Patrizia Scafato

A chemical/computational approach to the determination of absolute configuration of flexible and transparent molecules: aliphatic diols as a case study.

By reacting flexible and optically transparent in UV-vis molecules such as 1,2-, syn- and anti-1,3-diols, 1,3-sulfanylalcohols of known absolute configuration (AC) with fluorenone dimethyl acetal, the corresponding ketals are obtained. They are conformationally well-defined (only one conformer in most cases) compounds exhibiting medium-high optical rotation (OR) values, which are independent of the solvent, and electronic circular dichroism (ECD) spectra, which show several (up to five) Cotton effects in the 350-200 nm range due to valence shell pi-->pi* transitions. These features allow simulation of the chiroptical properties of these compounds at the TDDFT/B3LYP/6-31G* level of theory to obtain, using the known ACs of these compounds, a satisfactory reproduction of the OR values (sign and order of magnitude; quantitatively, the predicted values are twice the experimental ones), and a more than satisfactory reproduction of the ECD spectra (sign, intensity, and position of the lowest-energy four Cotton effects) for all the compounds studied. Therefore, this approach can be used to assign the AC of such flexible molecules, in particular, syn-1,3-diols, which are important substrates in organic synthesis and for which nonempirical methods of AC assignment have not been devised so far. Furthermore, since the fluorene chromophore leads to the presence of several Cotton effects from, say, 350 to 200 nm, their correct simulation of sign, intensity, and position is a guarantee of the correct assignment of AC: in this way, ECD spectroscopy gains the same advantages of VCD spectroscopy, that is, the need of reproducing many ECD bands and then a solid guarantee of a correct AC assignment.

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl4 solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)4/(R,R)-1,2-diphenylethane-1,2-diol/H2O/tert-butyl hydroperoxide and Ti(iso-PrO)4/l-diethyl tartrate/H2O/cumene hydroperoxide, respectively.

Application of deoxycholic acid-based copper-phosphite complexes as ligands in the enantioselective conjugate addition of diethylzinc to acyclic enones

Four phosphites obtained by linking enantiomerically pure binaphthylchlorophosphite to the two different hydroxy groups of deoxycholic acid were synthesized and used as chiral ligands in the enantioselective copper-catalyzed 1,4-addition of diethylzinc to acyclic enones. The ligands were screened for activity and enantioselectivity using chalcone as the substrate to establish the influence of the absolute configuration of the binaphthyl moiety as well as the position on the cholestanic backbone of the phosphite moiety. The ligand affording the best results was eventually used in the copper-catalyzed 1,4-addition to various acyclic enones, affording the alkylation products in good yields and e.e.s up to 78%.

Rational design of chiral 1,1′-binaphthylazepine-based ligands for the enantioselective addition of ZnEt2 to aromatic aldehydes

Abstract By rational design, novel atropisomeric 1,1-binaphthylazepine-based 1,2-amino alcohols 1f and 1g have been prepared in enantiopure form and tested as catalytic precursors in the enantioselective addition of diethylzinc to aromatic aldehydes: the corresponding ( S )-1-arylpropanols have been obtained in quantitative yields and e.e.s up to 95%. A rationale explaining the stereochemical outcome of the reaction, as well as the influence of structural features of the ligands on the enantioselectivity of the addition, is also provided.

1,1,1-TRIFLUOROACETONE AS AN EFFICIENT CATALYST FOR THE HYDROGEN PEROXIDE PROMOTED SELECTIVE OXIDATION OF SULFIDES TO SULFOXIDES

Abstract Organic sulfides are selectively oxidized to the corresponding sulfoxides in high yields and under very mild conditions using 35% hydrogen peroxide in CHCl3 in the presence of catalytic amounts of 1, 1, 1-trifluoroacetone.

A New Case of Induced Helical Chirality in a Bichromophoric System: Absolute Configuration of Transparent and Flexible Diols from the Analysis of the Electronic Circular Dichroism Spectra of the Corresponding Di(1-naphthyl)ketals

Di(1-naphthyl)ketals of 1, n-diols show couplet effects allied to the (1)B naphthalene transition in their CD spectra. This means that they assume a conformation with a prevailing sense of twist of the naphthalene rings, imposed by the absolute configuration (AC) of the starting diols and by the nature of the R 1 groups. A positive couplet for aliphatic diols is a probe of ( R, R), AC while the opposite sign is found for ( R, R) aromatic diols.

Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites

BACKGROUND Quantum mechanical simulations of chiroptical properties, such as electronic circular dichroism (ECD), optical rotation (OR), and vibrational circular dichroism (VCD), have rapidly become very popular to assign the absolute configuration of novel natural products. OBJECTIVE We review the application of the ECD/OR/VCD computational methodology to chiral metabolites of fungal origin. First, we summarize the fundamentals of the three spectroscopies; then, we focus on the specific experimental and computational issues allied to the application of their calculations. METHODS We surveyed the entire literature describing the use of ECD/OR/VCD computations for fungal metabolites, and catalogued all papers according to the method employed and to the structural family of compounds. Then, we chose several examples to illustrate the use of the techniques and highlight the practical application of the computational approach. RESULTS Our literature survey demonstrates that the simulation of ECD/OR/VCD spectra is nowadays widespread and accessible also to non-experts, although a good computational practice is necessary to avoid wrong assignments. ECD is still the most common technique used in the context of fungal metabolites. OR and VCD may be profitably employed when the compound of interest lacks chromophoric groups. Our examples illustrate that the combination of two or more chiroptical methods is strongly advisable in some cases, especially in the presence of high conformational flexibility, where a single technique does not lead to a safe conclusion. CONCLUSION The ECD/OR/VCD computational approach is a reliable and versatile method to assign the absolute configuration of fungal metabolites and related natural products.

Monobenzylethers of (R,R)-1,2-diphenylethane-1,2-diol as a possible alternative to cyclohexyl-based chiral auxiliaries in the stereoselective reduction of α-ketoesters

Abstract The monobenzylethers of (R,R)-1,2-diphenylethane-1,2-diol have been used as chiral auxiliaries in the stereoselective reduction of the corresponding phenylglyoxylates. The diastereoselectivity of the reduction with either l -selectride or DIBAL was found to be strictly dependent on the nature of the substitution on the aromatic ring of the auxiliary and a maximum d.r. of 87:13 was obtained with the p-CF3 substituted derivative. This investigation also shows that with open chain chiral auxiliaries diastereoselectivities of preparative interest can be achieved, suggesting that such auxiliaries can constitute a promising alternative to the commonest cyclohexyl-based ones.

Enantioselective oxidation of sulfides catalyzed by titanium complexes of 1,2-diarylethane-1,2-diols: effect of the aryl substitution.

The effects of the substitution on the aryl moiety on the asymmetric oxidation of sulfides mediated by Ti-complexes of chiral 1,2-diarylethane-1,2-diols were investigated. The substitution of the aryl ring of the diol with both EWG and EDG substituents generally decreased the enantioselectivity with respect to the use of unsubstituted 1,2-diphenylethane-1,2-diol (1a). Only in the presence of 1,2-di(4-t-butyl)phenyl-1,2-diol (1g) were higher ees obtained with aryl methyl and aryl benzyl sulfides affording ees up to 90 and 99%, respectively. Lower ees were achieved with larger naphthyl and aryl alkyl sulfides. Contrary to the other Ti-alcoholates used in the oxidation of sulfides, the Ti-complex of diol 1g was soluble in hexane, allowing us to perform the process with high enantioselectivity in this solvent, with great environmental advantages over the commonly used chlorinated solvents.

A vibrational circular dichroism approach to the determination of the absolute configuration of flexible and transparent molecules: fluorenone ketals of 1,n-diols.

The infrared absorption (IR) and vibrational circular dichroism (VCD) spectra for five ketal molecules, three of which obtained from 1,2-diols and two from 1,3-diols, were recorded in the mid-IR region. The spectra have been satisfactorily reproduced by DFT calculations, even with not too large wavefunction basis sets, especially due to the low number of conformers to be considered. The mobility of some moieties provides a recognizable signature. A characteristic couplet of VCD bands attributed to normal modes involving the methine and a phenyl ring bonded to the stereogenic carbon atom is evidenced for two ketals of the series as a signature of the absolute configuration; due comparison with existing literature is made. A relation is discussed of the present VCD data with the literature VCD data of simple alcohols and diols.