Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α‐methylbenzyl amine for cis‐aziridines from α‐diazo esters and for trans‐aziridines from α‐diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis‐aziridines involved the (R)‐amine with the (S)‐ligand, but curiously, for trans‐aziridines the matched case involved the (R)‐amine with the (R)‐ligand for imines derived from benzaldehyde and n‐butanal, and the (R)‐amine with the (S)‐ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.     

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na₂[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.     

Platinum(II) and palladium(II) complexes analogous to oxaliplatin with different cyclohexyldicarboxylate isomeric anions and their in vitro antitumour activity. Structural elucidation of [Pt(C2O4)(cis-dach)]

Several new Pt^II and Pd^II complexes bearing the enantiomerically pure (1R,2R)-(–)-l,2-cyclohexanediamine (dach) ligand, of general formula [MX₂{(1R,2R)-dach}], where M = Pt or Pd, X₂ = cis- or trans- or (1R,2R)-1,2-cyclohexyldicarboxylate anions, have been synthesized and characterized physicochemically and spectroscopically. These complexes have been screened in vitro against the three tumour cell lines K₅₆₂, HeLa and L₉₂₉, and the results obtained were compared with those of the reference standards, cisplatin, carboplatin and oxaliplatin; the known antitumour drugs. The single crystal X-ray structure determination of the [Pt(C₂O₄)(cis-dach)] complex has been discussed and compared with that of oxaliplatin, [Pt(C₂O₄){(1R,2R)-dach}].     

Determination of the binding epitope of lidocaine with AGP: minimizing the effects of nonspecific binding in saturation transfer difference experiments

The ligand epitope map and the effect of nonspecific binding is assessed for lidocaine binding to α₁-acid glycoprotein using the saturation transfer difference nuclear magnetic resonance experiment performed as a function of the ligand/protein ratio. The experimental design tested two different approaches for preparing solutions with various ligand/protein ratios; holding the protein concentration constant and increasing the ligand concentration; and holding the ligand concentration constant while decreasing the protein concentration. Nonspecific binding effects were more prevalent in experiments in which the ligand concentration was increased, although spectra with higher signal-to-noise ratios were obtained under these conditions. The epitope map determined for achiral lidocaine is compared with previously determined results for the (R)- and (S)-enantiomers of propranolol. The weaker binding affinity of lidocaine may be partially attributed to steric hindrance by the lidocaine N-ethyl groups which may prevent close contact of the lidocaine amine with the negatively charged amino acids at the apex of the protein binding pocket.     

Palladium-Catalyzed Arylation of Endocyclic 1-Azaallyl Anions: Concise Synthesis of Unprotected Enantioenriched cis-2,3-Diarylpiperidines

Unprotected cis-2,3-diarylpiperidines are synthesized through an unprecedented palladium-catalyzed cross-coupling reaction between aryl halides and elusive endocyclic 1-azaallyl anions. These intermediates are generated in situ by the deprotonation of 2-aryl-1-piperideines, precursors that are readily prepared in two operations from simple piperidines. An asymmetric version of this reaction with (2R, 3R)-iPr-BI-DIME as the ligand provides products in moderate to good yields and enantioselectivities. This study significantly expands the synthetic utility of endocyclic 1-azaallyl anions.     

The Absolute Configuration of (+)‐Ethyl cis‐1‐Benzyl‐3‐hydroxypiperidine‐4‐carboxylate and (+)‐4‐Ethyl 1‐Methyl cis‐3‐Hydroxypiperidine‐1,4‐dicarboxylate; a Revision

Discrepancies between chiroptical data from the literature and our determination of the structure of the title compounds (+)‐ 5 and (+)‐ 9a were resolved by an unambiguous assignment of their absolute configuration. Accordingly, the dextrorotatory cis‐3‐hydroxy esters have (3R,4R)‐ and the laevorotatory enantiomers (3S,4S)‐configuration. The final evidences were demonstrated on both enantiomers (+)‐ and (?)‐ 5 by biological reduction of 4 by bakers' yeast and stereoselective [Ru^II(binap)]‐catalyzed hydrogenations of 4 (Scheme 2), by the application of the NMR Mosher method on (+)‐ and (?)‐ 5 (Scheme 3), as well as by the transformation of (+)‐ 5 into a common derivative and chiroptical correlation (Scheme 4).     

