon numbering relative to the common precursor, limonene, the presence of an oxygenated group at C6 conjugated to a double bond at C1 and an isopropenyl group and S configuration at C4 are the major chemical features relevant for activity and potency. The most potent compound, (S)-(+)-carvone, significantly decreased the expression of NOS2 and IL-1β in macrophages and in a cell model of osteoarthritis using primary human chondrocytes. (S)-(+)-carvone may be efficient in halting inflammation-related diseases, like osteoarthritis.

Detoxification of the solanaceous phytoalexins rishitin, lubimin, oxylubimin and solavetivone via a cytochrome P450 oxygenase

ABSTRACT Solanaceous plants produce sesquiterpenoid phytoalexins to defend themselves against a variety of pathogens. These toxic compounds are not only harmful to the pathogen but also to the plant, and thus need to be detoxified by the plant after the threat has been eliminated. We report that the detoxification of rishitin, the major phytoalexin in potato tubers and tomato fruits, is mediated by a cytochrome P450 CYP76 family enzyme via the hydroxylation of the isopropenyl group resulting in the formation of 13-hydroxyrishitin, also known as rishitin-M1. We further observed hydroxylation of the potato phytoalexins solavetivone, lubimin and oxylubimin by the same enzyme. Constitutive expression of CYP76 in Nicotiana benthamiana also led to a reduction of the non-potato phytoalexins capsidiol and its derivative capsidiol 3-acetate. We therefore annotated this enzyme as sesquiterpenoid phytoalexins hydroxylase, SPH. This broad range of substrates indicates that SPH functions as a general phytoalexin detoxification enzyme in Solanaceae, and is therefore relevant for a better understanding of plant-pathogen interaction in solanaceous plants, which comprise many economically important crops, such as potato, tomato, eggplant and pepper.

Antiproliferative activity and energy calculations of a new triterpene isolated from the palm tree Acrocomia totai

Acrocomia totai Mart (Arecaceae) is a palm tree native to South America, widely studied for biodiesel production. The aim of this work was to perform the first phytochemical study of A. totai leaves, as well as to do biological assays against human cancer cell lines. A new triterpene of the hopane class named totaiol (1), three known triterpenes (2–4), and two phytosteroids (5–6) were identified. The new natural product was characterized using 1 D and 2 D NMR, single crystal X-ray diffraction analises, and high resolution mass spectrometry. The intercontacts in the crystal packing were also analised. Complete stereochemical characterization of compound 1 revealed an unusual positioning pattern for methyl and isopropenyl groups in the polycyclic skeleton. Compounds 1–5 were evaluated for the first time in antiproliferative assays against Ca Ski, MCF-7 and MCF-10 cells. The new natural product was active against Ca Ski cells with IC50 ≤ 6.25 µg mL−1.

Access to Natural Valparanes and Daucanes: Enantioselective Synthesis of (-)-Valpara-2,15-diene and (+)-Isodaucene.

The first total synthesis of a natural diterpene valparane, (-)-valpara-2,15-diene (1), has been achieved from all -trans-geranylgeraniol (9), a natural renewable compound. The key steps involve a Ti(III)-mediated radical cyclization of the chiral monoepoxypolyene (14 R,15 R)-14,15-epoxy,16- tert-butyldimethylsilyloxygeranyllinalyl acetate (8) to give the 6,6,7-tricyclic intermediate 7 with stereocontrolled formation of six stereocenters; a stereo- and regio-directed contraction of the A ring in 7 to produce a cyclopentane ring; and the ready generation of the target isopropenyl group. This research provides access to structurally related natural products such as the sesquiterpene (+)-isodaucene (3), the synthesis of which is also reported herein.

The axial/equatorial conformational landscape and intramolecular dispersion: new insights from the rotational spectra of monoterpenoids.

Intramolecular non-covalent interactions determine the conformational preferences of many molecules, and their understanding is relevant for a proper description of molecular structure. Here, by using rotational spectroscopy in combination with quantum chemistry calculations, we show that intramolecular dispersion forces involving a three-carbon substituent influence the relative energies and conformational landscape of the three monoterpenoids carvone, limonene and perillaldehyde. New equatorial and axial conformers have been identified for all three molecules. Comparison of experimental data with ab initio and density functional calculations shows that axial conformers are stabilised by dispersion interactions between the cyclohexene ring and the isopropenyl group of the monoterpenoids, and that an accurate account of these interactions is challenging for theoretical methods. This work demonstrates the potential of rotational spectroscopy for investigating non-covalent interactions and provides critical benchmarks for theory. Our results will inform future investigations of axial/equatorial isomerism and impact understanding of intramolecular dispersion in larger species.

