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The reduction of aromatic nitro compounds has been performed employing a catalytic amount of Wang resin-supported phenyl(2-quinolyl)methanol (Wang-PQM) in the presence of an excess of NaBH

Azetidinones and β-amino acids serve as useful building blocks in synthetic organic chemistry and their structural motifs are often found in biologically active compounds. Due to the importance of these compounds, several synthetic strategies have been developed and availability of new synthetic approaches is highly desirable. In this account, we describe the development of an original method that allows the preparation of β-lactam and β-homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a β-lactam by heating a mixture of an alkylidenecyclopropane tethered to a formyl group with N-methylhydroxylamine hydrochloride. Investigation of the process resulted in disclosing an alternative synthetic method of azetidinones based on an acid induced fragmentative rearrangement of cycloadducts of nitrones with suitable methylenecyclopropane derivatives. Herein, the scope of this process is reviewed. In addition, both experimental and computational studies of the mechanism for this peculiar fragmentative rearrangement are presented.

The complete path of the Brandi-Guarna rearrangement of 5-spirocyclopropane isoxazolidines has been investigated by means of density functional theory calculations to rationalize the competing formation of tetrahydropyridones and enaminones by the determination of the minimum energy reaction paths. Our calculations confirm that the rearrangement is triggered by the homolysis of the isoxazolidine N-O bond followed by cleavage of one of the two C-CH2 cyclopropane bonds as previously proposed by the Fabian group [ Eur. J. Org. Chem. 2001, 2001, 4223]. In addition, the results of this work suggest that in the presence of a stereogenic center at isoxazolidine C-4', the formation of a piperidinone or an enaminone as the final product depends on which of the two diastereotopic C-CH2 bonds of cyclopropane is cleaved in the second step of the process. The result can be of great interest for the understanding of other processes involving the opening of a cyclopropane ring.

The regioselectivity in the 1,3-dipolar cycloaddition (1,3-DC) between five-membered cyclic nitrone and methylenecyclopropane (MCP) has been studied through density functional theory (DFT) calculations. The computational study of 1,3-DC with different 1-alkyl- (or 1,1-dialkyl)-substituted alkenes and the comparison with MCP have evidenced that the electrostatic interaction has a central role in the regioselectivity of the reactions. It has been observed that the electronic effect of the substituent (donor or attractor groups) determines the polarization of the alkene double bond and the reaction mechanism, consequently determining the interaction with nitrones and favoring an orientation between this moiety and the dipolarophile.

Bromotrimethylsilane (TMSBr) is a very efficient reagent in the solvent-free conversion of glycerol into bromohydrins, useful intermediates in the production of fine chemicals. As glycerol is a relevant by-product in biodiesel production, TMSBr has been also tested as a mediator in transesterification in acidic conditions, providing FAME from castor oil in good yields, along with bromohydrins from glycerol. Subsequently the glycerol conversion was optimized and depending on the reaction conditions, glycerol can be selectively converted into α-monobromohydrin (1-MBH) or α,γ-dibromohydrin (1,3-DBH) in very good yields.

Batches of oxidized multiwalled carbon nanotubes differing in length were adopted to prepare two drug delivery systems (DDS) loaded with doxorubicin. The different internalization of the two batches, verified by atomic emission spectroscopy onto cell lysates, was also confirmed by the different toxicity of the same DDS loaded with doxorubicin. I n vitro experiments evidenced, after 48 h of incubation, the superior efficacy of the shortest nanotubes. However, upon prolonging the incubation time up to 72 h the difference in efficiency was minimized due to the spontaneous release of doxorubicin by the non-internalized long nanotubes.

The polymeric catalyst [MoO3(2,2′–bipy)]n has been employed in the oxidation of secondary amines to nitrones, and sulfides to sulfoxides or sulfones, using tert–butylhydroperoxide (TBHP) as the stoichiometric oxidant. Whereas the oxidation of amines occurs with less proficiency with respect to other previously studied polymeric Mo catalysts, the oxidation of sulfides occurs in high yield and selectivity. The catalyst is flexible in terms of substrate scope (aromatic, aliphatic and cyclic sulfides, thioheterocycles such as dimethyldibenzothiophene, the oxidation of which forms the basis of oxidation/separation processes for the desulfurization of fuels) and the ability to switch sulfoxide/sulfone product selectivities by adjusting the reaction conditions.

