Maria Annunziata M. Capozzi

Systematic investigation of CD spectra of aryl benzyl sulfoxides interpreted by means of TDDFT calculations.

The CD spectra of 13 crystalline aryl benzyl sulfoxides 1a-m with various substituents on the two aromatic rings were recorded in solution and in the solid state. Solution CD spectra were very homogeneous along the series, consisting in most cases of a couplet-like feature in the 200-300 nm region. The red-shifted component of the couplet, corresponding to the sulfoxide-centered n-pi* transition, is always positive for (R) absolute configuration in accordance with Mislows rule. The presence of a strong electron-withdrawing substituent on the phenyl ring (nitro or ester group) alters the shape of the CD spectrum. CD calculations using the TDDFT method were run for eight representative compounds using DFT-optimized geometries. In all cases, calculated spectra were in very good agreement with experimental ones and allowed for rationalization of the diverse spectral behaviors. It is demonstrated that TDDFT//DFT calculations represent a reliable option for assigning the absolute configuration of this class of compounds whenever crystals suitable for X-ray are not available. Solid-state CD spectra recorded with the KCl pellet technique were in some cases in agreement with those in solution. However, in other cases new and strong CD signals appeared which were interpreted as being due to intermolecular couplings in the crystals.

A combined theoretical and experimental investigation on the enantioselective oxidation of aryl benzyl sulfides in the presence of a chiral titanium catalyst.

An experimental investigation of the enantioselective oxidation of aryl benzyl sulfides by tert-butyl hydroperoxide in the presence of a titanium/hydrobenzoin catalyst has shown that these sulfides are ideal substrates for this catalytic system, with negligible interference by the substituents on the aryl groups. A reaction mechanism based on DFT computations has been proposed. The DFT MPWB1K functional was used in the theoretical investigation to account for weak hydrogen-bonding and pi interactions. The computed reaction profile explains the experimentally observed enantioselectivity, which is determined by the thermodynamics of the first phase of the reaction. A detailed discussion of the hydrogen-bonding and pi interactions that drive the reaction along the observed stereochemical path is given.

Self-assemblies of chiral p-haloaryl sulfoxides through C–H⋯O short contacts and halogen involving interactions

Single crystal X-ray structure determination of four crystals of alkyl or aryl p-haloaryl sulfoxides is reported. Intramolecular short contacts between the ortho-hydrogen of the aryl ring and the oxygen of the sulfinyl group were found to determine the conformations of the sulfoxides. On the other hand, in the absence of classical hydrogen bond donors, crystal packing arrangements are the results of intermolecular aryl hydrogen–oxygen short contacts and of interactions involving halogen atoms. From a comparison of the structures of the investigated sulfoxides with other literature data, the crystal packings of these types of compound appear to derive from a complex balance among different interactions.

Investigation on the weak interactions assembling the crystal structures of Betti bases

The crystal structures of (S, S)-aminobenzylnaphthols, easily produced by a chromatography-free highly stereoselective Betti reaction, were investigated by means of single crystal X-ray diffraction analysis, and the main intra- and intermolecular interactions were described. The presence of a strong intramolecular hydrogen bond was confirmed, whereas the whole crystal building was found to be due mainly to other bondings, such as CH⋯O and CH⋯π interactions. As far as the last interactions were concerned, we observed many short distances from one hydrogen atom to an aryl plane, together with the appropriate geometric requirements for the assemblies. The observations suggest that these interactions can play a relevant role in the crystal building. The absence of similar short distance CH⋯π interactions in the crystal of a diastereomeric (R, S)-aminobenzylnaphthol could be a suggestion of the preferential crystallisation of the (S, S)-stereoisomer and, consequently, its prevalence as a product of the Betti reaction.

