Stefano Valdo Meille

Synthesis of Nonracemic α-Trifluoromethyl α-Amino Acids from Sulfinimines of Trifluoropyruvate

We describe a novel and useful method for the synthesis of nonracemic α-trifluoromethyl α-amino acids (α-Tfm-AAs). Key building blocks are the sulfinimines (S)-1a and (S)-1b, prepared by Staudinger reaction from trifluoropyruvate esters and the chiral N-sulfinyl iminophosphorane (S)-8, which were treated with benzyl, allyl, and alkylmagnesium halides. The resulting diastereomeric N-sulfinyl α-Tfm α-amino esters, 12 and 13, were produced with moderate to good stereoselectivity and yields. When alkyl Grignard reagents were used, stereocontrol became progressively higher with increasing steric bulk, while reversed, though poor, stereocontrol was achieved with benzyl/allyl Grignard reagents. An explanation for the observed stereochemical outcome is proposed, on the basis of the exclusive E geometry (N-sulfinyl and CF3trans about the C=N bond) of the chiral sulfinimines 1. This assignment is the product of structural correlation and is supported by ab initio calculations and NOE experiments. Sulfinamides 12 and 13 were transformed into a series of nonracemic α-Tfm-AAs 16−22. The sulfinyl auxiliary can be regenerated and recycled.

Experimental Evidence for Intramolecular Attractive Nonbonded C–F…H–C Interactions in 2′,3′-Dideoxy-4′-(fluoromethyl)nucleosides – Through-Space JCF and JHF NMR Coupling Constants, Correlation with Empirical Parameters of Solvent Polarity and Single-Crystal X-ray Structures

A collection of 5′-O-benzyl-2′,3′-dideoxy-4′-(fluoromethyl)nucleosides carrying both purinic and pyrimidinic nucleobases (uracil, 5-Br-uracil, 5-O2N-uracil, 6-Cl-purine and inosine) were synthesized in both the α and the β form. Through-space-transmitted 6JCF NMR coupling constants between F and C-6 (pyrimidinic base) or C-8 (purinic base) were observed for all of the α anomers of the compounds examined, whilst the corresponding 7JHF coupling constants were resolved only for the 5-substituted uracil derivatives. The absolute values of all the through-space couplings were found to decrease monotonically with increasing solvent polarity (CDCl3, MeOD, [D6]acetone, [D6]DMSO). This trend suggests that the through-space interaction is mediated by an intramolecular (sp3)C–F…H–C(sp2) hydrogen bond. The possibility of any relevant solvent-induced conformational change influencing the F/base mutual spatial relationship in the molecules investigated was ruled out by heteronuclear steady-state 1H{19F}-NOE experiments. A linear correlation was observed between 6JCF and 7JHF coupling constants and the Kamlet–Tafts hydrogen bond basicity parameter β. The crystal structures of the α and β anomers of the 5-nitrouracil nucleoside show evidence that the H-6 of the nucleobase forms hydrogen-bond-like interactions involving the O-benzyl oxygen atom in the β anomer, and that in the case of the α anomer this is replaced by the F atom of the fluoromethyl group.

Donor–acceptor polythiophene copolymers with tunable acceptor content for photoelectric conversion devices

The synthesis and characterization of a new series of substituted polythiophenes containing an electron acceptor anthraquinone moiety in the side chain are reported. The acceptor molar content was varied by the co-polymerization of both alkylthiophene and thiophene bearing anthraquinone monomers in different ratios. NMR analysis shows a good correlation between the monomer feed composition at the beginning of the polymerization and the actual unit composition of the backbone. The conjugation length and the chemical composition of the copolymers as a function of the molecular weight have been studied by size exclusion chromatography. Small angle X-ray scattering and UV-Vis absorption spectra have been used to monitor the degree of order and chain organization in the solid state. The materials exhibit a lamellar organization, in which the anthraquinone units of neighboring side chains are also organized to some degree in layered structures parallel to the polythiophene main chains. The photoluminescence measurements in solution suggest that, upon photoexcitation of the polythiophene backbone, the anthraquinone moieties act as electron acceptors and the conjugated backbone as electron donor. The tunability of the donor–acceptor ratio and the morphology in the solid state make these photoactive copolymers interesting candidates for organic photoelectric conversion devices.

Crystallographic and nuclear magnetic resonance studies of carbonyl(η3-methylallyl)(trichlorostannyl) complexes of platinum(II) and palladium(II)

The complexes [M(η3-C4H7)(SnCl3)(CO)][C4H7= 2-methylallyl, M = Pt(1) or Pd(2)] have been prepared and characterized. Their solution behaviour has been studied by n.m.r. spectroscopy, the compounds being dynamic through dissociation of the CO ligand. The X-ray structures of (1) and (2) are reported. Complex (2) is the first mononuclear palladium carbonyl to be characterized by X-ray diffraction. The different stabilities of the two isostructural complexes are correlated with the subtle differences in bonding observed in the crystal structures.

