Asymmetric synthesis of axially chiral benzamides and anilides by enantiotopic lithiation of prochiral arene chromium complexes

Axially chiral benzamides and anilides were prepared by enantiotopic lithiation at the distinguished benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl 2,6-dimethylbenzamide (1) and N-methyl-N-acyl 2,6-dimethylaniline (14 and 21) with a chiral lithium amide base followed by electrophilic substitution in good yields with high optical purity. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized under air to give chromium-free axially chiral benzamides and anilides in an enantiomerically active form without axial bond rotation at room temperature.     

Asymmetric synthesis of axially chiral benzamides and anilides utilizing planar chiral arene chromium complexes

Optically active axially chiral 2,6-disubstituted benzamides and anilides were stereoselectively prepared by utilizing planar chiral (arene)chromium complexes. Nucleophilic addition to enantiomerically pure planar chiral tricarbonyl(N,N-diethyl-2-methyl-6-formyl- (or 6-acyl)benzamide)chromium complex gave axially chiral 2-methyl-6-substituted N,N-diethyl benzamide chromium complexes with high selectivity. An alternative method for the preparation of axial chiral benzamides or anilides is an enantiotopic lithiation at the benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl-2,6-dimethylbenzamide and N-methyl-N-acyl-2,6-dimethylaniline with a chiral lithium amide followed by electrophilic substitution. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized in air to give chromium-free axially chiral benzamides and anilides in enantiomerically enriched form without axial bond rotation at room temperature.     

Phase‐Transfer‐Catalyzed Asymmetric Synthesis of Axially Chiral Anilides

Catalytic asymmetric synthesis of axially chiral o‐iodoanilides and o‐tert‐butylanilides as useful chiral building blocks was achieved by means of binaphthyl‐modified chiral quaternary ammonium‐salt‐catalyzed N‐alkylations under phase‐transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N‐allyl‐o‐iodoanilide was transformed to 3‐methylindoline by means of radical cyclization with high chirality transfer from axial chirality to C‐centered chirality. Furthermore, stereochemical information on axial chirality in o‐tert‐butylanilides could be used as a template to control the stereochemistry of subsequent transformations. The transition‐state structure of the present phase‐transfer reaction was discussed on the basis of the X‐ray crystal structure of ammonium anilide, which was prepared from binaphthyl‐modified chiral ammonium bromide and o‐iodoanilide. The chiral tetraalkylammonium bromide as a phase‐transfer catalyst recognized the steric difference between the ortho substituents on anilide to obtain high enantioselectivity. The size and structural effects of the ortho substituents on anilide were investigated, and a wide variety of axially chiral anilides that possess various functional groups could be synthesized with high enantioselectivities. This method is the only general way to access a variety of axially chiral anilides in a highly enantioselective fashion reported to date.     

Synthesis of Axially Chiral Anilides Enabled by a Palladium/Ming-Phos-Catalyzed Desymmetric Sonogashira Reaction

Atropisomeric anilides are one of important C—N axially chiral compounds.Compared with the N-terminal functionalization to pre-pare such compounds,C-terminal fu...     

Enantioselective synthesis of axially chiral anilides through rhodium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides

We have developed a rhodium-catalyzed enantioselective intermolecular [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides for the synthesis of axially chiral anilides. The axial chirality is constructed at the formation of benzene rings with high enantioselectivity (up to 98% ee). It should be noted that the present reaction employs the readily prepared trimethylsilylynamides starting from commercially available bis(trimethysilyl)acetylene and the trimethylsilyl group of the product anilides is expected to be utilized for further functionalization.     

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.     

Axial Chirality in Alkylidene-Cyclic Molecules

Axial chirality is an interesting stereoisomeric phenomenon in organic chemistry and a key structural feature of several organic compounds. Atropisomers such as biaryls, anilides and diaryl ethers are one type of axially chiral compounds, whose axial chirality is resulted from rotationally blocked single bond. Allenes, spiranes and alkylidenecycloalkanes are another type of axially chiral compounds and their axial chirality come from the perpendicular geometry of two pairs of substituents. The axial chirality in atropisomers, allenes and spiranes has been widely investigated and well developed, while the similar chirality in alkylidene-cyclic molecules gained very limited attentions. This concept focuses on summarizing recent advances of axial chirality in alkylidene-cyclic molecules and arouses the research interests to this promising field.     

Structural optimization of a chiral selector for use in preparative enantioselective chromatography

Utilizing the immobilized-target strategy, the structure of a proline-derived chiral stationary phase was optimized for use in the preparative chromatographic separation of the enantiomers of two chiral selectors used in commercial chiral stationary phases. In this study, various N-acylated proline anilides were prepared and chromatographed on the commercial Pirkle-1J and -Burke 2 chiral stationary phases. The analyte which displayed the greatest retention without sacrifice of enantioselectivity (the 3,5-dimethoxyanilide of N-undecenoyl proline) was chosen for incorporation into the preparative chiral stationary phase. Once prepared, this phase shows increased analyte retention and enantioselectivity comparable to that of earlier phases derived from 3,5-dimethyl anilides of proline. The increased retention allows one to use mobile phases in which the target analytes are more soluble, hence greatly facilitating an increase in the through-put of a column of a given size.     

