Absolute configurational assignments of secondary amines by CD-sensitive dimeric zinc porphyrin host

A general chiroptical protocol for determination of absolute configuration of secondary amines including acyclic and cyclic aliphatic amines, aromatic amines, amino acids, and amino alcohols is described. The chiral substrate is linked to the achiral carrier moiety (3-N-Boc-amino-propyl-N-Boc-amino)acetic acid 1 (BocHNCH(2)CH(2)CH(2)BocNCH(2)COOH), which after deprotection, yields a bidentate conjugate, capable of forming a 1:1 host/guest complex with dimeric zinc porphyrin host 2. As in the cases of primary amines and secondary alcohols reported earlier, the complexation of secondary amine conjugates to porphyrin tweezer host 2 represents a stereodifferentiating process, where the large (L) group at the stereogenic center (assigned on the basis of conformational energies A value) protrudes from the porphyrin binding pocket. This leads to formation of host/guest complexes with a preferred porphyrin helicity that exhibit intense exciton split CD spectra. It was found that the chiral sense of porphyrin twist is clearly controlled by the stereogenic center despite the Z/E conformational complexity around the tertiary amide bond of secondary amine conjugates that has greatly hampered previous configurational assignments. Thus, in cases where there is no ambiguity regarding the relative steric size of substituents, the observed CD couplet can be applied for straightforward assignment of absolute configurations. In addition, to extend the application to more difficult cases a molecular mechanics calculation approach using the Merck Molecular Force Field (MMFFs) was developed; this provides conformational information of host/guest complexes and leads to prediction of preferred porphyrin helicity independent of conformational A values. This chiroptical protocol in combination with molecular modeling represents a general method for configurational assignments of secondary amines.     

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 2. Structural studies of host-guest complexes with chiral alcohol and monoamine conjugates.

A structural study of complexes formed between a dimeric zinc porphyrin tweezer (host) and chiral monoalcohols and monoamines derivatized by a bidentate carrier molecule (guest) confirmed that their CD couplets arise from the preferred porphyrin helicity of 1:1 host-guest complexes. NMR experiments and molecular modeling of selected tweezer complexes revealed that the preferred conformation is the one in which the L (larger) group protrudes from the porphyrin sandwich; this preferred helicity of the complex determines the CD of the complexes. It was found that the porphyrin ring-current induced (1)H chemical shifts and molecular modeling studies of the complex lead to the assignments of relative steric size of the L (large)/M (medium) substituents attached to the stereogenic center. The assignments, in turn, are correlated with the sign of the CD exciton couplet that establishes the absolute configuration at the stereogenic center. Variable-temperature NMR experiments proved that the observed increase in CD amplitude at lower temperatures derives from conformational changes in the preferred offset geometry between two porphyrin rings.     

Magnesium tetraarylporphyrin tweezer: a CD-sensitive host for absolute configurational assignments of alpha-chiral carboxylic acids

A protocol to determine the absolute configuration of alpha-chiral carboxylic acids based on a modified circular dichroic (CD) exciton chirality method has been developed. The protocol relies on a host-guest complexation mechanism: the chiral substrates are derivatized to give bifunctional amide conjugates ("guests") that form complexes with a dimeric magnesium porphyrin host, Mg-T (T stands for "tweezer") that acts as a "receptor". The two porphyrins in the complex adopt a preferred helicity dictated by the substituents at the chiral center in accordance with their steric sizes (assigned on the basis of conformational energy A-values) and, consequently, with the absolute configuration of the substrates under investigation. This chiroptical method, verified with a variety of chiral substrates, has been demonstrated to be reliable and generally applicable, including natural products with complex structures. Molecular modeling, NMR, and FTIR experiments of selected host-guest complexes revealed the mode of ligation of the substrates to the magnesium porphyrin species and led to clarification of the structure of the complex. When oxygen functionalities were directly attached to the chiral center, the signs of the CD couplets were opposite to those predicted on the basis of steric size. NMR and molecular modeling experiments indicated that this apparent inconsistency was due to conformational characteristics of the guest molecules. The stereochemical analysis is shown to be a sensitive technique, not only for the determination of absolute configurations of substrates but also for elucidation of their solution conformations.     

