Search

ConspectusEnantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97 : 3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.

The catalytic asymmetric synthesis of novel and chiral amino acid derivatives with unconventional chemo-, diastereo-, and enantio-selectivity remains a paramount challenge. Herein we reported a novel protocol for the use of highly enantioselective copper-catalyzed cycloaddition of α,β-unsaturated acylsilanes as a springboard reaction for the facile synthesis of structurally diversified pyrrolidines and complicated α-amino esters by desilylation. The newly developed process could provide a wide range of synthetically useful acylsilane-substituted pyrrolidines (ASiP) in high yields and excellent diastereo- and enantio-selectivities with Cu/(R)-XylBINAP complex as the catalyst. And the downstream desilylation transformation enables to expand the potntial applications of 1,3-dipolar cycloaddition in the construction of structurally unique amino acid derivatives, in which an unprecedented and concerted fluoride anion-promoted C–X (X=H, Si, N, C) bond cleavage occurred to the enantioselective construction of aldehyde-substituted pyrrolidines, linear cinnamaldehyde or alkene-substituted amino esters in high ee values.

An enantioselective oxidative C–H/N–H carbonylation process was developed in this work. A bimetallic Pd/Cu-based catalyst system was found to catalyze enantioselective C(sp2)–H carbonylation of prochiral arylsulfonamides via desymmetrization process in the presence of mono-N-protected amino acid ligands. This reaction provides a facile strategy to the stereoselective construction of the lactam-type products, such as isoindoline-1-ones and isoquinoline-1-ones, in good yields and enantioselectivities under balloon pressure with the mixture of CO/O2. The reaction mechanism was rationalized by using density functional theory (DFT) study.

An unprecedented and multiple C–H activation/N-dealkylative C–N bond activation provides a direct and facile access to indolo[1,2-a]quinoxalin-6-ones and phthalides., A novel Pd/Cu-cocatalyzed carbonylative cyclization by C–H activation and N-dealkylative C–N bond activation has been developed for the chemoselective construction of synthetically useful heterocycles. The N,N-dimethylamine group on o-indolyl-N,N-dimethylarylamines was found to act as both the directing group and reactive component in this C–H carbonylative cyclization reaction. Furthermore, a unique C–H oxidation/carbonylative lactonization of diarylmethylamines is firstly demonstrated under modified reaction conditions, which could be easily applicable to the one-step synthesis of multi-substituted phthalides bearing an N,O-ketal skeleton that is difficult to access by previously reported methods. Mechanistic studies implicate that Pd/Cu-cocatalyzed C–H oxidation/carbonylative lactonization is a sequential reaction system via Cu-catalyzed C(sp3)–H oxidation and Pd-catalyzed oxidative carbonylation of the C(sp2)–H bond. It was found that trace amounts of water are essential to promote the Cu-catalyzed C(sp3)–H oxidation of diarylmethylamine for the formation of the hydroxyl group, which could act as an in situ-formed directing group in the intramolecular carbonylative lactonization step.

A highly diastereo- and enantioselective silver-catalyzed azomethine ylide-imine (AYI) cycloaddition reaction of glycine aldimino esters with imines was developed in which the Xing-Phos-controlled syn-selective or DTBM-Segphos-induced anti-selective AYI cycloaddition reaction could be applied to the synthesis of a variety of stereodivergent 1-alkyl-2,5-substituted imidazolidines with high yields and excellent enantioselectivities (up to 99% ee) as well as good diastereoselectivities (up to 99:1 dr) under mild reaction conditions.

An unprecedented copper-catalyzed desymmetrization/cycloaddition of 1,1-disubstituted cyclopropenes to azabicyclo[3.1.0]hexane-based heterocycles containing cyclopropane and pyrrolidine motif has been developed. The salient features of the one-time simultaneous construction of five continuous carbon-stereogenic centers for the straightforward and atom-economical synthesis of chiral azabicyclo[3.1.0]hexane derivatives include a general and broad substrate scope with high yields as well as excellent diastereoselectivities (>99 : 1 dr) and excellent enantioselectivities (up to >99% ee). In addition, it is probable that the weak coordination of an amide moiety on 1,1-disubstituted cyclopropenes with the copper complex is the main reason for the tuning of the stereoselectivity of the cycloaddition reaction.

The direct olefination of aryl/alkyl halides with trimethylsilyldiazomethane (TMSD) as a C1- or C2-unit was achieved successfully via a metal carbene migratory insertion process, which offered a new access to afford (E)-vinyl silanes and (E)-silyl-substituted α,β-unsaturated amides in good yields and high chemoselectivity.

