Lewis Acid-Catalyzed Carbonyl-Ene Reaction: Interplay between Aromaticity, Synchronicity, and Pauli Repulsion.

The physical factors governing the catalysis in Lewis acid-promoted carbonyl-ene reactions have been explored in detail quantum chemically. It is found that the binding of a Lewis acid to the carbonyl group directly involved in the transformation greatly accelerates the reaction by decreasing the corresponding activation barrier up to 25 kcal/mol. The Lewis acid makes the process much more asynchronous and the corresponding transition state less in-plane aromatic. The remarkable acceleration induced by the catalyst is ascribed, by means of the activation strain model and the energy decomposition analysis methods, mainly to a significant reduction of the Pauli repulsion between the key occupied π-molecular orbitals of the reactants and not to the widely accepted stabilization of the LUMO of the enophile.

Synthesis of Tetrahydroazepines through Silyl Aza-Prins Cyclization Mediated by Iron(III) Salts.

A new methodology for the synthesis of seven-membered unsaturated azacycles (tetrahydroazepines) was developed. It is based on the powerful aza-Prins cyclization in combination with the Peterson-type elimination reaction. In a single reaction step, a C-N, C-C bond and an endocyclic double bond are formed. Under mild reaction conditions and using iron(III) salts as sustainable catalysts, tetrahydroazepines with different degrees of substitution are obtained directly and efficiently. DFT calculations supported the proposed mechanism.

Iron(III)-Catalyzed Synthesis of 2-Alkyl Homoallyl Sulfonyl Amides: Antiproliferative Study and Reactivity Scope of Aza-Prins Cyclization.

A direct, catalytic, and complementary method to obtain 2-substituted homoallyl sulfonyl amides is described, starting from sulfonyl amides, aldehydes, and allyltrimethylsilane using iron(III) chloride as a sustainable catalyst. The scope of the process and the reactivity in aza-Prins cyclization is evaluated and supported by density functional theory (DFT) studies. Finally, an evaluation of the antiproliferative activity for this family of sulfonyl amides is also included.

Iron-Catalyzed Prins-Peterson Reaction for the Direct Synthesis of Δ4-2,7-Disubstituted Oxepenes.

A direct iron(III)-catalyzed Prins-Peterson reaction involving α-substituted γ-triphenylsilyl bis-homoallylic alcohols and aldehydes is described. Thus, cis-Δ4-2,7-disubstituted oxepenes were synthesized in a diastereoselective reaction using sustainable catalytic conditions (3-5 mol %). This highly productive process is the result of a cascade of three chemical events with the concomitant formation of a C-O bond, a C-C bond, and a Δ4 endocyclic double bond, through a Prins cyclization followed by a Peterson-type elimination. This tandem reaction is chemoselective vs the classical Prins cyclization.

Enantiodivergent Synthesis of (+)- and (-)-Pyrrolidine†197B: Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular Hydroamination.

A highly efficient, diastereoselective, iron(III)-catalyzed intramolecular hydroamination/cyclization reaction involving α-substituted amino alkenes is described. Thus, enantiopure trans-2,5-disubstituted pyrrolidines and trans-5-substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l-α-amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)- and (-)-pyrrolidine 197B alkaloids from l-glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.

Prins Cyclization Catalyzed by a Fe(III) /Trimethylsilyl Halide System: The Oxocarbenium Ion Pathway versus the [2+2] Cycloaddition.

The different factors that control the alkene Prins cyclization catalyzed by iron(III) salts have been explored by means of a joint experimental-computational study. The iron(III) salt/trimethylsilyl halide system has proved to be an excellent promoter in the synthesis of crossed all-cis disubstituted tetrahydropyrans, minimizing the formation of products derived from side-chain exchange. In this iron(III)-catalyzed Prins cyclization reaction between homoallylic alcohols and non-activated alkenes, two mechanistic pathways can be envisaged, namely the classical oxocarbenium route and the alternative [2+2] cycloaddition-based pathway. It is found that the [2+2] pathway is disfavored for those alcohols having non-activated and non-substituted alkenes. In these cases, the classical pathway, via the key oxocarbenium ion, is preferred. In addition, the final product distribution strongly depends upon the nature of the substituent adjacent to the hydroxy group in the homoallylic alcohol, which can favor or hamper a side 2-oxonia-Cope rearrangement.

Shortest Enantioselective Total Syntheses of (+)-Isolaurepinnacin and (+)-Neoisoprelaurefucin.

The shortest enantioselective total syntheses of (+)-isolaurepinnacin and (+)-neoisoprelaurefucin have been accomplished. These syntheses were based on a common parallel synthetic strategy using Prins-Peterson cyclization in their core construction. In only one step, a seven-membered ring oxacycle with the correct cis-stereochemistry ring closure and the Δ4 position of the endocyclic double bond in (+)-isolaurepinnacin was obtained. This unsaturation was also necessary to accede to the bromodioxabicycle on (+)-neoisoprelaurefucin.

Iron(II) and Copper(I) Control the Total Regioselectivity in the Hydrobromination of Alkenes.

A new method that allows the complete control of the regioselectivity of the hydrobromination reaction of alkenes is described. Herein, we report a radical procedure with TMSBr and oxygen as common reagents, where the formation of the anti-Markovnikov product occurs in the presence of parts per million amounts of the Cu(I) species and the formation of the Markovnikov product occurs in the presence of 30 mol % iron(II) bromide. Density functional theory calculations combined with Fukui's radical susceptibilities support the obtained results.

Conformational domino effect in saccharides. 2. Anomeric configuration control.

