Synthesis of chiral azamacrocycles using the bis(α-chloroacetamide)s derived from chiral 1,2-diphenylethylenediamine

Optically active diphenyl-substituted tetraaza-12-crown-4 diamide ( 10 ), tetraaza-15-crown-5 diamide ( 12 ), tetraaza-18-crown-6 diamide ( 11 ), and hexaaza-18-crown-6 diamide ( 9 ) ligands were prepared by treating the appropriate secondary diamines with the (R,R)- and (S,S)- forms of 1,2-bis(N-methyl-α-chloracetamido)-1,2-diphenylethane ( 20 ). Macrocyclic diamides 9 and 10 were reduced to form the optically active diphenyl-substituted hexaaza-18-crown-6 ( 13 ) and tetraaza-12-crown-4 ( 14 ), respectively. Reduction of macrocyclic diamide ligands 11 and 12 gave a complex mixture of products from which the desired tetraaza-15-crown-5 and 18-crown-6 compounds could not be isolated. Dichloride 20 was prepared by treating the chiral forms of 1,2- diphenylethylenediamine with chloroacetic anhydride or chloroacetyl chloride. The crystal structures for the (R,R)-form of dichloride 20 and the (S,S)-forms of macrocycles 10 and 11 are reported.     

Asymmetric transfer hydrogenation of ketones catalyzed by rhodium and iridium complexes with chiral bidentate Schiff's bases

Rhodium and iridium complexes of Schiff's bases derived from (1R,2R)- and (1S,2S)-diaminocyclohexane catalyze asymmetric transfer hydrogenation of alkyl aryl ketones in PrⁱOH at room temperature to give chiral secondary alcohols (up to 65% ee).     

Cross-chiral examinations of molecular enantioselective recognition by fast atom bombardment mass spectrometry: Host–guest complexations between chiral crown ethers and chiral organic ammonium ions

Using fast atom bombardment (FAB) mass spectrometry (MS), cross-chiral relationships were confirmed for the first time for the diasteromeric host-guest complexations between the chiral crown ether host (1) and the chiral organic ammonium ion guest (2) on the basis of the relative peak intensities (RPI). Both host–guest combinations (R, R, R, R) – 1, (R) – 2 and (S, S, S, S) – 1, (S) – 2 obviously provided larger RPI values than the combination of both (R, R, R, R) – 1, (S) – 2 and (S, S, S, S) – 1, (R) – 2 by a factor of 1.6 as an averaged value: 1.87 (n = 4)/1.16 (n = 4) = 1.6. These results are consistent with the expected stabilities of the host-guest complexations by CPK model examinations. Successfully observed cross-chiral examinations strongly suggest a potentially useful FABMS/RPI methodology for rapidly searching newly designed and synthesized crown ether-like host compounds with a higher degree of enantioselectivity.     

Reagent control of stereochemistry in allylic additions to chiral aldehydes with CpMo(NO)(X)(2-methallyl) complexes of high enantiomeric purity

Reactions of (R)- and (S)-CpMo(NO)(η³-methallyl)X(X=camphorsulfonate, Cl, Br, I) with chiral α-substituted aldehydes yield homoallylic alcohols with high diastereoselectivity. Reactions of (R)- and (S)-CpMo(NO)(η³- methallyl)L ^S[L^S = (IS)-(+)-10-camphorsulfonate] with D -glyceraldehyde acetonide yield the corresponding homoallylic alcohols in >98% diastereomeric excess. Reactions with racemic 2-phenyl-propionaldehyde and nonracemic 3-benzyloxy-2-methylpropanol are also considered and show that there is very high reagent control of stereo-chemistry in additions to the carbonyl group.     