Enantioselective synthesis of chiral heterocycle derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, the first stereocontrolled dimerization-type homo-1,3-polar [3+2] cycloaddition reaction of glycine aldimino esters for creating new heterocycles bearing multiple stereogenic centers has been developed through the chiral phosphine ligand –involved silver catalysis. A variety of chiral imidazolidines could be obtained with high yields and good diastereoselectivities as well as excellent enantioselectivities by employing Xing-Phos as chiral P-ligand.

Direct functionalization of terpyridines is an increasingly important topic in the field of dyes and catalysis as well as supramolecular chemistry, but its synthesis and transformation is usually challenging. Herein, a HOMO-raising strategy is reported for the construction of a super-stable novel terpyridine chromophores, in which the selective oxidation of terpyridines at its 3-position was determined successfully to the synthesis of phenol-functionalization of terpyridines (TPyOHs) bearing a hydrogen bonding group. The corresponding TPyOHs displayed strong aggregation-induced emission and exhibited highly selective and visual detection of ZnII cation with a record green terpyridine-based luminophore with nanomolar sensitivity (125 nm).

One-pot formation of 1,2,4-triazolo[1,5-b]pyridazine derivatives is presented in this manuscript, in which the targets are offered via cooperative Cu(i)/Zn(ii)-catalyzed tandem C–N addition and I2/KI-mediated intramolecular N–N bond formation.

Simple modifications of our novel ligand (Xing-Phos) were presented in this work, and a series of aromatic tertiary amide derived non-biaryl atropisomers were successfully synthesized in good yields. In addition, it was found that the multifunctional aromatic tertiary amide derived non-biaryl atropisomers exhibited an excellent endo-selectivity in the silver-catalyzed [3+2]-cycloaddition of azomethine ylides with N-aromatic maleimide. And especially, good to high levels of enantioselectivity (up to 98% ee) was obtained with a wide range of substrates in the presence of syn-(R, RS)-2a (Xing-Phos). Furthermore, on the basis of the experimental data, it was demonstrated that a trace amount of water play an important role in the enhancement of enantioselectivity.

New Schiff bases derived from chiral d-camphor were determined to be effective phosphine ligands for the asymmetric palladium-catalyzed allylic alkylation of activated methylene compounds, the allylic etherification of alcohols, and the allylic amination of primary amines or secondary amines, in which the corresponding products with various functional groups were achieved in good yields with excellent enantioselectivities (up to >99 % ee). Remarkably, the palladium catalyst derived from Schiff base L2 afforded the highest level of enantioselectivity reported to date for allylic substitution reactions, including allylic etherification and allylic amination, which revealed the privileged role of d-camphor-derived Schiff bases in palladium-catalyzed allylic substitution reactions.

To shed light on the scope and limitations of palladium-catalyzed allylic alkylation in the presence of chiral trans-1,2-diaminocyclohexane-derived Fei-Phos as an effective phosphine ligand, the asymmetric palladium-catalysed alkylation of structurally diverse hard/soft nucleophiles, including allylic etherification of alcohols and the allylic alkylation of activated methylene compounds, indoles, and aromatic amines were investigated in this study; the corresponding products with various functional groups were achieved in good yield and with high enantioselectivity (up to 99% ee).

To shield light on the mechanism of palladium-catalyzed allylic substitutions with structurally diverse nucleophiles (up to 99% ee) in the presence of Fei-Phos ligand (chiral trans-1,2-diaminocyclohexane-derived biphosphine, CycloN2P2-Phos) as an effective chiral P-ligand, mechanistic studies were performed for clarification of the role of multifunctional Fei-Phos in this reaction. The cooperative action of nitrogen and phosphorous atoms in the present Pd-catalyzed allylic alkylation is proved to be a diphosphine-based catalyst system but not a nitrogen-controlled or monophosphine-involved transition state.

To shed light on the influence of reaction parameters on palladium-catalyzed tandem allylic alkylation in the presence of Fei-Phos (a chiral trans-1,2-diaminocyclohexane-derived phosphine ligand), the effect of different phosphine ligands, inorganic or organic bases, Bronsted acids, and other additives on the asymmetric palladium-catalysed alkylation of catechol with allylic diacetate was investigated. In this reaction, 2-vinyl-2,3-dihydro-benzo[1,4]dioxin products with promising enantioselectivity were achieved in good yields. In addition, a novel palladium-catalyzed three-component and one-pot allylic substitution/cyclization/reduction reaction assisted by methylphenylsilane was reported with good selectivity.