A series of alkyl beta-D-glucopyranosyl-(1-->6)-alpha-D-glucopyranosides were synthesized and analyzed by NMR and CD techniques. As in their beta-anomer series, the rotational populations of the hydroxymethyl group involved in the interglycosidic linkage (torsion angle omega) are shown to depend on the aglycon and the solvent. However, for this alpha-anomer series the rotational dependence arises directly from steric effects. Correlations between rotational populations and molar refractivity (MR) steric parameters, but not Taft's steric parameters (beta-anomers), of the alkyl substituents were observed. The conformational domino effect previously predicted from alkyl beta-(1-->6)-diglucopyranosides is now supported by the conformational properties of their alpha-anomers, the anomeric configuration controlling the domino effect. In addition, the rotational populations around the C5'-C6' bond (torsion angle omega') depend weakly on the structure of the aglycon and the anomeric configuration.

Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2'-Prins Cyclization.

A new, direct, and diastereoselective synthesis of activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an SN2'-Prins cyclization tandem process leading to the creation of three new stereocenters in one single step. These activated tetrahydro-2H-pyran units are easily derivatizable through CuAAC conjugations in order to generate multifunctionalized complex molecules. DFT calculations support the in situ SN2' reaction as a preliminary step in the Prins cyclization.

The silylalkyne-Prins cyclization: stereoselective synthesis of tetra- and pentasubstituted halodihydropyrans.

[reaction: see text] A new type of Prins cyclization using silylated secondary homopropargylic alcohols and aldehydes yielding tetra- and pentasubstituted dihydropyrans is described. The presence of the trimethylsilyl group in the triple bond favors the Prins cyclization and minimizes the 2-oxonia-[3,3]-sigmatropic rearrangement as a competitive alternative pathway. Ab initio theoretical calculations of the species involved in the rearrangements support the proposed mechanism. The process is highly stereoselective, affording cis-dihydropyran as the only isomer.

Iron(III)-promoted aza-Prins-cyclization: direct synthesis of six-membered azacycles.

[reaction: see text] A new iron(III) halide-promoted aza-Prins cyclization between gamma,delta-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of gamma-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon-carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products.

Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group.

The biological activity of compound 9 obtained by introducing an alpha-methylene-gamma-butyrolactone group into 3-(4-hydroxyphenyl)propionic acid, 1, was studied for possible effects on HL-60 cells, murine splenocytes, and human peripheral mononuclear cells (PBMC). 9 induced apoptosis in the HL-60 cell line and has a clear capacity to inhibit proliferation induced in murine splenocytes and PBMC by different mitogenic agents with no apparent toxic side effects. 9 was synthesized from 1, and its structure and stereochemistry were elucidated by spectroscopic methods.

Enantioselective synthesis and biological activity of (3S,4R)- and (3S,4S)-3-hydroxy-4-hydroxymethyl- 4-butanolides in relation to PGE2.

Compounds 9 and 13 were synthesized, and their structures and stereochemistry were elucidated by spectroscopic methods. In competition binding experiments, specific [(3)H]-PGE(2) binding was significantly displaced by compound 9 and, to a lesser extent, by 13, in a dose-dependent manner. The biological properties of compound 9 were studied on HL-60 cells, and several effects were found related to those of PGE(2). Compound 9 increases c-fos mRNA level as does PGE(2) and antagonizes TPA-induced terminal differentiation.

Iron(III)-catalyzed Prins-type cyclization using homopropargylic alcohol: a method for the synthesis of 2-alkyl-4-halo-5,6-dihydro-2H-pyrans.

[reaction: see text] A new Prins-type cyclization between homopropargylic alcohol and aldehydes in the presence of FeX(3) to obtain 2-alkyl-4-halo-5,6-dihydro-2H-pyrans in good yield is described. Osmium-catalyzed cis dihydroxylation provided direct access to trans-2-alkyl-3-hydroxy-tetrahydro-pyran-4-ones. Anhydrous ferric halides are also shown to be excellent catalysts for the standard Prins cyclization using homoallylic alcohol. Isolation of an intermediate acetal provides substantiation of a proposed mechanism.

Antiproliferative evaluation of N-sulfonyl-2-alkyl-six membered azacycles. A QSAR study.

A series of functionalized N-sulfonyl-piperidines and N-sulfonyl-tetrahydropyridines were evaluated for their antiproliferative activity against the representative panel of human solid tumor cells A2780 (ovarian), SW1573 (non-small cell lung) and WiDr (colon). The SAR study showed for WiDr cells a correlation between the biological activity and the length of the N-sulfonyl group, the nature of the substituents and the type of alkyl side chain. Further QSAR studies indicate that the size and nature of the N-sulfonyl group, the atomic polarizability (MP) and the partition coefficient are the most important descriptors for the activity. The major contribution is the size (F05C-S) of the N-sulfonyl group.

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.

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.

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.

Conformational domino effect in saccharides: a prediction from alkyl beta-(1-->6)-diglucopyranosides.

A series of alkyl beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosides, containing nonchiral and chiral aglycons, were synthesized and analyzed by NMR and CD. The results, collected from four sets of disaccharides, demonstrated that the rotational properties of the interglycosidic linkage depend on the structural natures of both the aglycon and the solvent. Stereoelectronic and steric factors explain this rotational dependence, the gauche- trans (gt) rotamer being the most stable. Furthermore, correlations between Taft's steric parameters or between the pKa values of the alkyl substituent (aglycon) versus corresponding rotamer populations were observed. These results point to a natural conformational domino effect in oligosaccharides, where the conformational properties of each (1-->6) interglycosidic linkage will depend on the structure of the previous residue or its aglycon. In addition, a very weak rotational population dependence of the hydroxymethyl group at residue II on the aglycon at residue I was observed. The population of the gauche- gauche (gg) rotamer decreased, and that of gt increased as the Taft's steric parameters of the remote aglycon increased, independently of the disaccharide series and of the solvent.