Racemic Ligand Research Articles

Synthesis, Resolution, and Application of Cyclobutyl‐ and Adamantyl‐Quinazolinap Ligands

AbstractAn expedient, seven‐step synthesis of two new members of the Quinazolinap ligand family, 2‐cyclobutyl‐ and 2‐(1‐adamantyl)‐Quinazolinaps, has been developed. The racemic ligands have been efficiently resolved by fractional crystallization of their diastereomeric palladacycle complexes. The enantioenriched ligands provide good levels of enantioselection (ee's up to 89 %) in a prototypical PdII‐catalyzed allylic alkylation reaction. 2‐Cyclobutyl‐Quinazolinap has been further functionalized at the 2‐position via metalation with a superbase followed by reaction with a range of electrophiles. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

New approach to chiral phosphapalladacycles: first optically active phosphinite PC-palladacycle with non-metallocenic planar chirality

A new proposed methodology for the preparation of phosphapalladacycles in enantiopure form includes the use of the same optically active cyclopalladated CN-reagent for both resolution of a racemic ligand and subsequent direct C–H bond activation of the enantiopure ligand via the cyclopalladated ligand exchange reaction. This protocol was successfully employed for the preparation of the complex, which is both the first PC-palladacycle with a non-metallocenic planar chirality based on the [2.2]paracyclophane framework and the first representative of chiral phosphinite PC-palladacycles.

Synthesis of Bis(catechol) Ligands Derived from Tröger's Base and Their Dinuclear Triple‐Stranded Complexes with Titanium(IV) Ions

AbstractBis(catechol) ligands derived from 2,8‐disubstituted analogues of Tröger's base and monofunctionalized MOM‐protected or unprotected catechols bearing both rigid and flexible spacers were synthesized, which gave rise to dissymmetric oxygen donor ligands whose geometry is defined by the V‐shaped and rigid structure of the core of Tröger's base. These racemic ligands undergo self‐assembly to dinuclear triple‐stranded helicates upon coordination to titanium(IV) ions as was proven by NMR spectroscopy and ESI‐MS experiments; however, these processes are not diastereoselective.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Comparative Study of Homochiral and Racemic Chiral Metal-Organic Frameworks Built from Camphoric Acid

The study of the crystallization of homochiral or racemic chiral framework materials from enantiopure or racemic ligands is an important step for the rational design of crystalline homochiral materials. The self-assembly of extended frameworks in the presence of enantiopure or racemic ligands is regulated by the differing symmetry requirements of the ligand. By employing both enantiopure and racemic ligands as cross-linking ligands, we have prepared three homochiral and three racemic chiral compounds and their synthesis and structural and topological properties are presented here. It is shown that depending on the chemical compositions and framework topologies, the effect of the ligand handedness on the resulting crystal structure can vary greatly. The ligand handedness can have negligible effect on the crystallization, which leads to an interesting example of two pairs of isostructural achiral and homochiral structures with two types of six-connected nets. In another example reported here, the racemic ch...

Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters

Labeling derivatives of dihydrotetrabenazine (DTBZ) with F-18 (T(1/2)=110 min) instead of C-11 (T(1/2)=20 min) would improve their utility and availability for imaging vesicular monoamine transporters (VMAT2) in clinical settings. The successful synthesis, reported previously, of two novel 9-fluoroalkyl(+/-)-DTBZ ligands prompted us to study the optically resolved active ligand 9-fluoropropyl-(+)-DTBZ (FP-(+)-DTBZ), which may have more promising characteristics. The inhibition constant (K(i)) estimated for FP-(+)-DTBZ (using [(3)H](+/-)-DTBZ as the labeled ligand in rat striatal homogenates) showed a lower value as compared to the racemic FP-(+/-)-DTBZ (0.10+/-0.01 vs 0.19+/-0.04 nM). The inactive isomer, FP-(-)-DTBZ, displayed a much lower binding affinity with a K(i) value >3000 nM. Biodistribution studies in mice after an iv injection of [(18)F]FP-(+)-DTBZ exhibited a ratio of striatum (ST, target) to cerebellum (CB, background) of 4.51 at 30 min postinjection, which is a higher value than previously obtained with the racemic ligand [(18)F]FP-(+/-)-DTBZ (ST/CB=2.95). Brain extraction at 30 min after the tracer injection in mice showed that >95% of the radioactivity corresponded to the parent, nonmetabolized, compound remaining in the ST, suggesting that the tracer has an excellent in vivo stability. Furthermore, localization of the tracer in the brain examined with ex vivo autoradiography displayed a typical distribution pattern consistent with VMAT2 sites. The highest labeling was observed in monoaminergic neuron regions (caudate putamen, olfactory tubercle, nucleus accumbens, substantia nigra, dorsal raphe and locus coerules). We also tested the selective labeling of this tracer at the dopamine neurons in unilateral-lesioned mice (treated with 6-hydroxydopamine). When [(18)F]FP-(+)-DTBZ and [(125)I]IPT ((N-(3'-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane, a selective marker for dopamine transporters (DATs) in dopaminergic neurons) were simultaneously injected into lesioned mice, we observed an excellent correlation (r=0.95) for these tracers. From these findings, we conclude that [(18)F]FP-(+)-DTBZ is a sensitive and selective tracer for VMAT2 binding sites and it may be useful for in vivo evaluation of diseases relating to changes of monoamine neuronal integrity.

New chiral [N,N,N]‐ligand containing titanium/zirconium precatalysts for 1‐hexene polymerization

AbstractThe ring‐opening reaction of (S)‐N‐tosyl‐2‐phenylaziridine by benzylamine in ethanol at 80 °C resulted in the formation of the (S,S)‐bis(N‐tosyl‐2‐amino‐2‐phenylethyl)benzylamine ligand in a 60% yield. The corresponding titanium complex, 1‐TiCl2, was prepared by the reaction of the dilithiated parent ligand with TiCl4. This precatalyst, in combination with methylaluminoxane, was capable of polymerizing 1‐hexene with good activities, resulting in the formation of good yields of low‐dispersity, high‐molecular‐weight polymers at low temperatures but higher yields of lower molecular weight polymers at higher temperatures. 1H and 13C NMR spectra of the polymers suggested high isotacticity and predominant chain termination via β‐hydride elimination. The enantiomerically pure catalysts, (R,R)‐1‐TiCl2 and (S,S)‐1‐TiCl2, showed nearly identical polymerization results at various polymerization temperatures. However, when the catalyst was prepared from a racemic ligand, the obtained polymers had lower molecular weights with a bimodal distribution. This observation suggested diastereomeric aggregation of the racemic catalyst, which was well supported by the NMR studies, and a modified Arrhenius plot (the natural logarithm of the number‐average molecular weight vs the reciprocal of the temperature) also showed sigmoidal behavior, indicating the existence of two or more active species. Analogous zirconium precatalysts showed similar results in the polymerization of 1‐hexene. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4006–4014, 2006

Closing in on the AMPA receptor: Synthesis and evaluation of 2-acetyl-1-(4′-chlorophenyl)-6-methoxy-7-[ 11C]methoxy-1,2,3,4-tetrahydroisoquinoline as a potential PET tracer

2-Acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, one of the most potent non-competitive AMPA antagonists described to date, has been labelled with carbon-11 and tritium and evaluated as a potential ligand for in vivo imaging of AMPA receptors using PET. The carbon-11 labelled compound showed good initial brain uptake in rats, but with rapid clearance and relatively homogenous distribution. In saturation binding studies, the tritiated racemic ligand was found to be highly potent with a K d of 14.8 ± 1.8 nM. We conclude that the low receptor density labelled with this compound, its rapid clearance from the CNS and low specific binding makes it unsuitable as an in vivo PET imaging agent for AMPA receptors.