Chiral recognition of amino acids and dipeptides by a water-soluble zinc porphyrin

A chiral water-soluble zinc porphyrin was optically resolved on a chiral HPLC column, and the binding of chiral amino acids and peptides to each of the enantiomers was examined spectrophotometrically in basic aqueous solution. The binding data apparently indicated that the zinc porphyrin has chiral selectivity for amino acids and dipeptides. This was reasonably explained in terms of the triple cooperation of coordination, Coulomb, and steric interactions of the chiral amino carboxylates with the porphyrin. A compensatory relationship among the thermodynamic parameters for chiral recognition was also shown.     

Zinc porphyrin tweezer in host-guest complexation: determination of absolute configurations of primary monoamines by circular dichroism

A nonempirical exciton chirality circular dichroic (CD) method for determining the absolute configurations of primary monoamines with amino group directly linked to the stereogenic center is described. Conventional exciton chirality CD method cannot be applied to these compounds since they lack the two sites for attaching the interacting chromophores. This was solved by covalently linking the monoamine to a trifunctional bidentate carrier moiety 1. Treatment of the carrier/monoamine conjugate with the porphyrin tweezer 4 consisting of two pentanediol-linked zinc porphyrins gives rise to 1:1 host-guest macrocyclic complexes that exhibit exciton-coupled CD spectra. The sign of the CD couplet can then be correlated with the absolute configuration of the monoamine as follows: a clockwise arrangement of the L, M, and S (large, medium, small) groups in the Newman projection of the monoamine with the amino group in the rear gives rise to a positive CD couplet, and vice versa; the assignments of L, M, S groups are based on conformational energies (A values). This method is applicable to cyclic and acyclic aliphatic amines, aromatic amines, amino esters, amides, and cyclic amino alcohols, and can be performed at the several microgram level.     

Chiral recognition of amino esters by a ruthenium porphyrin complex: kinetics of the exchange process determined by 1H NMR

The synthesis of a (carbonyl) (valine methyl ester) ruthenium(II) picket-fence complex bearing optically active α-methoxy-α(trifluoromethyl)phenylacetyl residues on both sides of the porphyrin plane (α,β,α,β-isomer) is described. For various amino esters, chiral recognition was observed for the complexation of the ligand with up to 52% enantiomeric excess for tert-leucine methyl ester. The dissociation rate constants of the two enantiomers of valine methyl ester were determined by ¹H NMR using magnetization transfer experiments, showing that the origin of the enantioselectivity in favour of the (l)-valine (ca. 2.6:1) resides in the difference between the kinetics of the axial ligand dissociation of the two enantiomers.     

Molecular recognition of amines and amino esters by zinc porphyrin receptors: binding mechanisms and solvent effects

Zinc porphyrin receptors bearing 12 ester groups in the meso phenyl groups (1-3) were prepared, and binding of amines and alpha-amino esters was studied with emphasis on the binding mechanisms. The X-ray crystallographic analysis of 5,10,15,20-tetrakis(2, 6-bis(carbomethoxymethoxy)-4-carbomethoxyphenyl)porphyrin (free base of 1) showed that the receptor has a binding pocket above the porphyrin plane. UV-visible titration experiments revealed that the zinc porphyrin receptors bound amines and alpha-amino esters with binding constants (K(a)) ranging from 0.5 to 52 700 M(-1) in CH(2)Cl(2) at 25 degrees C. The ester functional groups of 1 assisted the binding of aromatic alpha-amino esters (K(a) = 8 000-23 000 M(-1) in CH(2)Cl(2) at 25 degrees C) and inhibited the binding of bulky aliphatic alpha-amino esters (K(a) = 460 M(-1) for Leu-OMe in CH(2)Cl(2) at 25 degrees C), indicating that CH-pi type interactions and steric repulsions control the selectivity. The binding of amines and alpha-amino esters was tight both in a nonpolar solvent (CH(2)Cl(2)) and in a polar solvent (water) but loose in a solvent of intermediate polarity (H(2)O-MeOH (1:1)), demonstrating that two competitive driving forces are operating: (1) attractive electrostatic forces between host and guest such as coordination of the amino group to the zinc atom, and (2) entropic forces stemming from desolvation as well as enthalpic forces due to the host-guest dispersion forces. The former forces drive the binding in CH(2)Cl(2) while the latter forces drive the binding in water. The enthalpy changes in the binding in CH(2)Cl(2) and those in water range from -50 to -30 kJ mol(-1) and from -35 to 0 kJ mol(-1), respectively. The entropy changes in CH(2)Cl(2) and those in water range from -120 to -60 J K(-1) mol(-1) and from -50 to +60 J K(-1) mol(-1), respectively. Thus the binding in CH(2)Cl(2) is characterized by large negative enthalpy changes, while that in water by less negative entropy changes. These thermodynamic parameters also indicate that host-guest polar interactions (enthalpic forces) drive the binding in CH(2)Cl(2) while both host-guest dispersion interactions (an enthalpic force) and desolvation (an entropic force) drive the binding in water. Enthalpy-entropy compensation observed for the binding in water indicates that the binding of amines and amino esters in water by zinc porphyrins is associated with conformational changes as well as a high degree of dehydration. In CH(2)Cl(2), no clear compensation was observed, consistent with the mechanism that neither desolvation processes nor conformational changes contribute significantly to the binding energetics.     