Crystalline Stereocomplexed Polycarbonates: Hydrogen‐Bond‐Driven Interlocked Orderly Assembly of the Opposite Enantiomers

Four novel crystalline stereocomplexed polymers are formed by mixing isotactic (R)‐ and (S)‐polycarbonates in 1:1 mass ratio. They show the enhanced thermal stability and new crystalline behavior, significantly distinct from the component enantiomer. Two stereocomplexed CO₂‐based polycarbonates from meso‐3,4‐epoxytetrahydrofuran and 4,4‐dimethyl‐3,5,8‐trioxabicyclo[5.1.0]octane have high melting temperatures of up to 300 °C, about 30 °C higher than the individual enantiomers. Isotactic (R)‐ or (S)‐poly(cyclopentene carbonate) and poly(cis‐2,3‐butene carbonate) are typical amorphous polymeric materials, however, upon mixing both enantiomers together, a strong interlocked interaction between polymer chains of opposite configuration occurs, affording the crystalline stereocomplexes with melting temperatures of about 200 °C and 180 °C, respectively. A DFT study suggests that the driving force forming the stereocomplex is the hydrogen‐bonding between carbonate units of the opposite enantiomers.     

Synthesen von (1R)-cis-3-(2′,2′-Dihalovinyl)-2, 2-dimethylcyclopropan-carbonsäuren via Favorskii-Umlagerung von optisch aktiven Cyclobutanonen

Syntheses of (1R)-cis-3-(2′,2′-Dihalovinyl)-2,2-dimethylcyclopropane Carboxylic Acids via Favorskii-rearrangement of Optically Active Cyclobutanones The cis-cyclobutanones 7 are resolved by means of optically active amine salts of their sodium hydrogen sulfite adducts. The desired (1R)-cis-carboxylic acids 9 are obtained from the (+)-cis-cyclobutanones 7 via Favorskii-rearrangement and HX-elimination. The recycling of undesired (?)-cis-cyclobutanones 7 is carried out in good yield by their racemization, thus rendering the total synthesis 1 + 2 → 9 chirally economic.     

Enantiomeric recognition of α-(1-naphthyl)ethylammonium perchlorate by enantiomerically pure dimethylphenazino-18-crown-6 ligand in solid and gas phases

X-Ray crystallographic studies of enantiomerically pure dimethylphenazino-18-crown-6 ligand (R,R)-1 and its complexes with the enantiomers of α-(1-naphthyl)ethylammonium perchlorate NapEt were carried out. These studies clearly show that the heterochiral complex (R,R)-1–(S)-NapEt is more stable than the homochiral one (R,R)-1–(R)-NapEt. It was pointed out that besides the hydrogen bonding, mainly the π–π interaction between the aromatic systems of the host and guest, and the difference in steric repulsions were responsible for enantioselectivity. Molecular mechanical calculations using the LMOD/MINTA method also predicted the heterochiral complex to be more stable than the homochiral one in the gas phase.     

Gas chromatographic enantiomer separation of agrochemicals and polychlorinated biphenyls (PCBs) using modified cyclodextrins

The enantiomers of the polychlorinated polycyclic xenobiotics heptachlor, cis- and trans-chlordane, cis- and trans-heptachlorepoxide, oxychlordane, and bromocyclen have been resolved by gas chromatography with selectively substituted cyclodextrins. The order of elution of these compounds and of α-hexachlorocyclohexane (α-HCH) was determined by comparison with enantiomerically enriched reference compounds obtained by preparative enantioselective gas chromatography. A separation of the eight stereoisomers of the pyrethroid insecticide allethrin into seven peaks was achieved. Both trans-diastereomers were separated into their enantiomers and the order of elution could be determined by comparison with commercially available (S)-bioallethrin and trans-bioallethrin. Also one cis-diastereomer was separated, wheras the other cis-isomer could not be resolved. In addition 15 out of 19 stable atropisomeric polychlorinated biphenyls with 5, 6 and 7 chlorine substituents, some chiral organophosphorus pesticides, including acephate and malaoxon and the herbicide bromoacil were separated.     

