Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine

Anti-HIV nucleoside monophosphates have limited cellular uptake due to the presence of negatively-charged phosphate group. Bis-(cycloSaligenyl) derivatives containing two anti-HIV nucleosides, 3′-fluoro-3′-deoxythymidine (FLT) and 3′-azido-3′-deoxythymidine (AZT) were synthesized to increase intracellular delivery of nucleoside monophosphates. 2,5-Bis(hydroxymethylene)benzene-1,4-diol was selected as a monocyclic bidentate scaffold and synthesized by three different methods from bis(hydroxymethylene)cyclohexan-1,4-diene-1,4-diol, or diethyl 2,5-dihydroxyterephthalate. The reaction of the tetraol with diisopropylphosphoramidous dichloride in the presence of 2,6-lutidine, followed by conjugation reactions with nucleosides (i.e., FLT and AZT) and oxidation afforded symmetrical and unsymmetrical bis-(cycloSaligenyl) diphosphate triester products, AZT-AZT, FLT-FLT, and FLT-AZT conjugates, in 63-74% overall yields and modest anti-HIV activities (IC₅₀ = 2.8-69.6 μM).     

Synthesis and anti-HIV activity of l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides

An efficient synthetic method was developed for l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides. The key intermediate 11 was obtained from l-xylose, from which a series of pyrimidine and purine nucleosides were prepared in high yield by the coupling of 11 and various silyl-protected bases in the presence of TMSOTf. These nucleosides were eliminated, followed by deprotecting to give l-β-3′-C-cyano-2′,3′-unsaturated nucleosides. When selectively deprotected by hydrazine hydrate in buffered acetic acid-pyridine followed by treatment with potassium carbonate in methanol, l-3′-C-cyano-3′-deoxyribonucleosides were obtained. The synthesized nucleosides were tested for anti-HIV activity.     

Synthesis and anti-HIV activity of 5-haloethynyl and 5-(1,2-dihalo)vinyl analogues of AZT and FLT

In this paper, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleoside analogues of the anti-HIV AZT, and FLT drugs. The key step of those syntheses is a Pd(0) cross-coupling at C5 position under Sonogashira conditions. Finally, based on their in vitro anti-HIV activities and their cytotoxicity on PBM, CEM, and VERO cell lines, the best compounds were the 2′,3′-dideoxy-3′-fluoro-5-(bromo-2-iodo)vinyluridine (10b, EC₅₀ of 0.6 μM), and the 3′-azido-2′,3′-dideoxy-5-(bromo-2-iodo)vinyluridine (16b, EC₅₀ of 1.1 μM).     

Synthesis and anti-HIV activities of phosphate triester derivatives of 3′-fluoro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine

Fatty acyl-glycol phosphate triester conjugates of 3′-fluoro-2′,3′-dideoxythymidine (FLT) were prepared in three steps from the reaction of diisopropylphoramidous dichloride with fatty acyl-substituted glycols, followed by a coupling reaction with FLT and oxidation with tert-butyl hydroperoxide (t-BuOOH). Additionally, a number of fatty alcohols were reacted with diisopropylphoramidous dichloride to produce the phosphitylating intermediates, which underwent coupling reactions with 3′-azido-2′,3′-dideoxythymidine (AZT) and FLT followed by oxidation with t-BuOOH to yield fatty alcohol phosphate triester derivatives of AZT and FLT.     

Synthesis and anti-HCV activity of 1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil

Synthesis of a novel 1′,2′-oxetane-uridine bearing a 2′-C-methyl substituent, [1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil], is described. Key to its construction was the use of 6-O-(p-toluoyl)-1,2:3,4-di-O-isopropylidene-3-C-methyl-d-psicofuranose as a nucleosidation substrate, which itself was derived from d-fructose. Anti-HCV activity was examined for the corresponding triphosphate which was not found to be an inhibitor of HCV NS5B 1b wild type polymerase in vitro. The 1′,2′-oxetane uridine triphosphate without 2′-C-methyl substitution was similarly inactive, however, the guanosine analog displayed modest inhibition (IC₅₀ = 10 μM).     

