Chiral Pocket Research Articles

4,4'-Disubstituted BINAPs for highly enantioselective Ru-catalyzed asymmetric hydrogenation of ketones.

A family of tunable precatalysts Ru(4,4'-BINAP)(chiral diamine)Cl2 was synthesized and used for highly enantioselective hydrogenation of aromatic ketones. This result differs from previous chiral diphosphines that rely on the bis(xylyl)phosphino groups to control enantioselectivity. An X-ray structural study reveals that the bulky substituents on the 4,4'-positions of BINAP can effectively create a suitable chiral pocket in the transition state and thus provide a new mechanism for the enantiocontrol in such a remarkable asymmetric catalytic process.

High Molecular Weight Phosphazene Copolymers Having Chemical Functions Inside Chiral Pockets Formed by (R)‐(1,1′‐Binaphthyl‐2,2′‐dioxy)phosphazene Units

AbstractThe polyphosphazene {[NPCl2]x[NP(O2C20H12)]1−x}n (O2C20H12 = 1,1′‐binaphthyl‐2,2′‐dioxy) reacted in refluxing THF in the presence of Cs2CO3 with HOC5H4N or para‐substituted phenols HOC6H4R to give the random copolymers {[NP(OC5H4N)2]x[NP(O2C20H12)]1−x}n (1) or {[NP(OC6H4R)2]x[NP(O2C20H12)]1−x}n [R = CN (2), COMe (3), CO2nPr (4), PPh2 (5)] and with H2NnBu to give {[NP(NHnBu)2]x[NP(O2C20H12)]1−x}n (6). The reaction of the polymer {[NPCl2]x[NP(O2C20H10Br2)]1−x}n (O2C20H10Br2 = 6,6′‐dibromo‐1,1′‐binaphthyl‐2,2′‐dioxy) with HOC6H4PPh2 and Cs2CO3 gave {[NP(OC6H4PPh2)2]x[NP(O2C20H10Br2)]1−x}n (7). Those polymers have a very high glass‐transition temperature (Tg) and a chemical function or ligand that is in the interior of a chiral pocket. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Unusual effects in the pd-catalyzed asymmetric allylic alkylations: synthesis of chiral chromans.

An examination of earlier reports of poor-to-modest results using Pd-catalyzed asymmetric allylic alkylations (AAA) to effect cyclization to form tetrasubstituted carbons reveals several novel factors that can influence this class of reactions. Thus, carboxylate has a major effect on such cyclizations wherein the ee increases from 14% ee favoring the S with no carboxylate to 84% ee favoring the R enantiomer in the presence of 1 equiv of carboxylate. Changing the double bond geometry from E to Z further increases the ee to 97%. Furthermore, the chiral catalyst that forms the R enantiomer with the E-alkene forms the S enantiomer with the Z alkene. In contrast to trisubstituted alkene substrates, disubstituted ones show a decrease in ee in going from the E to Z alkenes. The role of carboxylate appears to be a ligand to Pd during the catalytic cycle, a previously unsuspected phenomenon since such reactions are generally believed to involve pi-allylpalladium cationic complexes. The dependence upon alkene geometry helps define the nature of the chiral pocket which better accommodates a Z alkene compared to an E alkene. The results are compatible with the enantiodiscriminating step being ionization which occurs by coordination of the palladium to one of the two prochiral faces of the double bond. A synthesis of (+)-clusifoliol, a constituent of a folk medicine for treatment of malignant tumors, which also assigns the absolute configuration, illustrates the utility of the method.

X-ray and NOE Studies on Trinuclear Iridium Hydride Phosphino Oxazoline (PHOX) Complexes

Two trinuclear iridium hydride clusters of the type [Ir3(μ3-H)(H)6(PHOX)3]X1X2 (X1 = PF6, X2 = OTf; X1 = X2 = PF6; X1 = X2 = OTf; PHOX = (S)-4-tert-butyl-2-[2-(di-o-tolylphosphinyl)phenyl]-4,5-dihydrooxazole, (S)-2-[2-(diphenylphosphinyl)phenyl]-4-isopropyl-4,5-dihydrooxazole) have been prepared and characterized by X-ray diffraction and multidimensional NMR. They contain a single bridging hydride in pseudo-trans position to the P-donors. The complexed PHOX ligands reveal a chiral pocket involving one pseudoequatorial P-aryl substituent and one pseudoaxial (proximate to the oxazoline substituent) P-aryl group. These trinuclear complexes are shown to be inactive as hydrogenation catalysts.