Avidin and streptavidin ligands based on the glycoluril bicyclic system

Glycoluril derivatives with a carboxylic acid side chain have been synthesized and shown to bind to both avidin and streptavidin. Introduction of a valerate side chain in glycoluril led to an increased binding to both proteins only when the valerate group was bound to a N atom and with the proper stereochemistry [(+)-enantiomer]. On the other hand, introduction of the valerate side chain either on the bridgehead carbon or on the N atom with the opposite stereochemistry [(-)-enantiomer] led to a decrease in binding constant compared with unsubstituted glycoluril. Direct spectrophotometric competitive titration of each protein with a racemic ligand allowed measurement of the enantioselectivity of the ligand-protein complexation, together with the binding constant of the two enantiomers. In the case of the N-substituted glycoluril, the extension of the side chain by one methylene group, from valerate to caproate, led to an increase in the binding constant to both proteins. Docking studies using AutoDock 3.05 have been performed in order to predict the binding modes of these ligands to streptavidin. The effect of the stereochemistry and the position of the side chain on the binding constant to streptavidin is discussed in view of the predicted binding modes.

Homochiral and Heterochiral Coordination Polymers and Networks of Silver(I)

The self-assembly of racemic and enantiopure binaphthylbis(amidopyridyl) ligands 1,1'-C(20)H(12){NHC(O)-4-C(5)H(4)N}(2), 1, and 1,1'-C(20)H(12){NHC(O)-3-C(5)H(4)N}(2), 2, with silver(I) salts (AgX; X = CF(3)CO(2), CF(3)SO(3), NO(3)) to form extended metal-containing arrays is described. It is shown that the self-assembly with racemic ligands can lead to homochiral or heterochiral polymers, through self-recognition or self-discrimination of the ligand units. The primary polymeric materials adopt helical conformations (secondary structure), and they undergo further self-assembly to form sheets or networks (tertiary structure). These secondary and tertiary structures are controlled through secondary bonding interactions between pairs of silver(I) centers, between silver cations and counteranions, or through hydrogen bonding involving amide NH groups. The self-assembly of the enantiopure ligand R-1 with silver trifluoroacetate gave a remarkable three-dimensional chiral, knitted network composed of polymer chains in four different supramolecular isomeric forms.

Selective binding of coumarin enantiomers to human α 1-acid glycoprotein genetic variants

Coumarin-type anticoagulants, warfarin, phenprocoumon and acenocoumarol, were tested for their stereoselective binding to the human orosomucoid (ORM; AGP) genetic variants ORM 1 and ORM 2. Direct binding studies with racemic ligands were carried out by the ultrafiltration method; the concentrations of free enantiomers were determined by capillary electrophoresis. The binding of pure enantiomers was investigated with quinaldine red fluorescence displacement measurements. Our results demonstrated that all investigated compounds bind stronger to ORM 1 variant than to ORM 2. ORM 1 and human native AGP preferred the binding of ( S)-enantiomers of warfarin and acenocoumarol, while no enantioselectivity was observed in phenprocoumon binding. Acenocoumarol possessed the highest enantioselectivity in AGP binding due to the weak binding of its ( R)-enantiomer. Furthermore, a new homology model of AGP was built and the models of ORM 1 and ORM 2 suggested that difference in binding to AGP genetic variants is caused by steric factors.

Stereochemical Influence of the Ligand on the Structure of Manganese Complexes: Implications for Catalytic Epoxidations