Phenyl (2-quinolyl) methanol (PQM) behaves as a new efficient reagent for metal-free reduction of nitro aromatic and heteroaromatic compounds. The reduction proceeds in mild reaction conditions affording anilines in good yields. Phenyl (2-quinolyl) ketone (PQK), the oxidation product of PQM, can be quantitatively recovered and reused after reduction making sustainable the overall process. The reduction outcome changes with electron-deficient nitroarenes that afford the expected anilines and electron-rich nitro compounds that give reductive amination products via reduction of imines formed by condensation of nucleophilic anilines with PQK. These multicomponent reactions were observed also with activated aldehydes and in the presence of acrylates for the synthesis of β-anilino esters. The synthetic value of the new metal-free reducing agent, unmatched by the well-known Hantzsch ester, has been exploited in metal-free Reissert indole and Friedlander quinoline syntheses.

In the course of studies directed toward the synthesis of 7,8-disubstituted 1,2-dihydroxyindolizidines as analogues of the proapoptotic iminosugar lentiginosine, marked reactivity differences of diastereomeric spiro[cyclopropane-1,2′(3H)-pyrrolo[1,2-b]isoxazolidines] precursors were observed. While one minor diastereoisomer gives the Brandi–Guarna rearrangement to indolizidinone very smoothly, and also easily undergoes fluorination of the primary alcohol, the main diastereoisomer behaves in a rather different way. The thermal rearrangement is less efficient and fluorinating agents mainly induce an unexpected cyclization to a highly strained tetracyclic derivative that, in turn, rearranges to form the uncommon 2-oxa-8-azatricyclo[6.2.1.04,9]undecan-5-one system with good yield. In this last process a remarkable macrocyclic dimer has been isolated that sheds light on an unprecedented different aspect of the Brandi–Guarna rearrangement.

Chiral discrimination in a racemic mixture of dipalmitoylphosphatidylcholine (DPPC) is induced by a new selector at the water-air interface: L-DPPC is segregated in the condensed phase of a Langmuir monolayer upon interactions with an enantiopure amphiphilic compound.

The four-step procedure involving bromination, reduction, and nucleophilic substitution via elimination/addition previously applied to 1-(2-pyridyl)-2-propen-1-ol for the synthesis of indolizidine systems has now been extended to 1-(2-quinolyl)-2-propen-1-ol allowing a general access to benzo-fused derivatives. For instance, (±)-benzo[e]lentiginosine has been easily synthesized in an 18% overall yield.

The reaction between castor oil and various alcohols in the presence of trimethylchlorosilane (TMSCl) as acidic mediator provides two remarkable one pot reactions: transesterification of triglycerides, relevant to BioDiesel production, and chlorination of glycerol, with formation of α-monochlorohydrin as the predominant product, relevant to the synthesis of epoxide resins. The reaction has been thoroughly investigated to optimize the reaction conditions and separation of the products obtained in good yields. This synthesis represents a highly sustainable production of industrial commodities from available biomass.

The production of nanohybrids formed by oxidized multiwalled carbon nanotubes (MWCNTs) and nanoparticles, produced by pulsed laser ablation in liquids process, is described. The use of linkers, obtained by transformation of pyrene-1-butanol, is mandatory to generate an efficient and stable interaction between the two components. Transmission electron microscopy and X-ray photoelectron spectroscopy analysis showed the obtainment of the efficient coverage of the MWCNTs by nanoparticles composed by metal gold and, partially, by oxides.

Highly functionalised tetrahydroquinolines have been obtained by a modular approach consisting of a nitrone 1,3-dipolar cycloaddition to 2-bromostyrene followed by isoxazolidine N–O cleavage and copper-catalysed aromatic N-substitution/cyclisation. A 1,2,3,4-tetrahydro-1,8-naphthyridine was obtained in the same way.

(+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (-)-lentiginosine, induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non-transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of lentiginosine and trans-1,2-dihydroxyindolizidine analogues.

A new method for the transformation of glycerol into mono- and dichlorohydrins has been studied. With trimethylchlorosilane as chlorinating agent and acetic acid as catalyst, mono- and dichlorohydrins have been obtained in high yields and selectivity. In fact, under different reaction conditions, the synthesis of α-monochlorohydrin (3-chloropropan-1,2-diol) or α,γ-dichlorohydrin (1,3-dichloropropan-2-ol) as predominant product has been achieved. This process was also exploited for the valorisation of the crude mixture of glycerol and monochlorohydrin (glyceric mixture), a by-product from an earlier BioDiesel production. A reaction mechanism has been proposed based on investigations on the chlorination of different alcohols.

The enantiopure (2S,3S,3aS,5S)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-2,3,5-triol (2,3,5-trihydroxybenzo[e]indolizidine) framework has been synthesized by a straightforward strategy consisting of 1,3-dipolar cycloaddition of a pyrroline N-oxide to 2-bromostyrene followed by isoxazolidine N–O bond reduction and cyclization by copper-catalyzed nucleophilic aromatic substitution of the intermediate pyrrolidine.

