Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds.

Asymmetric synthesis using organic catalysts has evolved since it was first realized and defined. Nowadays, it can be considered a valid alternative to transition metal catalysis for synthesizing chiral molecules. According to the literature, the number of asymmetric organocatalytic processes associated with atropisomer synthesis has rapidly increased over the past 10 years because organocatalysis addresses the challenges posed by the most widespread strategies used for preparing axially chiral molecules with satisfactory results.These strategies, useful to prepare a wide range of C-C, C-heteroatom, and N-N atropisomers, vary from kinetic resolution to direct arylation, desymmetrization, and central-to-axial chirality conversion. In this field, our contribution focuses on determining novel methods for synthesizing atropisomers, during which, in most cases, the construction of one or more stereogenic centers other than the stereogenic axis occurred. To efficiently address this challenge, we exploited the ability of catalysts based on a cinchona alkaloid scaffold to realize enantioselective organic transformations. Desymmetrization of N-(2-tert-butylphenyl) maleimides was one of the first strategies that we pursued for preparing C-N atropisomers. The main principle is based on the presence of a rotationally hindered C-N single bond owing to the presence of a large tert-butyl group. Following the peculiar reactivity of this type of substrate as a powerful electrophile and dienophile, we realized several transformations.First, we investigated the vinylogous Michael addition of 3-substituted cyclohexenones, where a stereogenic axis and two contiguous stereocenters were concomitantly and remotely formed and stereocontrolled using a primary amine catalyst. Subsequently, we realized desymmetrization via an organocatalytic Diels-Alder reaction of activated unsaturated ketones that enabled highly atropselective transformation with efficient diastereoselectivity, thereby simultaneously controlling four stereogenic elements. Employing chiral organic bases allowed us to realize efficient desymmetrizations using carbon nucleophiles, such as 1,3-dicarbonyl compounds, cyanoacetates, and oxindoles. These reactions, performed with different types of catalysts, highlighted the versatility of organocatalysis as a powerful strategy for atropselective desymmetrization of pro-axially chiral maleimides.Hereafter, we studied the Friedel-Crafts alkylation of naphthols with indenones, a powerful method for enantioselective synthesis of conformationally restricted diastereoisomeric indanones. We realized the first axially chiral selective Knoevenagel condensation using cinchona alkaloid primary amine as the catalyst. This reaction provided a powerful method to access enantioenriched olefins containing the oxindole core. Subsequently, we initiated an intense program for the computational investigation of the reaction mechanism of our atropselective processes. An understanding of the catalytic activity for vinylogous atropselective desymmetrization as well as of the role played by the acidic cocatalyst used for the experimental work was achieved.Recently, we have garnered interest in the novel frontiers of atropselective synthesis. As observed in recent publications, there is considerable interest in the development of methods for preparing N-N atropisomers, an emerging topic in the field of atropselective synthesis. We focused on the synthesis of hydrazide atropisomers by developing a one-pot sequential catalysis protocol based on two sequential organocatalytic reactions that provided high stereocontrol of two contiguous stereogenic elements.

On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides.

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms.

Enantioselective Strategies for The Synthesis of N-N Atropisomers.

Axially chiral compounds have been always considered a laboratory curiosity with rare prospects of being applied in asymmetric synthesis. Things have changed very quickly in the last twenty years when it was understood the important role and the enormous impact that these compounds have in medicinal, biological and material chemistry. The asymmetric synthesis of atropisomers became a rapidly expanding field and recent reports on the development of N-N atropisomers strongly prove how this research field is a hot topic open to new challenges and frontiers of asymmetric synthesis. This review focuses on the recent advances in the enantioselective synthesis of N-N atropisomers highlighting the strategies and breakthroughs to obtain this novel and stimulating atropisomeric framework.

Synthesis of Atropisomeric Hydrazides by One-Pot Sequential Enantio- and Diastereoselective Catalysis.

The first catalytic enantioselective and diastereoselective synthesis of atropisomeric hydrazides was achieved using a sequential catalysis protocol. This strategy is based on a one-pot sequence of two organocatalytic cycles featuring the enamine amination of branched aldehydes followed by nitrogen alkylation under phase-transfer conditions. The resulting axially chiral hydrazides were obtained directly from commercially available reagents in high yields and with good stereocontrol. The permutation of organocatalysts allowed easy access to all stereoisomers, enabling a stereodivergent approach to enantioenriched atropisomeric hydrazides.

