Laura Raimondi

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

Synthesis of enantiomerically pure C2-symmetric acyclic and cyclic 1,2-diamines via pinacol coupling of imines

Abstract The inter- and intramolecular coupling of imines promoted by samarium diiodide and Lewis acids or by Zn/MsOH was extensively studied. The intramolecular reaction of chiral, enantiomerically pure bis-imines was also considered, and allowed the efficient, stereoselective synthesis of 1,2-diamines with C2-symmetry.

Organocatalytic strategies for enantioselective metal-free reductions

One of the most important chemical transformations is the reduction of multiple bonds, carbon–carbon as well as carbon–heteroatom double bonds, since it leads very often to the generation of new stereocenters in the molecule. The replacement of metal-based catalysts with equally efficient metal-free counterparts is very appealing in view of possible future applications of non toxic, low cost, and environmentally friendly promoters on an industrial scale. This perspective will focus specially, but not exclusively, on the enantioselective reduction of the carbon nitrogen double bond; despite the historical need for and continued interest in chiral amines, their synthesis remains challenging. Three metal-free catalytic methodologies available for the reduction of carbon–nitrogen double bond will be discussed: i) binaphthol-derived phosphoric acids catalyzed reductions, with dihydropyridine-based compound as the reducing agent; ii) trichlorosilane mediated reductions, in the presence of catalytic amounts of chiral Lewis bases; iii) metal-free hydrogenation of imines through FLP (Frustrated Lewis Pair) methodology, that involves the use of a combination of a strong Lewis acid with a variety of sterically encumbered Lewis bases, for examples phosphines or tertiary amines, to activate hydrogen at ambient conditions. Special attention will be devoted to the most recent applications of the last five years.

Wettability of bare and fluorinated silanes: A combined approach based on surface free energy evaluations and dipole moment calculations

The assessment of the surface free energy (SFE) of a material permits to control and predict a large number of physicochemical properties of a solid surface and its reactivity. Here, the surface energies of a series of bare and fluorinated silanes are determined by means of different semi-empirical models on the grounds of contact angle determinations for different solvents. Literature data are also considered in order to produce a series of films with increasing SFE. Wetting envelopes (WE) are obtained for the various surfaces in order to predict the wettability of the films by numerous commonly employed solvents. The polar and disperse components of the surface energies are obtained by the Owens-Wendt-Rabel-Kaelbe (OWRK) method; the values of the polar components are compared with gas-phase dipole moments obtained by theoretical calculations employing semi-empirical Hamiltonians. The sequences of the polar components of the SFE and of the calculated dipole moments for the different molecules are strictly the same. The interplay between theoretical and experimental approaches proves efficient in predicting the behavior of different systems and it could be employed in tuning the SFE of a solid surface with respect to its final applications.

Modeling ganglioside headgroups by conformational analysis and molecular dynamics

The conformations and dynamics of gangliosides GM1, GM2, 6′-GM2 and GM4 have been studied by computational means, and the results compared to NMR data. Unconstrained conformational searches were run using the AMBER* force field augmented by MNDO derived parameters for the Neu5Ac anomeric torsion, the GB/SA water solvation model, and the MC/EM alogorithm; extended (10–12[emsp4 ]ns) dynamic simulations in GB/SA water were performed with the MC/SD protocol, and the stored structures were minimized. The overall mobility of the Neu5Acα2,3Gal linkage and the position of its minimum energy conformation have been shown to depend mainly on the presence or the absence of a GalNAc residue at the adjacent position. The best quantitative agreement with the available NOE data was achieved after minimization of the structures stored during the MC/SD dynamic runs. The latter protocol appears to reproduce satisfactorily the available experimental data, and can be used with confidence to build three-dimensional models of ganglioside headgroups.

