Asymmetric Synthesis of Axially Chiral Isoquinolones: Nickel‐Catalyzed Denitrogenative Transannulation

The first Ni⁰/bis(oxazoline)‐catalyzed asymmetric denitrogenative transannulation of 1,2,3‐benzotriazin‐4(3H)‐ones with bulky internal alkynes to form novel axially chiral isoquinolones in an atroposelective manner has been developed. This method provides direct asymmetric access to axially chiral isoquinolones with excellent functional‐group tolerance in excellent yields and stereoselectivities from readily available starting materials under mild reaction conditions. These axially chiral isoquinolones exhibit high cytotoxicity against a number of human cancer cell lines. DFT calculations reveal the nature of the transition state in the key annulation step.     

Phenol Tautomerization Catalyzed by Acid-Base Pairs in Lewis Acidic Beta Zeolites: A Computational Study

We investigate the tautomerization of phenol catalyzed by acid-base active pair sites in Lewis acidic Beta zeolites by means of density functional calculations using the M06-L functional. An analysis of the catalytic mechanism shows that hafnium on the Beta zeolite causes the strongest absorption of phenol compared to zirconium, tin, and germanium. This can be rationalized by the highest delocalization of electron density between the Lewis site and the oxygen of phenol which can in turn be quantified by the perturbative E⁽²⁾ stabilization energy. The reaction is assumed to proceed in two steps, the phenol O−H bond dissociation and the protonation of the intermediate to form the cyclohexa-2,4-dien-1-one product. The rate determining step is the first one with a free activation energy of 26.3, 25.0, 22.1 and 22.7 kcal mol⁻¹ for Ge-Beta, Sn-Beta, Zr-Beta, and Hf-Beta zeolites, respectively. The turnover frequencies follow these reaction barriers. Hence, the intrinsic catalytic activity of the Lewis acidic Beta zeolites studied here is in the order of Hf-Beta≈Zr-Beta>Sn-Beta> Ge-Beta for the tautomerization of phenol.     

Transition‐Metal‐Catalyzed Enantioselective [2+2+2] Cycloadditions for the Synthesis of Axially Chiral Biaryls

Tying up loose ends : Recent advances towards a development of novel transition‐metal‐catalyzed enantioselective [2+2+2] cycloadditions for the synthesis of biaryls are summarized in this Focus Review. Additionally, the enantioselective synthesis of axially chiral biaryls possessing non‐biaryl axial chirality is also presented. These novel asymmetric aromatization reactions allow the production of various axially chiral biaryl compounds with high enantioselectivity.

     

Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

N?C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal‐catalyzed atroposelective N‐arylations have been described. Herein, we disclose an unprecedented Cu‐catalyzed atroposelective N?C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N?C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post‐modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.     

Unprecedented Ring–Ring Interconversion of N,P,C‐Cage Ligands

The novel N,P,C‐cage complexes 5 a – f and 6 a – f have been obtained by the reaction of the P‐pentamethylcyclopentadienylphosphinidene complex 2 , generated thermally from 2H‐azaphosphirene complex 1 , with N‐methyl‐C‐arylcarbaldimines 3 a – f . Li/Cl phosphinidenoid complex 8 reacted with 3 a , b to give N,P,C‐cage complexes 6 a , b , whereas with 3 c – f , complexes 6 c – f were obtained in negligible amounts only. Both types of ligand N,P,C‐cage structures 5 and 6 were found to be in an unprecedented equilibrium, with 5 a , f as the predominant species. Transient electrophilic terminal phosphinidene complexes 10 a – f serve as intermediates in both ligand interconversions ( 5 a , f ? 6 a , f ), as evidenced through trapping reactions with phenylacetylene and N‐methyl‐C‐phenylcarbaldimine, thus leading to the novel N,P,C‐cage complexes 13 b and 15 . DFT calculations predicted a small difference in the relative energies of the two types of N,P,C‐cage ligands, and a remarkable stabilisation of the aminophosphinidene complex 10 as the common precursor, thereby providing an insight into this surprising 5‐ring–3‐ring interconversion. In depth analysis of intermediate 10 revealed the occurrence of both through‐bond (conventional inductive/mesomeric effects) and through‐space (non‐covalent interactions) mechanisms, which amount to 67.8 and 14.4 kcal mol^?1, respectively, and account for the remarkable stabilisation of this intermediate.     

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP-Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

Fluxional chiral DMAP-catalyzed kinetic resolutions of axially chiral biaryls were examined using density functional theory. Computational analyses lead to a revised understanding of this reaction in which the interplay of numerous non-covalent interactions control the conformation and flexibility of the active catalyst, the preferred mechanism, and the stereoselectivity. Notably, while the DMAP catalyst itself is confirmed to be highly fluxional, electrostatically driven π⋅⋅⋅π⁺ interactions render the active, acylated form of the catalyst highly rigid, explaining its pronounced stereoselectivity.     

