Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases.

Axially chiral biaryls are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Here, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls via dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal bridge-promoted racemization followed by an imine-reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality at ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98% yield and >99:1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules.

Temperature-Induced Sign Inversion of Circularly Polarized Luminescence of Binaphthyl-Bridged Tetrathiapyrenophanes.

D2-symmetric (R)-binaphthyl-bridged pyrenophanes containing thioether bonds were synthesized. The pyrenophanes exhibited the temperature-induced sign inversion of circularly polarized luminescence (CPL) while maintaining the emission wavelength and reversibility. The Δglum value reached 0.02, and the FL quenching by heat was negligible. The sign inversion of CPL originates from the inversion of intramolecular excimer chirality associated with excitation dynamics. The two pyrenes form a kinetically trapped left-handed twist excimer at low temperatures, while they form a thermodynamically favored right-handed twist excimer at high temperatures. The thioether linkers can impart flexibility suitable for the inversion of chirality of the excimers.

Overcrowded 14,14'-Bidibenzo[a,j]anthracenes: Challenges in Syntheses and Atypical Property of Lacking Symmetry-Breaking Charge Transfer (SBCT).

14,14'-Bidibenzo[a,j]anthracenes (BDBAs) were prepared by iridium-catalyzed annulation of 5,5'-biterphenylene with alkynes. The molecular geometries of overcrowded BDBAs were verified by X-ray crystallography. The two dibenzo[a,j]anthryl moieties are connected through the sterically hindered 14 positions, resulting in highly distorted molecular halves. The conformation with a small twist angle between two molecular halves can minimize steric conflicts between the substituents at 1 and 13 positions and the carbon atoms of the central axis, as well as steric clashes between those substituents. One such example is octafluoro-substituted BDBA, where the interplanar angle between two anthryl moieties is approximately 31° (currently the lowest reported value, cf. 81° in 9,9'-bianthracene). The intramolecular interactions and electronic couplings between two molecular halves resulted in upfield 1H NMR signals, redshifted absorption and emission bands, and a reduced HOMO-LUMO gap. Photodynamic investigations on BDBAs indicated that the formation of the conventional symmetry-breaking charge transfer (SBCT) state was suspended by restricted rocking around the central C-C bond. Such a mechanism associated with this highly constrained conformation was examined for the first time.

From the Total Synthesis of Semi-Viriditoxin, Semi-Viriditoxic Acid and Dimeric Naphthopyranones to their Biological Activities in Burkitt B Cell Lymphoma.

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,ß-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,ß-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.

Recent Advancements in Continuous-Flow Suzuki-Miyaura Coupling Utilizing Immobilized Molecular Palladium Complexes.

Immobilized Pd-catalyzed Suzuki-Miyaura coupling under continuous-flow conditions using a packed-bed reactor, representing an efficient, automated, practical, and safe technology compared to conventional batch-type reactions. The core objective of this study is the development of an active and durable catalyst. In contrast to supported Pd nanoparticles, the attachment of Pd complexes onto solid supports through well-defined coordination sites is considered a favorable approach for preparing highly dispersed and stabilized Pd species. These species can be directly employed in various flow reactions without the need for pre-treatment. This concept paper explores recent achievements involving the application of immobilized Pd complexes as precatalysts for continuous-flow Suzuki-Miyaura coupling. Our focus is to elucidate the significance of the designed catalyst structures in relation to their catalytic performance under flow conditions. Additionally, we highlight various reaction systems and catalyst packing methods, emphasizing their crucial roles in establishing a practical synthesis process.

Efficient Synthesis and Structural Analysis of Chiral 4,4'-Biazulene.

4,4'-Biazulene is a potentially attractive key component of an axially chiral biaryl compound, however, its structure and properties have not been clarified owing to the lack of its efficient synthesis. We report a breakthrough in the reliable synthesis of 4,4'-biazulene, which is achieved by the access to azulen-4-ylboronic acid pinacol ester and 4-iodoazulene as novel key synthetic intermediates for the Suzuki-Miyaura cross-coupling reaction. The X-ray crystallographic analysis of 4,4'-biazulene confirmed its axial chirality. The enantiomers of 4,4'-biazulene were successfully resolved by HPLC on the chiral stationary phase column. The kinetic experiments and DFT calculations indicate that the racemization energy barrier of 4,4'-biazulene is comparable to that of 1,1'-binaphthyl.

