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A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 μm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.

The reactivity of the ynamide tert-butyl N-ethynyl-N-phenylcarbamate (1) in the 1,3-dipolar cycloaddition (1,3-DC) with C-carboxymethyl-N-phenylnitrilimine was investigated. This [3+2] cycloaddition affords the 5-amino pyrazole as a single regioisomer. The obtained cycloadduct has been activated at the 4-position of the pyrazole ring through bromination and subsequently coupled with a phenyl group under Pd catalysis. A detailed computational study has been performed to fully explain the complete regioselectivity observed.

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with substituted acetylenes bearing thiol or sulfone groups were studied. The sulfur controls the regiochemistry of the reaction, and this protocol was applied to the synthesis of ring-fused thieno[2,3-c]pyrazoles.

1,3-Dipolar cycloaddition of C-aryl-N-aryl- and C-carboxymethyl-N-aryl-nitrile imines with functionalized acetylenes have been studied. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Under scandium triflate catalysis a reversal in the regiochemistry was observed, especially in the case of C-carboxymethyl-N-aryl-nitrile imines.

In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,β-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a “side chain” characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15–60 μM for exposure time of 24–72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

New enantiomerically pure 1,3-bis(2’-oxazolinyl)ferrocenes have been synthesized in good yields starting from 1,3-ferrocene dicarboxylic acid. Moreover, the possibility of performing a regioselective lithiation in position 2 of the disubstituted cyclopentadienyl ring of these compounds has been demonstrated.

The cyanobis(dibenzylamino)borane-mediated transformation of chiral aldehydes into the corresponding α-amino nitriles is described. Starting from these compounds short synthetic routes can be envisaged for obtaining diastereomerically pure functionalized 1,2-diamines and hydroxylated α-amino acids that are of interest as core key units of biologically active substances or as potential ligands for asymmetric catalysis. The stereochemical outcome of the aminative cyanation reaction is discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The synthesis of new 2-sulfanylferrocenylphosphonates and derivatives has been achieved through a P-S to P-C [1,3]-sigmatropic rearrangement. The asymmetric version of this reaction has been successfully performed starting from a ferrocenylphosphorodiamidothioate and afforded, as a single diastereoisomer, enantiomerically pure planar chiral ortho-thio-substituted ferrocenyl phosphorodiamidate.

Several new ligands featuring a rigid three ring skeleton have been prepared for the first time following a modular approach. Chirality has been introduced by use of an oxazoline moiety fused with a cyclopenta[b]thiophene backbone. The efficiency and stereochemical impact of these ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone was examined and enantiomeric excesses up to 79% were achieved using the ligand (R,R)-16 substituted with a methyl group at the cyclopenta moiety. Computational and ESI-mass spectral studies show that these new compounds behave as monodentate ligands towards Cu+. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Enantiomerically pure central and planar chiral ferrocenyl cyanohydrins have been used for the synthesis of previously unreported 5-ferrocenyl-oxazolines and a 5-ferrocenyl-thiazoline where the central chirality lies on the carbon bearing the oxygen or the sulfur atom. The epimerization at C 5 of the oxazoline ring has also been investigated.

Enantiopure fluorinated isoxazolidines and amino polyols were obtained from the 1,3-dipolar cycloaddition of allylic fluorides and Z-α-phenyl-N-methylnitrone under environment-friendly conditions.

A synthesis of ferrocenyl-oxazolines is described using an iodide-mediated ring expansion of N-ferrocenoyl-aziridine-2-carboxylic esters. The ring enlargements take place with full stereocontrol, namely net retention of configuration. Modification of the ester function by a Grignard reaction leads to three new types of ferrocenyl-oxazoline carbinol ligands, which were used as chiral ligands in the asymmetric addition of diethylzinc to benzaldehyde (e.e.s ranging from 46 to 62%). The planar chiral ferrocenyl-oxazoline carbinol ligand gave a very good result (e.e. 90%) in the palladium-catalyzed allylic substitution of 1,3-diphenyl prop-2-enylacetate with dimethyl malonate.

A new protocol is described for the stereocontrolled synthesis of pseudo-C(2)-symmetric core units of interest as candidates for HIV protease inhibition. Addition of unbranched and branched organolithium reagents to cyanohydrins from l-phenylalaninal and l-isoleucinal, followed by in situ reduction of the intermediate imines and CHT deprotection under MW irradiation, led to 1,3-diamino alcohols 6a and 8a as the major products in satisfactory to good yields. The first preparation of a previously unreported pseudo-C(2)-symmetric triamino derivative was accomplished expeditiously via high-yielding nitro-Mannich addition of the silylnitronate, from 2-phenyl-1-nitroethane, to the PMP imine derived from l-phenylalaninal. Reduction of the nitro group in the moderately unstable nitro diamine adduct, followed by chromatographic separation of the required diastereoisomer and CHT debenzylation under MW irradiation, led to the 2-PMP-protected triamine 19 isolated as a bis(sulfonamide).