Circularly Polarized Luminescence from Axially Chiral BODIPY DYEmers: An Experimental and Computational Study

With our new home‐built circularly polarized luminescence (CPL) instrument, we measured fluorescence and CPL spectra of the enantiomeric pairs of two quasi‐isomeric BODIPY DYEmers 1 and 2 , endowed with axial chirality. The electronic circular dichroism (ECD) and CPL spectra of these atropisomeric dimers are dominated by the exciton coupling between the main π–π* transitions (550–560 nm) of the two BODIPY rings. Compound 1 has strong ECD and CPL spectra (g_lum=4×10^?3) well reproduced by TD‐DFT and SCS‐CC2 (spin‐component scaled second‐order approximate coupled‐cluster) calculations using DFT‐optimized ground‐ and excited‐state structures. Compound 2 has weaker ECD and CPL spectra (g_lum=4×10^?4), partly due to the mutual cancellation of electric–electric and electric–magnetic exciton couplings, and partly to its conformational freedom. This compound is computationally very challenging. Starting from the optimized excited‐state geometries, we predicted the wrong sign for the CPL band of 2 using TD‐DFT with the most recommended hybrid and range‐separated functionals, whereas SCS‐CC2 or a DFT functional with full exact exchange provided the correct sign.     

Tungsten Biscorroles: New Chiral Sandwich Compounds

The oxidative metalation method, involving the interaction of free‐base meso‐triarylcorroles and W(CO)₆ in refluxing decalin, led to a set of three tungsten(VI) biscorroles, the first homoleptic sandwich compounds involving corroles. Single‐crystal X‐ray structures of two of the complexes revealed square‐antiprismatic coordination and strongly domed corroles with long W?N distances of 2.15–2.22 Å and a substantial displacement of ～1.17 Å of the metal relative to the mean N₄ planes of the ligands. The structures correspond to approximate C₂ symmetry and are thus chiral. DFT calculations strongly indicate that the enantiomers are configurationally stable and hence amenable to chiral resolution. Their other notable properties include a strongly blueshifted Soret band at (357±2) nm, a relatively intense π→W(d ) near‐IR feature at (781±3) nm, and a low electrochemical HOMO–LUMO gap of approximately 1.3 V. The results obtained herein suggest that metallobiscorroles may emerge as a new class of inherently chiral chromophores with novel optical and electrochemical properties.     

Quinine‐Catalyzed Asymmetric Synthesis of 2,2′‐Binaphthol‐Type Biaryls under Mild Reaction Conditions

Simple quinine as an organocatalyst mediates the addition of various naphthols to halogenated quinones to afford non‐C₂‐symmetrical, axially chiral biaryl products, which are promising compounds as chiral ligands and organocatalysts. The rotational barrier required to have two distinct atropisomers has been evaluated in the products generated from the addition of naphthols to various quinones by means of DFT calculations and HPLC. The use of halogenated quinones as reagents was necessary to have configurationally stable enantiomeric products which can be obtained in good yield and stereoselectivity. These compounds have also been prepared in gram quantities and recrystallized to near enantiopurity.     

Axially Chiral BODIPY DYEmers: An Apparent Exception to the Exciton Chirality Rule

The exciton chirality method (ECM) is commonly recognized as one of the best approaches to assign the absolute configuration of biaryls. This paper reports the first exception to this method for a simple biaryl system. ECD and VCD measurements in combination with DFT (B3LYP/6‐311G*), TDDFT (CAM‐B3LYP/6‐311G*), and Coupled‐Cluster (RI‐SCS‐CC2) calculations were used to determine the absolute configurations of axially chiral BODIPY DYEmers. The ECM fails to predict the sign of the intense CD couplet at 500 nm of the 1,1′‐coupled dimer. The odd behavior was rationalized by considering the strong transition magnetic dipole associated with the 500 nm transition, which leads to an unexpected dominance of the μm coupling at the expense of the μμ one in these compounds. This is the first case in which a strong μm coupling hampers the use of the ECM, but this behavior should not be restricted to the BODIPY chromophore.     

Construction of Axially Chiral Compounds via Central‐to‐Axial Chirality Conversion

Central‐to‐axial chirality conversion represents a fascinating class of chemical processes consisting of the destruction of stereogenic centers and the simultaneous installation of axial chiral elements, which provides efficient methods for the preparation of axially chiral compounds. Using the strategy, a wide range of axially chiral compounds, including biaryls, heterobiaryls, aromatic amides, allenes and vinyl arenes, have been synthesized with high efficiency and excellent enantioselectivity. In addition, central‐to‐axial chirality conversion strategy has been applied to the synthesis of natural products. The strategy has undoubtedly become and will continue to be a hot research topic in the field of asymmetric catalysis and synthesis. In this minireview, we selected some examples to introduce the developments and trends in the central‐to‐axial chirality conversion strategy up to April 2020.     

