Michele Mancinelli

Organocascade Reactions of Enones Catalyzed by a Chiral Primary Amine

Enantioselective catalysis is one of the most efficient chemical approaches to the challenging issues associated with structural and stereochemical complexity. This approach is attractive as it is the only rational means of producing useful chiral compounds with high optical purity in an economical, energy-saving, and environmentally benign way. Recently, the potential of asymmetric catalysis has been expanded by the introduction of simple chiral small organic molecules as highly efficient catalysts for many transformations. One of the most powerful organocatalytic strategies is organocascade catalysis. This process exploits the ability of chiral amines to efficiently combine two modes of catalytic activation of carbonyl compounds (iminium and enamine catalysis) into one mechanism, thereby allowing the rapid conversion of simple achiral starting materials into stereochemically complex products with multiple stereocenters and very high optical purity. This one-step strategy requires neither protection/deprotection steps, which can be time-consuming and costly, nor isolation of intermediates. The recent advances in the field of chiral secondary amine catalysis have set the scene for the development of many highly efficient organocascade reactions based on the selective activation of aldehydes. However, little progress has been achieved in the corresponding transformations of ketones, mainly because of the inherent difficulties in generating congested covalent intermediates from secondary amines and ketones. Herein, we show that chiral primary amine catalysis offers a powerful alternative in the design of novel and synthetically useful organocascade reactions, thus providing a practical solution to the issue of activating a,b-unsaturated ketones toward a well-defined enamine–iminium tandem sequence. Specifically, we have developed a series of organocascade approaches that affords straightforward access to a range of formal Diels–Alder adducts 4a–i, which have three or four stereogenic centers, with very high optical purity (Figure 1). Importantly, we found that catalyst 1, a chiral primary amine directly derived from natural cinchona alkaloids, efficiently activates acyclic enones while selectively directing the reaction manifold toward a stepwise double-Michael addition sequence instead of a pericyclic path. The resulting unique stereochemical outcome renders the presented methodology, which complements the venerable [4+2] cycloaddition transformations, a novel synthetic route to valuable cyclohexane derivatives. Recently, chiral secondary amine catalysis has proved efficient in promoting the stereoselective Diels–Alder reactions that use cyclic enones as dienes and involve in situ dienamine activation. On the other hand, the corresponding transformations with linear a,b-unsaturated ketones proceeded with essentially no enantioselectivity. We then investigated whether the versatility of 9-amino(9-deoxy)epi-hydroquinine 1, which we and other research groups have independently established as an effective catalyst for ketone activation, may be exploited to combine enamine–iminium activations of acyclic enones, as this cascade sequence would lead to a formal Diels–Alder adduct (Figure 1). This idea was mainly driven by our recent application of 1 to catalyze an intramolecular tandem reaction of linear enones, based on an iminium–enamine pathway. Initially, we focused on the identification of a suitable compound 3, which was able to initially act as a Michael Figure 1. Organocascade with enones promoted by chiral primary amine 1: enamine–iminium activation for a double-Michael sequence. EWG = electron-withdrawing group.

Enantioselective Gold-Catalyzed Synthesis of Polycyclic Indolines

The synthesis of architecturally complex polycyclic fused indolines is achieved in a chemo-, regio-, and stereodefined manner, via an enantioselective gold-catalyzed cascade hydroindolination/iminium trapping synthetic sequence. Highly functionalized tetracyclic fused furoindolines (2) and dihydropyranylindolines (4) are synthesized in moderate to good yields and enantiomeric excesses of up to 87%.

Remote Control of Axial Chirality: Aminocatalytic Desymmetrization of N-Arylmaleimides via Vinylogous Michael Addition

Remote control of the axial chirality of N-(2-t-butylphenyl)succinimides was realized via the vinylogous Michael addition of 3-substituted cyclohexenones to N-(2-t-butylphenyl)maleimides. 9-Amino(9-deoxy)epi-quinine promoted the enantioselective desymmetrization, leading to atropisomeric succinimides with two adjacent stereocenters.

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.

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).