The reactions of thioferrocenoylsilanes with organolithium reagents, dienes and reducing agents which afford α-silyl sulphides, dihydrothiopyranes and α-silyl ferrocenyl thiols, respectively, have been investigated. α-Silyl sulphides were further functionalised through carbodesilylation with aldehydes. We also report the synthesis of a new planar chiral thioferrocenoylsilane that gave good diastereomeric excess in the reaction with t-butyllithium, lithium lutidine and 2,3-dimethylbuta-1,3-diene. The 1,1′-bis-thioferrocenoylsilane, too unstable to be isolated, was trapped in situ with dienes.

Thioacylsilanes containing the ferrocene moiety, easily prepared from the corresponding acylsilanes with Lawesson's reagent at room temperature, can be transformed into vinyl silanes, sulfur heterocycles and sulfines.

The allylation of acylsilanes with tetraallyltin in the presence of catalytic amounts of Sc(OTf) 3 proceeded smoothly to afford the silylated homoallylic alcohols in good yields. Subsequent protiodesilylation gave the formal adducts of the corresponding aldehydes. The homochiral acylsilane 11 gave a reversal of asymmetric induction in the Sc(OTf) 3 catalyzed allylation and in the Sakurai reaction.

Cyclic and open chain α-silyl vinyl sulfides, obtained from thioacylsilanes, react with acid chlorides in the presence of Lewis acid to give thioannulated cyclopentenones and thiofunctionalized enones. The effect of the substituents at silicon on these reactions has been investigated.

A detailed investigation of the desilylation of (Z)-α-dimethylphenylsilyl vinyl sulfides with fluoride ion has shown that in substrates containing an electron-withdrawing group β to the sulfur, phenyl group migration occurs as a result of a fluoride ion catalyzed retro-Michael reaction.

ω-Haloacylsilanes 1 were selectively transformed via thioacylsilanes into Z-silyl-enethiols 4 with solid sodium hydrogen carbonate or into 2-silylthiacycloalk-2-enes 5 of common to large ring size with solid sodium hydroxide. Compounds 5 underwent protiodesilylation.

endo - and exo -trimethylsilyl-3-phenyl-2-thiabicyclo[2.2.1]hept-5-enes, the endo -trimethylsilyl- exo -S-oxide and their S,S-dioxide derivatives were protiodesilylated with fluoride ion. Stereoconvergent reactions were found, affording the endo -phenyl derivatives. These results can be rationalised with the hypothesis of a common carbanionic intermediate. In contrast, the desilylation of 3- endo -trimethylsilyl-3- exo -phenyl-2-thiabicyclo[2.2.1]heptane gave a mixture of endo - and exo -isomers, thus proving the involvement of the double bond in the control of the reaction stereoselectivity.

Aliphatic silyl thioketones containing an α-hydrogen atom undergo enethiolization to Z-α-silyl enethiols 2. Compounds 2 react with a variety of halides R3X to give open-chain α-silyl vinyl sulfides 3. Protiodesilylation of 3 was achieved upon treatment with fluoride ion to give vinyl sulfides 4. Reaction of 3 with Grignard reagents, in the presence of an appropriate nickel catalyst, results in a series of vinylsilanes 5 with a specific geometry.

Thiono-ester S-oxides, a rather neglected class of sulfines, can be readily obtained by nucleophilic substitution of chlorine in chlorosulfines by sterically demanding phenolates and alcoholates. The reaction occurs with predominant retention of the configuration of the starting chlorosulfine.

1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated five- and six-membered lactones, thiolactones and lactams gave ring-fused pyrazoles. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Only with the five-membered lactone the major product was the 4-acyl derivative. Computational studies, the use of the topological analysis of the Fukui functions and the potential energy surfaces (PES) theory allowed a theoretical description of the local reactivity in agreement with the observed high regiochemistry and with the role of the heteroatom adjacent to the carbonyl group.

1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated five- and six-membered lactones, thiolactones and lactams gave ring-fused pyrazoles. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Only with the five-membered lactone the major product was the 4-acyl derivative. Computational studies, the use of the topological analysis of the Fukui functions and the potential energy surfaces (PES) theory allowed a theoretical description of the local reactivity in agreement with the observed high regiochemistry and with the role of the heteroatom adjacent to the carbonyl group.

Reaction of dithioesters and trithiocarbonates with silylated nucleophiles under fluoride ion conditions affords a novel example of silyl mediated regiochemical control in the thiophilic functionalization.

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with substituted acetylenes bearing thiol or sulfone groups were studied. The sulfur controls the regiochemistry of the reaction, and this protocol was applied to the synthesis of ring-fused thieno[2,3-c]pyrazoles.