Diastereoselective synthesis of 1,2-diphenyl-1,2-diaminoethanes by Yb(OTf)3 accelerated reductive coupling of imines

Abstract New reaction protocols have been established to perform the reductive coupling of N -benzyl benzaldimines to 1,2-diphenyl-1,2-diaminoethanes in mild, stereoselective, and catalytic conditions by the use of SmI 2 and Yb(OTf) 3 .

Structural Basis for the Resistance of Tay-Sachs Ganglioside GM2 to Enzymatic Degradation

To understand the reason why, in the absence of GM2 activator protein, the GalNAc and the NeuAc in GM2 (GalNAcβ1→4(NeuAcα2→3)Galβ1→4Glcβ1–1′Cer) are refractory to β-hexosaminidase A and sialidase, respectively, we have recently synthesized a linkage analogue of GM2 named 6′GM2 (GalNAcβ1→6(NeuAcα2→3)Galβ1→4Glcβ1–1′Cer). While GM2 has GalNAcβ1→4Gal linkage, 6′-GM2 has GalNAcβ1→6Gal linkage (Ishida, H., Ito, Y., Tanahashi, E., Li, Y.-T., Kiso, M., and Hasegawa, A. (1997) Carbohydr. Res. 302, 223–227). We have studied the enzymatic susceptibilities of GM2 and 6′GM2, as well as that of the oligosaccharides derived from GM2, asialo-GM2 (GalNAcβ1→4Galβ1→ 4Glcβ1–1′Cer) and 6′GM2. In addition, the conformational properties of both GM2 and 6′GM2 were analyzed using NMR spectroscopy and molecular mechanics computation. In sharp contrast to GM2, the GalNAc and the Neu5Ac of 6′GM2 were readily hydrolyzed by β-hexosaminidase A and sialidase, respectively, without GM2 activator. Among the oligosaccharides derived from GM2, asialo-GM2, and 6′GM2, only the oligosaccharide from GM2 was resistant to β-hexosaminidase A. Conformational analyses revealed that while GM2 has a compact and rigid oligosaccharide head group, 6′GM2 has an open spatial arrangement of the sugar units, with the GalNAc and the Neu5Ac freely accessible to external interactions. These results strongly indicate that the resistance of GM2 to enzymatic hydrolysis is because of the specific rigid conformation of the GM2 oligosaccharide.

Stereoselective synthesis of β-lactams by condensation of titanium enolates of 2-pyridyl thioesters with imines bearing a chiral auxiliary

Abstract Several amines have been tested as chiral auxiliaries in the stereoselective synthesis of β-lactams by condensation of the titanium enolates of 2-pyridyl thioesters with chiral imines. The amines were selected among the following classes of compounds: benzylic amines, β-aminoalcohols, β-heterosubstituted α-aminoesters. Inexpensive and available in both enantiomeric forms α-methylbenzylamine was identified as the chiral auxiliary that generally combines good reactivity and satisfactory levels of stereocontrol. To illustrate the potential of the method a precursor of a component of a renin inhibitor was prepared. A tentative rationalization of the stereochemical results is presented.

Electrostatic effects in 1,3-dipolar cycloaddition reactions to chiral allyl ethers: a rationale for the experimentally observed diastereoselectivities

Abstract Semiempirical (PM3) and ab initio (RHF/3-21G) transition structures for 1,3-dipolar cycloadditions of 5 different dipoles to alkenes were analyzed; the differences in 1,3-dipole charge distribution offer a rationale for the different stereoselectivities experimentally observed in the reactions with chiral allyl ethers.

Synthesis of β-lactams by condensation of titanium enolates of 2-pyridylthioesters with imines. Influence of the imine structure on the trans/cis stereoselectivity

Abstract The condensation of the titanium enolates of C-2 alkyl substituted 2-pyridylthioesters with imines affords β-lactams in trans/cis ratios that largely depend on the structure of the C-imine residue. Bulky and non-chelating heteroatom-containing groups lead to the formation of trans β-lactams, while sterically non-requiring or chelating groups favour the formation of the cis-products. On the basis of NMR evidences a rationale is proposed to account for the observed stereoselectivity.