NH-sulfoximines are emerging as useful and important targets in drug discovery and synthetic organic chemistry. We report herein the development of an efficient, convenient, and sustainable continuous-flow strategy, for the direct, straightforward preparation of NH-sulfoximines by using sulfides or sulfoxides as suitable starting material. The flow process uses PhI(OAc)2 as the oxidant and aqueous solutions of ammonia as the N source. The scope of the reaction has been demonstrated by using several substituted sulfides and sulfoxides including enantioenriched and biologically relevant starting materials. The flow strategy was found to be more convenient with respect to conventional batch processing.

Pentafluorobenzyl pentafluorophenyl sulfide is oxidised with moderate e.e. value and a low yield by the usually highly successful oxidation protocol based upon tert-butyl hydroperoxide (TBHP) in the presence of a titanium/hydrobenzoin complex. This disappointing result resisted until the present work, in which the switch of the oxidation agent (from TBHP to cumene hydroperoxide), suggested by our previous computations, yielded the enantiopure sulfoxide. This valuable chiral compound was obtained in good yields (76%) without resorting to a chromatographic separation. DFT computations uncovered that this favourable reactivity was originated by a stabilizing ?-?-stacking between the phenyl group of the oxidant and the pentafluorophenyl moiety of the substrate.

A series of experiments was performed to test a theoretical model that we have recently proposed to explain the highly enantioselective oxidation of aryl benzyl sulfides with tert-butyl hydroperoxide in the presence of a complex between titanium and (S,S)- or (R,R)-hydrobenzoin. The studied variations involved the sulfides, the ligands, and the order of addition of reactants. The reaction path predicted by our model was confirmed in every experiment. In particular, aryl benzyl sulfides behaved as the ideal substrate for this type of asymmetric oxidation, which yields synthetically useful, enantiopure aryl benzyl sulfoxides in a straightforward manner. The theoretical model of the enantioselective oxidation of aryl benzyl sulfides in the presence of chiral titanium catalysts was tested with a series of experiments in which the reagents and conditions were varied. It was confirmed that aryl benzyl sulfides are an ideal substrate for this oxidation protocol, which yields the synthetically useful chiral non-racemic aryl benzyl sulfoxides. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The crystal structures of (S, S)-aminobenzylnaphthols, easily produced by a chromatography-freehighly stereoselective Betti reaction, were investigated by means of single crystal X-ray diffractionanalysis, and the main intra- and intermolecular interactions were described. The presence of a strongintramolecular hydrogen bond was confirmed, whereas the whole crystal building was found to bedue mainly to other bondings, such as CH...O and CH...p interactions. As far as the last interactionswere 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 suggestthat these interactions can play a relevant role in the crystal building. The absence of similar shortdistance CH...p interactions in the crystal of a diastereomeric (R, S)-aminobenzylnaphthol could be asuggestion of the preferential crystallisation of the (S, S)-stereoisomer and, consequently, itsprevalence as a product of the Betti reaction.

Regio- and stereo-selective reduction of substituted 1,3-aryldiketones, investigated in the presence of different whole cell microorganisms, was found to afford ?-hydroxyketones or 1,3-diols in very good yields (up to 95%) and enantiomeric excesses (up to 96%). The enantiomerically enriched aldols, obtained with the opposite stereo-preference by baker's yeast and Lactobacillus reuteri DSM 20016 bioreduction, could then be diastereoselectively transformed into optically active syn- or anti-1,3-diols by a careful choice of the chemical reducing agent (diastereomeric ratio up to 98:2). The latter, in turn, were stereospecifically cyclized into the corresponding oxetanes in 43-98% yields and in up to 94% ee, thereby giving a diverse selection of stereo-defined 2,4-disubstituted aryloxetanes.

Chiral nonracemic aminobenzylnaphthols were obtained by a Betti multicomponent 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 ?g/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. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

A series of ten chiral aryl benzyl sulfoxides with perfluorinated aryl or benzyl rings, obtained by enantioselective oxidation of sulfides, has been investigated by means of electronic circular dichroism (ECD) spectroscopy and time-dependent DFT (TDDFT) calculations. The (per)fluorination of the aromatic rings has a large impact on the conformer population, the molecular orbitals shape, and the character of electronic transitions. In this series, the transition responsible for the sulfoxide primary CD band has a large charge transfer (CT) character, as demonstrated by the CT metric index (NTO). As a consequence, global DFT hybrids such as B3LYP are largely inaccurate in the prediction of excited states; nevertheless, a correct simulation of CD spectra may be achieved by using range-separated functionals such as CAM-B3LYP. The use of the empirical Mislow's rule for assigning the absolute configuration is strongly discouraged for this class of compounds.

