Enantioselective Synthesis of Tetra-ortho-Substituted Axially Chiral Biaryls through Rhodium-Catalyzed Double [2 + 2 + 2] Cycloaddition

[reaction: see text] We have established an enantioselective synthesis of both C2 symmetric and unsymmetric tetra-ortho-substituted axially chiral biaryls through rhodium-catalyzed double [2 + 2 + 2] cycloaddition (up to >99% ee). This method serves as an attractive new route to enantioenriched tetra-ortho-substituted axially chiral biaryls in view of the one-step access to substrate diynes and tetraynes starting from readily available alkynes.     

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step

The pot-economical, highly enantioselective synthesis of axially chiral biaryls was developed by using one-pot organocatalyst-mediated domino and aromatization reactions as key steps. The axial information of the precursor, which also has central chirality, was completely inverted in the final biaryls. The inversion of the axial information occurred in the conversion of the central chirality to the axial chirality of an oxidative aromatization step.     

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.     

Synthesis of tetra-ortho-substituted, phosphorus-containing and carbonyl-containing biaryls utilizing a Diels-Alder approach

The application of the Diels-Alder approach to biaryls (DAB) is described for the synthesis of tetra-ortho-substituted biaryl compounds containing orthogonally functionalized substituents. The syntheses of phosphorus-containing, disubstituted alkynes and carbonyl-containing, disubstituted alkynes were accomplished in two to three steps from commercially available reagents. Subsequent Diels-Alder cycloadditions with a range of oxygenated dienes yielded the target biaryls. Further functionalization through palladium-couplings is demonstrated on the phosphorus-containing biaryls. In addition, selective manipulation of each of the remaining ortho substituents on the phosphorus-containing biaryls is demonstrated. One of these phosphorus-containing derivatives is utilized as a highly active catalyst for Suzuki coupling. For the carbonyl-containing series, a wide range of dienophile substituents were screened including esters, ketones, and amides. The key Diels-Alder cycloadditions proceeded smoothly with the commercially available 1-methoxy-1,3-cyclohexadiene to yield the resultant tetra-ortho-substituted biaryls with excellent regioselectivity. The scope of the cycloaddition process was also explored on the carbonyl-containing dienophiles with a series of cyclic dienes. Acyclic dienes were also screened; however, they did not prove effective in the Diels-Alder process with the carbonyl-containing acetylenes. The ability to isolate enantiomerically pure biaryl atropisomers using a benzyl oxazolidinone is disclosed. Finally, the subsequent conversion to an axially chiral anilino alcohol is also reported.     

The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions

Cycloaddition reactions compose one of the most important classes of reactions when it comes to the simultaneous formation of several bonds in one reaction step. The de novo construction of carbocyclic aromatic systems from acetylenes was also found as an excellent possibility for the assembly of heteroaromatic systems. The transition metal-catalysed [2 + 2 + 2] cycloaddition reaction constitutes a fascinating tool for the synthesis of pyridines from nitriles and the most recent developments demonstrate the ability to control the substitution pattern as well as the possibility of introducing chirality by the use of achiral substrates and a chiral catalyst under mild conditions. In this tutorial review we are focusing on the de novo construction of pyridine ring systems by the transition metal-catalysed [2 + 2 + 2] cycloaddition reaction. After surveying the mechanistic features and intermediates of the reaction depending on the different metal complexes used, we depict the preparation of achiral pyridine derivatives. The last section describes the advances in the synthesis of chiral pyridines and biaryls using the cyclotrimerization method. The various possibilities of introducing chirality by catalytic means are presented and illustrated by instructive examples. This review will be of interest for people active in: Organic Chemistry, Organometallic Chemistry, Transition Metal Chemistry, Stereoselective Synthesis, Heterocyclic Chemistry.     

Base-catalyzed inversion of chiral sulfur centers. A computational study

[reaction: see text] A theoretical study on the pyramidal inversion of the chiral sulfur compounds SO(X)(Me) (X = Cl, OMe, p-MePh) has been carried out by means of the DFT(Becke3LYP) method. Our results reveal that in the case of X = Cl, an organic tertiary amine such as NMe(3) can catalyze the racemization. The base-catalyzed inversion of SO(Cl)(Me) is proposed as a feasible dynamic kinetic resolution mechanism for the synthesis of chiral sulfoxides by the DAG method.     

Synthesis of Axially Chiral Biaryls through Sulfoxide‐Directed Asymmetric Mild CH Activation and Dynamic Kinetic Resolution

A mild and robust direct C? H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non‐prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated.     