Synthesis of chiral 3-substituted-3-aminomethyl-pyrrolidines and related compounds

The preparation of a series of chiral 3-methyl-3-substituted-pyrrolidines/pyrrolidinones starting from (R)-4-(methoxycarbonyl)-1-(1R-phenethyl)-2-pyrrolidinone ( 1 ) is described. The chiral α-methylbenzyl functionality serves not only as a nitrogen protecting group for the pyrrolidine nitrogen, but also as a chiral auxillary. The synthesis of the 4-position enantiomers was accomplished by converting the ester of 1 to the ketone, protecting the ketone as the benzyloxime and separation by chromatography. These key intermediates were converted to the (R) and (S)-3-methyl-3-aminomethylpyrrolidines by removal of the benzyl group followed by oxidation. The 3-methyl-3-(1-aminoethyl)pyrrolidines were obtained via a two step reduction of the corresponding oximes. The stereochemical assignments were determined by X-ray crystallography.     

Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.     

Ti-mediated addition of diethylzinc to benzaldehyde. The effect of chiral additives

In the presence of a chiral tridentate bissulfonamide, the titanium-mediated addition of diethylzinc to benzaldehyde gave alkylated products ranging from the (R)-enantiomer, formed with an e.e. of 26%, to the (S)-enantiomer, formed in 72% e.e. The enantioselectivity was also affected by the presence of additional chiral mono- and bidentate ligands, with the reactions proceeding via complexes containing the chiral sulfonamide and the additive. The addition of (1R,2R)-1,2-diphenyl-1,2-ethanediamine and (1S,2S)-1,2-diphenyl-1,2-ethanediamine gave the (S)-product with e.e. of 49% and the (R)-product with 16% e.e., respectively, whereas without additives the (R)-product was obtained in 26% e.e. In the presence of (1R,2R)-1,2-diphenyl-1,2-ethanediamine only (i.e. without the chiral sulfonamide), the (S)-product formed with a 3% e.e.     

Synthesis and in vitro cytotoxicity of platinum(II) complexes with chiral N-monosubstituted 1,2-cyclohexyldiamine derivatives as the carrier groups

Eight platinum(II) complexes with the new chiral ligands, (1R,2R)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (R) or (1S,2S)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (S) as the carrier groups were designed, synthesized, and spectrally characterized. All platinum(II) complexes showed much better aqueous solubility than cisplatin and oxaliplatin. In vitro cytotoxicity of the compounds against human HepG-2, MCF-7, A549, and HCT-116 cell lines was evaluated. Results indicate that all compounds with R as the carrier group showed cytotoxicity against HCT-116, A549, and MCF-7 cell lines; however, all compounds with S as carrier group exhibited disappointing cytotoxicity against tested cell lines. Compound R2, bearing ClCH₂COO^- as leaving group, exhibited better cytotoxicity than that of carboplatin against A549 and MCF-7 cell lines and also showed close activity to oxaliplatin against HCT-116 cell line.     

Synthesis of chiral epoxyalkynes

The synthesis of novel chiral propargylic epoxides ((R)-1-t-butyldimethylsilyl-3,4-epoxy-1-butyne, (3S,4S)-3,4-epoxy-1-octyne, (3R,4S)-1-t-butyldimethylsilyl-3,4-epoxy-1-pentyne) has been developed starting from the readily available tartaric acid derivative, (S,S)-(+)-2,3-O-isopropylidene-L-threitol.     

Standard values of vicinal coupling constants in the assignment of relative configurations and conformational analysis of acyclic chiral carbinols and hydrocarbons

Standard values of vicinal coupling constants are proposed in order to assign relative configuratations and analyse the conformational distribution of acyclic chiral carbinols and hydrocarbons. Thus, the assignment of relative configurations has been achieved for the diastereomeric carbinols, (2R4R, 2S4S)- and (2R4S, 2S4R)-5,5-dimethyl-4-phenyl-2-hexanol and (1R3R, 1S3S)- and (1R3S, 1S3R)-1-mesityl-4,4-dimethyl-3-phenyl-1-pentanol, through the analysis of the respective vicinal coupling constants and the corresponding conformational distribution. The analysis of the vicinal coupling constants allows the establishment of the monoconformational character of the (2R4S, 2S4R) diastereomer in the first case and the (1R3R, 1S3S) diastereomer in the second case.     

