Novel Chiral Bis-Phosphoramides as Organocatalysts for Tetrachlorosilane-Mediated Reactions.

The formation of novel chiral bidentate phosphoroamides structures able to promote Lewis base-catalyzed Lewis acid-mediated reactions was investigated. Two different classes of phosphoroamides were synthetized: the first class presents a phthalic acid/primary diamine moiety, designed with the aim to perform a self-assembly recognition process through hydrogen bonds; the second one is characterized by the presence of two phosphoroamides as side arms connected to a central pyridine unit, able to chelate SiCl4 in a 2:1 adduct. These species were tested as organocatalysts in the stereoselective allylation of benzaldehyde and a few other aromatic aldehydes with allyl tributyltin in the presence of SiCl4 with good results. NMR studies confirm that only pyridine-based phosphoroamides effectively coordinate tetrachlorosilane and may lead to the generation of a self-assembled entity that would act as a promoter of the reaction. Although further work is necessary to clarify and confirm the formation of the hypothesized adduct, the study lays the foundation for the design and the synthesis of chiral supramolecular organocatalysts.

HSiCl3-Mediated Reduction of Nitro-Derivatives to Amines: Is Tertiary Amine-Stabilized SiCl2 the Actual Reducing Species?

The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro-derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, and spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.

Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: an organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent.

An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-ß-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABAB receptor agonist baclofen.

Chiral hybrid inorganic-organic materials: synthesis, characterization, and application in stereoselective organocatalytic cycloadditions.

The synthesis of chiral imidazolidinones on mesoporous silica nanoparticles, exploiting two different anchoring sites and two different linkers, is reported. Catalysts 1-4 were prepared starting from l-phenylalanine or l-tyrosine methyl esters and supporting the imidazolidinone onto silica by grafting protocols or azide-alkyne copper(I)-catalyzed cycloaddition. The four catalysts were fully characterized by solid-state NMR, N2 physisorption, SEM, and TGA in order to provide structural assessments, including an evaluation of surface areas, pore dimensions, and catalyst loading. They were used in organocatalyzed Diels-Alder cycloadditions between cyclopentadiene and different aldehydes, affording results comparable to those obtained with the nonsupported catalyst (up to 91% yield and 92% ee in the model reaction between cyclopentadiene and cinnamic aldehyde). The catalysts were recovered from the reaction mixture by simple filtration or centrifugation. The most active catalyst was recycled two times with some loss of catalytic efficiency and a small erosion of ee.

Continuous-flow stereoselective organocatalyzed Diels-Alder reactions in a chiral catalytic "homemade" HPLC column.

Continuous-flow organocatalyzed Diels-Alder reactions have been performed with excellent enantioselectivity for the first time in a chiral "homemade" HPLC column, packed with silica on which a MacMillan catalyst has been supported by a straightforward immobilization procedure. The versatility of the system was also proven by running with the same column continuous-flow stereoselective reactions with three different substrates, showing that the catalytic reactor may efficiently work in continuo for more than 150 h; the regeneration of the HPLC column was also demonstrated, allowing to further extend the activity of the reactor to more than 300 operating hours.

Stereoselective synthesis and characterization of new enantiomerically pure phosphoric acids.

Starting from (R)-6,6'-dimethyldiphenyl-2,2'-dicarboxylic acid, a novel class of enantiomerically pure cyclic dialkyl phosphates was synthesized and properly characterized. The absolute configuration was determined by 2D NOESY experiments. The catalytic behavior of the new chiral Bronsted acids was investigated in the stereoselective addition of a silyl keteneacetal to aldimines. The Mannich-type reaction was promoted in up to 94% yields and enantioselectivities up to 55%. On the basis of preliminary molecular mechanic calculations, a model of stereoselection was also proposed to explain the sense of the enantioselectivity observed in the reaction.

Aromatic tripodal receptors for (C(60)-I(h))[5,6]fullerene.

Monotopic and ditopic tripodal benzene platforms featuring aromatic and perfluoroaromatic side-arms have been synthesized, and their binding properties toward C(60)-fullerene have been investigated by HPLC examining retention times on a fullerene-modified silica stationary phase, using highly polar eluants (acetonitrile and acetonitrile/water). By comparison of structurally homogeneous sets of receptors, a clear trend could be found, pointing to an increased retention for ditopic derivatives, in which binding can occur on both sides of the benzene platform, over their monotopic counterparts. Among the latter, monotopic receptors containing H-substituted aromatic residues showed stronger retention than their perfluorinated analogues. This effect was ascribed to the greater availability of the pi-electrons in a H-substituted aromatic ring with respect to the corresponding F-substituted counterpart in participating in a pi-pi interaction with the electron-poor surface of fullerene. Several NMR experiments aimed to investigate binding interactions in solution, using the much less polar solvents required by the fullerene solubility (1,1,2,2-tetrachloroethane, chloroform, toluene, and CS(2)), did not provide any evidence of binding interactions. We concluded that pi-pi interactions between fullerene and the investigated flexible tripodal receptors cannot compete with solvation in poorly polar solvents, and that the binding interactions observed by HPLC were essentially forced by the strongly polar eluant employed for the HPLC analysis.

