Cyclofarnesoids and methylhexanoids produced from ß-carotene in Phycomyces blakesleeanus.

The oxidative cleavage of ß-carotene in the Mucorales produces three fragments of 18, 15, and 7 carbons, respective heads of three families of apocarotenoids: the methylhexanoids, the trisporoids, and the cyclofarnesoids (named after their 1,6-cyclofarnesane skeleton). The apocarotenoids are easily recognized because they are absent in white mutants unable to produce ß-carotene. In cultures of Phycomyces blakesleeanus we detected thirty-two apocarotenoids by LC, UV absorbance, and MS. With additional IR and NMR we identified two methylhexanoids and the eight most abundant cyclofarnesoids. Four of them were previously-unknown natural compounds, including 4-dihydrocyclofarnesine S, the most abundant cyclofarnesoid in young cultures. We arranged the apocarotenoids of the Mucorales in a scheme that helps classifying and naming them and suggests possible metabolites and biosynthetic pathways. We propose specific biosynthetic pathways for cyclofarnesoids and methylhexanoids based on structural comparisons, the time course of appearance of individual compounds, and the bioconversion of ß-apo-12-carotenol, an early precursor, to three more oxygenated cyclofarnesoids by the white mutants. Some of the reactions occur spontaneously in the increasingly acidic culture media. Mating increased the contents of methylhexanoids and cyclofarnesoids by ca. threefold in young cultures and ca. twelvefold in old ones (five days); cyclofarnesine S, the most abundant cyclofarnesoid in old cultures, increased over one hundredfold. We found no differences between the sexes and no activity as sexual pheromones, but we suggest that methylhexanoids and cyclofarnesoids could mediate species-specific physiology and behavior.

First total synthesis of (+)-apotrisporin E and (+)-apotrientriols A-B: a cyclization approach to apocarotenoids.

The first total synthesis of the natural apocarotenoids (+)-apotrisporin E (1) and (+)-apotrientriols A and B (2-3) has been accomplished. The structure, relative stereochemistry and the assignation of the absolute configuration have been confirmed. This is a fast and easy access to this family of natural products whose key steps are a diastereoselective cyclization and a HWE olefination to attach the dienic side chain. This work also opens the door to the synthesis of other apocarotenoids such as trisporols and trisporic acids.

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. Finally, since some of the compounds generated are bioactive natural sesquiterpenes, the mechanisms of formation of these substances will provide new insights in their biosynthesis.

A minor dihydropyran apocarotenoid from mated cultures of Blakeslea trispora.

The heterocyclic C15 apocarotenoid 1 was isolated from mated cultures of the strains F986 (+) and F921 (−) of Blakeslea trispora. This new compound formed during sexual interaction is a minor constituent of the culture media and its structure was elucidated by spectroscopic data, including 2D-NMR. A plausible biosynthetic pathway involving a double degradation of β-carotene, followed by several oxidations of the resulting monocyclofarnesane C15 fragment is proposed.

Apocarotenoids in the sexual interaction of Phycomyces blakesleeanus.

A simple genetic test allowed us to carry out the first systematic study of the apocarotenoids in the Mucorales. We have identified 13 apocarotenoids in the culture media of the fungus Phycomyces blakesleeanus (Mucoromycota, Mucorales). Three of these compounds were novel apocarotenoids: (2S,8R,E)-8,14-epoxycyclofarnesa-4,6,9-triene-2,11-diol (6), (2S,6E,8E)-cyclofarnesa-4,6,8-triene-2,10,11-triol (7), and its 6Z isomer (8). Four of the remaining compounds have been reported previously from this fungus and six from other Mucorales. All of them belong to three families, the 18-carbon trisporoids, the 15-carbon cyclofarnesoids, and the 7-carbon methylhexanoids, derived from the three fragments that result when ß-carotene is cleaved at its 11',12' and 12,13 double bonds. The apocarotenoids were more varied and more abundant in mated cultures of strains of opposite sex than in single cultures. The presence of acetate in the medium blocked the production of many apocarotenoids while having little effect on the concentrations of the remaining ones.