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.     

Synthesis and study of heptasubstituted triphenylenes with chiral fragments and predictable type of mesomorphism

The forecasting of columnar and chiral mesomorphism was done for the new series of triphenylene derivatives. The mesomorphic properties of the two heptasubstituted triphenylenes containing chiral fragments were studied. The prediction results agreed well with the experimental data. Anilides of 1-amino-2,3,6,7,10,11-hexa(heptyloxy)triphenylene with abietic and dihydrocholic acids were found to exhibit the enantiotropic columnar dimesomorphism and to display the chiral columnar mesophases in the low-temperature range. The anilides obtained possess a lower thermal stability and extended interval of the mesophase existence than the initial amine.     

Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.     

Stereochemical control of both C-C and C-N axial chirality in the synthesis of chiral N,O-biaryls

A Rh(I)-catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral ynamides is described here. This work demonstrates a unique concept of stereochemical control of both the C-C and C-N axial chirality and provides an approach to the synthesis of chiral N,O-biaryls as well as chiral anilides.     

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β‐Lactams with contiguous tetra‐ and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4‐exo‐trig cyclization of axially chiral enolates generated from readily available α‐amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β‐lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β‐lactam enolates thus formed through reversible intramolecular conjugate addition (4‐exo‐trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work‐up procedure) to give β‐lactams in up to 97 % ee.     

A Strategy for Synthesizing Axially Chiral Naphthyl‐Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates

A new strategy for enantioselective synthesis of axially chiral naphthyl‐indoles has been established through catalytic asymmetric addition reactions of racemic naphthyl‐indoles with bulky electrophiles. Under chiral phosphoric acid catalysis, azodicarboxylates and o‐hydroxybenzyl alcohols served as bulky but reactive electrophiles that were attacked by C2‐unsubstituted naphthyl‐indoles, which underwent a dynamic kinetic resolution to afford two series of axially chiral naphthyl‐indoles in good yields (up to 98 %) and high enantioselectivities (up to 98:2 er).     

Palladium-catalyzed asymmetric synthesis of axially chiral (allenylmethyl)silanes and chirality transfer to stereogenic carbon centers in S(E)' reactions

[reaction: see text] Novel stereoselective reactions of 4-substituted-1-trimethylsilyl-2,3-butadienes ((allenylmethyl)silanes) were developed. The axially chiral (allenylmethyl)silanes were prepared from (3-bromopenta-2,4-dienyl)trimethylsilane by a Pd-catalyzed asymmetric reaction with soft nucleophiles with up to 88% enantioselectivity. The (allenylmethyl)silanes reacted with acetals in the presence of a TiCl(4) promoter to give 1,3-diene derivatives via an S(E)' pathway. The 1,3-dienyl products have (E)-geometry exclusively and up to 88%( )()chirality transfer from the axially chiral allenes to the centrally chiral 1,3-dienes was observed in the S(E)' reaction.     

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N′-Bisindoles

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N′-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.     

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II-catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III-catalyzed enantioselective C(sp³)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity-determining step.     

Phosphorus-bearing axially chiral biaryls by catalytic asymmetric cross-cyclotrimerization and a first application in asymmetric hydrosilylation

A novel and efficient, two-step route to axially chiral biaryls is demonstrated. In a direct asymmetric cross-cyclotrimerization in the presence of a chiral cobalt(I) catalyst, axially chiral biaryls bearing phosphoryl moieties have been prepared, and through indirect evidence the authors have been able to clarify the origin of the stereochemical induction and the nature of the central intermediate in the catalytic cycle. By subsequent reduction of the phosphoryl moiety to the corresponding phosphine, a very efficient and atom-economical approach to chiral systems has been developed. These chiral systems clearly have great potential use as axially chiral monodentate P- or bidentate P,O-ligands, as has been demonstrated by the employment of the novel NAPHEP as a new monodentate acting ligand in an asymmetric hydrosilylation reaction.     

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II‐catalyzed atroposelective C?H olefination. A broad range of axially chiral biaryl‐2‐amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram‐scale synthesis. The resulting axially chiral biaryl‐2‐amines also provide a platform for the synthesis of a set of chiral ligands.     

Synthesis of Axially Chiral Biaryl-2-amines by PdII-Catalyzed Free-Amine-Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II-catalyzed atroposelective C−H olefination. A broad range of axially chiral biaryl-2-amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram-scale synthesis. The resulting axially chiral biaryl-2-amines also provide a platform for the synthesis of a set of chiral ligands.