A chiral organogelating scaffold is functionalised with a stable organic radical pendant. The morphology and spectroscopic properties of the gels are investigated as a function of the organogelator concentration and temperature. The combination of AFM and ESR spectroscopy provides firm evidence that the architecture responsible for the formation of the macroscopic gel (i.e., the fibrillar structure) is maintained below the gelling concentration. This opens relevant perspectives in terms of the realisation of complex supramolecular chiral structures incorporating paramagnetic functions, and demonstrates that the ESR technique is suitable as a fast and direct check of the sample state (gel, solution, or small aggregates).

Diversity-oriented synthesis of derivatives of the potent glycosidase inhibitor lentiginosine can be achieved in an efficient and versatile way by two modular approaches on key intermediates. After assembling the indolizidine ring system through 1,3-dipolar cycloaddition of a dihydroxylated pyrroline N-oxide with 4-butenol followed by elaboration of the isoxazolidine moiety, the 7-amino and 7-azido derivatives synthesized can be conjugated with functionalised chains by coupling, respectively, with an amino acid, or an alkyne in copper-catalyzed Huisgen cycloadditions.

The inorganic–organic hybrid material {[MoO 3 (bipy)][MoO 3 (H 2 O)]} n (bipy = 2,2′-bipyridine) can be used as a water-tolerant catalyst for the oxidation of secondary amines under mild conditions using either urea hydrogen peroxide (UHP) or tert -butylhydroperoxide (TBHP) as the oxidant. Under optimized reaction conditions (2 mol % catalyst, 3–4 equiv TBHP, CH 2 Cl 2 as the solvent, 40 °C), the corresponding nitrones were obtained with different efficiency depending on the nature of the cyclic or acyclic amine used.

Protonation at the nitrogen of 5-spirocyclopropane-isoxazolidines induces clean thermal rearrangement/fragmentation to β-lactams and ethylene. Under the same conditions, homologous 5-spirocyclobutane-isoxazolidines undergo unselective fragmentation to give cyclobutyl derivatives through a completely different mechanism. Experimental data and DFT calculations show that the process is initiated with less-favored protonation at the isoxazolidine oxygen rather than nitrogen. Highly energetic O-protonated isoxazolidines undergo N–O cleavage with concomitant endo- or exocyclic deprotonation to give iminium ions that, in the presence of trifluoroacetate, evolve into 2-(1-hydroxycyclobutyl)ethanones and N-[2-(1-hydroxycyclobutyl)ethyl]trifluoroacetamides, respectively. DFT data validate protonation at oxygen of 5-spirocyclobutane-isoxazolidines, which requires higher energy than protonation at nitrogen, but can trigger the proposed process without any energy barrier. The N-protonated derivatives could rearrange to give oxazaspirooctane, with enlargement of the spirocyclobutane ring, but this process, owing to its high energy barrier, cannot compete with the reaction channel promoted by oxygen protonation and, in fact, is not experimentally observed. Being independent of the presence of a strained spirofused ring, acid-catalyzed fragmentation was also demonstrated to occur in normal isoxazolidines, such as those derived from cycloaddition of C–Ph–N–Me-nitrone to norbornene, suggesting that isoxazolidines, widely used in organic synthesis, should not be heated in the presence of protic acids.

An efficient approach to the organic functionalization of multiwalled carbon nanotubes (MWCNTs) for the production of highly soluble/dispersible materials has been accomplished by a class of highly reactive and thermally stable nitrones. Besides the unprecedented solubility in aprotic polar solvents of the functionalized samples (up to 10 mg of f-MWCNTs per mL of DMF), we have demonstrated, for the first time, that the CNT functionalization by nitrones preferentially occurs at the defective CNT sidewalls without any appreciable degradation of their sp2 network. The role of the reticular imperfections on the graphitic lattice of the MWCNTs has been experimentally and theoretically addressed. A complete chemical (TGA-MS, FT-IR, SSA) and morphological (TEM, AFM) characterization of the functionalized materials has accounted for the high degree of CNT functionalization, whereas Raman scattering, in combination with complementary XRPD and active surface area (ASA) measurements, has provided unambiguous evidence of the key role played by the structural “disorder” of the MWCNTs in the nitrone cycloaddition. Density functional theory (DFT) calculations on the reactivity of selected topological defects at the CNT sidewalls have contributed to trace-out a “defect-based” sidewall reactivity trend. The excellent processability of the functionalized MWCNTs has been finally exploited for the preparation of highly homogeneous CNT/polymer nanocomposites with CNT loadings as high as 3 wt%.

