Chiral 1,1′-Binaphthyl Molecular Clefts for the Complexation of Excitatory Amino-Acid Derivatives

The complexation of N-benzyloxycarbonyl (Cbz) derivatives of the excitatory amino acids L -aspartic acid (Asp; 1 ), L -glutamic acid (Glu; 3 ), and, for the first time, L -kainic acid ((2S,3S,3S)-2-carboxy-4-(1-methylethenyl)pyrrolidine-3-acetic acid; Kai; 5 ) was studied in CDCl₃ with a diversity of chiral receptors consisting of a 1,1′-binaphthyl spacer with (carboxamido)pyridine (CONH(py)) functionality attached to the 6,6′-positions in the major groove. Receptors of type A possess two N-(pyridin-2-yl)carboxamide H-bonding sites (e.g. 7 ), whereas type B-receptors have two N-(pyridine-6,2-diyl)acetamide residues attached (e.g. 8 and 9 ). Complexes of excitatory amino-acid derivatives and other, achiral α,β-dicarboxylic acids with these receptors are primarily stabilized by two sets of C?O···H? N and O? H ··· N H-bonds. Optically active type-A receptors such as (R)- and (S)- 7 showed a preference for the larger Glu derivative, whereas type- B receptors such as (R)- and (S)- 8 and (R)- and (S)- 9 formed more stable complexes with the smaller Cbz-Asp. To improve the poor enantioselectivity shown by 7–9 , additional functionality was introduced at the 7,7′-positions of the 1,1′-binaphthyl spacer, and the nature of the H-bonding sites in the 6,6′-positions was varied. Screening the diversity of new racemic receptors for binding affinity, which had been shown in many examples by Cram to correlate with enantioselectivity, demonstrated that (+)- 10 and (+)- 11 formed the most stable complexes with dicarboxylic acids, and these receptors were synthesized in enantiomerically pure form. Both are type- B binders and contain additional PhCH₂O ( 10 ) and MeO ( 11 ) groups in the 7,7′-positions. By ¹H-NMR binding titrations, the complexation of (R)- and (S)- 10 and (R)- and (S)- 11 with the excitatory amino-acid derivatives was studied in CDCl₃, and association constants K_a between 10³ and 2 · 10⁵ l mol^?1 were measured for the 1:1 host-guest complexes formed. Whereas both 10 and 11 formed stable complexes, enantioselective binding was limited to the PhCH₂O-substituted receptor 10 , with the (R)-enantiomer complexing Cbz-Asp by 0.7 kcal mol^?1 more tightly than the (S)-enantiomer. The structures of the diastereoisomeric complexes were analyzed in detail by experimental methods (complexation-induced changes in ¹H-NMR chemical shifts, ¹H{¹H} nuclear Overhauser effect (NOE) difference spectroscopy) and computer modeling. These studies established that an unusual variety of interesting aromatic interactions and secondary electrostatic interactions are responsible for both the high binding affinity (? ΔG° up to 7.2 kcal mol^?1) and the enantioselection observed with (R)- and (S)- 10 . In an approach to enhance the enantioselectivity by reducing the conformational flexibility of the 1,1′-binaphthyl spacer, an additional crown-ether binding site was attached to the 2,2′-positions in the minor groove of the type- B receptors (R)- and (S)- 48 . Both the binding affinity and the enantioselectivity (Δ(ΔG°) up to 0.7 kcal mol^?1) in the complexation of the excitatory amino-acid derivatives by (R)- and (S)- 48 were not altered upon complexation of Hg(CN)₂ at the crown-ether binding site, demonstrating lack of cooperativity between the minor- and major-groove recognition sites.     

Molecular Recognition of Pyranosides by a Family of Trimeric, 1,1′-Binaphthalene-Derived Cyclophane Receptors

