Juan I. Padrón

A new catalytic Prins cyclization leading to oxa- and azacycles.

A new Prins cyclization process that builds up one carbon-carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an oxa- and azacycle) relies on an iron catalyst system formed from Fe(acac)3 and trimethylsilyl halide. The method displays a broad substrate scope and is economical, environmentally friendly, and experimentally simple. This catalytic method permits the construction of chloro, bromo and iodo heterocycles, by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields.

Prins-Type Synthesis and SAR Study of Cytotoxic Alkyl Chloro Dihydropyrans

A series of functionalized tetrahydropyran and dihydropyran derivatives was synthesized by means of a Prins‐type cyclization between unsaturated alcohols and several aldehydes. An unprecedented dimer bearing two 4‐chloro‐5,6‐dihydro‐2H‐pyran scaffolds was obtained in high yield. A panel of three representative human solid tumor cells from diverse origin was used to assess the cytotoxicity of the compounds. Overall, the results show the relevance of the chlorovinyl group in the biological activity, and 2‐alkyl‐4‐chloro‐5,6‐dihydro‐2H‐pyrans represent interesting leads for further chemical modifications and biological studies.

Iron(III)-Catalyzed Consecutive Aza-Cope−Mannich Cyclization: Synthesis of trans-3,5-Dialkyl Pyrrolidines and 3,5-Dialkyl-2,5-dihydro-1H-pyrroles

An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain 3-alkyl-1-tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine.

Ferric chloride: An excellent reagent for the removal of benzyl ethers in the presence of p-bromobenzoate esters

Abstract Anhydrous FeCl 3 in dry CH 2 Cl 2 removed benzyl ethers from carbohydrates containing p -bromobenzoate esters, without hydrogenolysis of the bromine atoms. In addition, debenzylations of β-glycopyranosides occurred with simultaneous anomerization or retention of the anomeric configuration.

Iron(III) catalyzed direct synthesis of cis-2,7-disubstituted oxepanes. The shortest total synthesis of (+)-isolaurepan.

Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form 2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the shortest total synthesis of (+)-isolaurepan.

Factors Controlling the Alkyne Prins Cyclization : The Stability of Dihydropyranyl Cations

The relative stability of the intermediates involved in the alkyne Prins cyclization and the competitive 2-oxonia-[3,3]-sigmatropic rearrangement was studied. This rearrangement was shown to occur slowly under typical alkyne Prins cyclization conditions when the allenyl oxocarbenium ion that results from the rearrangement is similar to or higher in energy than the starting alkynyl oxocarbenium ion. The formal 2-oxonia-[3,3]-sigmatropic rearrangement may be disfavored by destabilizing the resultant allenyl oxocarbenium ion or by stabilizing an intermediate dihydropyranyl cation. The trimethylsilyl group as a substituent at the alkyne and electron-withdrawing groups (CH2Cl and CH2CN) located at the alpha-position to the carbinol center are shown to be effective. DFT calculations suggest that these substituents stabilize the dihydropyranyl cations, thus leading to a more uniform reorganization of the electronic density in the ring, and do not have a direct effect on the formally positively charged carbon atom.

Diterpenes from Laennecia sophiifolia

From the aerial parts of Laennecia sophiifolia (Kunth) G.L. Nesom, a neo-clerodane and an acyclic furano diterpene were isolated, along with four known compounds, 2beta-hydroxyhardwickiic acid, hawtriwaic acid, apigenin, and beta-sitosterol. Their structures were established as 12-epi-bacchotricuneatin A and (2E,6E)-9-(3-furyl)-6-methyl-2-(4-methylpent-3-enyl)-nona-2,6-dienoic acid, by analysis of spectral evidence. The absolute structure of 12-epi-bacchotricuneatin A was determined by a circular dichroism spectral comparison with that of bacchotricuneatin A.

ROTATIONAL POPULATION DEPENDENCES OF THE HYDROXYMETHYL GROUP IN ALKYL GLUCOPYRANOSIDES : ANOMERS COMPARISON

A CD and 1H NMR study of the rotamer population around the C5–C6 bond of alkyl α-d-glucopyranosides proved it to be dependent on the aglycon and its absolute configuration, showing a similar, but not identical, behavior to that of their β-anomers. Thus, the population of the gt rotamer increased as the pKa of the aglycon increased, whereas the population of the tg and gg rotamers decreased, mainly that of the tg rotamer. The results showed the existence of a clear correlation between the stereoelectronic exo-anomeric effect and the rotamer distributions, the endo-anomeric effect not being directly involved. In addition, the 1H NMR chemical shift differences (δD–δROH) of the alkyl α-d-glucopyranosides are characteristic of the absolute configuration of the aglycon, as occurred with the β-anomers. Therefore, the absolute configuration of secondary chiral alcohols or the aglyconic moiety of natural glycosides can be determined independently of the anomeric configuration, a single enantiomer being sufficient. Chirality 9:626–637, 1997.

β′-Hydroxy-α,β-unsaturated ketones: A new pharmacophore for the design of anticancer drugs. Part 2.†

Novel antiproliferative β′‐acyloxy‐α,β‐unsaturated ketones were obtained by means of an iron(III)‐catalyzed multicomponent domino process (ABB′ 3CR). The most active derivatives displayed GI50 values in the range of 0.5–3.9 μM against a panel of representative human solid tumor cell lines: A2780, SW1573, HBL‐100, T‐47D and WiDr. Analysis of cells following 24 h exposure to these drugs showed cell cycle arrest in the S and G2/M phase, in a dose‐dependent manner. Our data indicate that the β′‐acyloxy‐α,β‐unsaturated ketones cause permanent damage to the cells and induce apoptosis.

Catalysis by Means of Fe-Based Lewis Acids

The interest and use of iron salts as catalysts in organic chemistry has shown an exponential growth in the past years. There has been an increasing demand for environmentally friendly and sustainable chemical methods, distinguished by the low cost and environmentally benign character of the iron salts used. This chapter focuses on reactions in which iron salts produce activation on unsaturated functional groups provided by the Lewis-acid character of these salts.