Dienes embedded in quinolizidine and indolizidine structures can be prepared in four steps from cyclic nitrones and bicyclopropylidene. The key intermediates α-spirocyclopropanated N-heterocyclic ketones, generated via a domino 1,3-dipolar cycloaddition/thermal rearrangement sequence, were converted by Wittig methylenation to the corresponding vinylcyclopropanes (VCPs), which underwent rearrangement to 1,3-dienes in the presence of the Wilkinson Rh(I) complex under microwave heating. The previously unexplored Rh(I)-catalyzed opening of the VCP moiety embedded in an azapolycyclic system occurs at high temperature (110–130 °C) to afford the corresponding 1,3-dienes in moderate yield (34–53%).

As previously reported for 1-(2-pyridyl)-2-propen-1-ol, (2-pyridyl)phenyl methanol is able to react as hydrogen donor towards nitro aromatic and heteroaromatic compounds. Operating in the presence of methyl acrylate as an aza-Michael acceptor, a domino process involving reduction and conjugate addition steps allows the one pot formation of β-amino esters. The crucial role of the pyridine nucleus in making this purely thermal reactivity of carbinols possible has been shown.

4-Methoxycarbonyl-4-chloro-5-spirocyclopropaneisoxazolidines, easily obtained by in situ cycloadditions of nitrones to methyl 2-chlorocyclopropylideneacetate and 2-chlorospiropentylideneacetate, in contrast to their known thermal rearrangements leading to δ-lactams, undergo rearrangement to their respective tetrahydropyridones, when the nitrone nitrogen is substituted by an aryl moiety.

A peculiar thermal behaviour of hydroxyallylpyridyl derivatives, likely associated to the weak acidity of the ‘picoline-type’ hydrogen atom and responsible for the formation of allyl inversion products, has been reported. The ‘mobility’ of the same hydrogen atom allowed the unprotected title compound to behave regioselectively as C-1, C-2 or C-3 carbon nucleophile depending on the thermal or base-promoted experimental conditions and on the kind of electrophile; moreover, the corresponding Hantzsch-type pyridine tautomer displayed a biomimetic ability to transfer hydrogen to aromatic and heteroaromatic nitro derivatives.

1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (α-cyclopropyl-β-homoprolines) were prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced thermal fragmentative rearrangement. With the use of enantiopure pyrroline N-oxides derived from easily available chiral pool molecules, β-homoprolines were formed with high stereocontrol. The incorporation of one of these new cyclic β-amino acids into a simple tripeptide was also evaluated. In particular, the sterically hindered nitrogen atom of the highly substituted pyrrolidine 30 was smoothly acylated through the intermediate formation of a mixed anhydride.

The new 7S-aminolentiginosine has been synthesized by a diastereoselective 1,3-dipolar cycloaddition strategy starting from 3,4-dihydroxylated pyrroline N-oxides derived from L -tartaric acid in thirteen steps. The intermediate 7S-azidolentiginosine undergoes efficiently copper(I)-catalysed Huisgen cycloadditions to alkynes.

The synthesis of several α-substituted N-Boc-protected prolines has been achieved by cross metathesis (CM) of N-Boc-allylproline 5 with terminal long chain alkenes and alkenes bearing hydroxy, silyloxy, ester, and O-acetylglucosamido groups. The CM occurred with good selectivity and short reaction time under microwave heating conditions, affording yields in the range of 40–92 %. Addition of Ti(OiPr)4 as a Lewis acid allowed a slight increase of the yield in the case of alkenes with Lewis basic substituents. The CM was also successfully applied to allylproline protected with trichloroacetaldehyde 4, but the intermediate products were less practical for further deprotection and elaboration. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The 1,3-dipolar cycloaddition of enantiopure cyclic hydroxylated nitrones and allyl nucleobases has been exploited for the preparation of a novel class of homonucleoside mimetics, where the furanose ring is replaced by a pyrrolo[1,2- b ]isoxazolidine system. The nitrones were easily prepared starting from l -malic and l -tartaric acids and gave cycloadducts in a diastereoselective manner, which were deprotected to give good yields of the homo-N,O-nucleoside mimetics. The reduction of the isoxazolidine ring, a 1,3-aminoalcohol equivalent, allows easy access to other new pyrrolidine nucleoside mimetics.

The synthesis of new organogelators based on a triazine nucleus is described together with the analysis of the properties of the main compound 15. This compound revealed an efficient organogelator in both polar and apolar solvents and represents a promising precursor of other functionalized organogelators.

