C2-symmetric Structure Research Articles

Synthesis, Structural Investigation, and Reactivity of Neutral and Cationic Bis(guanidinato)zirconium(IV) Complexes

The mono(guanidinato) complex Cp(guan)ZrCl2 (1; guan = η2-(iPrN)2C(NMe2)) was prepared by treatment of CpZrCl3 (Cp = η5-C5H5) with the in situ generated lithium guanidinate salt 2. The dimethylamino group of 1 resists quaternization by alkylating and silylating reagents. Complex 1 undergoes ligand redistribution when treated with 2 equiv of MeLi, but reaction with 2 equiv of MeMgCl affords the dimethyl derivative Cp(guan)ZrMe2 (3). Insertion of 2 equiv of diisopropylcarbodiimide into the Zr−N bonds of (Me2N)2ZrCl2(THF)2 produces the bis(guanidinato)zirconium dichloride complex (guan)2ZrCl2 (4). Alkylation of 4 with 2 equiv of MeLi or PhCH2MgCl affords the dialkyl derivatives (guan)2ZrMe2 (5) and (guan)2Zr(CH2Ph)2 (6), respectively. Variable-temperature NMR experiments on 6 reveal a limiting C2-symmetric solution structure at 253 K. Complex 5 undergoes reaction with electrophiles (Me3SiOTf (OTf = OSO2CF3), B(C6F5)3, [Ph3C][B(C6F5)4]) to yield stable products of methide abstraction: neutral complexes (guan...

Photochemically Induced Silicon−Carbon Bond Cleavage in a Dimethylsilyl-Bridged Dicyclopentadienyl Diruthenium Complex

The synthesis and X-ray crystal structure of the novel permethylated dimethylsilyl-bridged diruthenium complex Me2Si[(C5Me4)Ru(CO)2]2 (1) is reported. The molecular structure displays a metal−metal bond of 2.7121(4) Å, which is supported by two symmetrical μ-bridging CO groups and, in addition, two terminal carbonyl ligands. In solution, exchange of these carbonyl groups is observed, as shown by 13C NMR EXSY and VT IR-measurements. It is suggested that the exchange process proceeds via the energetically disfavoured intermediate 1a, which displays four terminal CO ligands. This view is supported by density functional calculations, which indicate a C2-symmetrical structure for 1a. Photochemically induced cleavage of the silicon−carbon and Ru−Ru bonds in 1 results in complex 3, which is thermodynamically uphill from 1 according to our DFT calculations. The molecular structure of complex 3 was unambiguously confirmed by X-ray crystallography.

Chiral 2,6-lutidinyl-biscarbene complexes of palladium

Chiral complexes of palladium, 1, with the new tridentate ‘pincer’ ligand 2,6-lutidinyl-biscarbene (C⁁N⁁C), have been prepared; in the solid state they exhibit helical C2 symmetrical structures which are persistent in solution at least up to 80 °C; the chiral nature of 1 has been established by NMR methods using Pirkle’s acid as a chiral discriminating agent; racemic mixtures of 1 are highly active catalysts in Heck coupling reactions.

Quantitative Symmetry in Structure−Activity Correlations: The Near C2 Symmetry of Inhibitor/HIV Protease Complexes

We studied the way in which the binding of inhibitors of human immunodeficiency virus (HIV) protease causes the protein to deviate from its original C2 symmetric structure. We extended to C2 symmetry our findings that quantitative chirality is a useful, predictive parameter in enzymatic structure−activity correlations (J. Am. Chem. Soc. 1998, 120, 6152−6159). We provide a quantitative assessment of this deviation, the degree of C2-ness, S(C2), by employing the continuous symmetry measures methodology. The data analyzed was for a group of 13 inhibitor/protease complexes, for which the structures and the binding energies are known. S(C2) was determined for the inhibitors before and after binding, for each pair of amino acids of the protein, and for the whole protein complexes. We were able to track the spreading of the C2 distortion throughout the protein to various zones. Maps of iso-symmetry value proved to be a powerful descriptive tool for protein structure−deviation visualization. The main findings are the following: (i) For most inhibitors, the active site imposes its C2 symmetry on the bound inhibitor, rendering it more C2 symmetric than its free form and confirming the picture of enzymes as mechanical devices. (ii) The binding energy of the inhibitors correlates with this imposed C2 symmetry change: the smaller the symmetry change, the better the inhibition. (iii) Analysis of the enzyme's mutant strain V82A (raised against the inhibitors) shows that it has “learned” to cope better with an inhibitor by “following” this symmetry/binding energy correlation. (iv) Symmetry deviations occur in the protein upon binding at remote zones from the active site. Despite variations in the details of these deviations for the different HIV protease/inhibitor complexes, the protein as a whole responds to the various inhibitors with a very similar C2 symmetry change: a global symmetry-well for this protein, has been identified.