Manganese complexes of the ligand HphoxCOOR (R=H or Me) have been synthesized and characterized by X-ray analysis, ESI-MS, ligand-field spectroscopy, electrochemistry, and paramagnetic 1H NMR. The ligands, chirally pure or racemic, influence the structures of the complexes formed. Manganese(III) complexes of the ligand HphoxCOOMe are square-pyramidal or octahedral with two ligands bound in a trans fashion in the solid state. The racemic ligand (RS-HphoxCOOMe) as well as the enantiopure ligand (R-HphoxCOOMe) forms manganese complexes with similar solid-state structures. Ligand-exchange reactions occur in solution giving rise to meso complexes as confirmed by ESI-MS and deuteration studies. The manganese(III) complex of R-HphoxCOOH is octahedral, with two dianionic ligands bound in a fac-cct fashion in a tridentate manner. The manganese(III) complex of RS-HphoxCOOH is also octahedral with two dianionic ligands now bound in a trans fashion in a didentate manner and with two water molecules occupying axial sites. The paramagnetic 1H NMR spectra of the complexes have been interpreted on the basis of the relaxation times with the help of the inversion-recovery pulse technique. The binding of imidazole with the metal center depends on the chirality of the ligands in the metal complexes of HphoxCOOMe. Imidazole coordination was found to occur with the metal complex that contains two ligands with the same chirality (R and R) (R-1), while no imidazole coordination was found upon reaction with the metal complex that contains two ligands with opposite chirality (R and S) (RS-1). Epoxidation reactions of various alkenes with H2O2 as the oxidant reveal that the complexes give turnover numbers in the range of 10-35, the epoxide being the major product. The catalytic activity depends on the additives used, and a clear base effect is observed. The turnover numbers have been found to be higher in the complexes where no binding of N-Meim is observed. The latter fact unambiguously shows that imidazole binding is not a prerequisite for higher turnover numbers, in contrast to the Mn-Schiff base catalysts.

Synthesis and Structure−Activity Relationship of a Novel Series of Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography

A new series of CB(1) ligands with high binding affinity (K(i) = 0.7-100 nM) and moderate lipophilicity (cLogD(7.4)) in the range of 2.1-4.5 has been synthesized. A structure-activity relationship study demonstrated that for the studied set of aminoalkylindoles, the molecular dipole of the ground state conformation within the series was inversely related to the affinity. The racemic ligand with highest affinity (0.7 nM), 3-(4-fluoronaphthoyl)-1-(N-methylpiperidin-2-ylmethyl)indole, was radiolabeled with (18)F. This radioligand specifically labeled CB(1) receptors in mouse brain and accumulated in regions of high versus low CB(1) receptor density in a ratio of 1.6. The displaceable radioactivity of one enantiomer in the brains of mice determined in a pretreatment study using the CB(1) antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) was nearly double that of the racemate for the same determination; therefore, the active enantiomer is a candidate for PET studies in animals. A pretreatement study for the other enantiomer found no displaceable radioactivity in the same group of mice; this result suggested the enantiomer was inactive.

The preparation and resolution of 2-(2-pyridyl)- and 2-(2-pyrazinyl)-Quinazolinap and their application in palladium-catalysed allylic substitution

The preparation and resolution of two new axially chiral quinazoline-containing phosphinamine ligands, 2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap, is described. The ligands were synthesised in good yield over eight steps and included two Pd-catalysed reactions, a Suzuki coupling to form the biaryl linkage and the introduction of the diphenylphosphino group, as the key transformations. The racemic ligands were resolved via the fractional crystallisation of diastereomeric palladacycles derived from (+)-di-μ-chlorobis{( R)-dimethyl[1-(1-naphthyl)ethyl]aminato-C 2,N}dipalladium (II) X-ray crystal structures of the ( S, R)-2-pyridyl- and ( S, R)-2-pyrazinyl-palladacycles are included. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane gave enantiopure 2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap, new atropisomeric phosphinamine ligands for asymmetric catalysis. These ligands were applied in the palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate resulting in moderate conversions and enantioselectivities of up to 81%.

Two new polymeric chains derived from exo-bidentate binaphthol derivatives

Assembly of CdBr 2·4H 2O and 2,2′-substituted binol derivatives, ( S)-2,2′-bis(4-pyridylmethyleneoxy)-1,1′-bi-naphthalene [( S)-L], and ( Rac)-2,2′-bis(4-pyridylmethyleneoxy)-1,1′-bi-naphthalene [( Rac)-L], resulted in two one-dimensional chiral chain complexes, {Cd[( S)-L](H 2O)Br 2} n ·0.5 nH 2O ( 1) and {Cd 2[( R)-L][( S)-L](H 2O) 2Br 4} n ·2 nH 2O ( 2). In complex 1, chain chirality is from axial chirality of BINOL scaffold. In complex 2, racemic ligands including ( S)-L and ( R)-L locate in the two sides of the equatorial plane, which suggests the ligand self-discrimination during the assembly process.