An Experimental Study on the Effect of Substituents on Aromatic–Aromatic Interactions in Dithia[3,3]‐metaparacyclophanes

Simple model systems based on the 2,11-dithia[3,3]-metaparacyclophane skeleton were synthesized to study the effects of substituents on the intramolecular aromatic-aromatic interactions between benzene rings. X-ray crystallography established that, in their more stable conformations, these metaparacyclophanes featured partially overlapping aromatic rings (interplanar distances of about 3.5 Å), with the planes of the aromatic systems arranged in a slightly tilted disposition (interplanar angles in the range 5-19°). Calculations showed that these derivatives underwent topomerization by flipping of the meta-substituted ring over the para-substituted one, a process in which the two rings adopted a continuum of edge-to-face dispositions, including an orthogonal one, which were less stable than the starting face-to-face arrangement. The energy barriers to the isomerization process were experimentally determined by variable-temperature NMR spectroscopy, by using an internal temperature standard to assess even minor differences in energy (relative experimental error: (±0.1 kJ mol(-1)). The variation in the barriers as a function of the different substituents on the interacting ring was small and apparently unrelated to the effect of the substituents on the polarity of the π-systems. An explanation based on the charge-penetration effect seemed more-suitable to rationalize the observed trends in the barriers.

Atropisomers of Arylmaleimides: Stereodynamics and Absolute Configuration

4-Aryl-3-bromo-N-benzylmaleimides and 3,4-biaryl-N-benzylmaleimides have been synthesized by a modified Suzuki cross-coupling reaction from 3,4-dibromo-N-benzylmaleimide. The conformational studies by dynamic NMR and DFT calculations showed that the interconversion barrier between the two available skewed conformations is under steric control. When the aryl group was a 2-methylnaphthyl, thermally stable atropisomers were isolated by enantioselective HPLC and their absolute configurations were assigned by TD-DFT simulations of the ECD spectra.

Arylbiphenylene atropisomers: structure, conformation, stereodynamics, and absolute configuration.

Anti and syn conformers, due to restricted sp(2)-sp(2) bond rotation, were detected in hindered 1,8-diarylbiphenylenes, the aryl moieties being phenyl groups bearing 0micron-alkyl substituents such as Me, Et, i-Pr, and t-Bu. By means of low-temperature NOE experiments, the corresponding structures were assigned and were found to be in agreement with the results of single-crystal X-ray diffraction. The interconversion barriers of these conformers were determined by line-shape simulation of the variable-temperature NMR spectra and the experimental values were reproduced satisfactorily by DFT calculations. In the case of the bulkiest aryl substituent investigated (i.e., 2-methylnaphthalene), the syn and anti atropisomers were stable enough as to be separated at ambient temperature. The two enantiomers (M,M and P,P) of the isomer anti were also isolated by enantioselective HPLC, and the theoretical interpretation of the corresponding CD spectrum allowed the absolute configuration to be assigned.

The intramolecular interaction of thiophene and furan with aromatic and fluoroaromatic systems in some [3.3]meta(heterocyclo)paracyclophanes: a combined computational and NMR spectroscopic study.

Four thiophene- and furan-containing [3.3]meta(heterocyclo)paracyclophanes were designed and synthesized to study the intramolecular interaction between standard heteroaromatic rings and tetra-H- or tetra-F-substituted benzenes. A complete conformational analysis, carried out by DFT calculations and variable-temperature NMR techniques, showed that, despite their structural similarity, these adducts have different conformational preferences and undergo different types of isomerizations depending on the nature of the heterocycle. The thiophene-derived adducts adopted a parallel stacked arrangement of the aromatic systems in the ground-state conformations. Their isomerization pathways involved a thiophene ring-flip process passing through an edge-to-face arranged transition state in which the heterocycle is perpendicular to the benzene platform and its sulfur atom points toward the center of that ring. The threshold energy barrier to the ring-flip process was higher by 10 kJ mol(-1) in the case of the adduct featuring the perfluorinated benzene. This difference was rationalized by assuming that the ground-state conformations of the H- and F-substituted compounds have different stability. On the contrary, the furan-derived adducts were shown by calculations and NMR spectroscopy to adopt, in their ground-state conformations, a perpendicular edge-to-face disposition of the rings with the oxygen atom pointing toward the benzene platform. The adoption of this arrangement was confirmed by X-ray crystallography. In the case of these compounds, the isomerization process involved distortion of the CH(2)SCH(2) bridges connecting the aromatic systems and the adoption of transition-state geometries for which the rings were arranged in a parallel-stacked orientation. Once again a very nice agreement was observed between the predicted and the experimentally determined geometries and pathways. In the case of the furan-containing compounds, the threshold barriers were found to be much lower in energy that those observed for the thiophene derivatives. Remarkably, they were virtually independent of the presence of fluorine atoms on the platform benzene ring.

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.