Structures of XH 4 + and XH 6 + (X = B, Al and Ga) Cations

Structures and energies of XH4+ and XH6+ (X = B, Al and Ga) have been calculated at the density functional theory (DFT) B3LYP/6-311++G(3df,2pd) level. Calculations indicate that although the structure with a three center two electron (3c-2e) bond is the global minimum for BH4+, the global minima of AlH4+ and GaH4+ are not those with one 3c-2e bond, but those with two 3c-2e bonds. For calibration, both structures of AlH4+ were also calculated at the ab initio CCSD(T)/cc-pVTZ level and results in agreement with the DFT results were found. Similar calculations also indicate that although the C2v symmetrical structure with two 3c-2e bonds is the global minimum for BH6+, the global minima of AlH6+ and GaH6+ are not the C2v symmetrical structures with two 3c-2e bonds but the C2 symmetrical structures with three 3c-2e bonds.

Chiral N2O2 Schiff-base complexes of titanium with a biaryl backbone: highly diastereoselective migratory insertion of alkyl at imine

The C2-symmetric Schiff-base proligand (H2L) synthesized by condensation of 2,2′-diamino-6,6′-dimethylbiphenyl and 3,5-di-tert-butylsalicylaldehyde reacted in its deprotonated form with TiX4 (X = Cl or Br) to give the isomeric mixtures α-cis- and β-cis-[MLX2]. The molecular structure of α-cis-[TiLBr2] was determined. The two bromide ligands occupy mutually cis co-ordination sites in a C2-symmetric structure. Reaction of the isomeric mixture X = Cl with LiNMe2 leads to the single isomer α-cis-[TiL(NMe2)2] as determined by NMR spectroscopy. Reaction of the latter complex with BCl3 reconverts it into the chloride complex in a similar isomeric mixture as above. While attempts to alkylate the halides were unsuccessful, the reaction of H2L with [Ti(CH2Ph)4] leads to α-cis-[TiL(CH2Ph)2] which rapidly converts into a complex [TiLBn(CH2Ph)] in which one of the Ti bound benzyl groups has undergone a highly diastereoselective 1,2-migratory insertion process with one imine group. The molecular structure of this compound shows that the co-ordination sphere of the Ti atom is approximately trigonal bipyramidal. The configuration of the new chiral centre at the former imine group indicates the expected mode of cis migration in the formation of the complex. The migrated benzyl group forms an edge–face interaction with the remaining metal bound benzyl. Controlled hydrolysis of [TiLBn(CH2Ph)] leads to a dimeric species [{Ti(HLBn)}2-(μ-O)2] in which the amide bond in the starting complex has been protonated to form an amine ligand.

Flexibility and Function in HIV Protease: Dynamics of the HIV-1 Protease Bound to the Asymmetric Inhibitor Kynostatin 272 (KNI-272)