In this work, we have successfully determined that the aromatic amide-derived nonbiaryl atropisomer/silver complex (silver-Xing-Phos) is an effective catalyst system for the solvent-dependent exo-selective cycloaddition of glycine aldimino esters with chalcones or less-reactive methyl cinnamates to give the corresponding chalcone- or cinnamate-derived pyrrolidines with multiple stereogenic centers in good yields and high diastereoselectivities as well as excellent enantioselectivities. Remarkably, it is the first example of highly enantioselective silver-catalyzed [3 + 2] cycloaddition of methyl cinnamates with glycine aldimino esters.

The synthesis of a series of aromatic amide-derived non-biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo- and enantioselectivities (up to >99:1 d.r., 95–99 % ee) as well as yields in the silver-catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro-substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction.

An enantioselective magnesium-catalyzed conjugate addition of trimethylsilyl cyanide to chalcones in the presence of Py-BINMOL with multiple stereogenic centers, through dual activation of substrates, has been successfully developed with moderate to good enantioselectivities and in good yields.

The enantioselective construction of a family of chiral glycine-derived aldimino esters is described. The asymmetric tandem conjugate addition–elimination procedure is characterized by its exceptional mild reaction conditions and features with an exquisite enantioselectivity profile using commercially available silver/DTBM-SegPhos catalyst, allowing for the facile preparation of a variety of substituted and chiral glutamic acid derivatives (up to 99% ee) bearing Schiff base in a straightforward manner.

It was found that 1,2-trifluoromethylation reactions of ketones, enones, and aldehydes were easily accomplished using the Prakash reagent in the presence of catalytic amounts of cesium carbonate, which represents an experimentally convenient, atom-economic process for this anionic trifluoromethylation of non-enolisable aldehydes and ketones.

A palladium-catalyzed allylic alkylation of unsubstituted 2-cyanoacetates using a 1,1′-bi-2-naphthol-derived multifunctional N,O,P ligand is reported. A number of chiral monosubstituted 2-cyanoacetates with two adjacent stereogenic carbon centers are obtained in this Pd-catalyzed asymmetric allylic alkylation reaction, in which the multistereogenic and multifunctional 1,1′-bi-2-naphthol-derived N,O,P ligand-promoted Pd-catalyzed asymmetric allylic alkylation reaction proceeds smoothly in high diastereo- and enantioselectivity (up to >99:1 dr and up to 96 % ee).

Remote stereocontrol through conformational transmission along a carbon chain is highly important in synthetic systems and molecular architectures. In this work, the interactional reactivity between a remote silicon-based bulky group and an O-/N-containing functional group has been revealed and determined by lateral lithiation-substitution, desilylation, as well as desilylation-olefination with benzaldehyde. The results suggest considerable information transmission and steric hindrance that can be exploited for the controllable synthesis of atropisomeric molecules. Based on the remote steric effect of a functional group across the aromatic ring of an amide, the construction of isolable atropisomeric amides with functional groups, such as alcohol, amine, and olefin was successfully achieved. All these new atropisomers were obtained in reasonable yield in pure diastereomeric form, and the specific configuration of representative products was confirmed by X-ray crystallography.

Chlorotrimethylsilane (TMSCl) was a highly efficient catalyst in the allylic alkylation of 1,3-diaryl-2-propenyl acetates with a diethylzinc reagent, in which various 1,3-diaryl-2-propenyl acetates are efficiently transferred to 1,3-diarylpent-1-enes in good to excellent yields.

Direct functionalization of terpyridines is an increasingly important topic in the field of dyes and catalysis as well as supramolecular chemistry, but its synthesis and transformation is usually challenging. Herein, a HOMO-raising strategy is reported for the construction of a super-stable novel terpyridine chromophores, in which the selective oxidation of terpyridines at its 3-position was determined successfully to the synthesis of phenol-functionalization of terpyridines (TPyOHs) bearing a hydrogen bonding group. The corresponding TPyOHs displayed strong aggregation-induced emission and exhibited highly selective and visual detection of Zn

The catalytic activity of an in situ forming palladium catalyst system generated from PdCl2(PPh3)2 and hydrosilane [(EtO)3SiH] was revealed in the one-carbon migration and isomerization of 4,4-biaryl-substituted 1-butenes, in which the (EtO)3SiH plays a key role in the palladium-catalyzed one-carbon migration and subsequent isomerization of terminal alkenes. This catalytic protocol is applied in the synthesis of a key building block of cassumunin C in high yield and promising selectivity.