Efficient synthesis of 5′-O(N)-carbamyl and -polycarbamyl nucleosides

A simple and efficient method for the preparation of 5′-O(N)-carbamyl and 5′-O(N)-polycarbamyl nucleoside derivatives is reported. The method consisted of treatment of 2′,3′-O-protected purine (Ado, Ino) or pyrimidine nucleosides (Thd, Urd) with trichloroacetylisocyanate, followed by cleavage of the trichloroacetyl moiety by silica-gel promoted methanolysis during column chromatography. Iterative application of this method gave mono, di, and tricarbamyl derivatives in good to excellent yields (ave = 80%).     

Nitrile ligands activation in dinuclear aminocarbyne complexes

The diiron complexes [Fe(Cp)(CO){μ-η²:η²-C[N(Me)(R)]NC(C₆H₃R′)CCH(Tol)}Fe(Cp)(CO)] (R = Xyl, R′ = H, 3a; R = Xyl, R′ = Br, 3b; R = Xyl, R′ = OMe, 3c; R = Xyl, R′ = CO₂Me, 3d; R = Xyl, R′ = CF₃, 3e; R = Me, R′ = H, 3f; R = Me, R′ = CF₃, 3g) are obtained in good yields from the reaction of [Fe₂{μ-CN(Me)(R)}(μ-CO)(CO)(p-NCC₆H₄R′)(Cp)₂]⁺ (R = Xyl, R′ = H, 2a; R = Xyl, R′ = Br, 2b; R = Xyl, R′ = OMe, 2c; R = Xyl, R′ = CO₂Me, 2d; R = Xyl, R′ = CF₃, 2e; R = Me, R′ = H, 2f; R = Me, R′ = CF₃, 2g) with TolCCLi. The formation of 3 involves addition of the acetylide at the coordinated nitrile and C-N coupling with the bridging aminocarbyne together with orthometallation of the p-substituted aromatic ring and breaking of the Fe-Fe bond. Complexes 3a-e which contain the N(Me)(Xyl) group exist in solution as mixtures of the E-trans and Z-trans isomers, whereas the compounds 3f,g, which posses an exocyclic NMe₂ group, exist only in the Z-cis form. The crystal structures of Z-trans-3b, E-trans-3c, Z-trans-3e and Z-cis-3g have been determined by X-ray diffraction experiments.     

Photocytotoxic and anaerobic DNA cleavage activity of binuclear 3,3′-dithiodipropionic acid cobalt(II) complexes having phenanthroline bases

Dicobalt(II) complexes [{(B)Co^II}₂(μ-dtdp)₂] (1–3) of 3,3′-dithiodipropionic acid (dtdp) and phenanthroline bases (B), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3), have been prepared, characterized and their photo-induced anaerobic DNA cleavage activity studied. The elemental analysis and mass spectral data suggest binuclear formulation of the complexes. The redox inactive complexes have magnetically non-interacting dicobalt(II) core showing magnetic moment of ∼3.9 μ_B per cobalt(II) center. The complexes show good binding propensity to calf thymus DNA giving K_b values within 4.3 × 10⁵–4.0 × 10⁶ M⁻¹. Thermal melting and viscosity data predict DNA groove binding and/or partial intercalative nature of the complexes. The complexes show significant anaerobic DNA cleavage activity in green light under argon atmosphere possibly involving radical species generated from the disulfide moiety in a type-I pathway. The DNA cleavage reaction under aerobic medium in green light is found to involve hydroxyl radical species. The dppz complex 3 exhibits significant photocytotoxicity in HeLa cervical cancer cells with an IC₅₀ value of 2.3 μM in UV-A light of 365 nm, while it is essentially non-toxic in dark giving an IC₅₀ value of >200 μM. A significant reduction of the dark toxicity of the organic dppz base (IC₅₀ = 8.3 μM in dark) is observed on binding to the cobalt(II) center while essentially retaining its photocytotoxicity in UV-A light (IC₅₀ = 0.4 μM).     