A New Series of Sandwich-Type 5,5'-Biterphenylenes: Synthetic Challenge, Structural Uniqueness and Photodynamics.

A new series of biaryls, bi-linear-terphenylenes (BLTPs), were prepared using the tert-butyllithium-mediated cyclization as the key synthetic step. The three-dimensional structures of the studied compounds were verified using X-ray crystallography and DFT calculations. Tetraaryl(ethynyl)-substituted BLTPs are highly crowded molecules, and the internal rotation around the central C-C bond is restricted due to a high barrier (>50 kcal/mol). These structures contain several aryl/terphenylenyl/aryl sandwiches, where the through-space π-π (TSPP) interactions are strongly reflected in the shielding of 1 H NMR chemical shifts, reduction of oxidation potentials, increasing aromaticity of the central six-membered ring and decreasing antiaromaticity of the four-membered rings in a terphenylenyl moiety based on NICS(0) and iso-chemical shielding surfaces. Despite the restricted C-C bond associated intramolecular TSPP interactions for BLTPs in the ground state, to our surprise, the electronic coupling between two linear terphenylenes (LTPs) in BLTPs in the excited state is weak, so that the excited-state behavior is dominated by the corresponding monomeric LTPs. In other words, all BLTPs undergo ultrafast relaxation dynamics via strong exciton-vibration coupling, acting as a blue-light absorber with essentially no emission.

Divergent Acyl and Decarbonylative Liebeskind-Srogl Cross-Coupling of Thioesters by Cu-Cofactor and Pd-NHC (NHC = N-Heterocyclic Carbene) Catalysis.

Transition-metal-catalyzed cross-coupling reactions of thioesters by selective acyl C(O)-S cleavage have emerged as a powerful platform for the preparation of complex molecules. Herein, we report divergent Liebeskind-Srogl cross-coupling of thioesters by Pd-NHC (NHC = N-heterocyclic carbene) catalysis. The reaction provides straightforward access to functionalized ketones by highly selective C(acyl)-S cleavage under mild conditions. Most crucially, the conditions enable direct functionalization of a range of complex pharmaceuticals decorated with a palette of sensitive functional groups, providing attractive products for medicinal chemistry programs. Furthermore, decarbonylative Liebeskind-Srogl cross-coupling by C(acyl)-S/C(aryl)-C(O) cleavage is reported. Cu metal cofactor directs the reaction pathway to acyl or decarbonylative pathway. This reactivity is applicable to complex pharmaceuticals. The reaction represents the mildest decarbonylative Suzuki cross-coupling discovered to date. The Cu-directed divergent acyl and decarbonylative cross-coupling of thioesters opens up chemical space in complex molecule synthesis.

Gold-Catalyzed 1,2-Aryl Shift and Double Alkyne Benzannulation.

The tandem intramolecular hydroarylation of alkynes accompanied by a 1,2-aryl shift is described. Harnessing the unique electron-rich character of 1,4-dihydropyrrolo[3,2-b]pyrrole scaffold, we demonstrate that the hydroarylation of alkynes proceeds at the already occupied positions 2 and 5 leading to a 1,2-aryl shift. Remarkably, the reaction proceeds only in the presence of cationic gold catalyst, and it leads to heretofore unknown π-expanded, centrosymmetric pyrrolo[3,2-b]pyrroles. The utility is verified in the preparation of 13 products that bear six conjugated rings. The observed compatibility with various functional groups allows for increased tunability with regard to the photophysical properties as well as providing sites for further functionalization. Computational studies of the reaction mechanism revealed that the formation of the six-membered rings accompanied with a 1,2-aryl shift is both kinetically and thermodynamically favourable over plausible formation of products containing 7-membered rings. Steady-state UV/Visible spectroscopy reveals that upon photoexcitation, the prepared S-shaped N-doped nanographenes undergo mostly radiative relaxation leading to large fluorescence quantum yields. Their optical properties are rationalized through time-dependent density functional theory calculations. We anticipate that this chemistry will empower the creation of new materials with various functionalities.

