Atroposelective Synthesis of Axially Chiral Naphthylpyrroles by a Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Aromatization Sequence.

A straightforward methodology for the enantioselective preparation of axially chiral 2-naphthylpyrroles has been developed. This protocol is based on a CuI/Fesulphos-catalyzed highly enantioselective 1,3-dipolar cycloaddition of an azomethine ylide followed by pyrrolidine alkylation and pyrrolidine to pyrrole oxidation. The mild conditions employed in the DDQ/blue light-mediated aromatization process facilitate an effective central-to-axial chirality transfer affording the corresponding pyrroles with high atroposelectivity.

Sulfenate Anion Catalyzed Diastereoselective Synthesis of Aziridines.

Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans-aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO- ) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron-rich and electron-poor aryl groups were shown to be compatible with this method (33 examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring-opening reactions, with a cyclobutyl-substituted norephedrine derivative obtained through a four-step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans-diastereoselectivity.

Enantioselective transformations of 5-hydroxymethylfurfural via catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

A catalytic asymmetric 1,3-dipolar cycloaddition between iminoesters derived from 5-hydroxymethylfurfural (HMF) and different activated alkenes is reported. Excellent levels of diastereo and enantioselectivity were obtained when Fesulphos/CuI complex was used as catalyst. This metodology provides an effective and sustainable access to challenging enantioenriched heterocyclic scaffolds and represents one of the rare examples of catalytic asymmetric transformations using HMF as a starting material.

Catalytic enantioselective intramolecular 1,3-dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles.

An enantioselective synthesis of polycyclic fluorinated pyrrolidines has been achieved by Cu-catalyzed intramolecular 1,3-dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles. The method displays a wide scope and afforded the desired cycloadducts in high yields with up to 99% ee. These results demonstrate that fluoroalkyl substituents are excellent activating groups in this transformation.

Metal-Free Solvent Promoted Oxidation of Benzylic Secondary Amines to Nitrones with H2O2.

An environmentally benign protocol for the generation of nitrones from benzylic secondary amines via catalyst-free oxidation of secondary amines using H2O2 in MeOH or CH3CN is described. This methodology provides a selective access to a variety of C-aryl nitrones in yields of 60 to 93%. Several studies have been performed to shed light on the reaction mechanism and the role of the solvent.

Aldehydes as Photoremovable Directing Groups: Synthesis of Pyrazoles by a Photocatalyzed [3+2] Cycloaddition/Norrish Type Fragmentation Sequence.

A straightforward methodology for the regioselective synthesis of pyrazoles has been developed by a domino sequence based on a photoclick cycloaddition followed by a photocatalyzed oxidative deformylation reaction. Distinguishing features of this protocol include an unprecedented photoredox-catalyzed Norrish type fragmentation under green-light irradiation and the use of α,ß-unsaturated aldehydes as synthetic equivalents of alkynes, where the aldehyde is acting as a novel photoremovable directing group.

Catalytic asymmetric synthesis of diazabicyclo[3.1.0]hexanes by 1,3-dipolar cycloaddition of azomethine ylides with azirines.

Substituted 1,3-diazabicyclo[3.1.0]hexanes with two contiguous quaternary stereocentres are readily prepared by catalytic asymmetric [3+2] cycloaddition of α-substituted iminoesters with azirines. High diastereoselectivities and enantioselectivities (up to 98% ee) are achieved using CuI/(R)-Fesulphos as the catalytic system.

Stereochemical diversity in pyrrolidine synthesis by catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

The pyrrolidine ring is a privileged structural motif in synthetic and medicinal chemisty. This review aims to highlight the high versatility of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides for access to different types of stereochemical patterns in enantioselective pyrrolidine synthesis. Special attention will be paid to stereodivergent procedures giving rise to different stereoisomers from the same starting materials.

CuI-Catalyzed Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides with Cyclobutenones.

The catalytic asymmetric 1,3-dipolar cycloaddition of cyclobutenones with azomethine ylides provides straightforward access to densely substituted 3-azabicyclo[3.2.0]heptanes. In the presence of CuI/(R)-Fesulphos as the catalytic system, high levels of diastereoselectivity and enantioselectivity were achieved (up to 98% enantiomeric excess (ee)).

Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Hydroamination Sequence: Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives.

A three-step reaction sequence has been developed to prepare a variety of enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric azomethine ylide 1,3-dipolar cycloaddition followed by an intramolecular AuI-catalyzed alkyne hydroamination and enamine reduction.

Transition-metal-free chemo- and regioselective vinylation of azaallyls.

Direct C(sp3)-C(sp2) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals, special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein could pave the way for new approaches to transition-metal-free C-C bond formations.

Hybridizing Feature Selection and Feature Learning Approaches in QSAR Modeling for Drug Discovery.