Computational Investigation on the Origin of Atroposelectivity for the Cinchona Alkaloid Primary Amine-Catalyzed Vinylogous Desymmetrization of N-(2-t-Butylphenyl)maleimides.

Mechanistic studies clarifying how chiral primary amines control the stereochemistry of vinylogous processes are rare. We report a density functional theory (DFT) computational study for the comprehension of the reaction mechanism of the vinylogous atroposelective desymmetrization of N-(2-t-butylaryl)maleimide catalyzed by 9-amino(9-deoxy)epi-quinine. Our results illustrate how the origin of the atroposelectivity was realized by the catalyst through steric and dispersion interactions. The role of N-Boc-l-Ph-glycine was crucial for the formation of a closed transition-state geometry and the activation of both reaction partners.

Central-to-Axial Chirality Conversion Approach Designed on Organocatalytic Enantioselective Povarov Cycloadditions: First Access to Configurationally Stable Indole-Quinoline Atropisomers.

The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unreported axially chiral indole-quinoline biaryls. The methodology is also implemented for the design and the preparation of challenging compounds exhibiting two stereogenic axes. DFT calculations shed light on the stereoselectivity of the central-to-axial chirality conversion, showing unconventional behavior.

Organocatalytic Desymmetrization Reactions for the Synthesis of Axially Chiral Compounds.

The enantioselective synthesis of atropisomers is an emerging field, that in recent years reached fundamental results and put the bases for innovative applications. Organocatalysis is playing a central role in the realization of original synthesis for novel atropisomeric scaffolds.[1] In this short review, we would like to highlight the results obtained by our group and others in the field of axially enantioselective desymmetrization reactions using organocatalysis as main strategy.

Enantioselective Synthesis of Trifluoromethyl α,ß-Unsaturated δ-Lactones via Vinylogous Aldol-Lactonization Cascade.

The novel vinylogous aldol-lactonization cascade of alkylidene oxindole with trifluoromethyl ketones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of alkylidene oxindoles for the preparation of enantioenriched trifluoromethylated α,ß-unsaturated δ-lactones.

Vinylogous Reactivity of Oxindoles Bearing Nonsymmetric 3-Alkylidene Groups.

The γ-functionalization of oxindoles bearing nonsymmetric 3-alkylidene groups via vinylogous Michael-type addition to nitroolefins was realized. The suppression of the interconversion between the E and Z isomers of the starting oxindoles allowed a site-specific diastereoselective and enantioselective transformation. Specific experiments allowed us to establish the rate-determining step of the reaction and to advance a robust hypothesis for the exclusive formation of an s-cis enolate as the only reactive intermediate.

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.

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.

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis.

In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and ß positions, little progress has been achieved in the enantioselective carbon-carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,ß-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of ß-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde.

Recent advances in organocatalytic methods for the synthesis of disubstituted 2- and 3-indolinones.

In recent years, organocatalysis has enhanced its importance as a tool for the synthesis of enantiomerically enriched compounds. Among the candidates for organocatalysis, the construction of asymmetric quaternary carbons is regarded as a challenging problem in organic synthesis. In particular, 3,3'-disubstituted oxindoles have one or more asymmetric quaternary carbon atoms and they represent a large family of bioactive compounds and synthetic derivatives that mimicry natural products. Therefore they are good targets for drug candidates and in the last two years many papers have appeared on organocatalytic methods for the synthesis of 3,3'-disubstituted oxindoles. Moreover, in the last few years 2-substituted and 2,2'-disubtituted 3-indolinones have also attracted the interest of chemists. This review aims to cover the literature on these topics from its origin to the end of 2011.

Enantioselective α-benzoyloxylation of ketones promoted by primary amine catalyst.

