Synthesis of ß-Lactams and ß-Homoprolines by Fragmentative Rearrangement of 5-Spirocyclopropaneisoxazolidines Mediated by Acids.

Azetidinones and ß-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 ß-lactam and ß-homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a ß-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.

"Cyclopropylidene Effect" in the 1,3-Dipolar Cycloaddition of Nitrones to Alkylidene Cyclopropanes: A Computational Rationalization.

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.

Computational Investigation of the Selective Cleavage of Diastereotopic Cyclopropane Bonds in 5-Spirocyclopropane Isoxazolidines Rearrangement.

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.

A Stereoselective Synthesis of Lentiginosine.

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.

Azido-Substituted BODIPY Dyes for the Production of Fluorescent Carbon Nanotubes.

A series of azido-dyes were synthesized through Knoevenagel reactions of an azido-BODIPY with aromatic aldehydes. The nature of the substituents allowed the fine tuning of their spectroscopic properties. The dyes were used to decorate oxidized multiwalled carbon nanotubes (ox-MWCNTs), bearing terminal triple bond groups, by CuAAC reactions, affording fluorescent materials. This decoration allowed the efficient determination of the internalization of the ox-MWCNT derivatives by different model cancer cells, such as MCF7.

Urea vs. carbamate groups: a comparative study in a chiral C2 symmetric organogelator.

The effect of the replacement of molecular moieties (carbamates vs. urea) that drive self-assembly for two organogelators with an identical C(2) symmetric molecular structure is described. The main properties of the gels obtained from the urea-based organogelators are also discussed. The proposed organogelators are chiral molecules and are able to express chirality also at the supramolecular level, thus allowing the employment of electronic circular dichroism to gain insight into the molecular-scale structure of fibrillar aggregates. With the same technique, the behavior of enantiomeric mixtures of the urea-based organogelators was investigated, revealing the occurrence of different self-sorting phenomena at the molecular and supramolecular scale. The urea-based organogelators demonstrated to be more efficient gelators with respect to the carbamate-based analogues, showing a high gel-to-sol transition temperature (up to 66 °C) and a very low minimum gelling concentration (0.85 mg mL(-1)). This study is a starting point for a deeper investigation of structure/property relationships and, taking into account the peculiar behavior detected for the enantiomeric mixtures, also of self-sorting and molecular recognition phenomena.

Separation of Enantiomers of a Phospholipid in Langmuir Monolayers by a New Selector.

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.

Synthesis of 4-hydroxy-ß3-homoprolines and their insertion in α/ß/α-tripeptides.

The stereoselective syntheses of 2-cyclopropyl- and (2S)-2-hydroxymethyl-(3R,4S)-4-hydroxy-ß(3)-homoproline are described. The reported amino acids were constructed through 1,3-dipolar cycloaddition of strained alkylidenecyclopropanes with enantiopure pyrroline N-oxides derived from malic acid followed by thermal rearrangement of the adducts in the presence of trifluoroacetic acid. The two-step sequence afforded the homoprolines suitably protected to be directly used as building blocks in peptidomimetic synthesis as proved by the synthesis of the two model mixed α/ß/α tripeptides Phe-ß(3)-HPro-Val.

"Click" on tubes: a versatile approach towards multimodal functionalization of SWCNTs.

