Natural Occurring Terpene Cyclic Anhydrides: Biosynthetic Origin and Biological Activities.

Cyclic acid anhydride is a not very widespread structure in nature, but with a determining role in natural products possessing this functionality in their skeleton. To the best of our knowledge, no revision of terpenes containing cyclic anhydrides has been previously reported. The result was that more than 100 terpenic cyclic anhydrides and related compounds were found to be in need of being reported.

Bioinspired Synthesis of Platensimycin from Natural -Kaurenoic Acids.

The biomimetic formal synthesis of the antibiotic platensimycin for the treatment of infection by multidrug-resistant bacteria was accomplished starting from either -kaurenoic acid or grandiflorenic acid, each of which is a natural compound available in multigram scale from its natural source. Apart from the natural origin of the selected precursors, the keys of the described approach are the long-distance functionalization of -kaurenoic acid at C11 and the efficient protocol for the A-ring degradation of the diterpene framework.

Selectivity of Relative Humidity Using a CP Based on S-Block Metal Ions.

Herein, we present the syntheses of a novel coordination polymer (CP) based on the perylene-3,4,9,10-tetracarboxylate (pery) linkers and sodium metal ions. We have chosen sodium metal center with the aim of surmising the effect that the modification of the metal ion may have on the relative humidity (RH) experimental measurements of the material. We confirm the role of the ions in the functionalization of the deposited layer by modifying their selectivity towards moisture content, paving the way to the generation of sensitive and selective chemical sensors.

Diclofenac N-Derivatives as Therapeutic Agents with Anti-Inflammatory and Anti-Cancer Effect.

A series of diclofenac N-derivatives (, , , , , -) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound against all cell lines and both compounds and in human Hep-G2 and HT29 cell lines.

Synthesis of Cannabinoids: "In Water" and "On Water" Approaches: Influence of SDS Micelles.

We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of "on water" and "in water" reactions.

Novel Insect Antifeedant and Ixodicidal Nootkatone Derivatives.

Naturally occurring nootkatone, with reported insecticidal and acaricidal properties, has been used as a lead to generate molecular diversity and, consequently, new insect antifeedant and ixodicidal compounds. A total of 22 derivatives were generated by subjecting this molecule to several reactions including dehydrogenation with the iodine/DMSO system, oxidation with SeO, epoxidation with CPBA, oxidation or carbon homologations of the α-carbonyl position with TMSOTf (trimethylsilyl trifluoromethanesulfonate) followed by Rubottom and Dess Martin periodane oxidations, condensation with formaldehyde using Yb(OTf) as catalyst and dehydroxilation using the Grieco protocol. The insect antifeedant (against and ) and ixodicidal (against the tick ) activities of these compounds were tested.

Mimicking Halimane Synthases: Monitoring a Cascade of Cyclizations and Rearrangements from Epoxypolyprenes.

We have developed and rationalized a biomimetic transformation mimicking halimane synthases based on a Lewis acid-catalyzed cascade of cyclizations and rearrangements of epoxypolyprenes. Two rings, three stereogenic centers, and a new double bond were generated in a single chemical operation. Based on this cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of halimene-type terpenoids and analogues as a proof-of-concept study.

Germacrone Derivatives as new Insecticidal and Acaricidal Compounds: A Structure-Activity Relationship.

Currently, the use of synthetic pesticides is the main method of plant protection applied in agri- and horticulture. However, its excessive use leads to the development of pesticide resistance, a contamination of the environment, toxicity to non-target organisms, and risks for human health. With the ultimate aim of contributing to the develop of a more sustainable pest management, we used the natural product germacrone ( ), reported to possess significant insecticidal activity, as starting material for the generation of molecular diversity (-).

One-Step Synthesis of Furan Rings from α-Isopropylidene Ketones Mediated by Iodine/DMSO: An Approach to Potent Bioactive Terpenes.

The system I/dimethyl sulfoxide mediates the one-step transformation of α-isopropylidene ketones into furan rings following a biomimetic approach. This methodology has been used for the synthesis of terpene furans such as mintfurane, curzerene, atractylon, and isoatractylon, all of them possessing interesting biological activities. The synthesis of linderazulene directly from 4,5-epoxygermacrone via a cascade reaction shows the potential of this protocol.

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.

Studies in Cyclization of Aromatic Epoxy-acyclicpolyprenes: Lewis Superacids and Titanocene Chloride.

Two catalytic cascade cyclization methods (radical and 'cationic) to obtain aromatic polycyclic diterpenes hydroxylated at C3 starting from aromatic epoxypolyprenes were developed. The catalytic use of the Lewis superacid bismuth triflate produces a good yield of cyclized 2 from epoxypolyprene 3. This researchmay well direct future efforts to the synthesis of bioactive natural products.

Iodine, a Mild Reagent for the Aromatization of Terpenoids.

Efficient procedures based on the use of iodine for the aromatization of a series of terpenoids possessing diene and homoallylic or allylic alcohol functionalities are described. Different examples are reported as a proof-of-concept study. Furthermore, iodine also proved to mediate the dehydrogenation of testosterone.

Expedient access to enantiopure cyclopentanic natural products: total synthesis of (-)-cyclonerodiol.

Following the principles of collective total synthesis, a number of natural products sharing an optically pure, multifunctional, cyclopentanic core were synthesized from a common precursor: plinol A (1). This intermediate was efficiently obtained in only four steps from (-)-linalool (2) using as the key step a Ti(III)-mediated diastereoselective radical cyclization. The feasibility of this approach was confirmed with the expedient enantiospecific synthesis of cyclonerodiol (3), and the formal synthesis of chocol G (4) and piperitone (5).