The Effect of the Fluorine Substitution on the Enantioselective Oxidation of Sulfides with Chiral Titanium Catalysts: A Combined Computational and Experimental Investigation

The results of a combined computational‐experimental study of the oxidation of various fluorinated aryl benzyl sulfides using tert‐butyl hydroperoxide (TBHP) in the presence of a complex of titanium and (S,S)‐hydrobenzoin are presented. As observed in previous studies for other aryl benzyl sulfides, the reaction leads to enantiopure sulfoxides (ee>98 %) in good isolated yields (81–96 %) except the case of pentafluorobenzyl pentafluorophenyl sulfide for which a lower ee (61 %) is observed. DFT computations on a model‐system formed by the substrate, the oxidant TBHP and the [(S,S)‐hydrobenzoin]2‐Ti complex satisfactorily explain this unexpected item. The enantioselectivity is governed by the relative energy of the two diastereomeric octahedral complexes that form if TBHP approaches the initial complex between substrate and [(S,S)‐hydrobenzoin]2‐Ti before the oxygen transfer. For pentafluorobenzyl pentafluorophenyl sulfide, the two octahedral complexes are almost degenerate and, thus, they form in similar amounts. As the two corresponding diastereomeric transition states are similar in energy, the probability to follow one or the other diastereomeric reaction channel becomes comparable, which leads to the lower enantiomeric excess experimentally observed. Our computations indicate that the particular “folded conformation”, adopted by the substrate only if both phenyl rings are fluorinated, is the key factor that determines the near degeneracy of the two diastereomeric octahedral complexes.

Enantioselective Routes to Sulfoxides Based upon Carbon-for-Carbon Substitution Reactions on the Sulfinyl Group

Abstract Grignard reagents were found to displace carbanionic leaving groups from suitable sulfinyl compounds. Because the process occurred with full inversion at the sulfinyl group, it was possible to set up an easy and straightforward route to chiral nonracemic sulfoxides. The starting compounds were easily produced, mainly by enantioselective oxidation of prochiral sulfides, and then the carbon-for-carbon displacement was effected with formation of a variety of new enantiopure sulfoxides.

Stacked naphthyls and weak hydrogen-bond interactions govern the conformational behavior of P-resolved cyclic phosphonamides: a combined experimental and computational study.

P-Enantiomerically pure cyclic phosphonamides have been synthesized via a cyclization reaction of (S,S)-aminobenzylnaphthols with chloromethylphosphonic dichloride. The reaction is highly stereoselective and gives almost exclusively (S,S,SP)-cyclic phosphonamides in good yields. Analysis of the X-ray crystal structures shows clearly that the cyclization reaction forces the two naphthyl rings into a stable parallel displaced stacking assembly and indicates also the existence of intramolecular CH···π interactions and weak forms of intermolecular hydrogen bondings, involving the oxygen and the chlorine atoms. QM computations and NMR spectra in solution confirm the stacked molecular assembly as the preferred arrangement of the two naphthyl groups.

Stereochemical analysis of β-keto sulfoxides by circular dichroism

Three β-keto sulfoxides (1-3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.

The effect of nitrogen atoms in the enantioselective oxidation of aryl or heteroaryl benzyl sulfides

Some aminophenyl benzyl sulfides or benzyl pyridyl sulfides were asymmetrically oxidized with tert-butyl hydroperoxide in the presence of a complex between titanium i-propoxide and (S, S)-hydrobenzoin, an oxidation system that works particularly well with a vast set of aryl benzyl sulfides. Notwithstanding the presence of nitrogen-containing moieties that, in principle, could interfere with the correct co-ordination of the sulfide to the metal center, satisfactory levels of enantioselectivity (up to 78%) were measured for this oxidation process. GRAPHICAL ABSTRACT

Bioactivity of a family of chiral nonracemic aminobenzylnaphthols towards Candida albicans.

Chiral nonracemic aminobenzylnaphthols were obtained by a Betti multi-component reaction between 2-naphthol, aryl aldehydes and enantiopure arylethylamine. Moreover, some new aminobenzylnaphthols were synthesized by a similar reaction between 2-naphthol, aryl aldehydes and prolinol. These aminobenzylnaphthols, synthesized from different components and thus having different structural features, were tested as anti-yeast agents inhibiting Candida albicans. The effect towards the test strain was studied with a microdilution approach and three different concentrations (150, 300 and 450 µg/mL) were tested. The best results were found for the aminobenzylnaphthols obtained from 1-naphthylethylamine and from natural prolinol. The use of the two-way ANOVA highlighted the better performances of the prolinol derivative among the differently structured aminobenzylnaphthols that were screened. The activity towards C. albicans of this prolinol derivative resulted to be interesting and could represent a promising alternative to overcome the problem of the strains resistant to the traditional antifungals.