A highly enantioselective receptor for N-protected glutamate and anomalous solvent-dependent binding properties.

The development of enantioselective receptors continues to be a challenging endeavor for supramolecular chemists, and enantioselective recognition of biologically relevant molecules in competitive solvents is particularly demanding.[1] Although numerous receptors have been developed for dicarboxylic acids and dicarboxylates,[2] only a few enantioselective receptors for chiral dicarboxylic acids (in the neutral diprotonated form) have been described,[3] and very few examples of enantioselective receptors for chiral dicarboxylates have been reported.[4] We recently described an acyclic monothiourea receptor 1a, which bound a range of N-protected amino acid carboxylate salts with modest enantioselectivity.[5] Building on this work, we have now prepared macrocyclic receptor 2, which features two thiourea moieties flanked by carboxypyridines and separated by a chiral diamine. The receptor was designed to produce a chiral pocket for dicarboxylates by forming up to eight hydrogen-bonding interactions with the carboxylate oxygen atoms and intramolecular hydrogen bonding with the pyridine unit to help preorganize[6] the receptor (Scheme 1). Binding measurements, by NMR titration and isothermal

Syntheses, Structures, and Catalytic Reactions of Palladium Adducts of Chiral Diphosphines That Contain a Rhenium Stereocenter in the Backbone

Reactions of the title diphosphines [(η5-C5H4PPh2)Re(NO)(PPh3)((CH2)nPPh2)] (n=0, (R)-1; n=1, racemic or (S)-2) with [PdCl2(PhCN)2] give the palladium/rhenium chelate complexes [(η5-C5H4PPh2)Re(NO)(PPh3)((μ-CH2)nPPh2)PdCl2] (n=0, (S)-5; n=1, racemic or (S)-6) in 75–92% yield. The crystal structure of racemic 6 shows a twisted-boat conformation of the chelate ring, giving a chiral pocket very different from that in a related rhodium chelate. However, NOE experiments suggest a similar ensemble of conformations in solution. Catalysts are generated from various combinations of a) Pd(OAc)2 and (R)-1 or (S)-2 (1 : 2), b) (S)-5 or (S)-6 and (R)-1 or (S)-2 (1 : 2), or c) (i-Bu)2AlH with the preceding recipes. These factors effect the Heck arylation of 2,3-dihydrofuran with phenyl trifluoromethylsulfonate. In contrast to analogous reactions with (R)-binap (=(R)-2,2′-bis(diphenylphosphanyl)-1,1′-binaphthalene), the major product 2-phenyl-2,3-dihydrofuran is nearly racemic (≤12% ee).

Biomimetic macrocyclic receptors for carboxylate anion recognition based on C-linked peptidocalix[4]arenes.

Two neutral macrobicyclic anion receptors 4 and 6, containing a calix[4]arene in the cone conformation, two l-alanine units, and a 2,6-diacylpyridine or a phthaloyl bridge, are described. The x-ray crystal structure of the acetone complexes of the pyridine containing macrocycle 6 shows the four amide NH groups to be in close proximity to the chiral pocket delimited by the pyridine and one aromatic nucleus of the calix[4]arene. This conformation is also the most stable in acetone-d6 solution, as proven by one- and two-dimensional NMR spectral measurements. Electrospray ionization-MS and (1)H NMR experiments reveal that the two ligands strongly bind carboxylate anions in acetone solution. H-bonding interactions between the carboxylate anions and the amide NH groups, together with pi/pi stacking, are invoked to explain the efficiency and the selectivity of these anion receptors.