Exploiting Aromatic Interactions for β‐Peptide Foldamer Helix Stabilization: A Significant Design Element

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side‐chains in β‐peptide oligomers by intramolecular backbone–side chain CH–π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self‐assembly in a polar medium for the β‐peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis‐[1S,2S]‐ or cis‐[1R,2R]‐1‐amino‐1,2,3,4‐tetrahydronaphthalene‐2‐carboxylic acid (ATENAC) and cis‐[1R,2S]‐ or cis‐[1S,2R]‐2‐aminocyclohex‐3‐enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side‐chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain‐length. The hydrophobically driven self‐assembly was achieved for the helix‐forming oligomers, seen as vesicles in transmission electron microscopy images. The self‐association phenomenon, which supports the helical secondary structure of these oligomers, depends on the hydrophobic surface area, because a higher number of aromatic side‐chains yielded larger vesicles. These results serve as an essential element for the design of helices relating to the H10/12 helix. Moreover, they open up a novel area for bioactive foldamer construction, while the hydrophobic area gained through the aromatic side‐chains may yield important receptor–ligand interaction surfaces, which can provide amplified binding strength.     

Reduction of carbonyl compounds via hydrosilylation: V. Synthesis of optically active allylic alcohols via regioselective asymmetric hydrosilylation

Regioselective asymmetric reduction of prochiral α,β-unsaturated ketones to optically active allylic alcohols was performed via hydrosilylation catalyzed by a rhodium(I) complex with (+)-BMPP, (+)-DIOP and (?)-DIOP as chiral ligands. The allylic alcohols with optical purity up to 69% e.e. were obtained in good yields. The extent of asymmetric induction was found to depend on the stereo-electronic matching of the chiral ligand, ketone and hydrosilane employed. In the asymmetric reduction of (R)-carvone, leading to carveol, the extent of asymmetric induction was found to depend markedly on the ligand/rhodium ratio. Either trans-(5R,1S)-carveol or cis-(5R,1R)-carveol was obtained with good stereoselectivity by using (?)-DIOP or (+)-DIOP as chiral ligand, and it turned out that the chiral center present in carvone had only a slight influence on the asymmetric induction by the chiral catalysts.     

Synthesis and biological evaluation of water-soluble trans-[bicyclo[2.2.2]octane-7R,8R-diamine]platinum(II) complexes with linear or branched alkoxyacetates as leaving groups

Four platinum(II) complexes, trans-[bicyclo[2.2.2]octane-7R,8R-diamine]bis(alkoxyacetato-O,O’) platinum(II) (alkoxyacetate = methoxyacetate (2), ethoxyacetate (3), isopropoxyacetate (4), and tert-butoxyacetate (5)) were synthesized and spectrally characterized. The cytotoxicity of these water-soluble complexes was evaluated by CCK-8 assay in vitro against HCT-116, HepG-2, and A549 cancer cell lines. Most of the complexes had cytotoxic activity against the tested cancer cell lines. Among them, 3 showed more potent antitumor effect than cisplatin or oxaliplatin. Complex 3 could cause HCT-116 cell line death based on an apoptotic pathway since it has a dicyclic moiety similar to 1R,2R-diaminocyclohexane in oxaliplatin. Agarose gel electrophoresis on the interaction between 3 and DNA indicated that it has different behavior from that of cisplatin or oxaliplatin, which has a high correlation with the ligand used.     

