Highly enantioselective synthesis of atropisomeric anilide derivatives through catalytic asymmetric N-arylation: conformational analysis and application to asymmetric enolate chemistry

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).     

Conformationally imprinted receptors: atropisomers with "write", "save", and "erase" recognition properties

[reaction: see text] An atropisomeric receptor with "write", "save", and "erase" recognition properties is presented. The receptor adopts a complementary conformation when heating in the presence of an ethyl adenine-9-acetate guest molecule. This complementary hydrogen bonding conformation is "saved" upon cooling to room temperature due to the reestablishment of restricted rotation and is stable even upon removal of the guest. Finally, the atropisomeric receptor can be "erased" by heating in the absence of the guest.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Convenient synthesis of selected meta- and ortho-substituted pentaarylpyridines via the Suzuki-Miyaura cross-coupling reaction

The first synthesis of sterically demanding, stable at room temperature atropisomeric derivatives of penta-(ortho-substituted phenyl)pyridines is described. The Suzuki-Miyaura cross-coupling reaction of pentabromopyridine and selected meta- and ortho-tolylboronic acids afforded a series of pentaarylpyridine derivatives. The structures of two room temperature stable atropisomeric derivatives of penta-(o-tolyl)pyridines were confirmed by single-crystal X-ray analysis. Racemic atropisomers were examined by ¹H NMR spectroscopy with a chiral solvating agent in order to visualize the presence of individual enantiomers.     

253. 1 H-NMR investigation of droso- and isodrosopterin--a contribution to structure elucidation. Pteridines. LV

The NMR. spectra of droso- and isodrosopterin ( 1 ) in DMSO-d₆, 1% DCl/D₂O solution, CF₃CO₂D, and conc. sulfuric acid are discussed in detail. Missing of methine and methyl groups and proof for the presence of three isolated methylene functions of which two show a geminal coupling are consistent with the proposed structure of atropisomeric di(7,8-dihydropterinyl)- methane dye stuffs.     

Asymmetric Construction of Axially Chiral 2‐Arylpyrroles by Chirality Transfer of Atropisomeric Alkenes

Axially chiral 2‐arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by organocatalytic asymmetric N‐alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2‐arylazepine atropisomers were realized through a rationally designed ene reaction.     

Directed metalation/ligand coupling approach to the enantioselective synthesis of 1,1′-binaphthyls

Introduction of a 2-isopropoxycarbonyl or 2-NN-dimethylcarbamoyl group into homochiral 1-p-tolyl- or 1-t-butyl-sulfinylnaphthalenes, via directed metalation reaction, followed by ligand coupling reaction with 1-naphthylmagnesium bromide, furnished atropisomeric 1,1′-binaphthyls in 82–95% enantiomeric excess (e.e.).     

Rapid screening of a receptor with molecular memory

[reaction: see text] Atropisomeric receptor 1 can change conformation and maintain the new conformation when heated and cooled in the presence of a guest molecule. This molecular memory can be used as a rapid method of screening potential guests. Heating atropisomeric diacid 1 with various hydrogen-bonding guests leads to a shift in the syn/anti ratio that could be easily monitored as it is stable at room temperature even in the absence of the guest molecules.     

Efficient synthesis of optically active atropisomeric anilides through catalytic asymmetric N-arylation reaction

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, N-arylation of ortho-tert-butyl-NH-anilides with 4-nitroiodobenzene proceeds with high enantioselectivity (89-95% ee) to give optically active atropisomeric anilides possessing N-C chiral axis. Furthermore, the intramolecular version of the present catalytic asymmetric N-arylation gave atropisomeric lactams with high optical purity (94-96% ee).     

Easy access to medium rings by entropy/strain reduction,Part 3. Competition between dihydroazepine and enamine formation in reaction of tetrahalosubstituted dibromides with primary amines

The reaction of Z,Z‐2,3,4,5‐tetrahalo‐2,4‐dien‐1,6‐dibromides ( 3 , R¹ ‐ R⁴ = Cl, Br) with primary amines in the presence of potassium carbonate leads to both the dihydroazepines 4 and secondary enamines 5 . The formation of enamine is suppressed with toluene sulfonamide as nitrogen source. (2Z,4Z)‐2,3,4,5‐Tetrabromo‐hexa‐2,4‐diene‐1,6‐diol (2, R¹ ‐ R⁴ = Br) is atropisomeric in solution.     