Unsymmetrical chiral salen Schiff base ligands: Synthesis and use in metal-based asymmetric epoxidation reactions

Six novel unsymmetrically substituted chiral non-racemic salen ligands were prepared from resolved trans-1,2-diaminocyclohexane and two different salicylaldehydes. These were then used to construct cationic chromium(III) and manganese(III) complexes that were employed in studies relevant to catalytic asymmetric epoxidation of alkenes. In the case of the chromium complexes, the yields and enantioselectivities obtained were compared to those obtained with the analogous symmetrically substituted counterparts. In individual cases improved enantioselection and a very strong beneficial effect of phosphine oxide additive was found, but in general the selectivity varied in an unpredictable manner. The results are rationalised through the formation of a mixture of diastereomeric active oxidants. In the case of the manganese complexes, where one of the salicylaldehydes is the 3,5-di- tert-butyl case, the standard preparative method leads to substantial scrambling of the ligand and the isolation of mainly Jacobsen's catalyst. One of the preparative methods investigated for the ligand synthesis worked for racemic ligand but failed for the non-racemic version.

Transfer of chirality by dithiophosphate ligands and chiral discrimination in the stereoselective formation of square-planar Ni(II) complexes.

In the formation reaction of Ni(2+) with the chiral racemic ligand, (R)(R)bdtp(-)/(S)(S)bdtp(-), bdtp(-) = [SSPOCH)CH(3))CH(CH(3))O](-), cyclo- O,O'-[1,2-dimethylethylene] dithiophosphato ion, the meso-complex Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)-bdtp] is stereoselectively produced. The meso-complex was compared with the enantiopure crystals of (+)(589)Ni[(R)(R)(lambda)bdtp](2) or (-)(589)Ni[(S)(S)(delta)bdtp](2), as well as racemic crystals, rac-(+/-)Ni[bdtp](2), which were prepared from the solution containing the two enantiomers in a 1:1 ratio. Dissociation constants in solutions indicate different stability of the meso and enantiopure complexes depending on the solvent, whereas a more efficient crystal packing, weak H-bonding, and nonbonding interactions contribute to stabilization of the meso-species over the racemic one. Molecular structures show that the outer five-membered ligand ring adopts the half-chair conformation C(2) with either the lambda or the delta chirality and the methyl groups are in equatorial (e) positions. Enantiopure ligands of (+)(589)Ni[(R)(R)(lambda)bdtp](2) and (-)(589)Ni[(S)(S)(delta)bdtp](2) induce chirality into the symmetric SSNiSS chromophore with slightly helical distortion. Thus, their CD spectra exhibit weak negative or positive Cotton effects at 662 nm. CD spectra in L(+)- and D(-)diethyltartrate of the meso-complex and racemic crystal, rac-(+/-)Ni[bdtp](2), exhibit different weak Cotton effects of opposite sign. Complexes dissociate in methanol; rac-(+/-)Ni[bdtp](2) in methanol undergoes a crystallization-induced second-order asymmetric transformation which finally yields crystals of the meso-Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)bdtp] complex.