Selective recognition of configurational substates of zinc cyclam by carboxylates: implications for the design and mechanism of action of anti-HIV agents

The interaction of metal cyclams with carboxylate groups is thought to play an important role in their binding to the CXCR4 chemokine receptor and in their anti-HIV activity. Here we report the synthesis of acetate, phthalate, perchlorate and chloride complexes of Zn(II) cyclam (1,4,8,11-tetraazacyclotetradecane). The X-ray crystal structures of [Zn(cyclam)(phthalate)](n)(CH(3)OH)(2n) and [Zn(cyclam)(H(2)O)(2)](OAc)(2) contain octahedral Zn(II) centres. Phthalate acts as a bridging ligand in the former complex, binding through monodentate carboxylate groups, and giving rise to infinite chains in the lattice together with extensive hydrogen bonding between carboxylate donor oxygen atoms and amine and methanol acceptor atoms. The uncoordinated acetate groups and the aqua ligand in the acetate complex are also involved in a rich network of hydrogen bonds and this may account for the unusually long Zn[bond]O distance (2.27 A). In both crystalline complexes, the macrocycle adopts the trans-III (S,S,R,R) configuration. 1D (1)H NMR spectra of all four complexes have been fully assigned by a combination of 2D [(1)H, (1)H] COSY and TOCSY, and [(1)H, (13)C] and [(1 )H, (15)N] HSQC NMR data. In aqueous solution, the stable trans-III configuration found in the solid-state equilibrates slowly (hours at 298 K) with trans-I (R,S,R,S) and cis-V (R,R,R,R) configurations. The trans-III configuration is predominant in aqueous solution for both the chloride and perchlorate complexes, but for the acetate and phthalate complexes, the cis-V configuration dominates. Carboxylate groups appear to stabilize the cis-V configuration in solution through Zn(II) coordination and hydrogen bonding. Titration of the chloride Zn(II)-cyclam complex with acetate confirmed that carboxylates strongly induce formation of the cis-V configuration. This implies that carboxylates can exert a strong influence over configurational selectivity. Cyclam NH hydrogen bonding is prevalent both in the solid state and in solution, and is relevant to the anti-HIV activity of Zn(II) and other metal cyclam complexes and to their ability to recognize the CXCR4 transmembrane co-receptor.     

Chiral recognition of alkene and arene hydrocarbons by 1H and 13C NMR. determination of enantiomeric purity

Simultaneous presence of the salt $\text{1}$ and one of the lanthanide complexes (+)-$\text{2}$, (+)-$\text{3}$, or (+)-$\text{4}$ splits ¹H or ¹³C NMR signals of the chiral alkenes $\text{5}$, $\text{6}$, and $\text{8}$ as well as of the chiral arene $\text{7}$; the enantiomeric purity of a mixture of (+)- and (?)-$\text{8}$ was determined successfully.     

Identification of modified natural porphyrin isomers: 1H and 13C NMR assignments by NOESY and reverse heteronuclear shift correlation

The efficiency of two-dimensional homonuclear ¹H ¹H NOE spectroscopy in characterizing and fully assigning the ¹H NMR spectra of several isomers of meso- or ring-substituted deuteroporphyrins is demonstrated. The carbon resonances of the skeleton and the substituents were fully assigned using two-dimensional reverse heteronuclear shift correlation spectroscopy.     

