Enantioselective Preparation, Conformational Analysis and Absolute Configuration of Highly Substituted Aziridines.

The first example of organocatalytic aziridination reaction of α-substituted-α,ß-unsaturated ketones is presented. The reaction was found to be highly enantio- and diastereoselective, yielding N-tosylated aziridines. Low-temperature nuclear magnetic resonance (NMR) spectra allowed for the determination of the N-inversion barrier, that was found to be quite lower with respect to unsubstituted aziridines. A thorough conformational analysis supported by low-temperature NMR data allowed for the determination of the absolute configuration of the main stereoisomer by means of time-dependent Density Functional Theory simulation of the electronic circular dichroism spectra.

Atropisomers of hindered triarylisocyanurates: structure, conformation, stereodynamics, and absolute configuration.

The syn and anti diastereoisomers of some 1,3,5-triarylisocyanurate derivatives were isolated and their configuration assigned by NOE experiments and by X-ray diffraction. The kinetics of the syn/anti interconversion were determined, and the experimental activation energies matched satisfactorily the values predicted by DFT computations. Low-temperature NMR spectra were employed to determine the rotation barrier of N-bonded unhindered aryl substituents: these barriers, too, are satisfactorily reproduced by DFT computations. In the case of racemic diastereoisomers, the two expected enantiomers (atropisomers) were isolated by enantioselective HPLC and the absolute configuration established by DFT simulation of the electronic and vibrational circular dichroism spectra.

Rotational barriers of biphenyls having heavy heteroatoms as ortho-substituents: experimental and theoretical determination of steric effects.

The free energies of activation for the aryl-aryl rotation of 17 biphenyl derivatives, bearing a heavy heteroatom (S, Se, Te, P, Si, Sn) as ortho substituent, have been measured by variable temperature NMR. These numbers, so called B values, represent a meaningful measure of the steric hindrance exerted by the selected substituents. DFT computations match quite satisfactorily the experimental barriers and the ground state geometries as well (determined, in two cases, by X-ray diffraction). The present values extend the available list of B values and thus provide an enlarged basis for the compilation of the space requirements of standard substituents, based solely on experimental determinations.

Structure, conformation, stereodynamics, and absolute configuration of the atropisomers of fluorenylidene derivatives.

The barrier for the interconversion of the conformational atropisomers of an aryl fluorenylidene derivative was determined by variable-temperature NMR technique. In the case of a more hindered compound the two atropisomers were isolated and the structure determined by X-ray diffraction. The absolute configuration was assigned by theoretical interpretation of the Electronic Circular Dichroism spectrum (ECD).

The torsional barriers of 2-hydroxy- and 2-fluorobiphenyl: small but measurable.

By making use of a novel diastereotopicity probe, namely C(CF(3))(2)OH, it has been possible to measure by very low temperature (19)F NMR spectroscopy the elusive aryl-aryl rotation barriers of biphenyls bearing an OH or F group in one ortho position. The experimental values (5.4 and 4.4 kcal mol(-1), respectively) are matched by those from ab initio calculations (5.3 and 4.3 kcal mol(-1), respectively).

Stereomutation of axially chiral aryl coumarins.

Coumarins substituted by an aryl group in position 4 display restricted rotation about the Ar-C4 bond, giving rise to conformational or configurational enantiomers (atropisomers) when such a restricted motion leads to a C(1) symmetry. The dynamics of the stereomutation processes of these axial enantiomers was monitored by dynamic NMR, dynamic enantioselective HPLC, or racemization kinetics, depending on the activation energies involved. These results were further supported by DFT computations. In the two cases where the enantiomers were sufficiently long living as to be physically separated at ambient temperature, the absolute configuration was determined by means of a theoretical simulation of their electronic circular dichroism spectra (ECD).

Structure and stereodynamics of aryldiimino derivatives.

Aromatic diimino derivatives, having two N=CPh(2) moieties bonded at the 1,8 positions of the anthraquinone, anthracene, biphenylene, and naphthalene rings, have been investigated by variable-temperature NMR spectroscopy, X-ray diffraction, and DFT calculations. In all the compounds, the imino substituents are essentially orthogonal to the aromatic plane and the phenyl groups bonded to the C=N carbons are diastereotopic (i.e., cis or trans to the aromatic N-substituent of the N=C moiety). The barriers for the cis/trans interconversion of the phenyl groups by planar nitrogen inversion have been determined. In the cases of anthracene and anthraquinone derivatives, the presence of syn and anti conformers was detected, and their interconversion barriers, due to the Ar-N rotation, were measured. At very low temperature, restricted rotations of the phenyl groups, displaying barriers in the range 4.8-6.9 kcal mol(-1), were also observed for all compounds: the barriers for the rotation of the cis were found to be larger than for the trans phenyl groups.

