Ferrocenes with simple chiral substituents: an in-depth theoretical and experimental VCD and ECD study.

Circular dichroism spectra in the IR range (VCD = vibrational circular dichroism) and in the UV range (ECD = electronic circular dichroism) have been recorded for both enantiomers of simple mono-substituted ferrocenes containing chiral pendants: 1-acetoxyethylferrocene, 1, 1-methoxyethylferrocene, 2, and 1-hydroxyethylferrocene, 3; the related disubstituted 1,1'-bis(1-hydroxyethyl)ferrocene, 4, was also considered. These two types of spectra, with the support of DFT calculations, concur to unequivocally confirm the absolute configuration for 1-4. In particular, our computational results point out the clear advantage of using an anharmonic oscillator model for the interpretation of VCD spectra of chiral ferrocenes. Interesting conformational properties are either confirmed or established by the technique, like the eclipsed conformation of the two cyclopentadienyl rings and an intra-molecular interaction involving the OH for 3. For 4, NMR, VCD and IR spectra are compatible with dimer formation and in this case a distorted conformation is predicted. Of utmost importance for the absolute configuration assignment in mono-substituted ferrocenes, we were able to identify a diagnostic VCD band at 950 cm-1 and a (low intensity) ECD band that clearly indicate the absolute configuration of the whole series.

Enantioseparation of aldols by high-performance liquid chromatography on polysaccharide-based chiral stationary phases that bear chlorinated substituents.

Two families of aldols, obtained from the condensation of aromatic aldehydes with cyclohexanone or acetone (ten examples in each group), were analyzed by high-performance liquid chromatography in normal phase elution mode on three polysaccharide-based chiral stationary phases of the Lux series, namely, Lux Cellulose-2, Lux Cellulose-4 and Lux Amylose-2, which share the common feature of chlorinated substituents in the chiral selectors. Following simple optimization steps, the enantioseparation of all aldols derived from cyclohexanone was achieved and the highest values of separation factor (α, 1.32 < α < 2.20) and resolution (Rs , 4.5 < Rs <17.2) were observed on Lux Cellulose-2, with the only exception of the 4-nitro-substituted derivative that was better resolved on Lux Cellulose-4. On the contrary, Lux Amylose-2 was the best choice for aldols derived from acetone and only specific analytes in this group were resolved on the cellulose-based supports. A variable-temperature study of selected compounds allowed us to determine thermodynamic parameters of the enantioseparation process, which was enthalpy-controlled in all the cases except one.

A novel cationic ß-cyclodextrin decorated with a choline-like pendant exhibits Iodophor, Mucoadhesive and bactericidal properties.

Iodine is a vital microelement and a powerful antiseptic with a rapid and broad spectrum of action. The development of iodophor compounds to improve the solubility and stability of iodine is still challenging. Here, we report the synthesis of a novel cationic ß-cyclodextrin bearing a choline-like pendant (ß-CD-Chol) designed to complex and deliver iodine to bacterial cells. The characterization of ß-CD-Chol and the investigation of the inclusion complex with iodine were performed by NMR spectroscopy, mass spectrometry, UV-vis spectrophotometry, isothermal titration calorimetry, and dynamic light scattering. The functionalization with the positively charged unit conferred improved water-solubility, mucoadhesivity, and iodine complexation efficiency to the ß-CD scaffold. The water-soluble ß-CD-Chol/iodine complex efficiently formed both in solution and by solid-vapor reaction. The solid complex exhibited a significant stability for months. Iodine release from the inclusion complex was satisfactory and the bactericidal activity was proved against a Staphylococcus epidermidis strain. The absence of cytotoxicity tested on human keratinocytes and the improved mucoadhesivity make ß-CD-Chol a promising drug delivery system and an appealing iodophor candidate for iodine-based antisepsis including mucosa disinfection.

Spectroscopic investigation on 1,2-substituted ferrocenes with only planar chirality: How chiroptical data are related to absolute configuration and to substituents.

Single enantiomers of three 1,2-substituted ferrocene derivatives, i.e. 1-methoxymethyl-2-hydroxymethylferrocene (1), 1-formyl-2-hydroxymethylferrocene (2) and 1-iodo-2-hydroxymethylferrocene (3), sharing the common hydroxymethyl substituent and the presence of planar chirality only, were investigated for their spectroscopic (IR and UV) and chiroptical (VCD and ECD) properties. Both enantiomers of 1 were obtained for the first time in optically pure form by lipase-catalyzed kinetic resolution of the corresponding racemate (±)-1 and separately converted into formyl derivatives (+)-2 and (-)-2. The experimental spectroscopic and chiroptical data were compared with DFT calculated spectra and excellent correspondence was found for all compounds, allowing one to confirm the previously assigned absolute configurations. The common features in the VCD spectra of a doublet between 940 and 965 cm-1 and the short-wavelength (about 200 nm) doublet and the longest wavelength band in the ECD spectra were analyzed to test whether they may be taken as markers of the absolute configuration (AC). The predominance of conformers with intramolecular hydrogen bond for the first two investigated compounds is predicted by conformational analysis and also confirmed by NMR.

Synthesis and characterization of some chiral metal-salen complexes bearing a ferrocenophane substituent.