Copolymerization of Ethene and Carbon Monoxide with (Diphosphine)nickel Catalysts

This work presents the results of the ethene–CO copolymerization with in situ generated catalysts based on atropisomeric 1,4‐diphosphines and nickel(II). The influence of the reaction conditions and the NMR characterization of the copolymers are described.     

Unexpected racemization behavior of 8,8′-dialkyl-1,1′-biisoquinoline

The racemization behavior of a series of atropisomeric 8,8′-dialkyl-1,1′-biisoquinolines, in which methyl, ethyl, and isopropyl groups are introduced for enhancing the transannular steric hindrance, is reported. Contrary to prior expectations, their configurational stability was inversely proportional to the steric size of the alkyl groups.     

A new route to methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (pheromone of Acanthoscelides obtectus) utilizing a palladium-catalyzed asymmetric allene formation reaction

[reaction: see text] A formal total synthesis of the sex attractant of male dried bean beetle, methyl (R,E)-(-)-tetradeca-2,4,5-trienoate, was achieved by a new efficient route utilizing the Pd-catalyzed asymmetric allene synthesis reaction. It was found that the atropisomeric biaryl bisphosphine (R)-segphos showed better enantioselectivity than (R)-binap in the Pd-catalyzed reaction for preparing alkyl-substituted axially chiral allenes.     

Dynamic kinetic resolution of atropisomeric amides

[reaction: see text] Using L-proline as catalyst in the asymmetric aldol reaction and a series of benzamides and naphthamides, we have accomplished a dynamic kinetic resolution that simultaneously establishes the stereochemistry of the atropisomeric amide's chiral axis and a stereogenic center. The enantioselectivities ranged from 82% to 95% and the diastereoselectivities from 2.1:1 to 7.0:1.     

Application of the Suzuki reaction as the key step in the synthesis of a novel atropisomeric biphenyl derivative for use as a liquid crystal dopant

A heavily functionalized atropisomeric biphenyl derivative (4), which is designed to possess a large lateral dipole moment, has been synthesized with use of a Suzuki coupling as the key step and resolved by chiral HPLC. The final coupling reaction is complicated by rapid hydrolytic deboronation of the sterically hindered, electron poor boronate 22. Rigorously anhydrous conditions are therefore necessary to achieve the coupling.     

Determination of atropisomeric and planar polychlorinated biphenyls, their enantiomeric fractions and tissue distribution in grey seals using comprehensive 2D gas chromatography

High prevalence of uterine occlusions and sterility is found among Baltic ringed and grey seal. Polychlorinated biphenyls (CBs) are suspected to be the main cause. The CB concentrations are higher in affected than in healthy animals, but the natural variation is considerable. Thus, it might be possible to assess the health status of seals by CB analysis. The ratios of chiral compounds (enantiomeric fractions (EFs)) such as atropisomeric CBs are of particularinterest, since these may reflect differences in metabolic rates. An analytical procedure was developed and used to determine the levels of atropisomeric CBs, planar-CBs (WHO-PCBs) and total CBs in seals of different health status. Comprehensive 2D gas chromatography (GC x GC) was used to separate the target analytes from other CBs and interferences and a micro electron-capture detector (microECD) was used for detection. EFs of the atropisomeric CBs were difficult to determine as the levels were low and the interferences many. Two column combinations bad to be used to avoid biased results-both had a chiral column as first-dimension column. The second-dimension column was coated with either a high-polarity cyanopropyl or a liquid crystal phase. EFs were determined for five atropisomeric CBs, i.e. CBs 91,95, 132, 149 and 174. The results were verified by GC x GC-time-of-flight mass spectrometry (TOF-MS). Some atropisomeric CBs had EFs that deviated strongly from the racemic-mixture value. The deviations were larger in liver than blubber, which indicates enantioselective metabolism. However, there was no selective passage of the studied atropisomeric CBs across placenta and no selective blood-brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between the total CB levels and health status.     

Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off‐target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure‐based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds.     

Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement

A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.     

Enantioselective Synthesis of Atropisomeric Amides by Dynamic Resolution: Thermodynamic Control with a Proline-Derived Diamine Resolving Agent

By exploiting the thermal instability about the Ar–CO axis at high temperature, atropisomeric amides can be dynamically resolved to provide material with up to 96.5 % ee in 70–80 % overall yield from racemic starting material. The amides are coupled with a diamine resolving agent and equilibrated to single diastereoisomers. Hydrolysis returns enantiomerically enriched amide (see reaction scheme).     

Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O?H???NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol^?1, thereby facilitating the observed dynamic kinetic resolution.