Communic acids: occurrence, properties and use as chirons for the synthesis of bioactive compounds.

Communic acids are diterpenes with labdane skeletons found in many plant species, mainly conifers, predominating in the genus Juniperus (fam. Cupresaceae). In this review we briefly describe their distribution and different biological activities (anti- bacterial, antitumoral, hypolipidemic, relaxing smooth muscle, etc.). This paper also includes a detailed explanation of their use as chiral building blocks for the synthesis of bioactive natural products. Among other uses, communic acids have proven useful as chirons for the synthesis of quassinoids (formal), abietane antioxidants, ambrox and other perfume fixatives, podolactone herbicides, etc., featuring shorter and more efficient processes.

Comparison of the essential oils of leaves and stem bark from two different populations of Drimys winteri a Chilean herbal medicine.

The chemical composition of the essential oils obtained by hydrodistillation of stem bark and leaves of Drimys winteri J.R. et G. Foster var. chilensis /DC A. Gray (Winteraceae) from Chiloe Island (ID) and Continental Chile (Santiago) (CD) were studied by GC and GC/MS. Sesquiterpene hydrocarbons constituted the main chemical groups in the stem bark oils, with alpha-santalene, trans-beta-bergamotene and curcumenes as the major components. Monoterpenes constituted the main chemical groups in the leaves of Island plants with alpha-pinene (23.1%) beta-pinene (43.6%) and linalool (10.5%) as the main components whereas sesquiterpenes (germacrene D 17.6%) and phenylpropanoids (safrole 20.8%) are the most abundant in the leaves of Continental plants.

New apocarotenoids and ß-carotene cleavage in Blakeslea trispora.

Mixed cultures of strains of opposite sex ("mated" cultures) of Blakeslea trispora contain trisporic acids and other apocarotenoids, some of which mediate the sexual responses of this fungus and other Mucorales. In mated cultures of the wild-type strains F986 and F921 we identified eleven apocarotenoids: two C(18) trisporoids, three C(15) compounds with a monocyclofarnesane skeleton, a C(13) compound, and five C(7) compounds with a 2-methylhexane skeleton. Six of them are new natural products and two others are new for Blakeslea. Their structures were established by NMR and mass spectra and those of the C(7) and C(13) compounds were confirmed by chemical synthesis. The finding of these compounds and the presence of approximately equimolecular amounts of the C(18), C(15), and C(7) families led to the conclusion that ß-carotene is initially split in three fragments by cleavage of its 13,14 and 11',12' double bonds.

Use of the plant Bellardia trixago for the enantiospecific synthesis of odorant products.

An easy procedure to obtain extracts enriched in trixagol monomalonylesther (1) from aerial parts of the plant Belladia trixago chemotype Trix was developed. Preparation of (+)-dihydro-gamma-ionone (4) was carried out directly from the extracts with good yields by selective oxidation. Other interesting odorant products as alpha-ambrinol (5), ambraldehyde (6) and the tricyclic compound 7 were synthesized very efficiently using (4) as intermediate.

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 ß-elemene and other bioactive elemanes from sustainable germacrone.

Highly efficient preparations of anticancer ß-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.

Splitting of beta-carotene in the sexual interaction of Phycomyces.

Two new 7-carbon compounds, 1 and 2, have been found in the culture medium of Phycomyces blakesleeanus. A genetic test showed that they derive from beta-carotene. These new molecules represent the missing link that proves that beta-carotene is split into fragments of 18, 15 and 7 carbon fragments, each head of a separate family of apocarotenoids.