The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents.

The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. Alpha-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl.

B values as a sensitive measure of steric effects.

Someone who says "A" should be prepared to also say "B": In contrast to cyclohexane model-based A values, biphenyl model-derived B values are powerful tools to quantify steric repulsion in and conformational behavior of ortho-substituted aromatic compounds.Torsional barriers of 15 ortho-substituted biphenyls have been determined computationally using the B3LYP density functional and experimentally by variable-temperature ("dynamic") nuclear magnetic resonance. Taking advantage of the 3'-isopropyldimethylsilyl group as a novel and superior diastereotopicity probe and tracking coalescence temperatures down to -173 degrees C (100 K), activation energies of aryl-aryl rotation as small as 5 kcal mol(-1) can be assessed. The 2-X/2'-H repulsion increments thus derived are powerful parameters for rationalizing and predicting the conformational behavior of aromatic compounds carrying ortho substituents.

Structure, stereodynamics and absolute configuration of the atropisomers of hindered arylanthraquinones.

Anthraquinone substituted by 2-methyl-1-naphthyl groups in positions 1,8 yields syn (meso) and anti (racemic) isomers (red and yellow colored, respectively) that interconvert with a barrier of 35.4 kcal mol(-1) in solution. Their structures were identified by NOE experiments in solution and X-ray diffraction in the solids. The racemic anti form (C(2) point group) entails two atropisomers that were separated by enantioselective HPLC: the absolute configuration was assigned by TD-DFT simulation of the ECD spectrum. Two atropisomers were also separated and assigned in the case of anthraquinone bearing a single 2-methyl-1-naphthyl substituent in position 1.

Steric effects which determine the conformational preferences and stereodynamic processes of aryl fluorenyl ketones.

The stereodynamic processes and conformational preferences of two classes of aryl fluorenyl ketones have been investigated by means of dynamic NMR spectroscopy, DFT calculations and X-ray diffraction. When the aryl substituent has two hydrogens in the ortho positions, its rotation is independent of that of the fluorene ring. In contrast, if the two ortho hydrogens are replaced by the bulkier methyl groups (e.g. mesityl fluorenyl ketones), the motion of the aryl ring interacts with the fluorene, and the two rings rotate in a correlated manner.

Conformation and absolute configuration of 2-naphthylalkylsulfoxides by combined use of dynamic NMR, ECD spectroscopy, DFT computations, and X-ray diffraction.

The E/Z conformer ratios of five 2-naphtylalkylsulfoxides were determined by means of dynamic NMR spectroscopy at very low temperatures and this information was used to predict, by means of DFT calculations, the ECD spectra of the R and S enantiomers. The latter were separated by enantioselective HPLC technique and the comparison of theoretical and experimental ECD spectra allowed the absolute configurations to be determined. In the case of 2-naphtyl tert-butylsulfoxide (1), the assignment was independently confirmed by anomalous dispersion using single crystal X-ray crystallography.

Stereodynamics and conformational chirality of the atropisomers of ditolyl anthrones and anthraquinone.

Syn and anti conformers in similar proportions were observed at ambient temperature for the title compounds. The conformational assignment of the two anthrones was obtained by the observation of different multiplicity of the methylene NMR signals, whereas that of the anthraquinone derivative was determined by NOE experiments. The anti-to-syn interconversion barriers were obtained by line-shape simulation of the temperature-dependent NMR spectra, and by saturation transfer experiments. In one case the X-ray diffraction indicated that the syn is the only structure observed in the crystals.

Stereomutation of conformational enantiomers of 9-isopropyl-9-formylfluorene and related acyl derivatives.

Low-temperature NMR spectra show that the title compound exists as a pair of conformational enantiomers, generated by the restricted rotation about the C9-Pr (i) bond, the corresponding interconversion barrier being 6.9 kcal mol (-1). This interpretation is supported by theoretical (MM and DFT) calculations and by the experimental determination of the analogous barriers occurring in the related MeC=O and Bu(t)C=O derivatives.

Enantiomerization of chiral uranyl-salophen complexes via unprecedented ligand hemilability: toward configurationally stable derivatives.

In the search for configurationally stable inherently chiral uranyl-salophen complexes, the newly synthesized compound 3 featuring a dodecamethylene chain was expected to be a promising candidate. Unexpectedly, dynamic HPLC on a enantioselective column showed that it still undergoes enantiomerization at high temperature. By comparison with the dynamic behavior of compounds 4 and 5, it was found that the enantiomerization rate is independent of the size of the ligand. This finding definitely rules out a jump rope-type mechanism for the enantiomerization process and points to reaction pathways involving preliminary rupture of one of the O...U coordinative bonds. This provides unprecedented evidence of the occurrence of ligand hemilability in metal-sal(oph)en complexes. Such findings inspired the synthesis of compound 6 endowed with a more rigid spacer, i.e., that derived from 4,4'-(1,4-phenylenediisopropylidene)bisphenol. DHPLC investigations showed that the new structural motif imparts a higher configurational stability, thus raising the half-life for the enantiomerization to more than 2 months at room temperature. This clearly establishes that this compound represents the first member of a new class of inherently chiral receptors, whose potential in chiral recognition and catalysis now can be feasibly explored.