We have demonstrated a highly diastereoselective synthesis of optically pure Ar-BINMOL-derived diols and their analogues. The present study demonstrates a unique cascade chirality transfer in a [1,2]-Wittig rearrangement that leads to chiral diols with three stereogenic centers, which include a chiral sp 3 center at the alcohol and C 2 -axial chirality. Screening these ligands in the arylation of aromatic aldehydes with Grignard reagents shows that the naphthyl-substituted BINMOL promotes the aryl transfer reaction in good yields (70-92%) and moderate-to-good enantioselectivities (up to 72% ee ), and a series of control experiments substantiates that the axial chirality and the chiral sp 3 center at the alcohol of the Ar-BINMOLs are the pivotal enantioselectivitycontrolling structure elements. In addition, this study demonstrated the importance of the chiral sp 3 center at the alcohol on Ar-BINMOL for the aryl transfer reaction. Finally, we found that the chiral Ar-BINMOL ligand 2h mediated the titanium- promoted 1,2-addition of MeMgBr to aldehydes to give the desired products in good yields with excellent enantioselectivities (up to 92% ee ).

The mechanism-oriented reaction design for the divergent synthesis of chiral molecules from simple starting materials is highly desirable. In this work, aromatic amide-derived nonbiarylatropisomer/silver (silver/Xing-Phos) complex was used to catalyze the Michael addition of glycine aldimino esters to chalcones and successfully applied to the subsequent cyclocondensation to afford substituted cis-Δ(1)-pyrroline derivatives with up to 98 % ee. Besides the inherent performance of the chiral Ag/Xing-Phos catalyst system, it was found that the workup of such reactions played an important role for the stereoselective construction of stereodivergent Δ(1)-pyrrolines, in which an epimerization of the cis-Δ(1)-pyrrolines to the trans-isomers during was revealed.

To shed light on the scope and limitations of palladium-catalyzed allylic alkylation in the presence of chiral trans-1,2-diaminocyclohexane-derived Fei-Phos as an effective phosphine ligand, the asymmetric palladium-catalysed alkylation of structurally diverse hard/soft nucleophiles, including allylic etherification of alcohols and the allylic alkylation of activated methylene compounds, indoles, and aromatic amines were investigated in this study; the corresponding products with various functional groups were achieved in good yield and with high enantioselectivity (up to 99% ee).

New Schiff bases derived from chiral d-camphor were determined to be effective phosphine ligands for the asymmetric palladium-catalyzed allylic alkylation of activated methylene compounds, the allylic etherification of alcohols, and the allylic amination of primary amines or secondary amines, in which the corresponding products with various functional groups were achieved in good yields with excellent enantioselectivities (up to >99 % ee). Remarkably, the palladium catalyst derived from Schiff base L2 afforded the highest level of enantioselectivity reported to date for allylic substitution reactions, including allylic etherification and allylic amination, which revealed the privileged role of d-camphor-derived Schiff bases in palladium-catalyzed allylic substitution reactions.

Simple modifications of our novel ligand (Xing-Phos) were presented in this work, and a series of aromatic tertiary amide derived non-biaryl atropisomers were successfully synthesized in good yields. In addition, it was found that the multifunctional aromatic tertiary amide derived non-biaryl atropisomers exhibited an excellent endo-selectivity in the silver-catalyzed [3+2]-cycloaddition of azomethine ylides with N-aromatic maleimide. And especially, good to high levels of enantioselectivity (up to 98% ee) was obtained with a wide range of substrates in the presence of syn-(R, RS)-2a (Xing-Phos). Furthermore, on the basis of the experimental data, it was demonstrated that a trace amount of water play an important role in the enhancement of enantioselectivity.

A highly efficient catalytic protocol for the isomerization of substituted amide-derived olefins is presented that successfully uses a hydride palladium catalyst system generated from [PdCl(2)(PPh(3))(2)] and HSi(OEt)(3). The Z to E isomerization was carried out smoothly and resulted in geometrically pure substituted olefins. Apart from the cis-trans isomerization of double bonds, the selective reduction of terminal olefins and activated alkenes was performed with excellent functional group tolerance in the presence of an amide-derived olefin ligand, and the products were obtained in high isolated yields (up to >99 %). Furthermore, the palladium/hydrosilane system was able to promote the reductive decarbonylation of benzoyl chloride when a (Z)-olefin with an aromatic amide moiety was used as a ligand.