Variable Ca-Caryl Hapticity and its Consequences in Arylcalcium Dimers.

The dimeric ß-diketiminato calcium hydride, [(Dipp BDI)CaH]2 (Dipp BDI = HC{(Me)CN-2,6-i-Pr2 C6 H3 }2 ), reacts with ortho-, meta- or para-tolyl mercuric compounds to afford hydridoarylcalcium compounds, [(Dipp BDI)2 Ca2 (µ-H)(µ-o-,m-,p-tolyl)], in which dimer propagation occurs either via µ2 -η1 -η1 or µ2 -η1 -η6 bridging between the calcium centers. In each case, the orientation and hapticity of the aryl units is dependent upon the position of the methyl substituent. While wholly organometallic meta- and para-tolyl dimers, [(Dipp BDI)Ca(m-tolyl)]2 and [(Dipp BDI)Ca(p-tolyl)]2 , can be prepared and are stable, the ortho-tolyl isomer is prone to isomerization to a calcium benzyl analog. Computational analysis of this latter process with density functional theory (DFT) highlights an unusual mechanism invoking the generation of an intermediate dicalcium species in which the group 2 centers are bridged by a toluene dianion formed by the formal attachment of the original hydride anion to the initially generated ortho-tolyl substituent. Use of a more sterically encumbered aryl substituent, {3,5-t-Bu2 C6 H3 }, facilitates the selective formation of [(Dipp BDI)Ca(µ-H)(µ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)], which can be converted into the unsymmetrically-substituted σ-aryl calcium complexes, [(Dipp BDI)Ca(µ-Ph)(µ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)] and [(Dipp BDI)Ca(µ-p-tolyl)(µ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)] by reaction with the appropriate mercuric diaryl. Conversion of [(Dipp BDI)Ca(H)(Ph)Ca(Dipp BDI)] to afford [{{(Dipp BDI)Ca}2 (µ2 -Cl)}2 (C6 H5 -C6 H5 )], comprising a biphenyl dianion, is also reported. Although this latter transformation is serendipitous, AIM analysis highlights that, in a related manner to the ortho-tolyl to benzyl isomerization, the requisite C-C coupling may be facilitated in an "across dimer" fashion by the experimentally-observed polyhapto engagement of the aryl substituents with each calcium.

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives.

The development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity- and stereoselectivity-control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring-opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL-derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio- and rate-determining.

Acenaphthoimidazolylidene-Ligated Palladacycle Enabled Suzuki-Miyaura Cross-Coupling Employing Equimolar Organoboron for Tri-Ortho-Substituted Bi(hetero)aryls and Teraryls.

The Pd-catalyzed Suzuki-Miyaura cross-couplings (SMRs) are utilized as the most practical method to construct C-C bond, especial for biaryls. However, a major disadvantage of current protocols is the requirement of excess organoboron coupling partner (1.5-3.0 equiv.). Herein, a novel palladacyclic 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene (AnIPr) precatalyst possessing a chiral oxazoline was designed, which enabled a general protocol towards bulky tri-ortho-substituted biaryls, ternaphthalenes and diarylanthracenes via the Pd-catalyzed SMR employing equimolar organoborons and aryl bromides. A remarkable scope of substrates with various functional groups and heterocycles were well compatible with an adaptability to synthesize useful ligands.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Dearomatization of Biaryls through Polarity Mismatched Radical Spirocyclization.

Dearomatization reactions involving radical cyclizations can facilitate the synthesis of complex polycyclic systems that find applications in medicinal chemistry and natural product synthesis. Here we employ redox-neutral photocatalysis to affect a radical spirocyclization that transforms biaryls into spirocyclic cyclohexadienones under mild reaction conditions. In a departure from previously reported methods, our work demonstrates the polarity mismatched addition of a nucleophilic radical to an electron rich arene, and allows the regioselective synthesis of 2,4- or 2,5-cyclohexadienones with broad functional group tolerance. By transforming biaryls into spirocycles, our methodology accesses underexplored three-dimensional chemical space, and provides an efficient means of creating quaternary spirocenters that we apply to the first synthesis of the cytotoxic plant metabolite denobilone A.

Tamarindus indica seed ash extract for C-C coupling under added organics and volatile organic solvent-free conditions: a waste repurposing technique for Suzuki-Miyaura reaction.