Chiral induction based on carbohydrate ligands in olefin platinum(0) complexes

A chiral N,N-ligand based on glucose is able to recognise selectively one enantioface of a prochiral olefin in a trigonal Pt environment. NMR and X-ray studies have been carried out aiming to disclose the factors, which govern this unexpected result. The selectivity originates from the ability of the ligand to create a chiral pocket of C 2 symmetry, which is retained in both solution and solid state.

Chiral mutagenesis of insulin’s hidden receptor-binding surface: structure of an Allo-isoleucine A2 analogue

The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain’s dual contribution to structure and function: Ile A2 is proposed both to stabilize the A1-A8 α-helix and to contribute to a “hidden” functional surface exposed on receptor binding. Substitution of Ile A2 by alanine results in segmental unfolding of the A1-A8 α-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile A2 to insulin’s functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile A2-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin’s core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile A2 side-chain inserts within a chiral pocket of the receptor as part of insulin’s hidden functional surface.

Highly efficient ligands for palladium-catalyzed asymmetric alkylation of ketone enolates.

[figure: see text] Ferrocene-modified chiral pocket ligands have been studied in the palladium-catalyzed asymmetric alkylation of simple ketone enolates, in which (R,R,Sp,Sp)-1 containing two pairs of matched chiralities, central chirality and planar chirality, behaved very efficiently in this reaction and up to 95% ee value was achieved.

A Novel Example of Chiral Counteranion Induced Enantioselective Metal Catalysis: The Importance of Ion-Pairing in Copper-Catalyzed Olefin Aziridination and Cyclopropanation

A new ion-pairing route to achieve asymmetric catalysis has been observed in the copper-catalyzed aziridination of styrene with a chiral counteranion. Structural studies suggest that enantioinduction occurs via ion-pairing of the cationic copper catalyst in the chiral pocket created by the anion. The degree of asymmetric induction can be tuned with features that affect ion-pairing, such as achiral and chiral ligands, temperature, and solvent polarity.

Towards Asymmetric Catalysis in the Major Groove of 1,1′-Binaphthalenes

Four new diphosphane ligands, (R)-4, (R)-5, (S)-6, and (R)-7 (Schemes 3, 4, 6, and 7), featuring metalcoordination sites located in the major groove of chiral 1,1′-binaphthalene clefts, were prepared in enantiomerically pure form. The performance of this new class of ligands was tested in enantioselective, Pd-catalyzed allylic alkylation reactions with acyclic and cyclic methyl carbonates 28 – 30 as substrates under various reaction conditions (Schemes 8 and 9). Using sodium phenyl sulfinate as a nucleophile, the reactivity of the catalysts formed with the new ligands and suitable palladium precursors was found satisfactory (>90%); however, the ee values were in all cases poor (<4%). Slightly better results were obtained using anions of dimethyl malonate as nucleophiles, but, also in these cases, the ee values never exceeded 17% (Table). 31P-NMR-Spectroscopic investigations revealed the formation of multiple-catalyst species in solution (Fig. 2), and molecular modeling suggested a lack of embedding of the coordinated substrate in a `chiral pocket' (Fig. 3), which probably accounts for the observed low level of enantioselectvity.

Chiral Quadridentate Ligands Derived from Amino Acids and Some Zinc Complexes Thereof

A series of three new quadridentate ligands was synthesized by reaction of the haloacetylated amino acid esters L-BrAc−Phe−OMe (4a), L-BrAc−Lys(Z)−OMe (4b), and ClAc−Gly−OEt (4c), respectively, with bis(picolyl)amine (bpa, 5). The obtained products L-bpaAc−Phe−OMe (3a), L-bpaAc−Lys(Z)−OMe (3b), and bpaAc−Gly−OEt (3c) were treated with Zn(OTf)2 (OTf = CF3SO3−) to yield the trigonal-bipyramidal complexes [(L-bpaAc−Phe−OMe)ZnOTf](OTf) (6a), [(L-bpaAc−Lys(Z)−OMe)ZnOTf](OTf) (6b), and [(bpaAc−Gly−OEt)ZnOTf](OTf) (6c). Crystal structures of 6c and the hydrolysis product [(L-bpaAc−Phe−OMe)(H2O)ZnOTf](OTf)2 (7a) are reported. The results suggest the formation of a chiral pocket at the metal center provided by the benzyl substituent in the L-phenylalanine derivative 7a. This observation is further supported by 1H-NMR and circular dichroism spectroscopic data. These methods indicate a significant ordering effect within the ligands upon metal coordination as well as interactions between the first coordination spheres and their chiral environments provided by the L-phenylalanine and L-lysine moieties of 3a and 3b, respectively. Our results are discussed with respect to the development of chiral building blocks for transition metal catalysts and biomimetic assemblies.