Amino alcohol based chiral solvating agents: synthesis and applications in the NMR enantiodiscrimination of carboxylic acids

Four optically active amino alcohols were synthesized via the ring opening of (R)-N-(2,3-epoxypropyl)phthalimide with (R)-2-phenyl glycinol, (1R,2S)-cis-1-amino-2-indanol, (R)-2-amino-1-butanol and (S)-phenyl ethylamine in 73-93% yields. The enantioselective recognition of these receptors towards the enantiomers of racemic carboxylic acids was studied by ¹H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of the guests were determined by using Job plots and a non-linear least-squares fitting method, respectively. Large non-equivalent chemical shifts (up to 30.0 Hz) can be achieved in the presence of chiral amino alcohols 2 and 5. Amongst the chiral receptors used, compound 5 was found to be the best chiral shift reagent, and was effective in the determination of the enantiomeric excess of chiral carboxylic acids.     

Improved synthesis of the enantiomers of propafenone using chiral building blocks

Summary A short and efficient synthesis of the enantiomers of the antiarrhythmic drug propafenone (1) is described using both (R)-isopropylideneglycerol tosylate and (S)-glycidyl tosylate as chiral building blocks. The key step of the high yield synthesis is the acetalization of the carbonyl group in 1-(2-hydroxyphenyl)-3-phenyl-1-propanone (2) which allows application of mild reaction conditions in the subsequent alkylation of the phenolic hydroxy group.With our best wishes dedicated to Prof. Dr.H. Achenbach on the occasion of his 65^th birthday     

Design,enantioselective synthesis,and antiviral activities against potato virus Y of axially chiral thiazine derivatives

A series of novel thiazine derivatives featuring axial chirality in both (R) and (S) configurations were successfully synthesized by N-heterocyclic carbene (NHC)-catalyzed enantioselective [3 + 3] annulations, and their potential as anti-plant virus agents against potato virus Y (PVY) was evaluated. Biological activity results demonstrated that most of these chiral thiazine derivatives exhibited significant activities against PVY. Notably, compound (S) -3g displayed a remarkable 58% inactivation effect against PVY at a concentration of 500 μg/mL, slightly surpassing the effectiveness of Ningnanmycin (NNM) at 57%. Additionally, (S) -3g exhibited curative activity of 57%, which is superior to NNM (53%). Molecular docking studies revealed preliminary insights into the distinct biological properties of the two different enantiomers, (R) or (S) -3g against PVY, wherein single enantiomer (S) -3g formed a more stable interaction with PVY-CP, as indicated by its lower binding free energy (−41.18 kcal/mol) compared to (R)- 3g (−36.9 kcal/mol). The findings in this study with a new class of axially chiral thiazine derivatives shall inspire further development of chiral heterocycles as potential drug candidates for the protection of plant virus infections.     

Synthesis of chiral oligopeptides by means of catalytic asymmetric hydrogenation of dehydropeptides

Asymmetric hydrogenations of Ac-ΔTyr(Ac)-(S)-Ala-Gly-OMe (6), Ac-ΔTyr(Ac)-(R)-AlaGly-(S)-Phe-OMe (7), Ac-ΔPhe-NH-CH(R) CH₂-OCH₂Ph (10), HCO-ΔPhe-(S)-Leu-OMe (16), X-AA-ΔPhe-AA'-OMe (5: X ^tBOC, CBZ, CF₃CO; AA, AA' = α-amino acid), and ^tBOC-AA-ΔPhe-AA'-NH-Y (21: Y=H, NH-AA'-ΔPhe-AA-^tBOC, NHPh), catalyzed by cationic Rh complexes, [L*Rh(NBD)]⁺ClO₄ (L* = chiral diphosphine), were performed to give the corresponding chiral oligopeptides with high stereoselectivities. It was found that the nature of the N-protecting group of dehydrotripeptides (5) exerted a significant influence on the asymmetric induction as well as catalyst efficiency. The chiral centers in AA' and AA' amino acid residues in 5 were also found to have some influence on the catalytic asymmetric induction. Possible mechanism which can accommodate these effects are discussed. Asymmetric reduction of RCOCO-AA-OMe (13) via hydrosilylation was carried out to give chiral depsipeptide units. The asymmetric hydrogenation of dehydropeptides was successfully applied to the synthesis of enkephalin analogs, Ac-(R)Tyr-(R) -Ala-Gly-(S)-Phe-(S)-Leu-OMe (23) and Ac-(S)Tyr-(R) -Ala-Gly-(S)-Phe-(S)- Leu-OMe (29)     