In this letter, an example of interesting metal-free relay airoxidation of α-hydroxysilanes, promoted by the hydroperoxidatedcarbonyl compounds derived from the Michael reaction of 5,5-dimethylcyclohexane-1,3-dioneand chalcone, is reported. A series of aromatic acylsilanes withTBDPS were obtained in promising isolated yields. In addition, asan extension of the relay oxidation under aerobic conditions, thiscatalyst-free relay oxidation induced by diketone can be appliedto the oxidation of general aromatic alcohols (up to 75% yield).

2 -Hydroxy-1,1 -binaphthalene-2-(arylmethanol) (Ar-BINMOLs), a family of new 1,1 -binaphthalene-2,2 -diol derivatives, prepared by a [1,2]-Wittig rearrangement, are introduced as new chiral molecules for the study of the modes of supramolecular aggregation on the basis of ESI-MS, NMR spectroscopy, differential scanning calorimetry (DSC), and Xray diffractometry. Characterization showed that Ar- BINMOLs exhibit different characteristics to BINOL and act as supramolecules due to hydrogen bonding and aromatic π–π/C–H···π interactions. In particular, CD measurements of chiral and racemic Ar-BINMOL 2a in solution and the solid state show a strong Cotton effect, which revealed that ampli-fication of chirality was observed because of the formation of a chiral supramolecular oligomer derived from the racemic monomer. To this end, the Ar-BINMOLs were used as supramolecular auxiliaries to mediate the Michael reaction of anthrone to (E)-β-nitrostyrene and could give theMichael adduct with comparable enantioselectivities. In addition, the Ar-BINMOLs act as ligands to promote asymmetric 1,2-addition of diethylzinc to aldehydes, which resulted in excellent yields and enantioselectivities (up to 99.9% ee) in the reactions of diethylzinc with a broad range of aromatic aldehdyes.

The synthesis of the title compounds bearing a phosphine group and multiple stereogenic centers is reported.

The presented asymmetric title reaction provides the products as mixtures of two diastereomers, each of which is formed with moderate to high enantiomeric excess (63-96% ee).

We report here the first example of the reduction of acylsilanes to α-hydroxysilanes, in which diethylzinc was used as a highly reactive agent in the presence of Ti(O i Pr) 4 or other Lewis acids. The reduction typically proceeds to give synthetically useful α-hydroxysilanes in good yields.

Triethoxysilane plays a key role in the palladium-catalyzed isomerization of terminal alkenes (I).

Allylic alkylation of 1,3-diaryl-2-propenyl acetates leads to 1,3-diarylpent-1-enes without any enantiomeric excess.

This publication also contains the syntheses of several Ar-BINMOL ligands including the one applied in the presented asymmetric Grignard reactions.

A simple method has been developed for the reductive deoxygenation of aromatic ketones and benzylic alcohols in the presence of polymethylhydrosiloxane (PMHS). The reductive deoxygenation of aromatic ketones and benzylic alcohols, including secondary alcohols, to the corresponding methylene hydrocarbons has been achieved in good to excellent yields using palladium chloride (PdCl 2 ) as catalyst and PMHS as hydride source. Such deoxygenations were successfully with aryl alkyl ketones and diaryl ketones, as exemplified by the reductive deoxygenation of acetophenone and benzopheneone, respectively. The corresponding benzylic alcohols and secondary alcohol analogues could also be converted into their respective methylene hydrocarbons by the PdCl 2 /PMHS system.

Hydrosilane serves as an activator of Pd-catalyst with bismuth, thus leading to a novel ligand-free Pd catalyst system for facile oxidative esterification of a variety of benzylic alcohols (I), (IV), and (VI).

A very simple, direct, bismuth-catalyzed conjugate reduction protocol that allows for the catalytic regioselective formation of substituted ketones from enones under mild conditions has been developed. We have shown for the first time that the combined poly(methylhydro)siloxane-malononitrile system can serve as an efficient reductant/reagent in 1,4-conjugate reduction of enones. The regioselectivity, efficiencies, and experimental simplicity of the present method complements the more complex methods previously employed in copper or palladium-catalyzed reduction. This method should prove attractive because of its mild reaction conditions and the interesting chemistry of combining the use of poly(methylhydro)siloxane and malononitrile for selective reduction.

Titanium(IV) isopropanolate is an efficient promotor in the preparation process of the synthetically important title compounds.

The catalyst- and metal free oxidation of α-hydroxysilanes and structurally related secondary alcohols is based on a hydroperoxidated carbonyl compound generated in situ from air and Michael adduct CHD.