Structural diversity from the transannular cyclizations of natural germacrone and epoxy derivatives: a theoretical-experimental study.

Treatment of germacrone (1) with different electrophiles, and of its epoxy derivatives germacrone-4,5-epoxide (2), germacrone-1,10-epoxide (3) and isogermacrone-4,5-epoxide (4) with Brönsted/Lewis acids and Ti(III), gives rise to a great structural diversity. Thus, by using a maximum of two steps, the production of more than 40 compounds corresponding to 14 skeletons is described. Computational calculations rationalizing the structural divergence produced are also described.

First synthesis of (+)-myrrhanol C, an anti-prostate cancer lead.

The first synthesis of (+)-myrrhanol C (1), an antitumor polypodane-type bicyclic triterpene with inhibitory activity against androgen insensitive prostate cancers, is reported herein (IC(50) 10 μmolar). A key step in our convergent synthesis of (+)-myrrhanol C and related analogues is the employment of a microbial stereo- and regioselective late stage C-H oxidation. A low-waste and sustainable process has been developed to prepare (+)-myrrhanol C for further biological studies.

Total synthesis of (+)-seco-C-oleanane via stepwise controlled radical cascade cyclization.

An asymmetric concise total synthesis of the (+)-seco-C-oleanane 1 was accomplished. The successful route to this natural product involves as the key step a stepwise regio- and stereocontrolled catalytic radical polyene cascade cyclization from preoleanatetraene oxide (16), a process mediated by Cp(2)TiCl. The use of this single-electron-transfer complex permits mild cyclization conditions without using unnecessary prefunctionalizations and stops the process at the bicyclic level.

Protecting-group-free synthesis of chokols.

As a result of a combined theoretical and experimental study, we describe a two-step protocol for the preparation of an optically pure, multifunctional, cyclopentanic core shared by a number of natural products. This process is based on a hitherto unreported Ti(III)-mediated diastereoselective cyclization in which the hydroxy-directed template effect played by the Ti(III) species was found to be crucial for the stereoselective outcome of the reaction. The viability of this concept was confirmed with the first protecting-group free synthesis of three enantiopure chokols, namely, chokols K, E, and B.

Efficient synthesis of the anticancer β-elemene and other bioactive elemanes from sustainable germacrone.

Highly efficient preparations of anticancer β-elemene and other bioactive elemanes were carried out using the natural product germacrone as a renewable starting material. The syntheses were achieved in only 3-5 steps with excellent overall yields (43-54%). An enantioselective approach to these molecules is also described.

Weakening C-O bonds: Ti(III), a new reagent for alcohol deoxygenation and carbonyl coupling olefination.

Investigations detailed herein, including density functional theory (DFT) calculations, demonstrate that the formation of either alkoxy- or hydroxy-Ti(III) complexes considerably decreases the energy of activation for C-O bond homolysis. As a consequence of this observation, we described two new synthetic applications of Nugent's reagent in organic chemistry. The first of these applications is an one-step methodology for deoxygenation-reduction of alcohols, including benzylic and allylic alcohols and 1,2-dihydroxy compounds.

Enantioselective total synthesis of the potent anti-inflammatory (+)-myrrhanol A.

The first total synthesis of potent anti-inflammatory polypodanes (+)-myrrhanol A (1), (+)-myrrhanone A (2), (+)-myrrhanone B (3), and (+)-myrrhanol B (4) has been achieved. Key steps in our convergent, highly stereocontrolled route are a Ti(III)-mediated radical cyclization of a chiral monoepoxide to furnish a bicyclic synthon that combines stereospecifically with an acyclic vinyl iodide via an intermolecular B-alkyl Suzuki-Miyaura cross-coupling.

Unusually cyclized triterpenes: occurrence, biosynthesis and chemical synthesis.

The biosynthetic origin of most of triterpenes lies in cascade cyclizations and rearrangements of the acyclic precursors squalene (S) and 2,3-oxidosqualene (OS), processes leading to tetra- and pentacyclic triterpene skeleta. Apart from these, a number of triterpenoid structures derived from cyclization processes, that are different from those leading to tetra- and pentacyclic triterpenes, are also found in Nature. We have defined these processes as unusual cyclizations, and grouped them in three blocks, namely, incomplete cyclizations of the corresponding S-derived precursors, cyclizations of S or OS towards polycyclic triterpenes and subsequent cleavage of the preformed ring systems, and two independent cyclizations of the S- or OS-derived precursor.

First total synthesis of (-)-achilleol B: reassignment of its relative stereochemistry.

The first total synthesis of (-)-achilleol B was achieved using a convergent approach with a longest linear sequence of 14 steps. Three key steps were employed, including an enantioselective Robinson annelation for the construction of the bicyclic moiety. The monocyclic synthon was prepared through a Ti(III)-mediated cylization of a chiral monoepoxide obtained via asymmetric dihydroxylation of geranylacetone.

Mild TiIII- and Mn/ZrIV-catalytic reductive coupling of allylic halides: efficient synthesis of symmetric terpenes.

Two new efficient methods for the regioselective homocoupling of allylic halides using either catalytic TiIII or the combination Mn/ZrIV catalyst have been developed. The regio- and stereoselectivity of the process proved to increase significantly when the Mn/ZrIV catalyst is used as the coupling reagent and when cyclic substituted allylic halides are used as substrates. The use of Lewis acids such as collidine hydrochloride allowed the quantity of catalyst to be lowered up to 0.