A series of 3-spirocyclopropanedihydro- and -tetrahydropyrid-4-ones have been synthesized by nitrone cycloaddition to 1,1′-bicyclopropylidene (BCP), chemoselective reduction of the N–O bond of the isoxazolidine ring, and PdII-catalyzed cascade rearrangement of the β-aminocyclopropanol derivatives into the final products. The new tetrahydropyridone derivatives were also prepared by thermal rearrangement of the isoxazolidines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Cycloadditions of chiral pyrroline N-oxides to levoglucosenone (1) and isolevoglucosenone (2) proceed with a high level of double asymmetric induction. Partial kinetic resolutions (KR) of both enantiomers of a racemic nitrone 3 were achieved, and a parallel kinetic resolution (PKR) experiment allowed the stereoselective divergent synthesis of two quasienantiomeric imino-C-disaccharide precursors.

A concise stereoselective synthesis of (−)-lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline N-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-lentiginosine can be synthesized by the same method but starting from l-tartaric acid.

To demonstrate the potential of azido-substituted carbon nanotubes for application in nanomedicine, multiple-decorated oxidized multi-walled carbon nanotubes as drug delivery systems have been synthesized. These DDSs were able to carry doxorubicin inside breast MCF-7 cancer cell lines resulting in an enhanced cytotoxic effect with respect to the free drug. Decoration of the carbon nanotubes was accomplished through both covalent and non-covalent approaches: versatile click reactions and π–π interactions were exploited. To assess the internalization of the carbon nanotubes inside cells, decoration with a BODIPY fluorescent molecule was performed. Furthermore, the nanotubes were decorated with a biotin selector molecule to increase the uptake of the system by cancer cells. Comparative studies were performed on the complete drug delivery system to highlight its effect with respect to the free drug and the contribution of the selector in the internalization efficiency. Finally, preliminary in vivo tests were performed on MCF-7 inoculated mice. A net improvement in efficiency, concerning the minor growth of the tumors, has been found when using doxorubicin loaded on our drug delivery system with respect to free doxorubicin.

This work presents an experimental and computational study of the intramolecular electronic energy transfer process occurring in two newly synthesized bichromophoric species: N-(7-nitro-2,1,3-benzoxadiazol-4-yl)amino-bis-ethyl-2-[(4-chloro-1-naphthyl)oxy]acetate ( f-Bi ) and N-(7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)-(3S, 4S)-pyrrolidin-3,4-bis-yl-2-[(4-chloro-1-naphthyl)oxy]acetate ( r-Bi ). In both f-Bi and r-Bi the donor chromophore is the [(4-chloro-1-naphthyl)oxy]acetate moiety, whereas the acceptor units belong to the family of the 4-dialkylaminonitrobenzoxadiazoles, well-known fluorescent probes. The two bichromophores differ in the structural flexibility. In f-Bi , acceptor and donors are linked by a diethanolamine moiety, whereas in r-Bi through a (3S, 4S)3,4-dihydroxypyrrolidine ring. By means of steady-state and time-resolved UV–vis spectroscopies we carried out a detailed analysis of the photo-response of donor and acceptor chromophores as individual molecules and when covalently linked in f-Bi and r-Bi . The intramolecular energy transfer process occurs very efficiently in both the bichromophores. The rate constant and the quantum efficiency of the process are k ET = (2.86 ± 0.16) × 10 11 s −1 and Q = 0.998 in f-Bi , and k ET = (1.25 ± 0.08) × 10 11 s −1 and Q = 0.996 in r-Bi . Semiempirical calculations were utilized to identify the energy and the nature of the electronic states in the isolated chromophores. Molecular mechanics calculations have been performed to identify the most stable structures of the bichromophoric compounds. The predictions of Forster theory are consistent with the experimental results and provide a suitable way to evaluate the structural differences between the two compounds.

(+)-Lentiginosine is a powerful and selective inhibitor of amyloglucosidases and has become a reference compound in the field among derivatives related to imino sugars. The present review focuses on the several total syntheses of this alkaloid, which rely on either a chiral pool or on enantioselective approaches that have appeared since its isolation in 1990. A summary of biological assays and molecular dynamic studies which allowed the assignment of the correct absolute configuration of natural (+)-lentiginosine is reported.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The synthesis of enantiopure cyclic nitrones has become a frequently addressed topic in discussions of their usefulness in the production of natural products and biologically active compounds. This emphasis has stimulated the development of a variety of synthetic approaches that are described in this review, organized on the basis of the size of the nitrone ring.