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. Additionally, we have also proved that Ti(III) is capable of mediating carbonyl coupling-olefination. In this sense, and despite the fact that for over 35 years it has been widely accepted that either Ti(II) or Ti(0) was the active species in the reductive process of the McMurry reaction, the mechanistic evidence presented proves the involvement of Ti(III) pinacolates in the deoxygenation step of the herein described Nugent's reagent-mediated McMurry olefination. This observation sheds some light on probably one of the mechanistically more complex transformations in organic chemistry. Finally, we have also proved that both of these processes can be performed catalytically in Cp(2)TiCl(2) by using trimethylsilyl chloride (TMSCl) as the final oxygen trap.

New pathways in transannular cyclization of germacrone [germacra-1(10),4,7(11)-trien-8-one]: evidence regarding a concerted mechanism.

The transannular cyclization of germacrone with HSO(3)Cl at -78 degrees C by means of a concerted and regioselective mechanism gives rise to a bicyclo[6.2.0]decan-2-ylium intermediate ion, which evolves to unusual skeletons through subsequent cyclization and Wagner-Meerwein rearrangements. This novel germacra-1(10),4-diene cyclization could suggest the existence of a new biosynthetic pathway to sesquiterpenes.

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 0.05 equiv. We have proved the utility of these protocols with the synthesis of different terpenoids such as (+)-beta-onoceradiene (1), (+)-beta-onocerine (2), squalene (5), and advanced key-intermediates in the syntheses of (+)-cymbodiacetal (3) and dimeric ent-kauranoids as xindongnin M (4a).

Couplings of benzylic halides mediated by titanocene chloride: synthesis of bibenzyl derivatives.

Titanocene monochloride catalyzes the homocoupling of benzylic halides and benzylic gem-dibromides to give the corresponding bibenzyl and stilbenyl systems. Exposure of benzylic bromides to Ti(III) in the presence of aldehydes gave rise to the Barbier-type products. Examples of the utility of the herein described processes are included.

Solid-phase selenium-catalyzed selective allylic chlorination of polyprenoids: facile syntheses of biologically active terpenoids.

Regioselective halogenation of the terminal isopropylidene unit of different acyclic polyolefinic polyprenoids (farnesyl acetate, geranylgeranyl acetate, squalene, etc.) using NCS/catalytic polymer-supported selenenyl bromide is described; good to excellent yields are obtained (68-96%). The first applications of this protocol include the concise synthesis of bioactive terpenoids 1-3.

Antioxidant activity of diterpenes and polyphenols from Ophryosporus heptanthus.

The antioxidant activity of 14 compounds (1-14) isolated from the ether and butanolic extracts of the aerial parts of Ophryosporus heptanthus has been assayed using a beta-carotene bleaching method and the DPPH technique. Compounds 1 and 13 showed the most potent antioxidant activity. Their structures have been established by spectroscopic techniques (mainly NMR). Compounds 7 and 12 are new natural products, and their structures have been confirmed by chemical synthesis.

Reductive coupling of terpenic allylic halides catalyzed by Cp2TiCl: a short and efficient asymmetric synthesis of onocerane triterpenes.

[reaction: see text] Titanocene chloride catalyzes the regioselective alpha,alpha'-homocoupling of terpenic allylic halides. This process has been employed in the short and effective synthesis of terpenoids such as beta-onoceradiene (1), beta-onocerin (2), and squalene (3). Evidence is presented for eta1-allyltitanium species being involved in the coupling.

Antimicrobial activity of sesquiterpenes from the essential oil of Juniperus thurifera.

Chemical analysis of the essential oil of Juniperus thurifera wood led to the identification of fifty-eight sesquiterpene compounds, of which twenty-eight have been isolated, two of them being new natural cedrane derivatives (1 and 2). Their structures were established on the basis of 1D NMR and 2D NMR spectra. The antimicrobial activities of different pure compounds of this oil were tested against nine microorganisms (Gram-positive and Gram-negative bacteria, and yeasts). Seven of the tested compounds exhibited a relevant activity, with the known alpha- and beta-cedrenes and sesquithuriferol showing minimum inhibitory concentrations of 3.06 microg/mL against Bacillus subtilis and Proteus sp.