N-Cbz-Trifluoropyruvaldehyde N,S-ketal: Absolute stereochemistry and addition of Grignard reagents. Highly stereoselective entry to trifluoro analogues of Ephedra alkaloids

Abstract The chiral non racemic N -Cbz-trifluoropyruvaldehyde- N , S -ketal 1a (enantiomeric excess up to 74%) is a new trifluoro 3-C building block, which has been reacted with several Grignard reagents, stereoselectively affording the corresponding secondary carbinols 2 . The N , S -ketal stereocentre, whose absolute stereochemistry has been determined by X-ray analysis of the α-phenylpropionate 3 , is able to provide excellent stereocontrol. Highly stereoselective p -tolylthio group displacement afforded the N -Cbz-phenyl derivative 2d , transformed into trifluoro-norephedrine (S,S)- 5 and -ephedrine (S,S)- 6 .

Palladium(II) and platinum(II)η3-methylallyl trichlorotin complexes. Part 3. Crystal structure analysis of [Pt(η3-C4H7)(cod)]2[Pt(η3-C4H7)(SnCl3)3](cod = cyclo-octa-1,5-diene)

The dimer [{Pt(η3-C4H7)Cl}2] reacts with cyclo-octa-1,5-diene (cod) and SnCl2 to give [Pt(η3-C4H7)(cod)]2[Pt(η3-C4H7)(SnCl3)3](1). The compound crystallizes as discrete anionic and cationic platinum(II) complexes in space group P with a= 13.256(4), b= 19.960(4), c= 8.615(3)A, α= 101.75(2), β= 104.69(2), and γ= 86.62(2)°. The anionic complex displays a distorted square-pyramidal co-ordination while the two isostructural cations have irregular square-planar co-ordination. Analysis of bond distances using SnCl3 as a probe suggests that the trans influence of the methylallyl ligand is comparable to that of olefin ligands. While no n.m.r. data are available for (1) due to its very poor solubility, n.m.r. results for the palladium(II) analogue (2) obtained by the same synthetic route are compatible with the structure determined for (1).

Chrysanthone, a bioactive alkaloid from Ascochyta chrysanthemi

Abstract The structure and relative configuration of chrysanthone, a new isoquinoline alkaloid isolated from a culture of Ascochyta chrysanthemi , have been elucidated on the basis of X-ray analysis and NMR evidence.

Unusual nonchelation controlled allylation of a N-monoprotected α-amino aldehyde: stereoselective entry to nonracemic trifluoromethyl dipeptide isosteres

Abstract An efficient synthesis of the non-racemic (66–68% e.e.) homoallylic β-trifluoromethyl β-amino alcohol (2S,3R)-9, a key intermediate in the synthesis of trifluoromethylated dipeptide isosteres and oligopeptides, was developed starting from N-Cbz-trifluoropyruvaldehyde-N,S-ketal (R)-1a. The correct syn-stereochemistry was achieved by combining two moderately stereoselective steps: (1) addition of allylmagnesium chloride to (R)-1a, occurring with unusual nonchelation control; (2) reductive desulfenylation of the phenylacetate 6 with NaBH4/pyridine.

Synthesis of (−)-(1S,5R)- and (+)-(1R,5S)-trifluoroanalogues of frontalin

Abstract The synthesis of enantiomerically pure (−)-(1 S ,5 R )-1-trifluoromethyl frontalin 7 starting from (−)-(1 R )-menthyl ( S )-toluene-4-sulfinate, 5-pentenylmagnesium bromide and methyl trifluoroacetate is described. The synthetic procedures to obtain the enantiomer (+)-(1 R ,5 S )- 7 are also mentioned. Absolute stereochemistry was unambiguously assigned by X-ray analysis of intermediates 3 and 5 .

Crystalline organization and bonding of N-perfluoroacylpyridiniumaminides

Abstract N -Perfluoroacylpyridiniumaminides are stable crystalline solids characterized by a potentially useful set of properties. The molecular geometries resulting from the determination of the crystal structures of three members of the series suggest that, due to the presence of the perfluoroalky chains, the electron density on the formally negatively charged nitrogen of the ylide system is reduced. The N–N and the OC–N bonds in the systems are shortened and the whole molecules are stabilized as compared to non-fluorinated N -alkanoylpyridiniumaminides. The packing in the crystals can be qualitatively understood as a compromise between two distinct effects: 1. the tendency to segregate, of the fluorocarbon groups on one hand and the bipyridinium blocks on the other, as in the case of 4b or c , 2. the formation of weak interactions involving the pyridinium hydrogens and the most effective hydrogen bond accepting atoms (i.e. O and N). nThe latter effect leads to disorder of the perfluoroalkyl chains in 4a . In 4b and c , even at room temperature, a surprisingly ordered arrangement of the segregated perfluoropropyl chains is observed, showing a clear tendency to helicoidal conformation related to fluorine–fluorine repulsion.