乳酸类合成子构建的四连接螺旋手性配位聚合物的合成、结构和光催化性质

通过乳酸衍生物和3-溴-4-羟基苯甲酸的组合得到对映体3-溴-4-(((1R)-1-羧基乙基)氧基)苯甲酸(R-H₂bba)和3-溴-4-(((1S)-1-羧基乙基)氧基)苯甲酸(S-H₂bba)。以其为手性合成子在水热条件下分别与1,3-二(吡啶-4-基)丙烷(1,3-dpp)和Ni²⁺反应,构建了对映手性配位聚合物{[Ni(R-bba)(1,3-dpp)(H₂O)_0.5]·1.5H₂O}_n(HU12-R)和{[Ni(S-bba)(1,3-dpp)(H₂O)_0.5]·1.5H₂O}_n(HU12-S)。结构分析揭示HU12-R和HU12-S是具有dia网络特征的三维螺旋骨架。在骨架中,阴离子配体R-bba^2-和S-bba^2-分别与Ni²⁺中心连接在一起围绕2,螺旋轴得到一对小的对映螺...     

乳酸类合成子构建的四连接螺旋手性配位聚合物的合成、结构和光催化性质

通过乳酸衍生物和3-溴-4-羟基苯甲酸的组合得到对映体3-溴-4-(((1R)-1-羧基乙基)氧基)苯甲酸(R-H₂bba)和3-溴-4-(((1S)-1-羧基乙基)氧基)苯甲酸(S-H₂bba)。以其为手性合成子在水热条件下分别与1,3-二(吡啶-4-基)丙烷(1,3-dpp)和Ni²⁺反应,构建了对映手性配位聚合物{[Ni(R-bba)(1,3-dpp)(H₂O)_0.5]·1.5H₂O}_n (HU12-R)和{[Ni(S-bba)(1,3-dpp)(H₂O)_0.5]·1.5H₂O}_n (HU12-S)。结构分析揭示HU12-R和HU12-S是具有dia网络特征的三维螺旋骨架。在骨架中,阴离子配体R-bba^2-和S-bba^2-分别与Ni²⁺中心连接在一起围绕2₁螺旋轴得到一对小的对映螺旋链,而1,3-dpp与Ni²⁺中心则围绕4₁螺旋轴构建出另外一对大的对映螺旋链。电化学测试显示HU12-R属n型半导体,具有低阻抗性质,对紫外可见光有很强的吸收能力。进一步光催化实验证实在紫外光照射下所得配合物对染料降解有明显催化效果。     

Ferroelectric liquid crystals with axially chiral 2,2′-spirobiindan-1,1′-dione cores