A mixture of 9-amino-(9-deoxy)epi-dihydroquinidine and salicylic acid was able to promote the direct reaction of various cyclohexanones with dibenzoyl peroxide, thus affording the corresponding protected α-hydroxy carbonyl compounds in high yield and enantioselectivity. Interestingly the same catalytic salt was found to be active when 1-indanones derivatives were directly employed in the reaction with dibenzoyl peroxide furnishing chiral 1-oxo-2,3-dihydro-1H-inden-2-yl benzoates in high yields and enantioselectivity. Furthermore their treatment with NaBH(4) gives easy access to the corresponding enantioenriched 1,2-diols in high yields and without any loss of stereoselectivity.

Organocatalytic strategies for the asymmetric functionalization of indoles.

The desire for new synthetic methodologies for the rapid construction of enantiomerically pure substituted indole has been a fruitful driving force for chemical research in the last few years. This research line has produced a stunning array of enantioselective technologies either metal or organocatalyzed. This critical review documents the development of organocatalytic indole alkylation strategies, until the end of 2009 (127 references).

Controlling stereoselectivity in the aminocatalytic enantioselective Mannich reaction of aldehydes with in situ generated N-carbamoyl imines.

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines has been developed. Both alpha-imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N-tert-butoxycarbonyl (Boc) or N-carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N-carbamate-protected imines are generated in situ from stable and easily handled alpha-amido sulfones.

EPR and ENDOR spectroscopic study of the reactions of aromatic azides with gallium trichloride.

The reactions of gallium trichloride with phenyl and deuterio-phenyl azides, as well as with 4-methoxyphenyl azide and deuterium isotopomers, were examined by product analysis, CW EPR spectroscopy and pulsed ENDOR spectroscopy. The products included the corresponding anilines together with 4-aminodiphenylamine type dimers, and polyanilines. Complex CW EPR spectra of the radical cations of the dimers [ArNHC(6)H(4)NH(2)](+)˙ and trimers [ArNHC(6)H(4)NHC(6)H(4)NH(2)](+)˙ were obtained. These EPR spectra were analysed with the help of data from the deuterium-substituted analogues as well as the pulse Davies ENDOR spectra. DFT computations of the radical cations provided corroborating evidence and suggested the unpaired electrons were accommodated in extensive π-delocalised orbitals. A mechanism to account for the reductive conversion of aromatic azides to the corresponding anilines and thence to the dimers and trimers is proposed.

Radical allylations by reaction of azides with allylindium dichloride.

Allylindium dichloride is an effective reagent for carrying out photolytically initiated radical allylation reactions, as also proved by EPR experiments. In the presence of suitable azides that can give rise to electrophilic radicals, a homolytic chain reaction occurs with formation of allylated compounds. With delta-azido esters and chlorides generation of primary indiumaminyl radicals is followed by a very efficient 1,5-H shift process that gives rise to electrophilic carbon-centred radicals, whose subsequent allylation by the starting indium reagent, followed by aqueous workup, eventually affords allylated nitrogen heterocycles in good yields. Some comparative theoretical calculations accounted for the observation that analogous reactions with an organoallyltin reagent did not work at all. The results show that the reaction with allylindium dichloride seems strongly favoured by both a lower BDE of the allyl-metal bond and a considerably faster, exothermic 1,5-H migration step.

EPR and pulsed ENDOR study of intermediates from reactions of aromatic azides with group 13 metal trichlorides.

The reactions of group 13 metal trichlorides with aromatic azides were examined by CW EPR and pulsed ENDOR spectroscopies. Complex EPR spectra were obtained from reactions of aluminium, gallium and indium trichlorides with phenyl azides containing a variety of substituents. Analysis of the spectra showed that 4-methoxy-, 3-methoxy- and 2-methoxyphenyl azides all gave 'dimer' radical cations [ArNHC6H4NH2](+•) and trimers [ArNHC6H4NHC6H4NH2](+•) followed by polymers. 4-Azidobenzonitrile, with its electron-withdrawing substituent, did not react. In general the aromatic azides appeared to react most rapidly with AlCl3 but this reagent tended to generate much polymer. InCl3 was the least reactive group 13 halide. DFT computations of the radical cations provided corroborating evidence and suggested that the unpaired electrons were accommodated in extensive π-delocalised orbitals. A mechanism to account for the reductive conversion of aromatic azides to the corresponding anilines and thence to the dimers and trimers is proposed.