Steric and Electronic Effects on the Configurational Stability of Residual Chiral Phosphorus‐Centered Three‐Bladed Propellers: Tris‐aryl Phosphanes

A series of tris‐aryl phosphanes, structurally designed to exist as residual enantiomers or diastereoisomers, bearing substituents differing in size and electronic properties on the aryl rings, were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation potential determined by voltammetry. The configurational stability of residual phosphanes, evaluated by dynamic HPLC on a chiral stationary phase or/and by dynamic ¹H and ³¹P NMR spectroscopy, was found to be rather modest (barriers of about 18–20 kcal mol^?1), much lower than that shown by the corresponding phosphane oxides (barriers of about 25–29 kcal mol^?1). For the first time, the residual antipodes of a tris‐aryl phosphane were isolated in enantiopure state and the absolute configuration assigned to them by single‐crystal anomalous X‐ray diffraction analysis. In this case, the racemization barrier could be calculated also by CD signal decay kinetics. A detailed computational investigation was carried out to clarify the helix reversal mechanism. Calculations indicated that the low configurational stability of tris‐aryl phosphanes can be attributed to an unexpectedly easy phosphorus pyramidal inversion which, depending upon the substituents present on the blades, can occur even on the most stable of the four conformers constituting a single residual stereoisomer.     

Computed CH Acidity of Biaryl Compounds and Their Deprotonative Metalation by Using a Mixed Lithium/Zinc‐TMP Base

With the aim of synthesizing biaryl compounds, several aromatic iodides were prepared by the deprotonative metalation of methoxybenzenes, 3‐substituted naphthalenes, isoquinoline, and methoxypyridines by using a mixed lithium/zinc‐TMP (TMP=2,2,6,6‐tetramethylpiperidino) base and subsequent iodolysis. The halides thus obtained, as well as commercial compounds, were cross‐coupled under palladium catalysis (e.g., Suzuki coupling with 2,4‐dimethoxy‐5‐pyrimidylboronic acid) to afford various representative biaryl compounds. Deprotometalation of the latter compounds was performed by using the lithium/zinc‐TMP base and evaluated by subsequent iodolysis. The outcome of these reactions has been discussed in light of the CH acidities of these substrates, as determined in THF solution by using the DFT B3LYP method. Except for in the presence of decidedly lower pK_a values, the regioselectivities of the deprotometalation reactions tend to be governed by nearby coordinating atoms rather than by site acidities. In particular, azine and diazine nitrogen atoms have been shown to be efficient in inducing the reactions with the lithium/zinc‐TMP base at adjacent sites (e.g., by using 1‐(2‐methoxyphenyl)isoquinoline, 4‐(2,5‐dimethoxyphenyl)‐3‐methoxypyridine, or 5‐(2,5‐dimethoxyphenyl)‐2,4‐dimethoxypyrimidine as the substrate), a behavior that has already been observed upon treatment with lithium amides under kinetic conditions. Finally, the iodinated biaryl derivatives were involved in palladium‐catalyzed reactions.     

Prediction of Raman Optical Activity Spectra of Chiral 3‐Acetylcamphorato‐Cobalt Complexes

We examine calculated vibrational Raman optical activity (ROA) spectra of octahedral cobalt complexes containing different combinations of acetylacetonato and 3‐acetylcamphorato ligands. Starting from the Δ‐tris(acetylacetonato)cobalt(III) complex, the ROA spectra of isomers generated by successive replacement of acetylacetonato ligands by chiral (+)‐ or (?)‐3‐acetylcamphorato ligands are investigated. In this way, it is possible to assess the influence of the degree of ligand substitution, ligand chirality, and geometrical isomerism on the ROA spectra. In addition, the effect of the Λ‐configuration is studied. It is found that the ROA spectra contain features that make it possible to identify each of the isomers, demonstrating the great sensitivity of ROA spectroscopy to the chiral nature of the various complexes.     

Kinetic Resolution of the Racemic 2‐Hydroxyalkanoates Using the Enantioselective Mixed‐Anhydride Method with Pivalic Anhydride and a Chiral Acyl‐Transfer Catalyst

A variety of optically active 2‐hydroxyalkanoates and the corresponding 2‐acyloxyalkanoates are produced by the kinetic resolution of racemic 2‐hydroxyalkanoates by using achiral 2,2‐diarylacetic acid with hindered carboxylic anhydrides as the coupling reagents. The combined use of diphenylacetic acid, pivalic anhydride, and (+)‐(R)‐benzotetramisole ((R)‐BTM) effectively produces (S)‐2‐hydroxyalkanoates and (R)‐2‐acyloxyalkanoates from the racemic 2‐hydroxyalkanoates (s‐values=47–202). This protocol directly provides the desired chiral 2‐hydroxyalkanoate derivatives from achiral diarylacetic acid and racemic secondary alcohols that do not include the sec‐phenethyl alcohol moiety by using the transacylation process to generate the mixed anhydrides from the acid components with bulky carboxylic anhydrides under the influence of the chiral acyl‐transfer catalyst. The transition state that provides the desired (R)‐2‐acyloxyalkanoate from (R)‐2‐hydroxyalkanoate included in the racemic mixture is disclosed by DFT calculations, and the structural features of the transition form are also discussed.