The C(2)-symmetrical "salen" ligand (+)-9 bearing two [5]ferrocenophane substituents has been prepared in five steps starting from readily available diacetylferrocene, p-hydroxybenzaldehyde and (R,R)-N,N'-diphenylethylenediamine. Reaction of (+)-9 with Mn(OAc)(3), Co(OAc)(2) ZnEt(2) or UO(2)(OAc)(2) gave the corresponding metal-complexes which were characterised by spectroscopic methods.

Synthesis and physico-chemical characterization of a ß-cyclodextrin conjugate for sustained release of Acyclovir.

We report the synthesis of an oligomeric prodrug of the antiviral agent Acyclovir (Acy) conjugated to ß-cyclodextrin (ß-CyD). The drug was selectively linked through a succinic spacer to one of the primary hydroxyl groups of ß-CyD by ester linkage in a 1:1 molar ratio. The conjugate was purified by semipreparative reverse-phase chromatography and characterized by FAB mass spectrometry and NMR experiments. The release of Acy from the conjugate was evaluated both in acidic and in neutral conditions and in the presence of porcine liver esterase. In all cases we observed the release of both free Acy and Acy succinate (AcySucc) at differing rates as a function of the hydrolysis conditions. In the presence of esterase the release of free Acy was favoured over AcySucc, showing a release rate of 100% of Acy within 7 days.

Molecular Recognition of Amino Acids by Copper(II) Complexes of 6(A),6(X)-Diamino-6(A),6(X)-dideoxy-beta-cyclodextrin (X = B, C, D).

The three regioisomers of beta-cyclodextrin 6-difunctionalized with NH(2) groups (6(A),6(X)-diamino-6(A),6(X)-dideoxy-beta-cyclodextrin, A,X-CDNH(2), X = B, C, or D) were synthesized. Their binary and ternary copper(II) complexes with amino acids were characterized by ESR and electronic spectroscopy. Furthermore, the binary copper(II) complexes were used as eluent in ligand exchange chromatography (LEC), to resolve racemates of unmodified amino acids. HPLC separation of enantiomers of aromatic amino acids was obtained only when the complex [Cu(A,B-CDNH(2))](2+) was used as eluent. The two complexes with the other two regioisomers did not show chiral recognition ability. Circular dichroism (c.d.) spectroscopy studies of the ternary complexes with D- and L-amino acids carried out in the presence and in the absence of 1-adamantanol, suggested a recognition mechanism that involves the cyclodextrin cavity, only in the case of ternary A,B-CDNH(2) complexes.

Chiral HPLC analysis of milnacipran and its FMOC-derivative on cellulose-based stationary phases.

The HPLC enantioseparation of the last generation antidepressive drug milnacipran (+/-)-1 was investigated on different cellulose-based chiral stationary phases (CSPs). On carbamate-type columns, Chiralcel OD and OD-H (+/-)-1 could be separated with alpha value about 1.20 but the resolution was quite low because of the tailing of the peaks. Direct determination of (+/-)-1 with high selectivity and resolution was obtained on Chiralcel OJ in normal phase mode elution. Precolumn derivatization of milnacipran with Fmoc-Cl gave compound (+/-)-2 which was enantioseparated on all the investigated CSPs and allowed enhanced UV or fluorimetric detection. The Chiralpak IB, that could be considered the immobilized version of Chiralcel OD-H, was found completely ineffective in the chiral recognition of (+/-)-1 and moderately efficient in the separation of (+/-)-2.

Comparative HPLC enantioseparation of ferrocenylalcohols on two cellulose-based chiral stationary phases.

The direct HPLC enantiomeric separation of several ferrocenylalcohols on the commercially available Chiralcel OD and Chiralcel OJ columns has been evaluated in normal-phase mode. Almost all the compounds were resolved on one or both chiral stationary phases (CSPs) with separation factor (alpha) ranging from 1.06 to 2.88 while the resolution (R(s)) varied from 0.63 to 12.70 In the separation of the alpha-ferrocenylalcohols 1a-e and the phenyl analogues 2a-e, which were all resolved except 1c, a similar trend in the retention behavior for the two series of alcohols was evidenced and the selectivity was roughly complementary on the two investigated CSP. For three ferrocenylacohols, chosen as model compounds, the influence of the mobile phase composition and temperature on the enantioseparation were investigated and additional information on the chiral recognition mechanism were deduced from the chromatographic behavior of their acetylderivatives.

Preparation of a chiral ferrocenyl derivative containing a biphenyl unit via nickel-mediated homocoupling.

Ferrocenyl derivative 2, which possesses a biphenyl unit, was prepared by nickel(0)-mediated homocoupling of a chiral ferrocenyloxazoline. Compound 2 exists as an equilibrium mixture of two diastereomers, in a ratio dependent on temperature and solvent, due to the partially hindered rotation around biaryl bond. Upon complexation with Cu(I) or Zn(II), complete fixation of the stereogenic axis was obtained and a single stable atropoisomer was formed, whose absolute configuration was assigned on the basis of its NOESY spectrum. The 2-Cu(I) complex was used as catalyst in the cyclopropanation of styrene.