Enantiopure aryl benzyl sulfoxides were easily obtained by an enantioselective oxidation of the corresponding sulfides with tert-butyl hydroperoxide in the presence of a complex between titanium and (S, S)-or (R, R)-hydrobenzoin. Theoretical and experimental investigations confirmed that these aryl benzyl sulfides represent an ideal substrate for the asymmetric oxidation system. Copyright © Taylor and Francis Group, LLC.

The Betti reaction is a straightforward three components condensation of 2-naphthol, an aryl aldehyde and an amine, that yield easily an aminobenzylnaphthol [1].In previous work, we investigated the intermolecular interactions in the crystal structures of chiral aminobenzylnaphthols synthesized with this procedure [2]. The crystal packings of some cyclic phosphorus derivatives of these intermediates were also investigated [3].The most peculiar interactions that we observed in all these molecules were many short distance CH···? interactions [2]. Moreover, we observed that the use of different p-halobenzaldehydes (X = F, Cl, Br) in the Betti reaction yielded almost isostructural aminobenzylnaphthols [2].Now, we wish to report our investigation on the crystal packings of newly synthesized aminobenzylnaphthols deriving from a Betti reaction of 2-naphthol, aryl aldehydes and valine methyl ester (Scheme 1). Significant differences with our previous work were observed mainly due to the presence of a further hydrogen bonding acceptor in the molecules (the carbonyl oxygen atom of the valine moiety).Furthermore, we observed that different para-substitutions on the starting aryl aldehyde yielded crystal structures having different packings and new intermolecular interactions.

Our sequential coupling of Grignard reagents with suitable sulfinyl compounds involving the displacement of carbanionic leaving groups is now a well established procedure1 for the synthesis of enantiopure sulfoxides.After our synthetic and mechanistic investigation on the straightforward synthesis of selected sulfinyl precursors through a highly enantioselective oxidation of the sulfides with hydroperoxide in the presence of a complex between titanium and hydrobenzoin, more than 40 enantiopure aryl benzyl sulfoxides are now easily available as starting materials.2 Thus, we decided to give a deep insight into the reaction of organometallic reagents with the enantiopure items of this chemical library.We found that the nucleofugality of the leaving groups, and the order in the sequence of substitution, can be tuned by choosing the aryl benzyl sulfoxide that bears appropriate substituents on both the phenyl groups.We report now that the nucleofugality of the carbanionic leaving groups can be predicted by comparing analogous NMR chemical shifts of signals of the starting sulfoxides. The agreement between the experimental results and the expectations will be briefly surveyed.

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···? interactions and weak forms of ntermolecular 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.

Three beta-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 ?-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 multi-component Betti reaction of 2-naphthol, benzaldehyde and (S)-amines, that usually provides highly valuable aminobenzylnaphthol bearing two stereogenic centers, yielded a completely racemic product, when (S)-valine methyl ester was employed as the amine in the usual reaction protocol. The cause of this drawback, that appears to be overlooked in the literature, was investigated. As a result, new reaction conditions were set up, that were able to yield the expected useful product, having two fully resolved stereogenic centers. Furthermore, when the effect of substituents on the phenyl ring was preliminarily studied, we found that 4-fluoro- and 4-chlorobenzaldeyde gave stereoisomerically pure compounds also in the original reaction protocol.

A two-step stereoselective chemoenzymatic synthesis of optically active ?-aryl-substituted oxygen heterocycles was developed, exploiting a whole-cell mediated asymmetric reduction of ?-, ? -, and ? -chloroalkyl arylketones followed by a stereospecific cyclization of the corresponding chlorohydrins into the target heterocycles. Among the various whole cells screened (baker's yeast, Kluyveromyces marxianus CBS 6556, Saccharomyces cerevisiae CBS 7336, Lactobacillus reuteri DSM 20016), baker's yeast was the one providing the best yields and the highest enantiomeric ratios (up to 95:5 er) in the bioreduction of the above ketones. The obtained optically active chlorohydrins could be almost quantitatively cyclized in a basic medium into the corresponding ?-aryl-substituted cyclic ethers without any erosion of their enantiomeric integrity. In this respect, valuable, chiral non-racemic functionalized oxygen containing heterocycles (e.g., (S)-styrene oxide, (S)-2-phenyloxetane, (S)-2-phenyltetrahydrofuran), amenable to be further elaborated on, can be smoothly and successfully generated from their prochiral precursors.