Spectroscopy and photophysics of self-organized zinc porphyrin nanolayers. 1. Optical spectroscopy of excitonic interactions involving the soret band

The photophysical properties of excited singlet states of zinc tetra-(p-octylphenyl)-porphyrin in 5-25-nm-thick films spin-coated onto quartz slides have been investigated by optical spectroscopy. Analysis of the polarized absorption spectra using a dipole-dipole exciton model with two mutually perpendicular transition dipole moments per molecule shows that the films are built from linear aggregates, i.e., stacks with a slipped-deck-of-cards configuration. The molecular planes of the porphyrins in the stacks are found to be perpendicularly oriented with respect to the substrate plane. Assuming a value of 2-3 for the dielectric constant of the film, from the excitonic shift, an angle of 44 degrees +/- 3 degrees and an interplanar distance of 0.35-0.36 nm between adjacent porphyrins are calculated, close to the ground-state geometry in solution. The ordering in these films was further investigated by the effects of various solvents and temperature annealing. Spin-coating from toluene as a solvent results in highly ordered films, and annealing of these films has little effect on their absorption spectra. However, spin-coating from chloroform or pyridine or exposure of the films to these solvents in their vapor phases changes their ordering presumably due to incorporation of residual solvent molecules. Annealing yields absorption spectra identical to those of films spin-coated from toluene. The absorption spectra are insensitive to atmospheric moisture, in contrast to those of zinc tetraphenylporphyrin films lacking octyl substituents.     

Chiral recognition of borneol by association with zinc(II) and l-tryptophan in the gas phase

Chiral recognition of the racemic borneol was obtained in the gas phase by using electrospray ionization time-of-flight mass spectrometry (ESI-TOFMS) and electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTMS). Both single stage MS and tandem MS were employed for investigating the chiral recognition depending strongly on the stereochemistry of the ligands in the zinc(II)-l-tryptophan-borneol multimeric cluster ions. It was found that the type of acid which was used for adjusting the pH of the mixed solution played an important role in the chiral recognition, which was obtained when acetic acid or propanoic acid was used as an additive. No chiral recognition was observed using hydrochloric acid or formic acid. Furthermore, the nozzle potential was an important parameter for optimizing the discrimination of chirality. In tandem MS, the difference in intensity between two diastereomeric complex ions showed chiral recognition behavior. Such a difference could be determined by two approaches. One was using the fragment ion as an internal standard, the other was a new approach of using the isotopic form of parent complex ion as an internal standard.     

Chiral recognition of selenides and iodides by 1H NMR spectroscopy in the presence of a chiral dirhodium complex

Chiral recognition of aryl alkyl selenides and alkyl iodides can be achieved by ¹H NMR spectroscopy in the presence of dirhodium tetra-(R)-or tetra-(S)-α-methoxy-α-(trifluoromethyl)-phenylacetate [Rh₂(MTPA)₄, 1 ]. Generally, these classes of compounds are weak donors and fail when using the classical chiral lanthanoid shift reagent. Alkyl bromides do not show similar effects. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:471–474, 1998     

Investigation of formation,recognition, stabilization,and conversion of dimeric G-quadruplexes of HIV-1 integrase inhibitors by electrospray ionization mass spectrometry

The dimeric G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (S1) and d(GTGGTGGGTGGGTGGGT) (S2), the potent nanomolar HIV-1 integrase inhibitors, were detected by electrospray ionization mass spectrometry (ESI-MS) for the first time. The formation and conversion of the dimers were induced by NH(4)(+), DNA concentration, pH, and the binding molecules. We directly observed the specific binding of a perylene derivative (Tel03) and ImImImbetaDp in one system consisting of the intramolecular and the dimeric G-quadruplexes of the HIV-1 integrase inhibitor, which suggested that Tel03 could shift the equilibrium to the dimeric G-quadruplex formation, while ImImImbetaDp induces preferentially a structural change from the dimer to the intramolecular G-quadruplex. The results of this study indicated that Tel03 and ImImImbetaDp favor the stabilization of the dimeric G-quadruplex structures.     