Catalytic and Structural Studies on Complexes of a Binaphthyl−Phosphino−Oxazoline Auxiliary: The Meta Dialkyl Effect on Enantioselectivity

The chiral phosphino-oxazoline ligand (S,R)-2-[4-(isopropyl)oxazol-2-yl]-2‘-bis(3,5-dimethylphenylphosphino)-1,1‘-binaphthyl, 6b, its Pd-dichloro complex, 9, the p-cyanoaryl complex [PdBr(p-NC−C6H4](6b)], 10, a model for the Heck reaction, the cationic 1,3-diphenylallyl derivative [Pd(η3-PhCHCHCHPh)(6b)]OTf, 11, a model for the allylic allylation, and the Rh- and Ir-1,5-COD compounds [M(1,5-COD)(6b)]BF4, 12 and 13, respectively, have been prepared. In enantioselective catalytic experiments, the presence of the 3,5-dimethylphenyl groups generally increases the observed ee. The solid-state structure of PdCl2(6b), 9, has been determined. 2-D and variable-temperature NMR experiments suggest that one of the two 3,5-dimethyl P-aryl rings interacts selectively with the remaining ligands. Consequently, the entire chiral pocket becomes slightly more rigid and the correlation with substrate improves.

Synthesis and Structure of Enantiomerically Pure Platinum Complexes of Phosphino-oxazolines and Their Use in Asymmetric Catalysis

Novel organoplatinum complexes of the enantiomerically pure P, N ligand, (4S)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-1,3-oxazoline, have been synthesized and shown to act as Lewis acids. These complexes consist of the bidentate P, N ligand, an achiral organic ligand, and a solvent ligand that can be readily displaced by organic substrates. The solvent ligand is situated cis to the nitrogen donor and, as such, is in a “chiral pocket” created by the oxazoline ring. The complexes are readily prepared from the well-known, and versatile, precursors (COD)PtR2 and are obtained as single isomers. Two of the complexes have had their structures elucidated by X-ray crystallography. The cationic complexes were shown to be enantioselective catalysts in the Michael reaction of α-cyano carboxylates with methyl vinyl ketone.

New, Axially Chiral, Bimetallic Catalysts for Asymmetric Alkylation of Aldehydes with Diethylzinc

Axially chiral bis(salicylidene)ethylenediamine (H2salen)-type ligands 3 (cf. Schemes 1 and 3) are efficient ligands for the enantioselective addition of diethylzinc to aldehydes. There is ample evidence that an active bimetallic catalyst forms an effective chiral pocket (see Fig. 2); of a series of first-row transition-metal complexes with these ligands, the most stereoselective were the CoII complexes (see Fig. 1). Best ee values as well as the fastest rates (see Tables 2 and 3) were obtained with these CoII complexes when an EtO substituent was present at C(3) of the salicylaldehyde residues of ligand 3 (R1=EtO), i.e., complex [CoII(3′h)] produced up to 93% ee with aromatic aldehydes and 78% ee for aliphatic aldehydes (see Table 4).