Au(I)/Ag(I)-catalyzed annulation of sugar aldehyde tethered with 3-phenylprop-2-yn-1-yl ether with aryl amines for the pyrano[4,3-b]quinoline derivatives

Aryl amines undergo smooth annulation with O-phenylpropynyl sugar aldehyde in the presence of the Ph₃PAuCl (10 mol %)/AgSbF₆ (10 mol %) catalytic system to afford the corresponding tetrahydro-3aH-spiro[[1,3]dioxolo[4″,5″:4′,5′]furo[3′,2′:5,6]pyrano[4,3-b]quinoline-2,1′-cyclohexane] derivatives in good yields and selectivity.     

Syntheses and structures of overcrowded silanedichalcogenols and their applications to the syntheses of silanedichalcogenolato complexes

Overcrowded silanedichalcogenols Tbt(Mes)Si(EH)(E′H), such as silanedithiol (E = E′ = S), hydroxysilanethiol (E = O, E′ = S) and hydroxysilaneselenol (E = O, E′ = Se), bearing an efficient combination of steric protection groups, Tbt and Mes (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl, Mes = 2,4,6-trimethylphenyl), were synthesized and isolated as air- and moisture-stable crystals, and their structures were fully characterized by spectroscopic and elemental analyses together with X-ray crystallographic analyses. The results of IR spectroscopy and the X-ray structural analyses suggested that these compounds exist as monomers without any intra- and intermolecular interactions such as hydrogen bonds even in the solid state and in solution. Novel four-membered-ring compounds, such as Tbt(Mes)Si(μ-S)₂PnBbt and [Tbt(Mes)Si(μ-E)(μ-E′)ML_n] [E, E′ = O, S, Se; Pn = Sb, Bi; Bbt = 2,6-bis[bis(trimethylsilyl)methyl]-4-[tris(trimethylsilyl)methyl]phenyl; ML_n = Pd(PPh₃)₂, Pt(PPh₃)₂, Ru(η⁶-benzene)] were synthesized by utilizing the silanedichalcogenols as key building blocks. The molecular structures of these newly isolated compounds were determined by NMR spectroscopic data together with X-ray crystallographic analyses.     

Multiple one-electron oxidation and reduction of trinuclear bis(2,4-pentanedionato)ruthenium complexes with substituted diquinoxalino[2,3-a:2′,3′-c]phenazine ligands

The complexes (μ₃-L¹/L²)[Ru(acac)₂]₃, acac⁻ = 2,4-pentanedionato, L¹ = 2,3,8,9,14,15-hexachlorodiquinoxalino[2,3-a:2′,3′-c]phenazine and L² = 2,3,8,9,14,15- hexamethyldiquinoxalino[2,3-a:2′,3′-c]phenazine, undergo stepwise one-electron oxidation involving a total of three electrons and stepwise one-electron reduction with three (L²) or four electrons (L¹). All reversibly accessible states were characterized by UV–Vis–NIR spectroelectrochemistry. Oxidation leads to mixed-valent intermediates {(μ₃-L)[Ru(acac)₂]₃}⁺ and {(μ₃-L)[Ru(acac)₂]₃}²⁺ of which the Ru^IIIRu^IIRu^II combinations exhibit higher comproportionation constants K_c than the Ru^IIIRu^IIIRu^II states – in contrast to a previous report for the unsubstituted parent systems {(μ₃-L³)[Ru(acac)₂]₃}^+/2+, L³ = diquinoxalino[2,3-a:2′,3′-c]phenazine. No conspicuous inter-valence charge transfer absorptions were observed for the mixed-valent intermediates in the visible to near-infrared regions. The monocations and monoanions were characterized by EPR spectroscopy, revealing rhombic ruthenium(III) type signals for the former. Electron addition produces ruthenium(II) complexes of the reduced forms of the ligands L, a high resolution EPR spectrum with ¹⁴N and ^35,37Cl hyperfine coupling and negligible g anisotropy was found for {(μ₃-L¹)[Ru(acac)₂]₃}⁻. DFT calculations of (μ₃-L¹)[Ru(acac)₂]₃ confirm several ligand-centered low-lying unoccupied MOs for reduction and several metal-based high-lying occupied MOs for electron withdrawal, resulting in low-energy metal-to-ligand charge transfer (MLCT) transitions.     