Synthesis of Axially Chiral Biaryls through Sulfoxide‐Directed Asymmetric Mild C?H Activation and Dynamic Kinetic Resolution

A mild and robust direct C H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non‐prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated.     

Enantiodivergent Atroposelective Synthesis of Chiral Biaryls by Asymmetric Transfer Hydrogenation: Chiral Phosphoric Acid Catalyzed Dynamic Kinetic Resolution

Reported herein is an enantiodivergent synthesis of chiral biaryls by a chiral phosphoric acid catalyzed asymmetric transfer hydrogenation reaction. Upon treatment of biaryl lactols with aromatic amines and a Hantzsch ester in the presence of chiral phosphoric acid, dynamic kinetic resolution (DKR) involving a reductive amination reaction proceeded smoothly to furnish both R and S isomers of chiral biaryls with excellent enantioselectivities by proper choice of hydroxyaniline derivative. This trend was observed in wide variety of substrates, and various chiral biphenyl and phenyl naphthyl adducts were synthesized with satisfactory enantioselectivities in enantiodivergent fashion. The enantiodivergent synthesis of synthetically challenging, chiral o‐tetrasubstituted biaryls were also accomplished, and suggests high synthetic potential of the present method.     

Enantiodivergent One-Pot Synthesis of Axially Chiral Biaryls Using Organocatalyst-Mediated Enantioselective Domino Reaction and Central-to-Axial Chirality Conversion

Enantiodivergent one-pot synthesis of biaryls was developed using a catalytic amount of a single chiral source. A domino organocatalyst-mediated enantioselective Michael reaction and aldol condensation provided centrally chiral dihydronaphthalenes with excellent enantioselectivity, from which an enantiodivergent chirality conversion from central-to-axial chirality was achieved. Both enantiomers of biaryls were obtained with excellent enantioselectivity. All transformations can be conducted in a single reaction vessel. A plausible reaction mechanism for the enantiodivergence is proposed.     

Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary

Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed C−H olefination, using tert-leucine as an inexpensive, catalytic, and transient chiral auxiliary, has been realized. This strategy provides a highly efficient and straightforward access to a broad range of enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (95 to >99 % ee). Kinetic resolution of trisubstituted biaryls bearing sterically more demanding substituents is also operative, thus furnishing the optically active olefinated products with excellent selectivity (95 to >99 % ee, s-factor up to 600).     

Construction of Axially Chiral Arylpyrroles via Atroposelective Diyne Cyclization

Axially chiral biaryls widely exist in natural products and pharmaceuticals and are used as chiral ligands and catalysts in asymmetric synthesis. Compared to the well-established axially chiral 6-membered biaryl skeletons, examples of 5-membered biaryls have been quite scarce, and mono-substituted 3-arylpyrrole atropisomers have not been reported. Here, we disclose a copper-catalyzed atroposelective diyne cyclization for the construction of a range of axially chiral arylpyrrole biaryls in good to excellent yields with generally excellent enantioselectivities via oxidation and X−H insertion of vinyl cations. Importantly, this protocol not only represents the first synthesis of mono-substituted 3-arylpyrrole atropisomers, but also constitutes the first example of atroposelective diyne cyclization and the first atropisomer construction via vinyl cations. Theoretical calculations further support the mechanism of vinyl cation-involved cyclization and elucidate the origin of enantioselectivity.     

Synthèse photochimique de biaryles et hétérobiaryles à partir d'aryl-et hétéroarylamines,d'un nitrite d'alkyle et d'un substrat aromatique ou hétéroaromatique

Photochemical synthesis of biaryls and heterobiaryls from aryl and heteroarylamines, alkylnitrite and aromatic or heteromatic substrates The photochemical reaction of aromatic and heteroaromatic amines with excess t-butyl nitrite in aromatic solvents (benzene, p-xylene, mesitylene) and in hetero-aromatic solvents (furan, thiophene) leads to biaryls or heterobiaryls. t-Butyl nitrite is more convenient than isopentyl nitrite which gives by-products. This new method has been used to synthesize 28 compounds in 17 to 60% yield.     