A tremendous research has been appeared on Pd-catalyzed Suzuki-Miyaura cross-coupling (SMC) during the last four decades due to its high prominence in constructing biaryl motifs of several complexes as well as simple organic compounds of high biological and commercial significance. The use of organic solid waste-derived materials for SMC in benign solvents like water/aqueous media is a very good achievement in these cases. We report in this article the usability of water extract of Tamarindus indica seeds ash (WETS) as a renewable base and reaction medium for Pd(OAc)2-catalyzed SMC reaction at room temperature (RT). The WETS has been characterized using powder XRD, EDAX, SEM, and FTIR analysis. Furthermore, this process is highly environmentally beneficial by the waste repurposing to prominent chemical transformation along with the advantages such as ambient condition and avoids non-renewable chemicals like volatile organic solvents, ligands, promoters, and bases. Based on these merits and the quick reactions with high yields of products, this method can attain the interest of the scientific community in exploring the waste-derived ashes to significant chemical transformations. Tamarindus indica seed ash extract for C-C coupling under added organics and volatile organic solvent-free conditions: a waste repurposing technique for Suzuki-Miyaura reaction.

Atroposelective Access to 1,3-Oxazepine-Containing Bridged Biaryls via Carbene-Catalyzed Desymmetrization of Imines.

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product.

Chemoenzymatic Synthesis of Sterically Hindered Biaryls by Suzuki Coupling and Vanadium Chloroperoxidase Catalyzed Halogenations.

Halogenated biaryls are vital structural skeletons in bioactive products. In this study, an effective chemoenzymatic halogenation by vanadium-dependent chloroperoxidase from Camponotus inaequalis (CiVCPO) enabled the transformation of freely rotating biaryl bonds to sterically hindered axis. The yields were up to 84 % for the tribrominated biaryl products and up to 65 % when isolated. Furthermore, a one-pot, two-step chemoenzymatic strategy by incorporating transition metal catalyzed Suzuki coupling and the chemoenzymatic halogenation in aqueous phase were described. This strategy demonstrates a simplified one-pot reaction sequence with organometallic and biocatalytic procedures under economical and environmentally beneficial conditions that may inspire further research on synthesis of sterically hindered biaryls.

Palladium-Catalyzed Directed Atroposelective C-H Iodination to Synthesize Axial Chiral Biaryl N-Oxides via Enantioselective Desymmetrization Strategy.

The discovery of enantioselective desymmetrization reactions to provide practical synthesis of enantio-enriched atropisomeric biaryls is a challenging topic in the field of asymmetric catalysis. Herein, we report a highly enantioselective desymmetrization reaction for the synthesis of axially chiral biaryl N-oxides by atroposelective C-H iodination by using Pd(II) coordinated by N-benzoyl-l-phenylalanine as a chiral catalyst at room temperature. A broad range of products were obtained in high yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee). The products could be synthesized in gram scale, one of which was proved to be a powerful organocatalyst in asymmetric allylation reaction. Mechanistic evidence as well as DFT calculations point towards the factors that lead to high reactivity and excellent enantiocontrol in this reaction.

A Modular Approach to Atropisomeric Bisphosphines of Diversified Electronic Density on Phosphorus Atoms.

The series of C2-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6'-diiodo-2,2',4,4'-tetramethylbiphenyl-3,3'-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity.

Palladium-Catalyzed Stereoselective Cleavage of C-P Bond: Enantioselective Construction of Atropisomers Containing a P-Stereogenic Center.

The transition-metal-catalyzed C-P bond cleavage has emerged as a powerful tool for the formation of both C-C and C-P bond. However, the transition-metal-catalyzed stereoselective cleavage of C-P bond is still undeveloped. Herein, we report a palladium-catalyzed stereoselective cleavage of C-P bond for the construction of P-stereogenic phosphines and stereogenic axis. This protocol enables the quick synthesis of atropisomers bearing a P-stereogenic center in high yields, diastereo- and enantioselectivities of up to 98 % ee, >25 : 1 dr. The product is able to serve as chiral catalyst in phosphine catalyzed [3+2] cycloaddition of allenoates to imines, showing the great potential of the present methodology.