Mechanistic Investigation of the Oxidation of Aromatic Alkenes by Monooxoruthenium(IV). Asymmetric Alkene Epoxidation by Chiral Monooxoruthenium(IV) Complexes

The oxoruthenium(IV) complexes [RuIV(terpy)(6,6‘-Cl2-bpy)O](ClO4)2 (1a; terpy = 2,2‘:6‘,2‘ ‘-terpyridine; 6,6‘-Cl2-bpy = 6,6‘-dichloro-2,2‘-bipyridine), [RuIV(terpy)(tmeda)O](ClO4)2 (1b; tmeda = N,N,N‘,N‘-tetramethylethylenediamine), [RuIV(Cn)(bpy)O](ClO4)2 (1c; Cn = 1,4,7-trimethyl-1,4,7-triazacyclononane), and [RuIV(PPz*)(bpy)O](ClO4)2 (1d; PPz* = 2,6-bis[(4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methanoindazol-2-yl]pyridine) are effective for the epoxidation of aromatic alkenes in acetonitrile at ambient conditions. Their reactions with cis-alkenes such as cis-β-methylstyrene and cis-β-deuteriostyrene afford epoxides nonstereospecifically. The observation of the inverse secondary kinetic isotope effect for the β-d2-styrene oxidations [kH/kD = 0.87 (1b), 0.86 (1d)], but not for α-deuteriostyrene (kH/kD = 0.98 for 1b and 1d), indicates that C−O bond formation is more advanced at the β-carbon atom than at the α carbon, i.e., a stepwise mechanism. The second-order rate constants (k2) for the styrene oxidations are weakly dependent on the E°(RuIV/III) values of the oxoruthenium(IV) complexes, and both electron-withdrawing and -donating para substituents mildly accelerate the oxidation reaction of styrene. These findings discount strongly the intermediaries of an alkene-derived cation radical and a carbocation. A linear free-energy relationship between the second-order rate constants for the para-substituted styrene oxidations and the total substituent effect (TE) parameters has been established: ρTE• = +0.43 (R = 0.99) for 1b, +0.50 (R = 0.98) for 1c, and +0.37 (R = 0.99) for 1d (Wu, Y.-D.; Wong, C.-L.; Chan, K. W.; Ji, G.-Z.; Jiang, X.-K. J. Org. Chem. 1996, 61, 746). This suggests that the oxidation of aromatic alkenes by oxoruthenium(IV) complexes should proceed via the rate-limiting formation of a benzylic radical intermediate. Oxidation of styrene and cis- and trans-β-methylstyrenes by the chiral oxoruthenium(IV) complex 1d attains moderate enantioselectivities, in which the production of cis-epoxide is more enantioselective than the trans counterpart. The ligand dissymmetry of PPz* together with the bipyridine ligand create a “chiral pocket” around the RuIVO moiety, leading to enantiofacial discrimination through nonbonding interaction. Because the acyclic benzylic radical intermediate would undergo cis−trans isomerization before the second C−O bond formation, the overall product enantioselectivity (% eeobs) cannot be determined exclusively by facial selectivity (eefacial) of the first irreversible C−O bond formation step. The extent of the isomerization, measured by the cis−trans-epoxide selectivity or diastereoselectivity of epoxide ring closure, is an important element in controlling the enantiomeric excess of the epoxides.

Structural Chemistry of Methyl- and Allylpalladium(II) Complexes Containing Chiral Thioether Auxiliaries

The molecular structures of three PdII compounds are reported: a) the two [PdCl(Me)] complexes 7a and 8a each containing a different chiral N,S-chelate based on {[(dihydrooxazolyl)phenyl]methyl}-thioglucose backbones, e.g., chloro({2-[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl-κN]phenyl}methyl 2,3,4,6-tetra-O-acetyl-1-(thio-κS)-β-D-glucopyranoside)methylpalladium(II) (7a) and b) one [Pd(η3-C3H5)(P-S)]+ cation in which the P,S-chelate stems from a phosphinoferrocene and thioephedrine-derived thioether donor, i.e., [(S)-1-(diphenylphosphino-κP)-2-((1R)-1-{[(1R,2S)-1-phenyl-2-(piperidin-1-yl)propyl]thio-κS}ethyl)ferrocene] (η3-prop-2-enyl)palladium trifluoromethanesulfonate (11). In the methylpalladium compounds 7a and 8a the thioglucose-κS moiety is pseudo-axial (Figs. 2 and 3), whereas in the allyl complex, the thioephedrine-κS moiety is markedly pseudo-equatorial (Fig. 5). It is suggested, based on these results, that the shape (chiral pocket) of such coordinated chiral thioethers may not be readily predictable.