The intramolecular edge-to-face interactions of an aryl C-H bond and of a pyridine nitrogen lone-pair with aromatic and fluoroaromatic systems in some [3,3]metaparacyclophanes: a combined computational and NMR study.

Simple model systems based on the [3,3]metaparacyclophane skeleton have been designed to study the effect of fluorination of the "face" ring on the edge-to-face (EtF) interactions with the C(Ar)-H bond of a phenyl ring or the nitrogen lone-pair of pyridine. Calculations established that in their more stable conformation the model systems adopt a tilted EtF disposition with the rim of the meta-substituted ring pointing towards the face of the para-substituted ring. Topomerization occurs by flipping of the meta-substituted ring, a process that involves the formation of an intermediate featuring an orthogonal EtF disposition of the arenes, which is less stable than the tilted arrangement. The energy barriers to the isomerization were determined by variable-temperature NMR spectroscopy and were well reproduced by DFT calculations. The variation in the energy barrier as a function of the substitution of the para-substituted ring could be rationalized well by a polar interpretation of the EtF interaction in the cases of model systems presenting the PyN...pi interaction but not in the cases of models featuring the C(Ar)-H...pi interaction.

Poly(amidoamine) conjugates with disulfide-linked cholesterol pendants self-assembling into redox-sensitive nanoparticles.

Poly(amidoamine) (PAA) networks that are obtained by the use of cystamine as a cross-linking agent in the reaction with 2,2'-dithiodipyridine turn into linear PAAs with dithiopyridyl side groups that easily undergo an exchange reaction with thiocholesterol. The resultant products represent the first examples of amphiphilic PAA-cholesterol conjugates in which lipophilic cholesterol moieties are linked to the hydrophilic PAA chain by S-S bonds that are stable in blood but cleavable inside cells. In aqueous media, these conjugates self-assemble into nanoaggregates whose inner cores consist of lipophilic cholesterol domains. A series of PAA-cholesterol conjugates that are derived from two different bis-acrylamides, namely 2,2-bis(acrylamido)acetic acid and 1,4-bis(acryloyl)piperazine, and that have different cholesterol contents were obtained. All products were characterized by (1)H and (13)C NMR spectroscopy, and the average molecular weights of the soluble polymers were determined by size exclusion chromatography. In all instances, the segregation of cholesterol residues from the aqueous medium was revealed by the comparison of their NMR spectra in CDCl3 and D2O, respectively. The TEM analysis of the PAA-cholesterol aggregates in aqueous buffers revealed homogeneous round nanospheres whose dimensions and dimension distributions were determined by DLS. Preliminary cytocompatibility tests demonstrated that all prepared PAA-cholesterol samples are cytocompatible and thus show potential for biotechnological applications.

Through-space interactions between parallel-offset arenes at the van der Waals distance: 1,8-diarylbiphenylene syntheses, structure and QM computations.

A model for studying polar-pi interactions between arenes spaced at van der Waals distances is developed on the basis of peri-diarylbiphenylenes. A set of 1,8-diarylbiphenylenes is synthesized comprising two Hammett series, one with reference to mesityl ring interactions and the other with reference to pentafluorophenyl ring interactions. X-Ray crystal structures of several derivatives are determined. Barriers to rotation of the probe aryl ring are derived from dynamic NMR data and show a trend for the mesityl reference series (DeltaG(not equal) vs. sigma(0)). The model is also used as a test for comparison of modern density functional methods, including B3LYP, M06-2X and BMK functionals; dispersive effects are seen to be an important factor in the proper theoretical treatment of arene interactions.

Synthesis of new enantiomerically pure macrocycles containing phenanthroline subunits.

New enantiomerically pure macrocycles have been prepared by combining 1,10-phenanthroline 2,9-dicarboxylic acid and two alpha-amino-acids linked through spacers. Different diamine linkers have been employed in order to modify the dimensions and the properties of the macrocycles whose structures have been studied by 1H and 13C NMR spectroscopy. The ability of the (L)-valine containing macrocycles to bind metal ions and phenolic molecules has been investigated by 1H NMR experiments and Molecular Mechanics calculations.

NMR spectroscopy and MALDI-TOF MS characterisation of end-functionalised PVP oligomers prepared with different esters as chain transfer agents.

