Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)‐2‐aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring‐opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P?O bond. Interestingly, the use of a P^III phosphine precursor afforded a P‐epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.     

Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C−H Amidations of Phosphine Oxides

An enantioselective C−H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert‐leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P‐chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P‐chiral phosphorus(III) compounds.     

Chiral Cp‐Rhodium(III)‐Catalyzed Asymmetric Hydroarylations of 1,1‐Disubstituted Alkenes

Metal‐catalyzed functionalizations at the ortho position of a directing group have become an efficient bond‐forming strategy. A wide range of transformations that employ Cp*Rh^III catalysts have been described, but despite their synthetic potential, enantioselective variants that use chiral versions of the Cp* ligand remain scarce (Cp*=pentamethyl cyclopentadienyl). Cyclopentadienyl compounds with an atropchiral biaryl backbone are shown to be suitable ligands for the efficient intramolecular enantioselective hydroarylation of aryl hydroxamates. Dihydrofurans that bear methyl‐substituted quaternary stereocenters are thus obtained by C? H functionalization under mild conditions.     

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.     

Aromatic Amide‐Derived Non‐Biaryl Atropisomers as Highly Efficient Ligands in Silver‐Catalyzed Asymmetric Cycloaddition Reactions

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.     

Enantioselective Construction of Axially Chiral Amino Sulfide Vinyl Arenes by Chiral Sulfide‐Catalyzed Electrophilic Carbothiolation of Alkynes

The enantioselective construction of axially chiral compounds by electrophilic carbothiolation of alkynes is disclosed for the first time. This enantioselective transformation is enabled by the use of a Ts‐protected bifunctional sulfide catalyst and Ms‐protected ortho‐alkynylaryl amines (Ts=tosyl; Ms=mesyl). Both electrophilic arylthiolating and electrophilic trifluoromethylthiolating reagents are suitable for this reaction. The obtained products of axially chiral vinyl–aryl amino sulfides can be easily converted into biaryl amino sulfides, biaryl amino sulfoxides, biaryl amines, vinyl–aryl amines, and other valuable difunctionalized compounds.     

Copper-Catalyzed Dynamic Kinetic Asymmetric P−C Coupling of Secondary Phosphine Oxides and Aryl Iodides

Transition-metal-catalyzed enantioselective P−C cross-coupling of secondary phosphine oxides (SPOs) is an attractive method for synthesizing P-stereogenic phosphorus compounds, but the development of such a dynamic kinetic asymmetric process remains a considerable challenge. Here we report an unprecedented highly enantioselective dynamic kinetic intermolecular P−C coupling of SPOs and aryl iodides catalyzed by copper complexes ligated by a finely modified chiral 1,2-diamine ligand. The reaction tolerates a wide range of SPOs and aryl iodides, affording P-stereogenic tertiary phosphine oxides (TPOs) in high yields and with good enantioselectivity (average 89.2 % ee). The resulting enantioenriched TPOs were transformed into structurally diverse P-chiral scaffolds, which are highly valuable as ligands and catalysts in asymmetric synthesis.     

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.     

Rhodium(III)‐Catalyzed Enantiotopic C−H Activation Enables Access to P‐Chiral Cyclic Phosphinamides

Compounds with stereogenic phosphorus atoms are frequently used as ligands for transition‐metal as well as organocatalysts. A direct catalytic enantioselective method for the synthesis of P ‐chiral compounds from easily accessible diaryl phosphinamides is presented. The use of rhodium(III) complexes equipped with a suitable atropochiral cyclopentadienyl ligand is shown to enable an enantiodetermining C−H activation step. Upon trapping with alkynes, a broad variety of cyclic phosphinamides with a stereogenic phosphorus(V) atom are formed in high yields and enantioselectivities. Moreover, these can be reduced enantiospecifically to P ‐chiral phosphorus(III) compounds.     

Simultaneous Induction of Axial and Planar Chirality in Arene–Chromium Complexes by Molybdenum‐Catalyzed Enantioselective Ring‐Closing Metathesis

The molybdenum‐catalyzed asymmetric ring‐closing metathesis of the various C_s‐symmetric (π‐arene)chromium substrates provides the corresponding bridged planar‐chiral (π‐arene)chromium complexes in excellent yields with up to >99 % ee. With a bulky and unsymmetrical substituent, such as N‐indolyl or 1‐naphthyl, at the 2‐positions of the η⁶‐1,3‐diisopropenylbenzene ligands, both biaryl‐based axial chirality and π‐arene‐based planar chirality are simultaneously induced in the products. The axial chirality is retained even after the removal of the dicarbonylchromium fragment, and the chiral biaryl/heterobiaryl compounds are obtained with complete retention of the enantiopurity.     

Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double‐Site Lewis Base Catalyst

The enantioselective bromocyclization of allylic amides catalyzed by phosphorus‐containing Lewis bases was examined in detail. A series of control experiments and NMR studies showed that a partially oxidized bis‐phosphine generated in situ serves as the actual enantioselective catalyst. The reaction mechanism involves distinct roles of two Lewis basic sites, P and P=O, with P⁺Br serving as a fine‐tuning element for substrate fixation in the chiral environment, and P⁺OBr as the Br⁺ transfer agent to the olefin. Catalyst loading could be reduced to as little as 1 mol %, and the reaction affords enantioenriched oxazolines with up to >99.5 % ee.     

Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C−H Amidations of Phosphine Oxides

An enantioselective C−H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert-leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P-chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P-chiral phosphorus(III) compounds.     

Enantioselective Copper‐Catalyzed Alkylation of Quinoline N‐Oxides with Vinylarenes

An asymmetric copper‐catalyzed alkylation of quinoline N ‐oxides with chiral Cu–alkyl species, generated by migratory insertion of a vinylarene into a chiral Cu−H complex, is reported. A variety of quinoline N ‐oxides and vinylarenes underwent this Cu‐catalyzed enantioselective alkylation reaction, affording the corresponding chiral alkylated N‐heteroarenes in high yield with high‐to‐excellent enantioselectivity. This enantioselective protocol represents the first general and practical approach to access a wide range of chiral alkylated quinolines.     

Enantioselective Allylic Amination of Morita‐Baylis‐Hillman Acetates Catalyzed by Chiral Thiourea‐Phosphine

The enantioselective allylic amination of Morita‐Baylis‐Hillman acetates catalyzed by chiral cyclohexane‐based thiourea‐phosphine catalysts was investigated. In the presence of 20 mol% rosin‐derived thiourea‐phosphine 3j , the chiral amines were obtained in up to 88% yield and up to 85% ee.     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C?H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Non‐biaryl atropisomers. part 1. configurationally stable 1,2‐diaryl‐3‐methyl‐1,4,5,6‐tetrahydropyrimidinium salts

In the present communication we describe two examples of a new kind of configurationally stable non‐biaryl atropisomers in which the Ar‐N bond is the chiral axis, namely 1‐(o‐nitrophenyl)‐2‐aryl‐3‐methyl‐1,4,5,6‐tetrahydropyrimidinium iodides 1. Stereochemical features of such compounds are analyzed on the basis of their ¹H and ¹³C one‐ and two‐dimensional nmr spectra. A comparison is made with the corresponding amidines 2 .     

β‐Cyclodextrin Functionalized Nanoporous Graphene Oxides for Efficient Resolution of Asparagine Enantiomers

Efficient resolution of racemic mixture has long been an attractive but challenging subject since Pasteur separated tartrate enantiomers in 19^th century. Graphene oxide (GO) could be flexibly functionalized by using a variety of chiral host molecules and therefore, was expected to show excellent enantioselective resolution performance. However, this combination with efficient enantioselective resolution capability has been scarcely demonstrated. Here, nanoporous graphene oxides were produced and then covalently functionalized by using a chiral host material‐β‐cyclodextrin (β‐CD). This chiral GO displayed enantioselective affinity toward the l ‐enantiomers of amino acids. In particular, >99 % of l ‐asparagine (Asn) was captured in a racemic solution of Asn while the adsorption of d ‐enantiomer was not observed. This remarkable resolution performance was subsequently modelled by using an attach‐pull‐release dynamic method. We expect this preliminary concept could be expanded to other chiral host molecules and be employed to current membrane separation technologies and finally show practical use for many other racemates.     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C−H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Rhodium(III)‐Catalyzed Asymmetric Access to Spirocycles through C−H Activation and Axial‐to‐Central Chirality Transfer

Axial‐to‐central chirality transfer is an important strategy to construct chiral centers, where the axially chiral reagents are mostly limited to atropomerically stable ones. Reported herein is a Rh^III‐catalyzed enantioselective spiroannulative synthesis of nitrones. The coupling proceeds via C?H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer.     

Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols through NHC‐Catalyzed Atroposelective Acylation

We present here a highly efficient NHC‐catalyzed kinetic resolution of a wide range of 1,1′‐biaryl‐2,2′‐diols and amino alcohols to provide them in uniformly ≥99 % ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process.