The axially chiral mesogens 5-alkoxy-5′-[(4-alkoxybenzoyl)oxy]-2,2′-spirobiindan-1,1′-dione (QL7-n) were synthesised as racemic mixtures and resolved as single enantiomers by preparative chiral phase HPLC. The shorter homologues (R)-QL7-8 and QL7-9 form enantiotropic N* and SmC* phases, whereas the longer homologues (R)-QL7-10 and QL7-12 form an enantiotropic SmC* phase only. Texture analysis showed that the helical pitch of the N* phase is below the wavelength range of visible light; a helical pitch of 187 nm was measured at T – T_NI = –5 K by selective reflection using enantiomerically enriched mixtures of (R)- and (S)-QL7-8 (0.35 ≤ ee ≤ 0.80). Spontaneous polarisations were measured as a function of temperature in the SmC* phase by the triangular wave method. P_S values at saturation range from 102 nC cm^–2 for (R)-QL7-8 to 120 nC cm^?2 for (R)-QL7-9, which are up to three times greater than the highest polarisation previously reported for an axially chiral SmC* mesogen. Optical tilt angles θ were measured as a function of temperature and showed a sharp rise consistent with first-order N*–SmC* or I–SmC* transitions, with values at saturation ranging from 42 to 44°.     

A convenient synthesis and the mesomorphic properties of new chiral ferroelectric thiobenzoates

A secondary chiral (R)-(?)-2-alcohol underwent the Mitsunobu reaction with triphenylphosphine, diethyl azodicarboxylate and ethyl 4-hydroxybiphenylcarboxylate, resulting in the desired (S)-(+)-product with high enantiomeric purity (>99% ee), with the chiral branched chain attached to the biphenyl. This method is operationally simple and provides the very important chiral precursor in good yields (62% in dry THF and 72% in dry Et₂O). The condensation of the (S)-(+)-acid chloride from this material and a suitable 4-n-alkylthiophenol in toluene in the presence of pyridine or triethylamine furnishes the chiral (S)-(+)-thiobenzoate liquid crystals in good yields (80–83% in pyridine and 65–68% in Et₃N). (S)-(+)-4-(1-Methylheptyloxy)biphenyl 4-alkylthiobenzoates are abbreviated (S)-MHOBSn , where n varies from 4 to 10 and denotes the number of carbon atoms in the alkyl chain. DSC, polarizing microscopy and X-ray diffraction showed that the (S)-MHOBSn series possesses a rich phase polymorphism: two highly ordered tilted phases CrG* and SmI*, as well as the ferroelectric smectic C (SmC*) and chiral nematic (N*) phase. In this series, the seldom observed transition between the chiral phases SmI*–SmC* is seen. All the compounds possess stable enantiotropic SmC* and N* phases. The existence of weak intermolecular hydrogen-bonding in (S)-MHOBSn was confirmed by FTIR spectroscopy.     

Synthesis, characterization, DNA binding and cleavage studies of chiral Ru(II) salen complexes

Interaction of chiral Ru(II) salen complexes (S)-1 and (R)-1 with Calf Thymus DNA (CT-DNA) was studied by absorption spectroscopy, competitive binding study, viscosity measurements, CD measurements, thermal denaturation study and cleavage studies by agarose gel electrophoresis. The DNA binding affinity of (S)-1 (6.25 × 10³ M⁻¹) was found to be greater than (R)-1 (3.0 × 10³ M⁻¹). The antimicrobial studies of these complexes on five different gram (+)/(−) bacteria and three different fungal organisms showed selective inhibition of the growth of gram (+) bacteria and were not affective against gram (−) and fungal organisms. Further, the (S)-1 enantiomer inhibited the growth of organisms to a greater extent as compared to (R)-1 enantiomer.     

Stereocontrolled enantioselective addition of diethylzinc to aldehydes using new chiral aminoalcohols

The new chiral β-aminoalcohols of indolinylmethanols ( 1 ) and their reduced derivatives ( 2 ) were synthesized from (S)-indoline-2-carboxylic acid. Both (R) and (S) enantiomers of the optically active secondary alcohols have been successfully obtained in high enantiomeric excess from the stereoselective addition of diethylzinc to the aldehydes catalyzed by the chiral aminoalcohols ( 1 and 2 ). The sense of the asymmetric induction and the degrees of enantioselectivities turned out to be highly dependent on the structure of the catalysts: The presence of the catalyst 1 afforded the (S)-configuration of the corresponding alcohols; on the other hand, the presence of 2 afforded the (R)-configuration of the alcohols in high enantiomeric selectivity.