The synthesis and carbohydrate-recognition properties of a new family of optically active cyclophane receptors, 1 – 3 , in which three 1,1′-binaphthalene-2,2′-diol spacers are interconnected by three buta-1,3-diynediyl linkers, are described. The macrocycles all contain highly preorganized cavities lined with six convergent OH groups for H-bonding and complementary in size and shape to monosaccharides. Compounds 1 – 3 differ by the functionality attached to the major groove of the 1,1′-binaphthalene-2,2′-diol spacers. The major grooves of the spacers in 2 are unsubstituted, whereas those in 1 bear benzyloxy (BnO) groups in the 7,7′-positions and those in 3 2-phenylethyl groups in the 6,6′-positions. The preparation of the more planar, D₃-symmetrical receptors (R,R,R)- 1 (Schemes 1 and 2), (S,S,S)- 1 (Scheme 4), (S,S,S)- 2 (Scheme 5), and (S,S,S)- 3 (Scheme 8) involved as key step the Glaser-Hay cyclotrimerization of the corresponding OH-protected 3,3′-diethynyl-1,1′-binaphthalene-2,2′-diol precursors, which yielded tetrameric and pentameric macrocycles in addition to the desired trimeric compounds. The synthesis of the less planar, C₂-symmetrical receptors (R,R,S)- 2 (Scheme 6) and (S,S,R)- 3 (Scheme 9) proceeded via two Glaser-Hay coupling steps. First, two monomeric precursors of identical configuration were oxidatively coupled to give a dimeric intermediate which was then subjected to macrocyclization with a third monomeric 1,1′-binaphthalene precursor of opposite configuration. The 3,3′-dialkynylation of the OH-protected 1,1′-binaphthalene-2,2′-diol precursors for the macrocyclizations was either performed by Stille (Scheme 1) or by Sonogashira (Schemes 4, 5, and 8) cross-coupling reactions. The flat D₃-symmetrical receptors (R,R,R)- 1 and (S,S,S)- 1 formed 1 : 1 cavity inclusion complexes with octyl 1-O-pyranosides in CDCl₃ (300 K) with moderate stability (ΔG⁰ ca. −3 kcal mol⁻¹) as well as moderate diastereo- (Δ(ΔG⁰) up to 0.7 kcal mol⁻¹) and enantioselectivity (Δ(ΔG⁰)=0.4 kcal mol⁻¹) (Table 1). Stoichiometric 1 : 1 complexation by (S,S,S)- 2 and (S,S,S)- 3 could not be investigated by ¹H-NMR binding titrations, due to very strong signal broadening. This broadening of the ¹H-NMR resonances is presumably indicative of higher-order associations, in which the planar macrocycles sandwich the carbohydrate guests. The less planar C₂-symmetrical receptor (S,S,R)- 3 formed stable 1 : 1 complexes with binding free enthalpies of up to ΔG⁰=−5.0 kcal mol⁻¹ (Table 2). With diastereoselectivities up to Δ(ΔG⁰)=1.3 kcal mol⁻¹ and enantioselectivities of Δ(ΔG⁰)=0.9 kcal mol⁻¹, (S,S,R)- 3 is among the most selective artificial carbohydrate receptors known.     

Towards Allosteric Receptors: Adjustment of the Rotation Barrier of 2,2′‐Bipyridine Derivatives

What a difference ! The energy differences between anti and syn conformers as well as the energy barrier for the rotation around the aryl–aryl bond of a number of 2,2′‐bipyridine molecules were examined by quantum‐chemical methods. The energy differences were found to be governed by the substituents directly attached to the bipyridine and their ability to form intramolecular hydrogen bonds.

     

Functionalized 3,3′,5,5′‐Tetraaryl‐1,1′‐Biphenyls: Novel Platforms for Molecular Receptors

This paper describes the development of novel aromatic platforms for supramolecular construction. By the Suzuki cross‐coupling protocol, a variety of functionalized m‐terphenyl derivatives were prepared (Schemes 1–4). Macrolactamization of bis(ammonium salt) (S,S)‐ 6 with bis(acyl halide) 7 afforded the macrocyclic receptor (S,S)‐ 2 (Scheme 1), which was shown by ¹H‐NMR titration studies to form ‘nesting' complexes of moderate stability (K_a between 130 and 290 M ^?1, 300 K) with octyl glucosides 13 – 15 (Fig. 2) in the noncompetitive solvent CDCl₃. Suzuki cross‐coupling starting from 3,3′,5,5′‐tetrabromo‐1,1′‐biphenyl provided access to a novel series of extended aromatic platforms (Scheme 5) for cleft‐type (Fig. 1) and macrotricyclic receptors such as (S,S,S,S)‐ 1 . Although mass‐spectral evidence for the formation of (S,S,S,S)‐ 1 by macrolactamization between the two functionalized 3,3′,5,5′‐tetraaryl‐1,1′‐biphenyl derivatives (S,S)‐ 33 and 36 was obtained, the ¹H‐ and ¹³C‐NMR spectra of purified material remained rather inconclusive with respect to both purity and constitution. The versatile access to the novel, differentially functionalized 3,3′,5,5′‐tetrabromo‐1,1′‐biphenyl platforms should ensure their wide use in future supramolecular construction.     