Quantitative structure-activity relationship modeling using machine learning techniques constitutes a complex computational problem, where the identification of the most informative molecular descriptors for predicting a specific target property plays a critical role. Two main general approaches can be used for this modeling procedure: feature selection and feature learning. In this paper, a performance comparative study of two state-of-art methods related to these two approaches is carried out. In particular, regression and classification models for three different issues are inferred using both methods under different experimental scenarios: two drug-like properties, such as blood-brain-barrier and human intestinal absorption, and enantiomeric excess, as a measurement of purity used for chiral substances. Beyond the contrastive analysis of feature selection and feature learning methods as competitive approaches, the hybridization of these strategies is also evaluated based on previous results obtained in material sciences. From the experimental results, it can be concluded that there is not a clear winner between both approaches because the performance depends on the characteristics of the compound databases used for modeling. Nevertheless, in several cases, it was observed that the accuracy of the models can be improved by combining both approaches when the molecular descriptor sets provided by feature selection and feature learning contain complementary information.

Alkenyl Arenes as Dipolarophiles in Catalytic Asymmetric 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides.

The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a CuI or AgI catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.

Catalytic Asymmetric Synthesis of Bicycloprolines by a 1,3-Dipolar Cycloaddition/Intramolecular Alkylation Strategy.

The diastereoselective one-pot synthesis of hexahydrocyclopenta[b]pyrrole derivatives (bicycloprolines) has been achieved by base-mediated reactions of (E)-tert-butyl 6-bromo-2-hexenoate with α-imino esters. The catalytic asymmetric version of this process has been efficiently achieved using the Cu(I)/(R)-DTBM-Segphos complex as a catalyst following a two-step 1,3-dipolar cycloaddition/intramolecular alkylation sequence.

Stereoselective Ag-Catalyzed 1,3-Dipolar Cycloaddition of Activated Trifluoromethyl-Substituted Azomethine Ylides.

A silver-catalyzed 1,3-dipolar cycloaddition of fluorinated azomethine ylides and activated olefins is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of fluorinated pyrrolidines. Broad scope and high levels of diastereoselectivity have been achieved simply by using AgOAc/PPh3 as the catalyst system. The high efficiency of the cycloaddition relies on the presence of a metal-coordinating group on the imine moiety, such as an ester or heteroaryl group. The asymmetric version of the cycloaddition has been developed by using Taniaphos as a chiral ligand.

Highly selective copper-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with acyclic 1,3-dienes.

The first examples of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acyclic activated 1,3-dienes (and 1,3-enynes) are described. Under copper catalysis, a selective cycloaddition at the terminal γ,δ-C=C bond is observed. In addition, depending on the ligand used, either the exo or the endo adduct can be obtained with high selectivity. Under appropriate reaction conditions, the acyclic 1,6-addition product is detected, suggesting a stepwise mechanism. The resulting C4-alkenyl-substituted pyrrolidines are suitable substrates for further access to polycyclic systems, as highlighted by the preparation of hexahydrochromeno[4,3-b]pyrrole and the tetracyclic core of the alkaloid gracilamine.

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions.

Diarylmethylamines are of great interest due to their prevalence in pharmaceutical chemistry. As a result, new methods for their synthesis are in demand. Herein, we report a versatile protocol for the synthesis of diarylmethylamine derivatives involving palladium-catalyzed arylation of in situ generated 2-azaallyl anion intermediates. The 2-azaallyl anions are generated by reversible deprotonation of readily available aldimine and ketimine precursors. Importantly, the arylated aldimine and ketimine products do not undergo isomerization under the reaction conditions. Scale-up of the arylation and hydrolysis of the resulting products to furnish diarylmethylamines were also successfully performed.

Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

Catalytic asymmetric 1,3-dipolar cycloadditions of azomethine ylides have turned out to be one of the most efficient methods for the preparation of enantioenriched pyrrolidines. The past decade has witnessed the development of a bunch of well-defined catalytic systems capable of affording excellent diastereo and enantioselectivities. Recently, a great effort has been focused on expanding the scope of the cycloaddition with regard to both reaction partners. In this review, we will discuss important advances that have been reported in this area since 2011.

Enantioselective synthesis of α-heteroarylpyrrolidines by copper-catalyzed 1,3-dipolar cycloaddition of α-silylimines.

α-Heteroarylpyrrolidines have been efficiently prepared via 1,3-dipolar cycloaddition between silylimines and activated olefins. In the presence of Cu(CH3CN)4PF6/Walphos as catalytic system, high levels of enantioselectivity (up to ≥99% ee) and diastereoselectivity were achieved (major formation of C-2/C-4 trans-substituted pyrrolidines). The reaction is compatible with a broad variety of dipolarophiles including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into bioactive pyrrolidine derivatives.

Ni-Catalyzed [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters.

A variety of cycloheptapyrane derivatives were prepared via Ni-catalyzed formal [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters. The asymmetric version of the process can be achieved using either an enantiomerically enriched cyclopropane as the starting material or a racemic cyclopropane and a chiral Lewis acid.