The HIV-1 protease is a 22 kDa homodimeric protein essential for function of the AIDS virus, and protease inhibitors have been developed into effective HIV drugs. In order to better understand HIV-1 protease−inhibitor interactions, we have investigated amide backbone dynamics by correlated 1H−15N NMR spectroscopy. To date, HIV-1 protease/inhibitor complexes studied by NMR spectroscopy have been limited to C2 symmetric structures, consisting of the protease bound to a symmetric inhibitor. Herein we report studies of the dynamics of HIV-1 protease complexed to KNI-272, a potent (Ki ca. 5 pM), asymmetric inhibitor which lifts the chemical shift degeneracy of the protease monomers and allows us to ascertain if the individual protease monomers have significantly different backbone motions. Using isotope filtered/edited spectra of 15N/13C protease complexed with unlabeled KNI-272, together with distances derived from the protease/KNI-272 X-ray structure, we obtained monomer specific NMR signal assignments. We derived information about monomer dynamics from a Lipari-Szabo analysis of amide 15N T1, T2, and NOE values. Modeling the complex as an axially symmetric rotor yielded an average overall correlation time of 9.65 ns and an anisotropy, D||/D⊥, of 1.27. Over 90% of the backbone amide sites are highly ordered with the squared order parameter, averaged over all measured residues, being 0.85. High amplitude internal motions are observed in several loops in the protease, especially those in the elbows of the flaps, while millisecond to microsecond time scale motion is observed at the flap-tips. While these results are similar to those reported for complexes with symmetric inhibitors, we find differences in internal motions between several residues in the flap of one monomer and the corresponding residues on the other monomer. Residue Gly 149 has a significantly larger order parameter than Gly 49; in addition, the motions on the chemical exchange time scale contribute to the relaxation of Gly 152 and Phe 153 but not to the relaxation of Gly 52 and Phe 53. These differences in flexibility correlate with differences in interactions made by these residues with KNI-272, as seen in the crystal structure. We also find that the average of the order parameters measured for residues in monomer 1 is less than for monomer 2, a result that correlates with the observation that average B factor for these residues is less in monomer 2 than in monomer 1.

Selective Derivatization of Resorcarenes. 3. C2-Symmetrical and Transcavity Bridged Bis-Benzoxazines Derived from C2v-Symmetrical Tetratosylates

The regioselective condensation of resorcarene tetratosylates 3/4 with formaldehyde and various primary amines readily gives bis-benzoxazines 5/6 in 65−86% yield. The chiral, C2-symmetrical structure of these compounds has been proved by NMR-spectroscopy and single-crystal X-ray analysis. Bis-benzoxazines 5f and 5i assume in the crystalline state a boat conformation in which the two resorcinol rings bearing the oxazine fragments are nearly parallel. The tosylated resorcinol units are horizontally arranged in a propeller-like fashion, and two intramolecular hydrogen bonds are formed between the phenolic hydroxy groups and the oxygens of the neighboring sulfonyl fragments. Molecular mechanics calculations suggest that the regioselective formation of the C2-isomer is caused by the repulsion between the substituents or the unpaired electrons at the nitrogen atoms of the two benzoxazine rings and by slightly better geometrical conditions for intramolecular SO···H−O hydrogen bonding in comparison with the meso-...

Transition-Metal Aqua Complexes of 4,6-Dibenzofurandiyl-2,2‘-bis(4-phenyloxazoline). Effective Catalysis in Diels−Alder Reactions Showing Excellent Enantioselectivity, Extreme Chiral Amplification, and High Tolerance to Water, Alcohols, Amines, and Acids

Cationic aqua complexes are prepared from a trans-chelating tridentate ligand, (R,R)-4,6-dibenzofurandiyl-2,2‘-bis(4-phenyloxazoline) (DBFOX/Ph), and various transition-metal(II) perchlorates. These complexes are effective catalysts in the Diels−Alder reactions of cyclopentadiene with 3-alkenoyl-2-oxazolidinone dienophiles and show excellent enantioselectivities. The active catalyst complex prepared from nickel(II) perchlorate hexahydrate has an octahedral structure with three aqua ligands, and it can be isolated and stored for months without loss of catalytic activity. Iron(II), cobalt(II), copper(II), and zinc(II) complexes are similarly active. The absolute configuration induced in the reaction can be readily predicted on the basis of the C2-symmetric structure of the complexes as well as the simple structure of the substrate complex. The aqua complex prepared from Ni(II) or Zn(II) perchlorate results in highly effective chiral amplification in the Diels−Alder reaction. Use of the DBFOX/Ph ligand of a ...