Structure, conformation, and dynamic processes of the stereolabile atropisomers of hindered terphenyl hydrocarbons.

[reaction: see text] Ortho-substituted p-terphenyl hydrocarbons exist as trans and cis atropisomers that were identified by low-temperature NMR spectroscopy. The interconversion barriers increase with the dimensions of the ortho substituents, the experimental values being matched by ab initio calculations. X-ray diffraction shows that only the trans atropisomer is present in the solids. Spectra of a tert-butyl derivative in nonequilibrium conditions indicate that the cis is more populated than the trans atropisomer in solution, favored by attractive interactions.

Conformational Studies by Dynamic NMR. 57.(1) Stereodynamics of Syn-Anti Interconversion of Disubstituted Acyl Durenes.

The orthogonal syn and anti isomers, originated by the restricted rotation about the Ar-C(O)Bu(t) single bonds in 1,4-bis(2,2-dimethylpropanoyl)durene (2e), have been separated by preparative thin layer chromatography. In solution they reach an equilibrium where the syn-anti ratio depends upon the polarity of the solvent. This allowed us to assign the anti structure, which has a null dipole moment, to the least retained isomer. The free energy of activation (DeltaG) for the interconversion was found to be 22.5 kcal mol(-)(1), a value high enough for identifying these species as configurational isomers. When less hindered derivatives, also having two RCO (R = Pr(i), Et, Me) substituents in the positions 1,4 of the durene moiety, were examined, the syn and anti forms could be detected only at low temperature by means of NMR spectroscopy. The corresponding interconversion barriers (DeltaG = 13.4, 11.7, 10.9 kcal mol(-)(1), respectively) are, in fact, much lower than for R = Bu(t), indicating that in these cases we are dealing with conformational rather than with configurational isomers.

Conformational Studies by Dynamic Nuclear Magnetic Resonance. 59.(1) Stereodynamics of Conformational Enantiomers in the Atropisomers of Hindered Naphthylcarbinols.

Naphthyldialkylmethanols ArRR'COH (Ar = 1-naphthyl or 1-naphthyl-2-methyl) exist as a pair of atropisomers created by the restricted rotation about the Ar-COH bond. They can be detected by low-temperature NMR spectroscopy but can also be separated as stable compounds at room temperature if both the alkyl substituents are bulky tert-butyl groups (one such example is provided by compound 1, R = R' = Bu(t) with Ar = 1-naphthyl). The free energies of activation (DeltaG()) for the interconversion of these atropisomers were found to vary between 7.6 kcal mol(-)(1) (as in 7, R = R' = Me, Ar = 1-naphthyl-2-methyl) and 32.9 kcal mol(-)(1) (as in 1). The syn-periplanar (sp) or anti-periplanar (ap) structures were assigned either by means of difference NOE experiments or by taking advantage of the H-8 chemical shifts which are vastly different in the two atropisomers. Depending on the substituents the more stable species at the equilibrium can be either the sp or the ap atropisomer. When R = R' = Pr(i) and R = R' = Et (respectively 2 and 3 if Ar = 1-naphthyl), the sp atropisomers adopt an asymmetric conformation, thus creating a pair of conformational enantiomers which interchange by rotating the isopropyl or the ethyl groups about the appropriate sp(3)-sp(3) bonds, with DeltaG() values of 7.2 and 6.1 kcal mol(-)(1), respectively. On the contrary the corresponding 3-ap and 2-ap atropisomers adopt a symmetric (meso) conformation, as predicted by molecular mechanics calculations. In the case of R = Pr(i), R' = Et, and Ar = 1-naphthyl (10-sp atropisomer), two asymmetric conformers were found to be appreciably populated (ratio 9:1 at -135 degrees C).

Unprecedented Detection of Distinct Barriers Involving Formally Enantiotopic Substituents: Phenyl Rotation in Solid Diphenyl Sulfoxide.

The formally enantiotopic phenyl rings of Ph2 SO (Cs symmetry) display different rotation rates about the Ph-S bonds in the crystalline state. For example, at 0°C one phenyl ring rotates (see picture; cylinder represents rotating phenyl ring), whereas the other does not. Two distinct barriers (13.0 and 14.0 kcal mol-1 ) were determined by solid-state NMR spectroscopy.