A series of 13 enantiopure aryl benzyl sulfoxides (1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m) with different substituents on the two aromatic rings has been previously analyzed by means of electronic circular dichroism (CD) spectroscopy. Most of these compounds are crystalline and their X-ray structure is established. For almost one-half of the series, CD spectra measured in the solid state were quite different from those in acetonitrile solution. We demonstrate that the difference is due to strong exciton couplings between molecules packed closely together in the crystal. The computational approach consists of time-dependent density functional theory (TDDFT) calculations run on "dimers" composed of nearest neighbors found in the lattice. Solid-state CD spectra are well reproduced by the average of all possible pairwise terms. The relation between the crystal space group and conformation, and the appearance of solid-state CD spectra, is also discussed. Chirality 26:102-110, 2013. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Aminobenzylnaphthols are a class of compounds containing a large aromatic molecular surface which makes them suitable candidates to study the role of C--H···pi interactions. We have investigated the effect of methyl or methoxy substituents on the assembling of aromatic units by preparing and determining the crystal structures of (S,S)-1-{(4-methylphenyl)[(1-phenylethyl)amino]methyl}-naphthalen-2-ol, C26H25NO, and (S,S)-1-{(4-methoxyphenyl)[(1-phenylethyl)-amino]methyl}naphthalen-2-ol, C26H25NO2. The methyl group influenced theoverall crystal packing even if the H atoms of the methyl group did not participate directly either in hydrogen bonding or C--H ···pi interactions. The introduction of the methoxy moiety caused the formation of new hydrogen bonds, in which the O atom of the methoxy group was directly involved. Moreover, the methoxy group promoted the formation of an interesting C--H ···pi interaction which altered the orientation of an aromatic unit.

A series of enantiopure crystalline aryl benzyl sulfoxides, bearing different substituents on both the aryl groups, were synthesized by an enantioselective oxidation of the corresponding sulfides. Structural investigations, achieved by means of single-crystal X-ray diffraction, allowed us to recognize the main assembling interactions. The same procedure was repeated for some corresponding fluorinated aryl benzyl sulfoxides. The synthesis of the enantiomers of a new fluorinated compound, which shows unusual structural patterns, prompted us to compare the structural motifs of the two families of sulfoxides (fluorinated and unfluorinated) and to investigate the changes due to the fluorine substitution. Some short contacts involving the fluorine atom were discussed in more details, taking into account the recent interest in these sometimes controversial interactions. (Chemical Equation Presented).

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 Mislow's 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.

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. © 2013 Taylor & Francis.

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 similaramounts. 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.

After the discovery of a few cases of lower enantioselectivity in the oxidation of aryl benzyl sulfides with hydroperoxides in the presence of a complex between titanium isopropoxide and (S, S)-hydrobenzoin, a screening of the oxidation of new substrates that are related to the structures that gave low ee values, was performed. From this screening, we confirmed that only a few sulfides remain as exceptions within a framework of exceptionally high stereoselectivity of the oxidation reaction. Moreover, the exceptions are clearly identified and are connected to particular coordinating moieties present on the aryl groups. (C) 2015 Elsevier Ltd. All rights reserved,

In this contribution, we report the first successful baker's yeast reduction of arylpropanones using deep eutectic solvents (DESs) as biodegradable and non-hazardous co-solvents. The nature of DES [e.g. choline chloride/glycerol (2:1)] and the percentage of water in the mixture proved to be critical for both the reversal of selectivity and to achieve high enantioselectivity on going from pure water (up to 98:2 er in favour of the S-enantiomer) to DES/aqueous mixtures (up to 98:2 er in favour of the R-enantiomer). As a result, both enantiomers of valuable chiral alcohols of pharmaceutical interest were prepared from the same biocatalyst by simply switching the solvent. The possible inhibition of some (S)-oxidoreductases making part of the genome of such a wild-type whole cell biocatalyst when DESs are used as co-solvents may pave the way for an anti-Prelog reduction. The scope and limitations of this kind of biotransformations for a range of aryl-containing ketones are also discussed. (Figure presented.).