Conformation of a Geminal Dicyclopropyl-Substituted Trimethylenemethane Triplet [2-(Dicyclopropylmethylidene)cyclopentane-1,3-diyl

Triplet 2-(dicyclopropylmethylidene)cyclopentane-1,3-diyl, CP2TMM, has a Deltam(s) = 2 ESR transition revealing hyperfine splitting consistent with coupling to two equivalent alpha hydrogens and five equivalent beta hydrogens and one other hydrogen with a small hyperfine coupling constant. This is consistent only with a conformation in which one cyclopropane ring conjugates with the pi triplet so that the other cyclopropane is twisted allowing the tertiary cyclopropyl hydrogen to hyperconjugate. Geometry optimization of the triplet state of CP2TMM was carried out using the 3-21G basis set with a UHF wave function and while the singlet state was optimized using a GVB perfect pairing wave function. The most stable conformation of each spin state is a C(2)-symmetric structure providing a 10 kcal/mol singlet-triplet energy gap favoring the triplet. This gap is reproduced at the 6-31G level using the 3-21G geometries. However, this structure cannot reproduce the hyperfine splitting observed; 1 kcal/mol higher in energy is an asymmetrical conformation of triplet CP2TMM which can account for the hyperfine interactions.

Achiral Cyclodextrin Analogues

AbstractThe synthesis of a new family of cyclodextrin (CD) analogues is described. This family consists of novel cyclic oligosaccharides built from monosaccharides that possess the same relative but opposite absolute (D‐ and L‐) configurations. The alternation of such D‐ and L‐ residues—specifically, D‐ and L‐rhamnose or D‐ and L‐mannose—in a macrocyclic structure results in Sn‐type symmetry and, consequently, optical inactivity. The synthesis of these cyclic oligosaccharides was achieved by an economical polycondensation/cycloglycosylation approach that relies on an appropriately‐derivatized disac‐charide monomer and that avoids the time‐consuming, and often low‐yielding, stepwise growth of long linear oligosaccharide precursors. In the cases reported, the key precursors are the disaccharide monomers 1‐RR and 1‐MM, which bear both a glycosyl donor (cyanoethylidene function) and a glycosyl acceptor (trity‐loxy group). These compounds are able to undergo Tr+‐catalyzed polycondensation which, under appropriate dilution conditions, can be terminated by cycloglycosyl‐ation. Thus, compound 1‐RR was converted into a range of protected cyclic rhamnooligosaccharides 15–19 in 64% overall yield. All these products, including the unique cyclic dodeca‐ and tetradecasaccharides 18 and 19, have been isolated by preparative HPLC. Unexpectedly, treatment of the manno analogue of the disaccharide 1‐RR (compound 1‐MM) under the same conditions produced only the cyclic hexasaccharide 28 and numerous apparently linear oligomers. Removal of the protecting groups from 16–19 afforded the free cyclic oligosaccharides 21–24, which exhibited the predicted zero optical rotation and very simple NMR spectra, indicating highly symmetrical structures. X‐ray crystallography reveals that in the solid state the cyclooctaoside 21 possesses a C2 symmetric structure, on account of a slight deformation of its cylindrical shape. The channel‐type crystal packing of molecules of 21 forms nanotubes with an internal diameter of around 1 nm. Conversely, the cyclic hexasaccharide 29 possesses a Ci symmetric solid‐state structure and its molecules pack to form a parquet‐like superstructure.

HIV-1 protease inhibitors containing a novel C2 symmetrical hydroxyalkylgem-diamino core structure.

Two series of peptidomimetics containing a novel C2 symmetrical hydroxyalkylgem-diamino core structure were prepared, from amino acid starting materials, and evaluated as inhibitors of HIV-1 protease (HIV-1 Pr). 1,1-Diamino-3-hydroxypropane (gHse) derivatives showed weak inhibitory potency (IC50 > 10 microM). In the 1,1-diamino-2-hydroxyethane (gSer) series, a compound containing P1/P1' benzyl and P2/P2'Fmoc substituents, displayed a significant HIV-1 Pr inhibition (IC50 = 440 nM).

Conformational Study of C2 Symmetrical Benzo[c]phenanthridine Alkaloid Derivatives

Abstract We report utilization of the phase-sensitive GSQMBC experiment for the study of benzo[c]phenanthridine derivatives. The technique allows determination of the C2 symmetrical structures by observation of two different scalar interactions between H6 and C6 atoms as well as measurement of long range 1H-13C coupling constant. A prefered conformation determined using a dihedral angle constraint extracted from the measured 3JH,C coupling constant and AM1 calculations is discussed.

