The titanocene-catalyzed cascade cyclization of epoxypolyenes, which are easily prepared from commercially available polyprenoids, has proven to be a useful procedure for the synthesis of C(10), C(15), C(20), and C(30) terpenoids, including monocyclic, bicyclic, and tricyclic natural products. Both theoretical and experimental evidence suggests that this cyclization takes place in a nonconcerted fashion via discrete carbon-centered radicals. Nevertheless, the termination step of the process seems to be subjected to a kind of water-dependent control, which is unusual in free-radical chemistry. The catalytic cycle is based on the use of the novel combination Me(3)SiCl/2,4,6-collidine to regenerate the titanocene catalyst. In practice this procedure has several advantages: it takes place at room temperature under mild conditions compatible with different functional groups, uses inexpensive reagents, and its end step can easily be controlled to give exocyclic double bonds by simply excluding water from the medium.

From a marine-derived strain of the fungus Emericella variecolor, varitriol (1), varioxirane (2), dihydroterrein (3), and varixanthone (4), besides the known mold metabolites ergosterol, terrein, shamixanthone, and tajixanthone hydrate, were identified. The chemical structures of 1-4 were established by means of spectroscopic techniques and some chemical transformations. In the NCI's 60-cell panel, varitriol (1) displayed increased potency toward selected renal, CNS, and breast cancer cell lines. Varixanthone (4) showed antimicrobial activity.Recently, increased interest in the chemistry of fungi isolated from the marine environment has been documented. 1 Marine fungi are interesting organisms from an ecological point of view, because they are serious pathogens in the marine environment. 2 Furthermore, since many can be cultured, they represent an important biomedical resource. During our studies on the chemistry and biology of fungi, 3,4 we have investigated a marine strain 5 (named M75-2) of the fungus Emericella variecolor, isolated from a sponge collected in Venezuelan waters of the Caribbean Sea. 6 E. variecolor Berk and Br. is the perfect state of Aspergillus variecolor (Berk and Br.) Thom and Raper. 7 From different terrestrial strains of A. variecolor terrein, 8 2-methoxy-6-(3,4-dihydroxyhepta-1,5-dienyl)benzyl alcohol, 9 4,7-dimethoxy-5-methylcoumarin, 10 a dihydroisocoumarin, 11 and two sesterterpenoids (variecolin 12 and astellatol 13 ), as well as numerous xanthones 14 and meroterpenoids 15 of mixed polyketide and terpenoid origins, have been isolated. Moreover, in a terrestrial strain of E. variecolor, asteltoxin has been found. 16,17 This report deals with the chemical analysis and biological screening of the metabolites from the first marine strain of E. variecolor. Results and DiscussionFrom a static culture of the fungus the new compounds 1-4 (Chart 1) were identified, in addition to the known mold metabolites ergosterol, 18 terrein, 19 shamixanthone, 20 and tajixanthone hydrate. 21

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.

[reaction: see text] A general procedure for the synthesis of both 12,6- and 12,8-eudesmanolides has been developed. The key step is the titanocene-catalyzed radical cyclization of accessible epoxygermacrolides. The novel reagent 2,4,6-trimethyl-1-trimethylsilylpyridinium chloride, both compatible with oxiranes and capable of regenerating Cp(2)TiCl(2) from Cp(2)Ti(Cl)H and Cp(2)Ti(Cl)OAc, played an important role in the catalytic cycle leading to exocyclic alkenes.

No abstract

The Cp(2)TiCl-mediated rearrangement of 1,10-epoxy-11beta,13-dihydrocostunolide (4) was carried out using different solvents and additives to develop an expeditious procedure for the synthesis of natural eudesmanolides via free-radical chemistry. In the nonhalogenated solvents THF, benzene, and toluene the transannular cyclization, initiated by the homolytic opening of the oxirane ring, selectively led to the desired exocyclic alkene 5. When water was added to THF, however, the main product was reduced eudesmanolide 8. Experiments with D(2)O confirmed that the H-4 of 8 comes from water. To rationalize these results, a mechanistic hypothesis based on a water-solvated Cp(2)TiCl complex is proposed. Finally, the usefulness of Cp(2)TiCl for the synthesis of natural eudesmanolides has been proved using this reagent in the key step for the chemical preparation of (+)-3alpha-hydroxyreynosin (1) and (+)-reynosin (17). These syntheses confirmed the chemical structure of 1 and established the absolute stereochemistry of the natural products 1 and 17. The results obtained suggest that the combination of the biomimetic strategy employed, with Ti(III)-mediated free-radical chemistry, may come to represent a general method for the enantiospecific synthesis of more than 170 natural eudesmanolides containing an exocyclic double bond between C-4 and C-15.

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. Apart from the molecules obtained from intact organisms, we will also consider the compounds obtained from in vitro cyclizations promoted by enzyme systems. After establishing which compounds could unambiguously be grouped under the term 'unusually cyclized triterpenes', this review moves on to the advances achieved in this kind of structure during the last ten years. These advances are presented in three parts. The first one presents the structure and biological properties of the unusual triterpenes reported in the last decade. The second part considers the main biosynthetic pathways which justify the formation of these triterpenes from their corresponding acyclic precursors. Finally, we look at the achievements made in different synthetic strategies directed at some of these molecules. One hundred and twenty-three references are cited.

No abstract