Structural, spectral and thermal studies of substituted N-(2-pyridyl)-N′-phenylthioureas

N-2-(3-picolyl)-N′-phenylthiourea, 3PicTuPh, monoclinic, P2₁/n, a=7.617(2) b=7.197(5), c=22.889(5) Å, β=94.63(4)°, V=1250.7(1) Å³ and Z=4; N-2-(4-picolyl)-N′-phenylthiourea, 4PicTuPh, triclinic, P-1, a=7.3960(5), b=7.9660(12), c=21.600(3) Å, α=86.401(4), β=84.899(8), γ=77.769(8)°, V=1237.5(3) Å³ and Z=4; N-2-(5-picolyl)-N′-phenylthiourea, 5PicTuPh, monoclinic, P2₁/c, a=14.201(1), b=4.905(3), c=17.689(3) Å, β=91.38(1)°, V=1231.8(7) Å³ and Z=4; N-2-(6-picolyl)-N′-phenylthiourea, 6PicTuPh, monoclinic, C2/c2, a=14.713(1), b=9.367(1), c=18.227(1) Å, β=92.88(1)°, V=2515.5(1) Å³ and Z=8 and N-2-(4,6-lutidyl)-N′-phenylthiourea, 4,6LutTuPh, monoclinic, C2/c, a=11.107(2), b=11.793(2), c=20.084(4) Å, β=96.10(3)°, V=2616(1) Å³ and Z=8. Intramolecular hydrogen bonding between N′H and the pyridyl nitrogen and intermolecular hydrogen bonding involving the thione sulfur are affected by substitution of the pyridine ring, as is the planarity of the molecule. ¹H NMR studies in CDCl₃ show the NH′ hydrogen resonance considerably downfield from other resonances in the spectrum for each thiourea.     

The cyclopalladation reaction of 2-phenylaniline revisited

2-Phenylaniline reacted with Pd(OAc)₂ in toluene at room temperature for 24 h in a one-to-one molar ratio and with the system PdCl₂, NaCl and NaOAc in a 1 (2-phenylaniline):1 (PdCl₂):2 (NaCl):1 (NaOAc) molar ratio in methanol at room temperature for one week to give the dinuclear cyclopalladated compounds (μ-X)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}]₂ [1a (X = OAc) and 1b (X = Cl)] in high yield. Moreover, the reaction between 2-phenylaniline and Pd(OAc)₂ in one-to-one molar ratio in acid acetic at 60 °C for 4 h, followed by a metathesis reaction with LiBr, allowed isolation of the dinuclear cyclopalladated compound (μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}]₂ (1c) in moderate yield. A parallel treatment, but using monodeuterated acetic acid (DOAc) as solvent in the cyclopalladation reaction, allowed isolation of a mixture of compounds 1c, 1c_d1 [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄](μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)-3-d-C₆H₃] and 1c_d2 (μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)-3-d-C₆H₃}]₂ in moderate yield and with a deuterium content of ca. 60%. 1a and 1b reacted with pyridine and PPh₃ affording the mononuclear cyclopalladated compounds [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}(X)(L)] [2a (X = OAc, L = py), 2b (X = Cl, L = py), 3a (X = OAc, L = PPh₃) and 3b (X = Cl, L = PPh₃)] in a yield from moderate to high. Furthermore, 1a reacted with Na(acac) · H₂O to give the mononuclear cyclopalladated compound 4 [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}(acac)] in moderate yield. ¹H NMR studies in CDCl₃ solution of 2a, 2b, 3a, 3b and 4 showed that 2a and 3a presented an intramolecular hydrogen bond between the acetato ligand and the amino group, and were involved in a dynamic equilibrium with water present in the CDCl₃ solvent; and that the enantiomeric molecules of 2b and 4 were in a fast exchange at room temperature, while they were in a slow exchange for 2a, 3a and 3b. The X-ray crystal structures of 3b and 4 were determined. 3b crystallized in the triclinic space group with a = 9.9170(10), b = 10.4750(10), c = 12.0890(10) Å, α = 98.610(10)°, β = 94.034(10)° and γ = 99.000(10)° and 4 in the monoclinic space group P2₁/a with a = 11.5900(10), b = 11.2730(10), c = 12.2150(10) Å, α = 90°, β = 107.6560(10)° and γ = 90°.     

