Alejandro F. Barrero

New sources and antifungal activity of sesquiterpene lactones

In the search for new sources of sesquiterpene lactones, six Centaurea species have been analyzed. The activity against the fungus Cunninghamella echinulata of (+)-cnicin (1) and (+)-salonitenolide (2), isolated from the Centaurea plants, as well as that of (+)-costunolide (3), (-)-dehydrocostuslactone (4), (-)-lychnopholide (5) and (-)-eremantholide C (6), has been evaluated. Compounds 3 and 4 showed noticeable EC50 values, whilst more polar lactones were inactive. These results suggest that a relatively low polarity is one of the molecular requirements for the antifungal activity of sesquiterpene lactones.

Gibepyrones: α-pyrones from Gibberella fujikuroi

Abstract Six α-pyrones, called gibepyrones A-F, were identified in three different culture media of G. fujikuroi (IMI 58289). Their structures were determined using both spectroscopic techniques and chemical synthesis. Their antimicrobial activity has been screened.

SYNTHESIS AND ANTITUMOR ACTIVITY OF PUUPEHEDIONE AND RELATED COMPOUNDS

Abstract The first enantiospecific synthesis of bioactive marine puupehedione ( 2 ) and related compounds from (−)-sclareol ( 11 ) is reported. The antitumor activity of these compounds was assayed and compared with that of the natural products.

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 Nugents 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 Nugents 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.

Synthesis of biologically active drimanes and homodrimanes from (−)-sclareol

Abstract Three drimanes, polygodial (2), albicanyl acetate (3) and 7-oxo-8,12-drimen-11-al (5), and two homodrimanes, 13,14,15,16-tetranorlabd-7-en-12,17-dial (6) and 7-oxo-13,14,15,16-tetranorlabd-8(17)-en-12-al (7), were synthesized from (−)-sclareol (1), and their antifeedant, antitumor and antimicrobial properties tested. In most cases, 6 and 7 were found to be more active than 2.

Synthesis of Ambrox® from(-)-sclareol and (+)cis-abienol

Abstract Short and efficient syntheses of (−)-Ambrox® (12) from (−)-sclareol (1) and (+)-cis-abienol (11) are described. In constrast to previously described procedures, the transformation of 1 to 12, involving in the key step, an oxidative degradation by catalytic osmium tetroxide, in the presence of sodium periodate, has the advantage of using the more suitable sodium borohydride, as the reducing agent. The isolation and characterization of some reaction intermediates allowed us to confirm the degradation mechanism.

STUDY OF PUUPEHENONE AND RELATED COMPOUNDS AS INHIBITORS OF ANGIOGENESIS

Puupehenone, a sesquiterpene produced by certain sponges, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In our study, we compare the potential anti‐angiogenic activities of puupehenone and another 11 related compounds that were either natural products from marine origin or their synthetic derivatives. The effects of these compounds were determined with cell growth and differentiation assays on bovine aorta endothelial cells. Our results show that these compounds are weak inhibitors to cell growth and are not selective for endothelial cells. However, contrary to cell growth, the differentiation of endothelial cells into tubular structures was completely inhibited by 7 of these compounds at concentrations equal or lower than 3 μM. Three of these compounds, isozonarol, 8‐epipuupehedione and 8 epi‐9,11‐dihydropuupehedione, completely inhibited the in vivo angiogenesis in the CAM assay at doses equal or lower than 30 nmol/egg. Further characterisation showed that these 3 terpenes also inhibited endothelial cell production of urokinase and invasion. One compound (8‐epipuupehedione) inhibited endothelial cell migration in a dose‐dependent manner. The anti‐angiogenic properties of the selected compounds, the simplicity of their structures and the feasibility of their synthesis make them attractive drugs for further evaluation in the treatment of angiogenesis‐related pathologies.

Achilleol A: A new monocyclic triterpene skeleton from Achillea odorata L.

A new triterpene 1a from Achillea odorata L. has been isolated, and its structure established on the basis of its spectroscopic properties as well as those of its acetylderivative 1b. 1a shows the first example of monocyclic triterpene skeleton, biosynthetized in the first step of cyclization of squalene oxyde.

Terpenoids from leaves of Juniperus thurifera

Abstract Nineteen diterpenoids of the labdane, pimarane and abietane skeletons and four known sesquiterpenoids were isolated from Juniperus thurifera leaves. Thirteen of these diterpenoids are described for the first time as natural products. Their structures were elucidated principally by NMR techniques and chemical transformations.

Enantiospecific synthesis of (+)-puupehenone from (−)-sclareol and protocatechualdehyde

Abstract The first enantiospecific synthesis of the antitumor and cholesteryl ester transfer protein (CETP) inhibitor (+)-puupehenone (19) from (−)-sclareol (10) and protocatechualdehyde (4) is described. The key steps of the reaction sequence are the organoselenium-induced cyclization of the mixture of regioisomers 15a-b to give 16 and 17, with complete diastereoselectivity, and the simultaneous removal of benzyl and phenylselenyl groups of 16 and 17 by treating with Raney Ni.