Photochromic spironaphthoxazines: A theoretical study

Photochromic spironaphthoxazines and their open merocyanine forms were studied via semiempirical Hartree–Fock SCF quantum chemical calculations. The most stable of the merocyanine isomers were found to have a cis–trans–cis conformation and the zwitterionic form is, generally, more stable than is the quinoidal tautomer. The calculated activation energy for the thermal bleaching reaction is in good agreement with the experimental one.     

Amino Acid Ionic Liquids as Chiral Ligands in Ligand‐Exchange Chiral Separations

Recently, amino acid ionic liquids (AAILs) have attracted much research interest. In this paper, we present the first application of AAILs in chiral separation based on the chiral ligand exchange principle. By using 1‐alkyl‐3‐methylimidazolium L ‐proline (L ‐Pro) as a chiral ligand coordinated with copper(II), four pairs of underivatized amino acid enantiomers—dl ‐phenylalanine (dl ‐Phe), dl ‐histidine (dl ‐His), dl ‐tryptophane (dl ‐Trp), and dl ‐tyrosine (dl ‐Tyr)—were successfully separated in two major chiral separation techniques, HPLC and capillary electrophoresis (CE), with higher enantioselectivity than conventionally used amino acid ligands (resolution (R_s)=3.26–10.81 for HPLC; R_s=1.34–4.27 for CE). Interestingly, increasing the alkyl chain length of the AAIL cation remarkably enhanced the enantioselectivity. It was inferred that the alkylmethylimidazolium cations and L ‐Pro form ion pairs on the surface of the stationary phase or on the inner surface of the capillary. The ternary copper complexes with L ‐Pro are consequently attached to the support surface, thus inducing an ion‐exchange type of retention for the dl ‐enantiomers. Therefore, the AAIL cation plays an essential role in the separation. This work demonstrates that AAILs are good alternatives to conventional amino acid ligands for ligand‐exchange‐based chiral separation. It also reveals the tremendous application potential of this new type of task‐specific ILs.     

Electroweak Quantum Chemistry for Possible Precursor Molecules in the Evolution of Biomolecular Homochirality

The unified `electroweak' theory of the electromagnetic and weak nuclear interactions in physics predicts a small energy difference (ΔE_pv) between the left‐ and right‐handed enantiomers of chiral molecules. Thus, electroweak theory provides one of several possible explanations for the origin of biomolecular homochirality (nature's preference for L ‐amino acids and D ‐monosaccharides). Recent systematic electroweak quantum‐chemical studies find ΔE_pv to be an order of magnitude larger than previously anticipated, which has sparked renewed interest in the subject. The present paper addresses, for the first time, the question of the relative stability of certain possible prebiotic precursor molecules suggested in the work of A. Eschenmoser and co‐workers: aziridine‐2‐carbonitrile (CH₂NHCHCN) and oxiranecarbonitrile (CH₂OCHCN), also commonly referred to as 2‐cyanoaziridine and cyanooxirane, respectively. The cis/trans‐isomerization pathway of aziridine‐2‐carbonitrile is initially characterized by standard quantum‐chemical techniques. At the highest level of theory employed, the trans‐isomer is found to lie by 4.0 kJ mol⁻¹ above its cis‐counterpart. The transition state connecting the two is another 74 kJ mol⁻¹ higher in energy. After including unscaled, harmonic zero‐point energy corrections, these values change to 3.7 and 69 kJ mol⁻¹, respectively. Using the multi‐configuration linear response (MCLR) approach to electroweak quantum chemistry (R. Berger, M. Quack, J. Chem. Phys. 2000 , 112, 3148), the energy difference between the enantiomers of the various compounds and transition structures has been computed within the random phase approximation, a special case of the general MCLR technique. (S)‐Oxiranecarbonitrile and the (R)‐configurations of aziridine‐2‐carbonitrile are found to be energetically more stable than their mirror images at their equilibrium nuclear configurations. Use of a solvation model to approximate an aqueous environment has a modest, but consistent, effect on the computed parity‐violating energies. In the present examples, solvation increases the magnitude of the parity‐violating energy by ca. 10%.     

