Catalytic Atroposelective Synthesis of C-N Axially Chiral Aminophosphines via Dynamic Kinetic Resolution.

A ruthenium-catalyzed reductive amination via asymmetric transfer hydrogenation (ATH) has been used to perform an efficient dynamic kinetic resolution (DKR) of N-aryl 2-formyl pyrroles decorated with a phosphine moiety positioned at the ortho' position. The strategy relies on the labilization of the stereogenic axis in the substrate facilitated by a transient Lewis acid-base interaction (LABI) between the carbonyl carbon and the phosphorus center. The reaction features broad substrate scope of aliphatic amines and N-Aryl pyrrole scaffolds, and proceeds under very mild conditions to afford P,N atropisomers in good to high yields and excellent enantioselectivities (up to 99% ee) for both diphenyl and dicyclohexylphosphino derivatives.

Silver-Free Gold-Catalyzed Heterocyclizations through Intermolecular H-Bonding Activation.

Modulable monosulfonyl squaramides have been shown to exert activation of gold(I) chloride complexes through H-bonding in an intermolecular way. Combinations of (PPh3)AuCl or IPrAuCl complexes and an optimal sulfonyl squaramide cocatalyst bearing two 3,5-bis(trifluoromethyl)phenyl groups efficiently catalyzed diverse heterocyclizations and a cyclopropanation reaction, avoiding in all cases undesired side reactions. Computational studies indicate that the Au-Cl bond breaks by transligation to the triple bond in a ternary complex formed by the actual AuCl···HBD catalyst and the substrate.

Dynamic Kinetic Resolution of 2-(Quinolin-8-yl)Benzaldehydes: Atroposelective Iridium-Catalyzed Transfer Hydrogenative Allylation.

An atroposelective Ir-catalyzed dynamic kinetic resolution (DKR) of 2-(quinolin-8-yl)benzaldehydes/1-naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho-cyclometalated iridium-DM-BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid-base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.

Asymmetric Synthesis of Axially Chiral C-N Atropisomers.

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C-C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C-N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C-N axes. The preparation of different families of C-N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.

Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies.

This tutorial review provides a systematic overview of the available methodologies for the atroposelective transformation of (heterobiaryl)biaryl precursors toward the synthesis of enantiomerically enriched products and the conceptual aspects associated to each type of transformation. Depending on the presence or absence of symmetry in the starting material and the participation of racemization or dynamization events along the process, several strategies have been developed, including desymmetrization, classical kinetic resolution (KR), dynamic kinetic resolution (DKR) and dynamic kinetic asymmetric transformation (DYKAT). Seminal contributions and a handful of selected examples are discussed to illustrate the potential of these synthetic tools.

Enantio- and Diastereoselective Nucleophilic Addition of N-tert-Butylhydrazones to Isoquinolinium Ions through Anion-Binding Catalysis.

A highly enantio- and diastereoselective thiourea-catalyzed dearomatization of isoquinolines employing N-tert-butylhydrazones as neutral α-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

AuI-Catalyzed Hydroalkynylation of Haloalkynes.

The AuI-catalyzed reaction between terminal alkynes and aromatic haloalkynes proceeds through divergent pathways depending on the nature of the catalyst counteranion. Thus, cationic complexes containing strongly basic NHC ligands and noncoordinating anions such as BArF4 catalyze the cis haloalkynylation of the terminal alkyne, whereas introduction of a weakly basic triflate counteranion results in the stereoselective hydroalkynylation of the haloalkyne, yielding haloenyne products in good yields and complete trans selectivity. Experimental and computational studies suggest that the hydroalkynylation reaction takes place via nucleophilic attack of the terminal alkyne to the C2 carbon of the activated haloalkyne, assisted by a concerted proton abstraction by the triflate, and that the protodeauration is the turnover-limiting step, in agreement with an observed primary kinetic isotope effect.

Ir-Catalyzed Atroposelective Desymmetrization of Heterobiaryls: Hydroarylation of Vinyl Ethers and Bicycloalkenes.

A highly regio-, diastereo-, and enantioselective, scalable Ir-catalyzed hydroarylation of electron-rich acyclic and tensioned cyclic olefins with heterobiaryls is described. The reaction of acyclic vinyl ethers, dihydrofuran, and norbornenes with a variety of aryl isoquinoline, quinazoline, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching complete branched/linear or exo/endo ratios and excellent diastereo- and enantiomeric excesses when in situ formed [IrI/Tol-SDP] or [IrI/Tol-BINAP] complexes are used as the catalysts. Deuterium labeling experiments and a comprehensive computational study suggest that, despite fast double bond migratory insertion into Ir-H, the reaction proceeds through a modified Chalk-Harrod mechanism, starting with selectivity-determining insertion into Ir-CAryl. The regioselectivity is controlled by the electron-donating alkoxy group, whereas diastereo- and enantioselectivity have a complex origin, which depend on the relative orientation of the alkoxy group and the establishment of adequate π-π interactions between the biaryl and the phosphine.

AuI -Catalyzed Haloalkynylation of Alkenes.

The formal insertion of alkenes into aromatic chloro- and bromoalkynes takes place under cationic gold catalysis. This haloalkynylation reaction can be performed with cyclic, gem-disubstituted and monosubstituted alkenes, using BINAP, triazolo[4,3-b]isoquinolin-3-ylidene ligands or SPhos, respectively. The products were isolated in moderate to excellent yields and with complete diastereo- and regioselectivity; the halogen atom bonding the more substituted carbon of the alkene. Preliminary experiments showed that the enantioselective haloalkynylation of cyclopentene can be performed with (S)-BINAP to afford the insertion products with moderate to good enantioselectivities.

Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality.

A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl α-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N, N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a ß-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.

Bifunctional Squaramide Organocatalysts for the Asymmetric Addition of Formaldehyde tert-Butylhydrazone to Simple Aldehydes.

The nucleophilic addition of formaldehyde tert-butylhydrazone to simple aldehydes (a formal hetero-carbonyl-ene reaction) can be performed with good reactivity and excellent enantioselectivity by virtue of the dual hydrogen-bonding activation exerted by amide-squaramide organocatalysts. The resulting hydroxydiazenes (azo alcohols) were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent derivatization provides an entry to relevant amino alcohols, oxazolidinones, and derivatives thereof.

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation.

A diastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-ß-amino esters.

A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-ß-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-ß-amino esters.

Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald-Hartwig Amination.

The Pd(0)-catalyzed coupling of racemic heterobiaryl bromides, triflates, or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter and suggest that coordination of the amine to the Pd center is the stereodetermining step.

Hydrazones as Singular Reagents in Asymmetric Organocatalysis.

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile-electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.

Red-Emitting Tetracoordinate Organoboron Chelates: Synthesis, Photophysical Properties, and Fluorescence Microscopy.

Seven tetracoordinate organoboron fluorophores with heterobiaryl N,O- or N,N-chelate ligands were prepared and photophysically characterized (in toluene). The electronic variation of the heteroaromatic moiety provided a means for the fine-tuning of the UV/vis absorption and emission spectra. In the most interesting cases, the spectra were red-shifted to maximum absorbance at wavelengths longer than 500 nm and emission maxima between 620 and 660 nm. The pronounced intramolecular charge-transfer character of the dyes yielded large Stokes shifts (3500-5100 cm-1), while maintaining appreciable fluorescence quantum yields of up to 0.2 for emission maxima longer than 600 nm. The lipophilic character of the dyes enabled their application as stains of vesicle substructures in confocal fluorescence microscopy imaging.

Strongly Emissive and Photostable Four-Coordinate Organoboron N,C Chelates and Their Use in Fluorescence Microscopy.

Six strongly fluorescent four-coordinate organoboron N,C chelates containing an aryl isoquinoline skeleton were prepared. Remarkably, the fluorescence quantum yields reach values of up to 0.74 in oxygen-free toluene. The strong B-N interaction was corroborated by the single-crystal X-ray analysis of two dyes. The intramolecular charge-transfer character of the fluorophores was evidenced by solvatochromism studies and time-dependent DFT calculations at the PCM(toluene)/CAM-B3LYP/6-311++G(2d,p)//PCM(toluene)/B3LYP/6-311G(2d,p) level of theory. The compounds combine high chemical stability with high photostability, especially when equipped with electron-donating substituents. The strong fluorescence and the large Stokes shifts predestine these compounds for use in confocal fluorescence microscopy. This was demonstrated for the imaging of the N13 mouse microglial cell line. Moreover, significant two-photon absorption cross sections (up to 61 GM) allow the use of excitation wavelengths in the near-infrared region (>800 nm).

Organic fluorescent thermometers based on borylated arylisoquinoline dyes.

Borylated arylisoquinolines with redshifted internal charge-transfer (ICT) emission were prepared and characterized. Upon heating, significant fluorescence quenching was observed, which forms the basis for a molecular thermometer. In the investigated temperature range (283-323 K) an average sensitivity of -1.2 to -1.8% K(-1) was found for the variations in fluorescence quantum yield and lifetime. In the physiological temperature window (298-318 K) the average sensitivity even reaches values of up to -2.4% K(-1). The thermometer function is interpreted as the interplay between excited ICT states of different geometry. In addition, the formation of an intramolecular Lewis pair can be followed by (11)B NMR spectroscopy. This provides a handle to monitor temperature-dependent ground-state geometry changes of the dyes. The role of steric hindrance is addressed by the inclusion of a derivative that lacks the Lewis pair formation.

Enantioselective synthesis of α-aryl α-hydrazino phosphonates.

Catalysts generated in situ by the combination of pyridine-hydrazone N,N-ligands and Pd(TFA)2 have been applied to the addition of arylboronic acids to formylphosphonate-derived hydrazones, yielding α-aryl α-hydrazino phosphonates in excellent enantioselectivities (96 → 99% ee). Subsequent removal of the benzyloxycarbonyl (Cbz) N-protecting group afforded key building blocks en route to appealing artificial peptides, herbicides and antitumoral derivatives. Experimental and computational data support a stereochemical model based on aryl-palladium intermediates in which the phosphono hydrazone coordinates in its Z-configuration, maximizing the interactions between the substrate and the pyridine-hydrazone ligand.

Dynamic kinetic cross-coupling strategy for the asymmetric synthesis of axially chiral heterobiaryls.

A dynamic kinetic asymmetric transformation (DYKAT) technique has been designed for the synthesis of 2'-substituted 2-aryl pyridines/isoquinolines and related heterobiaryls. In this way, the Pd(0)-catalyzed coupling of racemic 2-triflates with aryl boroxines using a TADDOL-derived phosphoramidite as the ligand provides the corresponding coupling products with good to excellent enantioselectivities. Structural studies support that the formation of configurationally labile oxidative addition palladacycles is the key for the success of the methodology.