Synthesis, in vitro and in silico assessment of organometallic Rhenium(I) and Technetium(I) thymidine complexes

Thymidine kinases have been identified as suitable targets for non-invasive imaging of gene therapy and cancer. Thus, there is a high interest in new, reliable and inexpensive radiolabeled thymidine analogues for these applications. In this study we present the synthesis and in vitro evaluation of M(CO)₃-complexes of thymidine (M = ^99mTc, Re) for potential use in SPECT tumor imaging. 5′-amino-5′-deoxythymidine was derivatized at position C5′ with spacers of various lengths (∼0-30 Å) carrying tridentate metal chelating entities such as iminodiacetic acid and picolylamine-N-monoacetic acid. The nucleoside derivatives were reacted with the precursors [ReBr₃(CO)₃]²⁻ and [^99mTc(OH₂)₃(CO)₃]⁺, respectively. The organometallic thymidine complexes have been fully characterized by means of IR, NMR and mass spectrometry. Enzyme kinetic studies revealed mixed inhibition of the human cytosolic thymidine kinase with K_i values ranging from 4.4 to 334 μM for all thymidine complexes. Competitive inhibition of herpes simplex virus type 1 thymidine kinase was only achieved when thymidine and the metal core were separated by a spacer of approximately 30 Å length. These findings were supported by in silico molecular docking and molecular dynamic experiments.     

On the design of polymeric 5′-O-ester prodrugs of 3′-azido-2′,3′-dideoxythymidine (AZT)

A new 5′-O-AZT prodrug was synthesized by conjugating 3′-azido-2′,3′-dideoxythymidine (AZT) with poly(oxyethylene H-phosphonate) at room temperature under Atherton-Todd reaction conditions. The acute toxicity of poly(5′-O-AZT-oxyethylene phosphate) was reduced significantly in comparison with non-immobilized AZT.     

Preparation and structures of 6- and 7-coordinate salen-type zirconium complexes and their catalytic properties for oligomerization of ethylene

A series of salen-type zirconium complexes of the general formula LZrCl₂ (L = N,N′-ethylenebis(salicylideneiminate), 3a; N,N′-ethylenebis(3,5-di-tert-butylsalicylideneiminate), 3b; N,N′-ethylenebis(5-methoxysalicylideneiminate), 3c; N,N′-ethylenebis(5-chlorosalicylideneiminate), 3d; N,N′-ethylenebis(5-nitrosalicylideneiminate), 3e; N,N′-o-phenylenebis(salicylideneiminate), 4a; N,N′-o-phenylenebis(3,5-di-tert-butylsalicylideneiminate), 4b; N,N′-o-phenylenebis(5-methoxysalicylideneiminate), 4c; N,N′-o-phenylenebis(5-chloro-salicylideneiminate), 4d) were prepared. The crystal structures of 6- and 7-coordinate zirconium complexes 4b and [4b · OCMe₂] were determined by X-ray crystallography, which reveals that a salen-type zirconium complex possesses a labile coordination site on the Zr center with a relatively stable framework and that the coordination and the dissociation of O-donor molecules occur readily at this site. The catalytic properties of 3(a-e) and 4(a-d) were studied for ethylene oligomerization in combination with Et₂AlCl as co-catalyst. Complex 3c featuring a methoxy-substituted salen ligand displayed higher activity than its analogous precursors having chloro and nitro groups as substituents. The catalytic reactions by 3(a-e) and 4(a-d) gave C₄-C₁₀ olefins and low-carbon linear α-olefins in good selectivity.     