Stereospecificity of the sensory irritation receptor for nonreactive chemicals illustrated by pinene enantiomers

To clarify the existence of a receptor protein for sensory irritants in trigeminal nerve endings, D- [i.e. (+)] and L- [i.e. (-)] enantiomers of alpha- and beta-pinene as models of nonreactive chemicals were evaluated for their potency in outbred OF1 and NIH/S mice using ASTM E981-84 bioassay. All pinenes possess sensory irritation properties and also induced sedation and signs of anaesthesia but had no pulmonary irritation effects. According to the ratio of RD50 (i.e. concentration which causes a 50% decrease in respiratory rate,f) and vapour pressure (Po), all pinenes are nonreactive chemicals. For nonreactive chemicals, Po and olive oil-gas partition (Loil) can be used to estimate their potency as sensory irritant. Thus, for enantiomers with identical physicochemical properties, the estimated RD50 values are the same. In addition, although alpha- and beta-pinene do not have identical Po and Loil values, their estimated potencies are quite close. However, the experimental results showed that D-enantiomers of pinenes were the most potent as sensory irritants and a difference in potency also exists between alpha- and beta-pinene. RD50 for D-enantiomers of alpha- and beta-pinene were almost equal, 1053 ppm and 1279 ppm in OF1 strain and 1107 ppm and 1419 ppm in NIH/S strain, respectively. Values differed by a factor of approximately 4 to 5 from L-beta-pinene for which the RD50 was 4663 ppm in OF1 and 5811 ppm in NIH/S mice. RD50 could not be determined for L-alpha-pinene; this pinene was almost inactive. D-alpha-pinene seems to best fit the receptor because its experimental RD50 was one-half of the estimated value while for D-beta-pinene those values were equal. On the contrary, L-beta-pinene was about 3 to 4 times less potent than estimated. L-alpha-pinene was only slightly active although it was estimated to be as potent as D-alpha-pinene. The remarkable difference in potency between L-enantiometers is most likely due to a structural difference between alpha- and beta-pinene: the more flexible beta-pinene can bend to fit into the receptor better than the rigid alpha-pinene. The results showed that the commonly used physicochemical descriptors cannot fully explain the potency of these chemicals; their three-dimensional structure should also be considered. Because of the stereospecificity of pinenes, a target site for nonreactive sensory irritants is most likely a receptor protein containing a chiral lipophilic pocket.

Enantioselective Homogeneous Catalysis and the “3,5-Dialkyl Meta-Effect”. MeO−BIPHEP Complexes Related to Heck, Allylic Alkylation, and Hydrogenation Chemistry

The enantioselectivities arising from a Pd-catalyzed Heck reaction (>98% ee) and an allylic alkylation (>90% ee) using a 3,5-di-tert-butyl-MeO−BIPHEP chiral auxiliary (1) are reported. Higher ee's are observed with the 3,5-dialkyl substituents than with the unsubstituted parent MeO−BIPHEP. It is proposed that the observed dialkyl “meta-effect”, on enantioselectivity, is the combined result of a more rigid and slightly larger chiral pocket and that this effect will have some generality in homogeneous catalysis. Detailed NMR studies on the allyl complex [Pd(PhCHCHCHPh)(1)]PF6 (5), and the model hydrogenation catalyst [RuH(cymene)(1)]BF4 (6), reveal restricted rotation about several of the P−C(ipso) bonds of the phosphorus substituents containing the 3,5-di-tert-butyl groups. The X-ray structure of 6 reveals that the cymene ligand is not symmetrically bound to the Ru atom. This observation is interpreted as an expression of the chiral pocket of 1. MM3* calculations on 6 support the NMR findings and reproduce the X-ray results.