Ester-functionalised poly(1-vinylpyrrolidin-2-one) (PVP) oligomers obtained by radical polymerisation in methyl propionate, diethyl malonate and diethyl 2-methylmalonate were characterised by NMR spectroscopy, and MALDI-TOF mass spectrometry. The chain-transfer constants were determined as 5.54 x 10(-4), 1.22 x 10(-3) and 1.70 x 10(-2), respectively, by measuring the variation of the number-average molecular weight on conversion. These values were compared with those of methyl isobutyrate (1.65 x 10(-3)) and ethyl lactate (1.03 x 10(-2)), which had been previously determined. A clear dependence was found on the reactivity of the mobile hydrogen atoms alpha with the ester group. All of the macromolecules carried a single ester function. Therefore, the re-initiation step by the CTA-derived radicals overwhelmingly prevailed over initiation by the primary radicals.

Structurally simple pyridine N-oxides as efficient organocatalysts for the enantioselective allylation of aromatic aldehydes.

A series of structurally simple pyridine N-oxides have readily been assembled from inexpensive amino acids and tested as organocatalysts in the allylation of aldehydes with allyl(trichloro)silane to afford homoallylic alcohols. (S)-proline-based catalysts afforded the products derived from aromatic aldehydes in fair to good yields and in up to 84% enantiomeric excess (ee). The allylation of heteroaromatic, unsaturated, and aliphatic aldehydes was less satisfactory. By running the reaction in the presence of achiral and chiral additives and structurally different catalysts, we collected some insights into the relationship between the stereochemical outcome and the catalyst's structural features. Even if the ee's obtained are inferior to the best values observed with other catalysts, this work concurs to show that structurally simple pyridine N-oxides can also promote the allylation reaction with satisfactory stereocontrol.

End-functionalised 1-vinyl-2-pyrrolidinone oligomers bearing lactate functions at one end.

1-Vinyl-2-pyrrolidinone (VP) oligomers bearing a lactate group at one end (PVP-L) were obtained by chain-transfer controlled radical polymerisation carried out in the presence of ethyl L-lactate as chain-transfer agent (CTA). Their number-average molecular weights were in the range 1500-4000 with molecular weight distributions ranging from 1.4 to 1.8. The chain transfer constant, C(T), of the ethyl L-lactate/VP system was determined by monitoring the variation of PVP-L number-average molecular weight on conversion. The C(T) value so obtained was 1.03 x 10(-2), which is by about one order of magnitude higher than the C(T) value previously determined for a seemingly similar system, namely methyl isobutyrate/1-vinyl-2-pyrrolidinone (1.64 x 10(-3)). The resultant PVP-L oligomers were thoroughly characterised by means of (1)H and (13)C NMR, in order to ascertain the regular presence of the lactate functions at one of their chain terminals. NMR characterisations gave results in full agreement with the proposed structure. Moreover, the molecular weight values determined by NMR very closely agreed with those obtained by SEC. Preliminary biological evaluations of the PVP-L oligomers showed a complete lack of toxicity.

Through-space interactions between face-to-face, center-to-edge oriented arenes: importance of polar-pi effects.

Two series of conformationally restricted polycyclic compounds (1-3 and 4-7) have been synthesized as model systems for studying the through-space interactions between face-to-face, center-to-edge (parallel-offset) oriented arenes. These compounds feature different X substituents on one of the interacting rings. By monitoring the variation of the delta Gz for the rotation around the aryl-aryl bond in 1-7 as a function of X by 2D [1H,1H] EXSY NMR spectroscopy, it was found that the barriers increase on passing from electron-donating to electron-withdrawing substituted derivatives. Quantum mechanical calculations [MP2/DVZ (2d,p)//B3LYP/DVZ(2d,p)] gave barrier values and variations in agreement with the experimental data. The results are consistent with a repulsive arene-arene interaction dominated by electrostatic effects.

Efficient synthesis of an enantiopure beta-lactam as an advanced precursor of thrombin and tryptase inhibitors.

A new and efficient synthesis of a beta-lactam that is an advanced precursor of inhibitors of thrombin and tryptase is reported. The reaction sequence is based on the use of an inexpensive enantiomerically pure starting material and is designed to allow access to both enantiomers of the target molecules by epimerization of a side-product obtained along the synthesis. An improved procedure for the epimerization step that takes advantage of the use of a polymer-supported and recyclable phase-transfer catalyst is described.

Efficient and highly stereoselective synthesis of a beta-lactam inhibitor of the serine protease prostate-specific antigen.

An efficient synthesis of a beta-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stereoselective reactions that allow the introduction of the stereocenters at C-3 and C-4 of the azetidinone ring in a predictable manner.