A molecular electron density theory study of the mechanism, chemo- and stereoselectivity of the epoxidation reaction of R-carvone with peracetic acid.

The epoxidation reaction of R-carvone 8 with peracetic acid 9 has been studied within the molecular electron density theory at the B3LYP/6-311(d,p) computational level. The chemo- and stereoisomeric reaction paths involving the two C–C double bonds of R-carvone 8 have been studied. DFT calculations account for the high chemoselectivity involving the C–C double bond of the isopropenyl group and the low diastereoselectivity, in complete agreement with the experimental outcomes. The Baeyer–Villiger reaction involving the carbonyl group of R-carvone 8 has also been analysed. A bonding evolution theory analysis of the epoxidation reaction shows the complexity of the bonding changes taking place along this reaction. Formation of the oxirane ring takes place asynchronously at the end of the reaction by attack of anionic oxygen on the two carbons of the isopropenyl C–C double bond.

Synthesis of Javanicunines A and B, 9-Deoxy-PF1233s A and B, and Absolute Configuration Establishment of Javanicunine B.

Javanicunines A-B and 9-deoxy-PF1233s A-B belong to a family of natural diketomorpholines with a unique isopropenyl group at C-10b or C-5a and a hydroxyl group at C-11a or C-10b. We herein reported the first total synthesis of javanicunines A-B and 9-deoxy-PF1233s A-B. Pivotal features of the synthesis included a nucleophilic substitution reaction, followed by a Davis' oxaziridine oxidation to assemble javanicunines A-B, and a chemoselective and stereoselective oxidation with Murray's reagent to install the requisite C-10b hydroxyl group in 9-deoxy-PF1233s A-B. The present synthesis also established the absolute configuration of javanicunine B.

Highly syndioselective coordination (co)polymerization of isopropenylstyrene

Coordination (co)polymerization of para-isopropenylstyrene (pIPSt) and meta-isopropenylstyrene (mIPSt), initiated by scandium (Sc) based catalysts, afforded new type of products, bearing pendant isopropenyl groups with perfect syndiotacity (rrrr > 99%).

Total Synthesis of the Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis.

The first enantioselective total synthesis of the complex tricarbocyclic sesquiterpenoid periconianone A based on a postulated biogenesis is reported. Key elements of the synthetic route include the use of an isopropenyl group as a removable directing group for stereoselective synthesis, a sequence featuring a Rh-mediated O-H insertion/[3,3]-sigmatropic rearrangement and subsequent α-ketol rearrangement, and a late stage aldol reaction to furnish the complex cage-like framework.

Amalgamation of Synthetic Biology and Chemistry for High-Throughput Nonconventional Synthesis of the Antimalarial Drug Artemisinin

The development of a cost-effective process for the production of artemisinin, the precursor of all artemisinin-derived drugs, the first-line treatment for malaria, has been a long-pursued endeavor. The breakthrough achievement of coaxing genetically engineered yeast to express Artemisia annua genes for the commercial production of artemisinic acid, an advanced intermediate in the synthesis of artemisinin, has yet to fully realize an affordable malaria treatment for the poor because of the lack of a cost-effective chemical conversion into artemisinin. We describe herein a commercially feasible and pragmatic synthesis of artemisinin from amorpha-4,11-diene, an early-stage intermediate produced in 2-fold higher molar yield than engineered yeast cells can process into artemisinic acid. The key to this novel approach is an exceedingly effective functionalization of the isopropenyl group of amorphadiene via endo-epoxyamorphadiene to give dihydroartemisinic acid, which upon esterification followed by oxidation ...

Conformational Flexibility of Limonene Oxide Studied By Microwave Spectroscopy.

Monoterpenoids are biogenic volatile organic compounds that play a major role in atmospheric chemistry by participating in the formation of aerosols. In this work, the monoterpenoid (R)-(+)-limonene oxide (C10 H16 O) was characterized in the gas phase by Fourier-transform microwave spectroscopy in a supersonic jet. Five conformers of limonene oxide, four equatorial and one axial considering the configuration of the isopropenyl group, were unambiguously identified from analysis of the rotational spectrum. The observed conformers include cis and trans forms, which are stabilized by a subtle balance of hydrogen bonds, dispersive interactions, and steric effects. Estimated conformational relative abundances surprisingly reveal that the abundance of the axial conformer is similar to that of some of the equatorial conformers. In addition, the potential energy surface was extensively explored by using density functional theory and ab initio methods.