Asymmetric Phase-Transfer Catalysis by Quaternary Ammonium Ions Derived from Cinchona-Alkaloid Analogs Containing 1,1′-Binaphthalene Moieties

The synthesis and catalytic properties of a new type of enantioselective phase-transfer catalysts, incorporating both the quinuclidinemethanol fragment of Cinchona alkaloids and a 1,1′-binaphthalene moiety, are described. Catalyst (+)-(aS,3R,4S,8R,9S)- 4 with the quinuclidine fragment attached to C(7′) in the major groove of the 1,1′-binaphthalene residue was predicted by computer modeling to be an efficient enantioselective catalyst for the unsymmetric alkylation of 6,7-dichloro-5-methoxy-2-phenylindanone ( 1 ; Scheme 1, Fig. 1). Its synthesis involved the selective oxidative cross-coupling of two differently substituted naphthalen-2-ols to afford the asymmetrically substituted 1,1′-binaphthalene derivative (±)- 17 in high yield (Scheme 3). Chromatographic optical resolution via formation of diastereoisomeric camphorsulfonyl esters and functional-group manipulation gave access to the 7-bromo-1,1′-binaphthalene derivative (−)-(aS)- 11 (Scheme 4). Nucleophilic addition of lithiated (−)-(aS)- 11 to the quinuclidine Weinreb amide (+)-(3R,4S,8R)- 8 afforded the two ketones (aS,3R,4S,8R)- 27 and (aS,3R,4S,8S)- 28 as an inseparable mixture of diastereoisomers (Scheme 6). Stereoselective reduction of this mixture with DIBAL-H (diisobutylaluminum hydride; preferred formation of the C(8)−C(9) erythro-pair of diastereoisomers with 18% de) or with NaBH₄ (preferred formation of the threo-pair of diastereoisomers with 50% de) afforded the four separable diastereoisomers (+)-(aS,3R,4S,8S,9S)- 29 , (+)-(aS,3R,4S,8R,9R)- 30 , (−)-(aS,3R,4S,8S,9R)- 31 , and (+)-(aS,3R,4S,8R,9S)- 32 (Scheme 6). A detailed conformational analysis, combining ¹H-NMR spectroscopy and molecular-mechanics computations, revealed that the four diastereoisomers displayed distinctly different conformational preferences (Figs. 2 and 3). These novel Cinchona-alkaloid analogs were quaternized to give (+)-(aS,3R,4S,8R,9S)- 4 , (+)-(aS,3R,4S,8S,9S)- 5 , (+)-(aS,3R,4S,8R,9R)- 6 , and (−)-(aS,3R,4S,8S,9R)- 7 (Scheme 7) which were tested as phase-transfer agents in the asymmetric allylation of phenylindanone 1 . Without any optimization work, (+)-(aS,3R,4S,8R,9S)- 4 was found to catalyze the allylation of 1 yielding the predicted enantiomer (+)-(S)- 3b in 32% ee. The three diastereoisomeric catalysts (+)- 5 , (+)- 6 , and (−)- 7 gave access to lower enantioselectivities (6 to 22% ee's), which could be rationalized by computer modeling (Fig. 4).     

基于(R)-1,1’-联萘硫脲的手性荧光受体: 合成与手性识别

Two chiral fluorescent receptors 1 and 2 based on (R)-1,1‘-binaphthylene-2,2‘-bisthiourea were synthesized, and their chiral recognition properties for enantiomeric mandelate anions were studied by fluorescence spectra and molecular modeling. Addition of the L- and D-mandelate anions caused considerable fluorescent increases in the fluorescent intensity of the host solution. The L-enantiomer can enhance the fluorescence intensity of 1 much more than the D-enantiomer can do, and 1 shows a better enantioselective recognition ability than 2.     

Synthetic Receptors for the High‐Affinity Recognition of O‐GlcNAc Derivatives

The combination of a pyrenyl tetraamine with an isophthaloyl spacer has led to two new water‐soluble carbohydrate receptors (“synthetic lectins”). Both systems show outstanding affinities for derivatives of N‐acetylglucosamine (GlcNAc) in aqueous solution. One receptor binds the methyl glycoside GlcNAc‐β‐OMe with K_a≈20 000 m ^?1, whereas the other one binds an O‐GlcNAcylated peptide with K_a≈70 000 m ^?1. These values substantially exceed those usually measured for GlcNAc‐binding lectins. Slow exchange on the NMR timescale enabled structural determinations for several complexes. As expected, the carbohydrate units are sandwiched between the pyrenes, with the alkoxy and NHAc groups emerging at the sides. The high affinity of the GlcNAcyl–peptide complex can be explained by extra‐cavity interactions, raising the possibility of a family of complementary receptors for O‐GlcNAc in different contexts.     