Self-induced 1-D molecular chain growth of thiophene on Ge(100)

The adsorption of thiophene on Ge(100) has been studied using scanning tunneling microscopy (STM), high-resolution core-level photoemission spectroscopy (HRPES), and density functional theory (DFT) calculations. Until now, thiophene is known to react with the Ge(100) dimer through a [4 + 2] cycloaddition reaction at room temperature, similar to the case of thiophene on Si(100). However, we found that thiophene has two adsorption geometries on Ge(100) at room temperature, such as a kinetically favorable Ge-S dative bonding configuration and a thermodynamically stable [4 + 2] cycloaddition adduct. Moreover, our STM results show that under 0.25 ML thiophene molecules preferentially produce one-dimensional molecular chain structures on Ge(100) via the Ge-S dative bonding configuration.     

Total Synthesis of (+)‐Asteriscanolide: Further Exploration of the Rhodium(I)‐Catalyzed [(5+2)+1] Reaction of Ene‐Vinylcyclopropanes and CO

The total synthesis of (+)‐asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition of a chiral ene‐vinylcyclopropane (ene‐VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl‐radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene‐VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside–outside tricycle to the outside–outside structure by an ester‐reduction/elimination to enol‐ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis.     

1-Magnesiotetrahydroisoquinolyloxazolines as Chiral Nucleophiles in Stereoselective Additions to Aldehydes: Auxiliary Optimization, Asymmetric Synthesis of (+)-Corlumine, (+)-Bicuculline, (+)-Egenine, and (+)-Corytensine, and Preliminary (13)C NMR Studies of 1-Lithio- and 1-Magnesiotetrahydroisoquinolyloxazolines

Transmetalation of 1-lithiotetrahydroisoquinolyloxazolines with magnesium halides affords Grignard reagents that add to aldehydes with up to 80% selectivity for one of the four possible diastereomeric products. An oxazoline chiral auxiliary derived from camphor provides an optimal blend of diastereoselectivity and isomer separability. Synthetic applications of the optimal auxiliary, patterned after a literature approach in the racemic series, comprise an improved (formal) synthesis of bicuculline, egenine, and corytensine, as well as an efficient synthesis of corlumine. Preliminary NMR studies show that both 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines are dynamic mixtures in THF solution at low temperatures. The barrier to pyramidal inversion of the secondary Grignard reagent is in the 9.8-10.1 kcal/mol range, while an upper limit of about 8.2 kcal/mol can be assigned to the barrier to the organolithium inversion.     

Construction of Axial Chirality by Rhodium‐Catalyzed Asymmetric Dehydrogenative Heck Coupling of Biaryl Compounds with Alkenes

Enantioselective construction of axially chiral biaryls by direct C? H bond functionalization reactions has been realized. Novel axially chiral biaryls were synthesized by the direct C? H bond olefination of biaryl compounds, using a chiral [Cp*Rh^III] catalyst, in good to excellent yields and enantioselectivities. The obtained axially chiral biaryls were found as suitable ligands for rhodium‐catalyzed asymmetric conjugate additions.     

Bacterial dioxygenase- and monooxygenase-catalysed sulfoxidation of benzo[b]thiophenes

Asymmetric heteroatom oxidation of benzo[b]thiophenes to yield the corresponding sulfoxides was catalysed by toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and styrene monooxygenase (SMO) enzymes present in P. putida mutant and E. coli recombinant whole cells. TDO-catalysed oxidation yielded the relatively unstable benzo[b]thiophene sulfoxide; its dimerization, followed by dehydrogenation, resulted in the isolation of stable tetracyclic sulfoxides as minor products with cis-dihydrodiols being the dominant metabolites. SMO mainly catalysed the formation of enantioenriched benzo[b]thiophene sulfoxide and 2-methyl benzo[b]thiophene sulfoxides which racemized at ambient temperature. The barriers to pyramidal sulfur inversion of 2- and 3-methyl benzo[b]thiophene sulfoxide metabolites, obtained using TDO and NDO as biocatalysts, were found to be ca.: 25-27 kcal mol(-1). The absolute configurations of the benzo[b]thiophene sulfoxides were determined by ECD spectroscopy, X-ray crystallography and stereochemical correlation. A site-directed mutant E. coli strain containing an engineered form of NDO, was found to change the regioselectivity toward preferential oxidation of the thiophene ring rather than the benzene ring.     

The first asymmetric synthesis of alpha-sulfanylphosphonates

[reaction: see text] Diastereoselectivity of up to 88% was achieved for the synthesis of an alpha-mercapto gamma-unsaturated phosphonate using the readily available chiral dimenthylphosphonyl ester group and a carbanionic [2,3]-sigmatropic rearrangement. Absolute configuration of the newly formed chiral center of this nonracemic thiol was determined, and the corresponding phosphono thiolane and thiolane S-oxide were also stereoselectively prepared.     

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.