The prediction of the absolute stereochemistry of primary and secondary 1,2-diols by 1H NMR spectroscopy: principles and applications

The absolute configuration of 1,2-diols formed by a primary and a secondary (chiral) hydroxyl group can be deduced by comparison of the 1H NMR spectra of the corresponding (R)- and bis-(S)-MPA esters (MPA = methoxyphenylacetic acid). This method involves the use of the chemical shifts of substituents L1/L2 attached to the secondary (chiral) carbon, and of the hydrogen atom linked to the chiral center (C alpha-H) as diagnostic signals. Theoretical (AM1, HF, and B3 LYP calculations) and experimental data (dynamic and low-temperature NMR spectroscopy, studies on deuterated derivatives, constant coupling analysis, circular dichroism (CD) spectra, and NMR studies with a number of diols of known absolute configuration) prove that the signs of the delta delta(RS) obtained for those signals correlate with the absolute configuration of the diol. A graphical model for the reliable assignment of the absolute configuration of a 1,2-diol by comparison of the NMR spectra of its bis-(R)- and bis-(S)-MPA esters is presented.     

1D and 2D solid-state metallosupramolecular arrays of freebase 5,10,15,20-tetra(4-pyridyl)porphyrin, peripherally linked by zinc and manganese ions

Freebase 5,10,15,20-tetra(4-pyridyl)porphyrin (TPyP) is able to assemble into crystalline rigid 1D and 2D metallosupramolecular arrrays via exocyclic coordination with tetracoordinate and hexacoordinate metal ions, respectively. In this contribution we report on two coordination polymers of μ ⁴-bridging freebase TPyP with zinc and manganese halide moieties. The structure of [(ZnBr₂)₂TPyP] · 6 TCE (2) (TCE = 1,1,2,2-tetrachloroethane) consists of 1D polymeric chains. The topology of [(MnCl₂)TPyP] · 6 TCE (3) is the (4,4) square grid type. The crystal structure of the known compound [(HgI₂)₂TPyP] · 4 TCE (1) was redetermined by X-ray crystallography.     

1H NMR utilization of through-space effects in configurational assignments. I—application to nitriles; determination of the separate effects of the electric field and anisotropy of the CN group

The changes in chemical shift induced by isomerization for all the ring protons of the Z- and E-5,5-dimethyl-2-cyclohexenylidene acetonitriles depend only on the through-space effects of the cyano group. The configurational assignments were made taking into consideration the anisotropic and electric field effects, either separately or together. In the first case, the total effects are Δ_XCN^T=?14.7×10^?6cm³ mol^?1 and bμ_CN^T=14.7×10^?30 cm³, respectively. The second approach allows the estimation of the values Δ_XCN=?4.9 × 10^?6 cm³ mol^?1 and bμ_CN=9.8 × 10^?3 cm³, reflecting the combined contributions of magnetic anisotropy and electric field to the total effect.     

Supramolecular chirogenesis in zinc porphyrins: mechanism, role of guest structure, and application for the absolute configuration determination.

The achiral syn folded (face-to-face conformation) host molecule of the ethane-bridged bis(zinc porphyrin) transforms into the corresponding chiral extended anti bis-ligated species in the presence of enantiopure amine guests. The mechanism of the supramolecular chirogenesis is based upon the screw formation in bis(zinc porphyrin), arising from steric interactions between the largest substituent at the ligand's asymmetric carbon and peripheral alkyl groups of the neighboring porphyrin ring pointing toward the covalent bridge. The screw direction is determined by the guest's (amines) absolute configuration resulting in a positive chirality induced by (S)-enantiomers due to formation of the right-handed screw, and a negative chirality produced by the left-handed screw of (R)-enantiomers. The screw magnitude is strongly dependent upon the structure of the chiral guests. The amines with bulkier substituents result in stronger CD signals and larger (1)H NMR resonance splittings of enantiotopic protons. This system possesses a high degree of chiroptical activity, which allows the differentiation of one of the smallest homologous elements of organic chemistry, that is, the methyl and ethyl groups attached to the asymmetric carbon, and additionally, which senses a remote chiral center at a position beta to the amine binding group.