A Vibrational Raman Optical Activity Study of 1,1′‐Binaphthyl Derivatives

The Raman polarized and vibrational Raman optical activity (VROA) backward spectra are simulated for a series of 2,2′‐substituted 1,1′‐binaphthyl compounds presenting a variety of torsion angles between the two naphthalene rings. The substitution prevents free rotation along this torsion angle and the chirality of these compounds is thus called atropisomerism. However, the rotation is not completely frozen so that two different conformations, namely cisoid and transoid, are found and their Raman and VROA signatures are studied. As expected, the Raman spectra are not very sensitive whereas the VROA spectra present more complex patterns, which evolve as a function of the torsion angle between the two naphthalene groups. In particular, our analysis shows that some modes can be used as a probe for the determination of the torsion angle of these molecules in solution. The contributions of both invariants to the VROA backward intensity are also assessed.     

变构受体分子的设计及其在分子动态识别中的应用

变构调节(allostericregulation)普遍存在于自然界中,是生物体系实行精妙调控和准确表达的有效途径之一 [1]。在生物体系中,蛋白质分子具有的特定空间构象是表达其生物学功能所必需的,某些含有亚基的蛋白质,其功能往往是通过构象的变化来调节的。20世纪 60年代,Monod[2]在研究血红蛋白与氧结合时提出了蛋白质的变构效应。血红蛋白由两条α 亚基和两条β 亚基相互折叠彼此缠绕而成,亚基与亚基之间由于次级键的存在,处于T态 (tensestate),对氧的亲和力低于单独的α 亚基或β 亚基对氧的亲和力。随着氧浓度提高,氧首先与一个α 亚基中的亚…     

Recognition of Chiral Carboxylates by Synthetic Receptors

Recognition of anionic species plays a fundamental role in many essential chemical, biological, and environmental processes. Numerous monographs and review papers on molecular recognition of anions by synthetic receptors reflect the continuing and growing interest in this area of supramolecular chemistry. However, despite the enormous progress made over the last 20 years in the design of these molecules, the design of receptors for chiral anions is much less developed. Chiral recognition is one of the most subtle types of selectivity, and it requires very precise spatial organization of the receptor framework. At the same time, this phenomenon commonly occurs in many processes present in nature, often being their fundamental step. For these reasons, research directed toward understanding the chiral anion recognition phenomenon may lead to the identification of structural patterns that enable increasingly efficient receptor design. In this review, we present the recent progress made in the area of synthetic receptors for biologically relevant chiral carboxylates.     

Magnetic susceptibility of 1,1′,2,2′-tetramethylcobaltocene and 1,1′-diethylcobaltocene: Evidence for the dynamic Jahn-Teller effect

The magnetic susceptibility of 1,1′,2,2′-tetramethylcobaltocene, Co[C₅H₃(CH₃)₂]₂, and 1,1′-diethylcobaltocene, Co(C₅H₄C₂H₅)₂, has been studied between 0.99 and 296 K. The data are well reproduced by a calculation of the dynamic Jahn-Teller effect for the ²E_1g(a_1g²e_2g⁴e_1g) ground state of D_5d symmetry. A suitable set of parameter values is given by ζ = 100 cm⁻¹, δ = 150 cm⁻¹, k_JT = 0.40, κ = 0.70. The magnetism of cobaltocene, Co(C₅H₅)₂, may be described by parameter values of comparable magnitude. The results imply a significantly larger reduction of the spin-orbit coupling parameter ζ due to covalency than of the orbital reduction factor κ.     

New Synthetic Approach to Naphtho[1,2‐b]furan and 4′‐Oxo‐Substituted Spiro[cyclopropane‐1,1′(4′H)‐naphthalene] Derivatives

A one‐step synthesis of ethyl 2,3‐dihydronaphtho[1,2‐b]furan‐2‐carboxylate and/or ethyl 4′‐oxospiro[cyclopropane‐1,1′(4′H)‐naphthalene]‐2′‐carboxylate derivatives 2 and 3 , respectively, from substituted naphthalen‐1‐ols and ethyl 2,3‐dibromopropanoate is described (Scheme 1). Compounds 2 were easily aromatized (Scheme 2). In the same way, 3,4‐dibromobutan‐2‐one afforded the corresponding 1‐(2,3‐dihydronaphtho[1,2‐b]furan‐2‐yl)ethanone and/or spiro derivatives 8 and 9 , respectively (Scheme 6). A mechanism for the formation of the dihydronaphtho[1,2‐b]furan ring and of the spiro compounds 3 is proposed (Schemes 3 and 4). The structures of spiro compounds 3a and 3f were established by X‐ray structural analysis. The reactivity of compound 3a was also briefly examined (Scheme 9).     