Multifunctional Calix[4]arenes Containing Pendant Amide and Phosphoryl Groups: Their Use as Extracting Agents and Carriers for Alkali Cations

The complexing, extracting and mobile carrier properties of the tetra(phosphine oxide)-calix[4]arene 1 and the hybrid diamide-di(phosphine oxide)-calix[4]arene 2 were studied. Both ligands give 1 : 1 complexes with alkali cations in THF as shown by the picrate method. 1H NMR experiments were run to follow encapsulation of sodium and potassium cations. The corresponding spectra indicate C2-symmetrical structure. The observed extraction orders of the alkali picrates were as follows K+>Rb+>Li+>Cs+>Na+ for 1 and Li+>Na+>K+>Rb++ for 2. Transport kinetics was analysed by means of a model which assumes pure diffusion and which allows the evaluation of mass transfer coefficients in all systems. These coefficients and their influences on the transport rate are discussed in terms of size of the transporting species in the liquid membrane.

MCSCF vibrational spectra of the symmetric and asymmetric dihydronium cations

We report the first full geometry optimizations of the dihydronium cation performed at the MCSCF level. Large basis set effects are encountered. Depending on the basis set, we found, either the C2 symmetric or the Cs asymmetric species as global minima of the purely electronic PES. However, after harmonic ZPE correction, the C2 symmetric structure appears to be favoured. Supported by a display of MCSCF natural orbitals, we propose an analysis of the H5O2+ electronic structure in terms of a chemical-type binding. A “soft mattress” model of proton transfer, linked to this “chemical” picture, is set forward. MCSCF harmonic OH stretch frequencies, corrected for anharmonicity are compared with experimental data, and support the evidence of a C2 structure. The nature of proton motions is examined through a pictorial analysis of intermolecular vibrational motions. A tentative explanation is proposed for the very wide spectra starting near 3500 cm−1 down to 800 cm−1 in concentrated acidic solutions. Prospects related to on-going large scale MCSCF computations are sketched.

Conformations of 24-Membered Ring Pseudopeptides Containing N,N′-Ethylene-Bridged Dipeptides Constructed from (S)-Alanine, -Leucine, -Isoleucine, and -Phenylalanine

24-Membered ring pseudopeptides, cyclo[Gly-eXX-Gly]2 {eXX; N,N′-ethylene-bridged dipeptide, X = (S)-alanine(A), -leucine(L), -isoleucine(I), and -phenylalanine(F)} and cyclo[Sar-eXX-Gly]2 {X = (S)-A and -F} were prepared and their conformations were investigated by 1H and 13C NMR spectroscopy in dimethylsulfoxide-d6. It was found from NMR measurements that the major conformers ( ≥90% abundance) of the four cyclo[Gly-eXX-Gly]2 and major ones (≃70%) of the two cyclo[Sar-eXX Gly]2 have C2-symmetric structures, in which all peptide bonds of cyclo[Gly-eXX-Gly]2 (X = A, L, and I) and cyclo[Sar-eAA-Gly]2 are trans, while two Gly-eFF peptide bonds of cyclo[Gly-eFF-Gly]2 and two Sar-eFF ones of cyclo[Sar-eFF-Gly]2 are cis though the other peptide bonds are trans. 13C spin-lattice relaxation times (T1) of all macrocycles showed small contribution of segmental mobility to T1. The structures of cyclo[Gly-eAA-Gly]2 and cyclo[Sar-eAA-Gly]2 were optimized by molecular mechanics on the basis of NMR data.

Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease

Specific processing of the human immunodeficiency virus (HIV) gag and gag-pol polyprotein gene products by the HIV protease is essential for the production of mature, infections progeny virions. Inhibitors of HIV protease block this maturation and thus prohibit the spread of HIV in vitro. Previously, we reported a series of novel, symmetric inhibitors of HIV protease designed to match the C2 symmetric structure of the active site of the enzyme. In response to the poor aqueous solubility of those lead compounds, we designed a series of analogs with substantially improved (greater than 10(4) fold) solubility. These inhibitors showed anti-HIV activity in H9 and MT4 cells at 0.05 to 10 microM, and in most cases, they were noncytotoxic at concentrations in excess of 100 microM. Further examination of one inhibitor (A-77003) revealed broad-spectrum activity against both HIV types 1 and 2, including azidothymidine-resistant HIV, in a variety of transformed and primary human cell lines. After administration of the inhibitors to rats, short half-lives and, with two notable exceptions, moderate oral bioavailability were observed. Additional pharmacokinetic studies in dogs and monkeys revealed the potential utility of A-77003 as an intravenous anti-HIV agent.

A new chiral ferrocenylphosphine ligand with C 2 symmetry: prepration and use for palladium-catalysed asymmetric cross-coupling

A new chiral ferrocenylphosphine ligand, which has C2-symmetric structure and a functional group on the side chain, was prepared by ortho-lithiation and phosphination of 1,1′-bis[1-(N,N-dimethylamino)ethyl]ferrocene followed by optical resolution of the ditartrate salts and was found to be effective for palladium-catalysed asymmetric cross-coupling of 1-phenylethylzinc chloride with vinyl bromide giving 3-phenylbut-1-ene of over 90% e.e.

Cation-binding Properties of Ionophorous Cyclic Octapeptide in Acetonitrile Solution

Abstract Complex formation of synthetic cyclic octapeptide, cyclo[Gly–l-Lys(Z)–Sar–l-Pro]2, with alkali and alkaline earth metal ion was investigated by CD and NMR spectroscopy. Titration curves obtained from CD data revealed three kinds of CGLSP2(P)/cation(C) complexes. P2C (“peptide sandwich”), PC (“1:1”), and PC2 (“cation sandwich”) complexes occurred in the complexation between CGLSP2 and Ba2+. In the presence of Li+, Mg2+, or Ca2+, the existence of PC and PC2 was assumed. K+ and Na+ form only a PC species with CGLSP2. By analyzing the titration curves, 1 :1 complex-formation constants (K1) were evaluated. The K1 values decrease in the order Ba2+>Ca2+>Mg2+>Li+>>Na+, K+. 1H- and 13C-NMR data showed that CGLSP2 in acetonitrile exists in at least five different conformational states in a free state. A predominant conformer had a C2-symmetric structure containing two cis Lys–Sar peptide bonds. After the addition of equimolar amounts of Ba(ClO4)2, these conformations converged into a single C2-symmetric one with all-trans peptide bonds. This corresponds to a PC species. On further addition of the salt, CGLSP2 changed the conformation into an asymmetric structure with one cis Lys–Sar peptide bond. This corresponds to a PC2 species.

Solution Conformation of Cyclo(D-Leu-L-Glu-L-His)2 and Its Relation with Highly Efficient and Enantiomer-Selective Catalysis

A cyclic hexapeptide cyclo(D-Leu-L-Glu-L-His)2 was synthesized and its conformational properties in (CD3)2SO and D2O were investigated. The major conformation in (CD3)2SO was asymmetric and possessed either a gramicidine-type β-turn structure or a random structure in one molecule. The major conformation in D2O was a C2-symmetric random structure. When Cu(ClO4)2 was added to an aqueous solution of cyclo(D-Leu-L-Glu-L-His)2 (pH 6.95, phosphate buffer), the major conformation of the latter changed from a random to a type-II β-turn structure. The cyclic hexapeptide/Cu2+ molar ratio of the complex was unity, and Cu2+ was coordinated with Glu-COOH. Induced by copper-ion coordination the backbone plane, the Leu-isobutyl group, and the His-imidazolylmethyl group of cyclo(D-Leu-L-Glu-L-His)2 had the form of a hydrophobic pocket. The highly efficient hydrolysis of leucine or valine p-nitrophenyl ester hydrochloride by the cycloD-Leu-L-Glu-L-His)2–Cu2+ complex may be closely related to the binding of a substrate by the hydrophobic pocket. The weak enantiomer-selectivity may also be related to a streochemical fit of a bound substrate with the hydrophobic pocket.