Coordination‐Driven Macrocyclization for Locking of Photo‐ and Thermal cis→trans Isomerization of Azobenzene

Both trans and cis isomers of azobenzene‐linked bis‐terpyridine ligand L1 were incorporated in rigid macrocycles linked by Fe^II(tpy)₂ (tpy: terpyridine) units. The complex of the longer trans‐ L1 is dinuclear [(trans‐ L1 )₂ ? Fe^II₂], whereas the complex of the shorter cis‐ L1 is mononuclear [cis‐ L1? Fe^II]. The complex cis‐ L1? Fe^II was not only thermally stable but also photochemically inactive. These results indicate a perfectly locked state of cis‐azobenzene. The stable macrocyclic structure of cis‐ L1? Fe^II causes locking of the isomerization. To the best of our knowledge, this is first example of dual locking of photo‐ and thermal isomerization of cis‐azobenzene.     

Arithmetic manipulation of coupling constants to obtain torsional angles

Various arithmetic combinations of J_trans and J_cis from the AA′BB′ analysis of ? CH₂—CH₂– fragments in 6-membered rings have been examined for their relationship to the internal torsional angle Ψ. The simple ratio R (J_trans/J_cis) appears to offer the most complete removal of substituent electronegativity effects and hence the best values of Ψ. The Karplus equation is very inaccurate when the substituents are highly polar. The simple difference D (J_trans–J_cis) overcompensates for electronegativity effects and thus also gives relatively inaccurate torsional angles. An alternative, artificial linear combination of the coupling constants, such as D′ (J_trans–2J_cis), appears to be able to provide torsional angles that are almost as good as those from the R value, although the Karplus A value must be evaluated. Adjustment of the simple difference D for electronegativity is possible by including a function of the AA′ and BB′ chemical shifts. These results are fairly good, and the parameter A need not be evaluated. This approach may fail, however, with particularly anisotropic substituents, since the chemical shift may depend on factors other than electronegativity. Although all five methods give reasonably good results, the R value appears to offer the most reliable results for the full range of substituents.     

Enantioselective Synthesis of cis-Decalin Derivatives by the Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones

A novel strategy for the synthesis of cis-decalins by an ytterbium-catalyzed asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones and silyl cyclohexadienol ethers is reported here. A broad range of synthetically important cis-decalin derivatives with multiple contiguous stereogenic centers and functionalities are obtained in good yields and stereoselectivities. A full set of diastereomeric substituted cis-decalin motifs are readily accessible by tuning the absolute configurations of substituted silyl cyclohexadienol ethers (R or S) as well as the ligands (R or S). The synthetic potential is showcased by the enantioselective total synthesis of 4-amorphen-11-ol, and further demonstrated by the first total synthesis of cis-crotonin.     

Axially Chiral TADF-Active Enantiomers Designed for Efficient Blue Circularly Polarized Electroluminescence

The use of a chiral, emitting skeleton for axially chiral enantiomers showing activity in thermally activated delayed fluorescence (TADF) with circularly polarized electroluminescence (CPEL) is proposed. A pair of chiral stable enantiomers, (−)-(S)-Cz-Ax-CN and (+)-(R)-Cz-Ax-CN, was designed and synthesized. The enantiomers, both exhibiting intramolecular π-conjugated charge transfer (CT) and spatial CT, show TADF activities with a small singlet–triplet energy difference (ΔE_ST) of 0.029 eV and mirror-image circularly polarized luminescence (CPL) activities with large g_lum values. Notably, CP-OLEDs based on the enantiomers feature blue electroluminescence centered at 468 nm with external quantum efficiencies (EQEs) of 12.5 and 12.7 %, and also show intense CPEL with g_EL values of −1.2×10⁻² and +1.4×10⁻², respectively. These are the first CP-OLEDs based on TADF-active enantiomers with efficient blue CPEL.