Stereodiscrimination in Phosphanylthiolato Nickel(II) Complexes

AbstractThe presence of a stereogenic carbon centre (R or S) in the racemic ligand 1‐(diphenylphosphanyl)propane‐2‐thiol induces a conformational preference (λ or δ) in the five‐membered chelate ring of its 2:1 and 2:2 coordination compounds with NiII: the mononuclear trans‐[Ni{SCH(CH3)CH2PPh2‐P,S}2] (1) and the binuclear trans‐[Ni{μ‐SCH(CH3)CH2PPh2‐P,S}(Cl)]2 (2). Both complexes exist as mixtures of two diastereomers: racemic‐trans (Rλ, Rλ and Sδ, Sδ) and meso‐trans (Rλ, Sδ), in an equilibrium displaced towards the more stable isomer, the meso‐trans for 1 (calculated ΔE = < −0.1 kcal·mol−1) and the racemic‐trans for 2 (calculated ΔE = −5.1 kcal·mol−1). This phenomenon is especially evident for complex 2, in which an efficient chiral recognition between the two enantiomeric forms of the racemic ligand was observed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Non-Linear Effects in Asymmetric Reactions: Negative and Positive Stereoselectivity in the Formation of Homoleptic 1:2 Metal to Ligand Complexes of Chiral 1,9-Disubstituted Semicorrin Ligands

The stereoselectivity of the formation of bis-chelates with the 1,9-disubstituted chiral semicorrin ligands (1S,9S)-dimethyl 5-cyanosemicorrin-1,9-dicarboxylate (1) for Co2+, Ni2+, Cu2+, and Pd2+ and with its (1S,9S)-diethyl analogue 2 for Co2+ and Cu2+ have been measured by the method of continuous variation of enantiomers, and with 1 for Zn2+ by NMR. Positive selectivities were found for Co2+, Ni2+, and Zn2+ complexes, whereas very high negative selectivities prevail in the complexes of Cu2+ and Pd2+. These results are rationalised by X-ray structural determinations of some of the corresponding complexes. The optically active Cu2+ and Pd2+ complexes show distorted square planar structures with chirality predetermined by the chirality of the ligand. Ni2+ complexes are five or hexacoordinated and exhibit a distorted tetrahedral arrangement of the four coordinated nitrogen atoms. In the optically active compound the ester moiety is coordinated by the oxygen atom of the alkoxy group and the arrangement of the two N-N chelate rings shows ?-(S,S) chirality. Interestingly, with the racemic ligand, it is not the more stable heterochiral, but the racemic complex containing the two homochiral enantiomers which is obtained. The coordination of the ester groups occurs by the carbonyl oxygen and the chirality is opposite to the optically active compound, e.g ?(S,S)/?-(R,R). The structure of the optically active zinc compound shows very weak interaction with the alkoxy group of one ester moiety of each ligand molecule and the chirality of the N-N-chelate rings is ?-(S,S). Again, the compound obtained with the racemic ligand contains the enantiomers of the homochiral complex, the chirality of which is ?-(R,R)/?-(S,S). The results are discussed with respect to the possibility to perform asymmetric amplifications of the 1:1 complexes of semicorrin ligands as enantioselective catalysts.

Supramolecular Helical Stacking of Metallomesogens Derived from Enantiopure and Racemic Polycatenar Oxazolines

The present report undertakes a challenge of general interest in supramolecular chemistry: the achievement of helical organizations with controlled structure. To achieve this target we considered the possibility of inducing supramolecular chirality using molecules that were designed to organize into columnar mesophases. The use of oxazoline-derived ligands and metal coordination served as tools to prepare molecules with a phasmidic-like structure, which show columnar organization in the liquid crystalline state. To ensure the formation of chiral mesophases, these complexes bear stereogenic centers in the rigid coordination environment of the metal. X-ray and circular dichroism experiments have revealed that chirality transfer does indeed take place from the chiral molecule to the columnar liquid crystal organization. This chiral columnar organization appears as a helix consisting of stacks of molecules that rotate with respect to one another along the column while maintaining their mean planes parallel to each other. In fact, it has been concluded that packing of these polycatenar molecules must be more efficient upon rotation of a molecule with respect to the adjacent one along the column. Furthermore, the same type of helical supraorganization has been found to be present in the mesophase of the racemic mixture and the mixture of diastereomers prepared from the racemic ligand. In this case, segregation of the optical isomers is proposed to occur to give rise to both types of helix (right-handed and left-handed).

Tropos or Atropos? That Is the Question!

AbstractFor Abstract see ChemInform Abstract in Full Text.