3,3′-Oxybispyridine and the polarographic reduction of 1,1′-dimethyl-3,3′-oxybispyridinediium diiodide

3,3′-Oxybispyridine is prepared by reaction of 3-hydroxypyridine with 3-bromopyridine and converted to the 1,1′-dimethyl diquaternary salt with methyl iodide. The salt is reduced polarographically by a one electron transfer not involving hydrogen to an unstable radical cation at a potential (E_o) of ?0.81 V in the pH range 6.3-12.0.     

Colchicine models: Synthesis and Antitubulin Activity of 2′-Monosubstituted and 2′, 5-Disubstituted 2,3,4,4′-Tetramethoxy-1,1′-biphenyls. Synthesis of 4,4′, 5′, 6′-tetramethoxy-1,1′-biphenyl-2,3′-dicarboxylic acid

Reductive amination of 2,3,4,4′-tetramethoxtybiphenyl-2-carbaldehyde ( 4 ) with MeNH₂ afforded methylamine 5 (Scheme 1), Hydroxymethylation of amine 8 , prepared similarly from 4 by reductive amination with benzylamine followed by N-methylation, afforded alcohol 12 which was converted the 5-methyl-substituted methylamine 14 by conventional chemical reactions (Scheme 2), Methylamine 14 was also obtained from ester 16 after hydroxymethylation to alcohol 17 and conventional manipulation of alcohol and ester functions (Scheme 2). Both amines 5 and 14 as well as the 2′, 5-dimethyl-substituted biphenyl 26 prepared from the dialdehyde 25 by a Wolff-Kishner reduction, did not show noteworthy activity in the tubulin binding assay or as inhibitors of tubulin polymerization (Table). However, the 2′ethyl-substituted biphebyl 11 prepared from 4 by reaction with MeLi followed by dehyderation and catalytic reduction of styrene 10 (Scheme 1) showed appreciable activity in both assays, coming close to that of known phenyltropolone models. The X-ray analysis of 14 ·HCl and 11 showed significant difference in the orientation of the rings with respect to one another (Fig.).     

Stereoselective Synthesis of 1,1′‐Disaccharides by Organoboron Catalysis

The highly stereoselective synthesis of 1,1′‐disaccharides was achieved by using 1,2‐dihydroxyglycosyl acceptors and glycosyl donors in the presence of a tricyclic borinic acid catalyst. In this reaction, the complexation of the diols and the catalyst is crucial for the activation of glycosyl donors, as well as for the 1,2‐cis‐configuration of the products. The anomeric stereochemistry of the glycosyl donor depends on the employed glycosyl donor. Applications of the produced 1,1′‐disaccharides are also described.     

Recognition of Anions by Synthetic Receptors in Aqueous Solution

Natural anion binding systems achieve high substrate affinity and selectivity most often by arranging converging binding sites inside a cavity or cleft that is well shielded from surrounding solvent molecules by the folded peptide chain. Types of interactions employed for anion recognition are electrostatic interactions, hydrogen-bonding, and coordination to a Lewis-acidic metal center. In this review, successful strategies aimed at the development of synthetic receptors active in water or aqueous solvent mixtures are described. It is shown that considerable progress has been made during recent years in the development of potent anion receptors and that for every type of interaction used in nature for anion binding, corresponding synthetic models exist today. Representative examples of these systems are presented with a special emphasis on synthetic receptors whose characterization involved a detailed thermodynamic analysis of complex formation to demonstrate the important interplay between enthalpy and entropy for anion recognition in water.This revised version was published online in July 2005 with a corrected issue number.     

Recognition of Anions by Synthetic Receptors in Aqueous Solution

Natural anion binding systems achieve high substrate affinity and selectivity most often by arranging converging binding sites inside a cavity or cleft that is well shielded from surrounding solvent molecules by the folded peptide chain. Types of interactions employed for anion recognition are electrostatic interactions, hydrogen-bonding, and coordination to a Lewis-acidic metal center. In this review, successful strategies aimed at the development of synthetic receptors active in water or aqueous solvent mixtures are described. It is shown that considerable progress has been made during recent years in the development of potent anion receptors and that for every type of interaction used in nature for anion binding, corresponding synthetic models exist today. Representative examples of these systems are presented with a special emphasis on synthetic receptors whose characterization involved a detailed thermodynamic analysis of complex formation to demonstrate the important interplay between enthalpy and entropy for anion recognition in water.