Organic functionalization of carbon nanotube sidewalls is a tool of primary importance in material science and nanotechnology, equally from a fundamental and an applicative point of view. Here, an efficient and versatile approach for the organic/organometallic functionalization of single-walled carbon nanotubes (SWCNTs) capable of imparting multimodality to these fundamental nanostructures, is described. Our strategy takes advantage of well-established Cu-mediated acetylene-azide coupling (CuAAC) reactions applied to phenylazido-functionalized SWCNTs for their convenient homo-/heterodecoration with a number of organic/organometallic frameworks, or mixtures thereof, bearing terminal acetylene pendant arms. Phenylazido-decorated SWCNTs were prepared by chemoselective arylation of the CNT sidewalls with diazonium salts under mild conditions, and subsequently used for the copper-mediated cycloaddition protocol in the presence of terminal acetylenes. The latter reaction was performed in one step by using either single acetylene derivatives or equimolar mixtures of terminal alkynes bearing either similar functional groups (masked with orthogonally cleavable protecting groups) or easily distinguishable functionalities (on the basis of complementary analytical/spectroscopic techniques). All materials and intermediates were characterized with respect to their most relevant aspects/properties by TEM microscopy, thermogravimetric analysis coupled with MS analysis of volatiles (TG-MS), elemental analysis, cyclic voltammetry (CV), Raman and UV/Vis spectroscopy. The functional loading and related chemical grafting of both primary amino- and ferrocene-decorated SWCNTs were spectroscopically (UV/Vis, Kaiser test) and electrochemically (CV) determined, respectively.

Organocatalytic Reduction of Aromatic Nitro Compounds: The Use of Solid-Supported Phenyl(2-quinolyl)methanol.

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 NaBH4 to regenerate the reactive reducing species at the end of the process. The reduction products are easily isolated through a simple filtration/extraction protocol, and the catalyst can be efficiently recovered and recycled. The condensation route is generally preferred, and azo- and/or hydrazo-arenes can be easily prepared in high yields.

Synthesis of 1,2-dihydroxyindolizidines from 1-(2-pyridyl)-2-propen-1-ol.

1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.

Chirality driven self-assembly in a fluorescent organogel.

In this work, we present the characterization of an enantiomeric pair of fluorescent dye organogelators and the properties of their stable gel at low concentration in organic solvents. The gels of both enantiomers and of their mixtures were analyzed by differential scanning calorimetry, circular dichroism (CD), atomic force microscopy, UV-vis absorption, and fluorescence. The acquired data were supported by molecular modeling of the helical assembly of the gelators and by the simulation of their CD spectra by means of DeVoe method, and suggested the occurrence of an enantiomeric discrimination process during the formation of the gels.

Rh-Catalyzed rearrangement of vinylcyclopropane to 1,3-diene units attached to N-heterocycles.

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%).

Bromotrimethylsilane as a selective reagent for the synthesis of bromohydrins.

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.

The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine.

D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.

Stereocontrolled cyclic nitrone cycloaddition strategy for the synthesis of pyrrolizidine and indolizidine alkaloids.

The synthesis of polyhydroxylated indolizidines and pyrrolizidines belonging to the class of iminosugars, endowed with a vast and assorted biological activity, can be achieved in a straightforward manner by a general strategy consisting of a highly stereoselective 1,3-dipolar cycloaddition of polyhydroxylated pyrroline-N-oxides followed by simple transformations of the isoxazolidine adducts. The strategy allows the complete control of the relative and absolute stereochemistry of the numerous stereogenic centers decorating these compounds.

Pyrene-excimers-based antenna systems.

A series of dendrimeric compounds bearing pyrene units were synthesized to afford light-harvesting antennae based on the formation of intramolecular excimers. The synthetic plan profited from the efficiency of the Huisgen reaction, the 1,3-dipolar cycloaddition of azides and terminal alkynes, which allowed ready assembly of the different building blocks. The three molecular antennae obtained, of increasing generation, revealed efficient energy transfer both in solution and in the solid state.

Synthesis of alpha-cyclopropyl-beta-homoprolines.

1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (alpha-cyclopropyl-beta-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, beta-homoprolines were formed with high stereocontrol. The incorporation of one of these new cyclic beta-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.

Synthesis, SAR and in vitro evaluation of new cyclic Arg-Gly-Asp pseudopentapeptides containing a s-cis peptide bond as integrin alphavbeta3 and alphavbeta5 ligands.

The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid (GPTM) is described. Competition binding assays to purified alphavbeta3 and alphavbeta5 integrins with respect to [125I]echistatin showed a high inhibitory activity for the (2S,7aS)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2R,7aR)-GPTM and (2S,7aS)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp-d-Phe-[N-Me]Val) in complex with the extracellular fragment of the alphavbeta3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand-protein complex.