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with cyclic α,β-unsaturated ketones of various sizes have been studied. After cycloaddition, oxidative aromatization gives the ring-fused pyrazoles. Computational studies and the use of topological analyses of the Fukui functions allows a theoretical description of the local reactivity that is in agreement with the experimentally observed regiochemistry.

The 17O NMR shift values δo of 20 sulfinylamines R–NSO 2 and of 14 sulfines RR′CSO 3(R and R′ mostly arene groups) were compared with those of the isoelectronic SO21. They show δo at much lower field than practically all other classes of S–O compounds; at the same time they exhibit the high substituent sensitivity which is typical for true πp bond systems, and absent in S+–O– compounds. The difference is discussed in terms of bond order and electronic excitation energy. Comparison of the E- and Z isomers of O-methyldiaryl sulfines yields the conformation of these compounds: one arene ring is (nearly) coplanar with the CSO group and the other (nearly) perpendicular to it. This demonstration for the molecules in solution is supported by an X-Ray structure determination.

Several derivatives with the trans-stilbene oxide moiety as the central chiral core were synthesized. With the appropriate substituents, nematic and smectic C phases were observed. One derivative was obtained with an ee of 47 per cent by asymmetric synthesis. The chemical stability of these epoxides is low and they rearrange to give substituted phenyl benzylketones which are also liquid-crystalline. The structure of the two solid phases present in all the derivatives and of the smectic C phases was investigated by X-ray diffraction.

A variety of aryl, alkyl and cycloalkyl silyl thioketones have been synthesized, including silyl thioketones chiral at silicon or at carbon. The multifold of reactions of silyl thioketones allows the synthesis of compounds containing the Si-C-S unit, as well as thioaldehyde S-oxides and derivatives.

The reaction of acylsilanes 1 with Grignard reagents gives the diastereomeric α-hydroxysilanes 3 . The level of asymmetric induction depends on the nature of R 1 and R 2 . Good results were obtained for R 1 =t-Bu, R 2 =Me and R 1 =α-Napht, R 2 =Ph. Subsequent desilylation occurs with predominant inversion of configuration at carbon.

A variety of aryl, alkyl and cycloalkyl silyl thioketones have been synthesized, including silyl thioketones chiral at silicon or at carbon. The multifold of reactions of silyl thioketones allows the synthesis of compounds containing the Si-C-S unit, as well as thioaldehyde S-oxides and derivatives.

Photo-induced cycloadditions of phenyl triphenylsilyl thioketone 1 with electron-poor olefins (acrylonitrile, methyl acrylate and cis- and trans-1,2-dichloroethene) gave silyl thietanes in a regio- and highly stereo-selective manner. In contrast, reaction with vinyl ethers gave thietanes without any regio- or stereo-control. Reaction with α-methylstyrene and 2,3-dimethylbut-2-ene gave open chain products. Desilylation of silyl thietanes occurs with prevalent inversion of configuration at the carbon bearing the silicon group.

ω-Haloacylsilanes 1 were selectively transformed via thioacylsilanes into Z-silyl-enethiols 4 with solid sodium hydrogen carbonate or into 2-silylthiacycloalk-2-enes 5 of common to large ring size with solid sodium hydroxide. Compounds 5 underwent protiodesilylation.

The palladium-catalyzed desilylation−arylation of substituted vinylsilanes by p-iodoanisole in the presence of bidentate phosphine ligands is described. Apart from enhancing the rate of the reaction considerably, heteroatom-based functional groups in the vinylsilane moiety have a profound influence on the regiochemistry. A catalytic cycle for the chelation-controlled desilylation−arylation reaction involving five- and six-membered chelate rings is proposed.

Treatment of methyl 1-methylsulfanylvinyl sulfoxides with sodium thiophenolate in MeOH gives 1-methylsulfanylalk-1-en-3-ols.

A series of 4-acylamino-3-aryl substituted pyrazoles is synthesized and evaluated in vitro for their cytotoxicity against U87MG glioma cells.

Structural variations in acylsilane molecules allow a number of new selective synthetic processes to be performed which lead to sulfur-containing heterocycles, highly functionalized and unsaturated polycarbonyl derivatives, polyenes, and β - and γ -aminoalcohols. The synthesis of these compounds, most of them not easily accessible through conventional routes, takes advantage of the site-selective reactions occurring at the C–Si bonds, of the increased stability of acylsilanes with respect to that of the corresponding aldehydes and of the high diastereofacial selectivity introduced by the SiR 3 group. Herein we report the different synthetic strategies leading to the synthesis of several functionalized acylsilanes and their synthetic applications. The use of new selective polymetallic reagents for the nucleophilic silylation will be presented as well.