Synthesis and photophysics of a novel photocatalyst for hydrogen production based on a tetrapyridoacridine bridging ligand

Molecular photocatalysts allow for selectively tuning their function on a molecular level based on an in-depth understanding of their chemical and photophysical properties. This contribution reports the synthesis and photophysical characterization of the novel molecular photocatalyst [(tbbpy)₂Ru(tpac)PdCl₂]²⁺RutpacPd (with tpac = tetrapyrido[3,2-a:2′,3′-c:3″,2″-h:2?,3?-j]acridine) and its mononuclear building block. Furthermore, detailed photocatalytic activity measurements of RutpacPd are presented. The introduction of the tpac-ligand into the molecular framework offers a potential route to reduce the impact of water as compared to the well-studied class of RutpphzPd (with tpphz = tetrapyrido[3,2-a:2′,3′-c:3″,2″-h:2?,3?-j]phenazine) complexes. The distinct impact of water on the electron-transfer processes in tpphz-ligands stems from the possibility of water to form hydrogen bonds to the phenazine nitrogen atoms and will potentially reduced when replacing the phenazine by the acridine unit. The effect of this structural variation on the catalytic properties and the underlying ultrafast intramolecular charge transfer behavior will be discussed in detail.     

Excited-state intramolecular proton transfer in 2-(2′,6′-dihydroxyphenyl)benzoxazole: effect of dual hydrogen bonding on the optical properties

2-(2′,6′-Dihydroxyphenyl)benzoxazole (DHBO) has been synthesized by using palladium-catalyzed oxidative cyclization. The compound utilizes both O-H···N and O-H···O bonds to ensure a coplanar structure between the benzoxazole and phenol fragments. Optical comparison with the parent compound 2-(2′-hydroxyphenyl)benzoxazole (HBO) reveals that the dual hydrogen bonding in DHBO plays an essential role in raising the desirable keto emission for ESIPT and tuning the polarity sensitivity toward the molecular environment. DHBO also exhibits a higher quantum yield (?_fl = 0.108 in methanol) than HBO (?_fl = 0.0025) in the same solvent.     

Synthesis of efficient blue and red light emitting phenanthroline derivatives containing both hole and electron transporting properties

Two phenanthroline derivatives containing a hole transporting triphenylamine and an electron transporting 1,3,4-oxadiazole unit have been prepared with high yield. UV-vis absorption and fluorescence measurement indicated they are high efficient light-emitting materials. The compounds are 6-(5-(4-N,N′-diphenylaminophenyl)-1,3,4-oxadiazol-2-yl) quinoxalino[2,3-f] phenanthroline (9, λ_max = 635 nm, 40% quantum yield), and 1-ethyl-2-(4-(5-(4-N,N′-diphenylaminophenyl)-1,3,4-oxadiazol-2-yl)phenyl)imidazo[4,5-f]phenanthroline (14, λ_max = 461 nm, 78% quantum yield). Preliminary study on electroluminescence for the two fluorescent dyes prepared from vacuum evaporation resulted in blue and red light emitting organic light emitting diodes (OLED).     

Crystallization-based optical resolution of 1,1′-binaphthalene-2,2′-dicarboxylic acid via 1-phenylethylamides: control by the molecular structure and dielectric property of solvent

In the recrystallization of a diastereomeric mixture of amides (RS_a,S)-1 formed from racemic 1,1′-binaphthalene-2,2′-dicarboxylic acid and (S)-1-phenylethylamine, either of the diastereomers crystallizes out as a diastereomerically pure form, depending on the solvent employed; sterically undemanding solvents, acetone, dichloromethane, and acetonitrile, afford crystals formulated as (S_a,S)-1·solvent with an exception of ethanol, which affords (R_a,S)-1·EtOH, while sterically bulkier solvents afford (R_a,S)-1 including no solvent. The stereoselectivity can be rationalized by the crystal structures. A dielectrically controlled resolution (DCR) can also be carried out by using mixed solvents, which contain, for example, 25 vol % of acetone and varying ratios of hexane and 1-propanol in total 75 vol %; (S_a,S)-1·acetone is deposited as crystals from the solvents with a dielectric constant (ε) range 8.9 ? ε ? 10.2, while (R_a,S)-1 is deposited from the solvents with 14.8 ? ε ? 20.3.