Porphyrins and metalloporphyrins: versatile circular dichroic reporter groups for structural studies

During the last few years, porphyrins and metalloporphyrins have attracted widespread attention as chromophores for studies in circular dichroism (CD), an indispensable chiroptical tool for monitoring chiral interactions. This review summarizes the multifaceted properties of porphyrins and metalloporphyrins, powerful CD chromophores that are characterized by their intense and red-shifted Soret band, propensity to undergo pi-pi stacking, facile incorporation of metals, and ease in varying solubility. Such attributes make porphyrins one of the most attractive and sensitive chromophores used in CD studies. They offer possibilities for studying the stereochemistry of chiral porphyrin assemblies, large organic molecules, biopolymers, and compounds available in miniscule quantities. The tendency of porphyrins to undergo pi-pi stacking and zinc porphyrins to coordinate with amines enable the CD exciton chirality method to be extended to configurational assignments of flexible compounds containing only one stereogenic center. Various artificial porphyrin receptors have been synthesized for the recognition of biologically important chiral guests such as carbohydrates, amino acids, and their derivatives. The induced CD of the host porphyrin Soret band reflects the identity of guests and binding modes of host/guest complexation with high sensitivity.     

Single-walled carbon nanotube absolute-handedness chirality assignment confirmation using metalized porphyrin's supramolecular structures via STM imaging technique

This work reports confirmation of the experimental assignment of the absolute-handedness chirality of single-walled carbon nanotubes (SWNTs). This was achieved by applying the scanning tunneling microscopy (STM) imaging technique to a supramolecular composite consisting of a metalized porphyrin derivative (nickel-5,15-bisdodecylporphyrin [Ni-BDP]) affixed to the surfaces of chiral-concentrated SWNTs (with right-handed helix P- and left-handed helix M- ). On the basis of the handedness chirality, different chiral supramolecular structures of Ni-BDP were observed on the surfaces of the two SWNT enantiomers. The incorporation of a metal center into the porphyrin ring did not significantly affect the SWNT absolute-handedness chirality assignment, the large pi-system porphyrin ring being the crucial factor. These findings will effectively pave the way towards the clear selective synthesis, separation, chemistry, and applications of SWNT enantiomers.     

The use of circular dichroism spectroscopy for studying the chiral molecular self-assembly: an overview

Self-assembly plays an important role in the formation of many chiral biological structures and in the preparation of chiral functional materials. Therefore the control of chirality in synthetic or biological self-assembled systems is important either for the comprehension of recognition phenomena or to obtain materials with predictable and controllable properties. Circular dichroism was developed to study molecular chirality, however, because of its outstanding sensitivity to chiral perturbations of the system under investigation; it has been extended more recently to supramolecular chemistry. In particular, self-assembly processes leading to the formation of chiral supramolecular architectures (and eventually to gels or liquid crystal phases) can be monitored by CD. Furthermore, CD spectroscopy often allows one to obtain structural information on the assembled structures. This review deals with representative contributions to the study of supramolecular chirality by means of circular dichroism.     

Chiral porphyrin imine manganese complex as catalyst for asymmetric epoxidation of styrene derivatives

New chiral porphyrin imine was synthesized from (S)‐3‐benzyl‐2‐methyl‐4‐phenylbutanal according to dipyrromethane method using trifluoroacetic acid, BF₃ etherate, and p‐chloranil. Manganese complex of this chiral porphyrin imine ligand was used as catalyst in the asymmetric epoxidation of styrene derivatives possessing different substituents. Styrene derivatives possessing electron withdrawing groups gave the corresponding chiral epoxides in high yield up to 98% and ee up to 99%. The mechanism for the catalytic asymmetric epoxidation was also discussed based on transfer of oxygen.     

Preparation and study of chiral magnesium porphyrin-amino acid complexes

Mixtures of magnesium protoporphyrin or magnesium mesoporphyrin with a variety of chiral amino acids (L-histidine, D- and L-proline, L-serine and L-threonine) produce prominent induced Cotton effects in the UV-visible region. By contrast magnesium deuteroporphyrin mixtures exhibit no optical rotatory dispersion (ORD)/circular dichroism (CD) spectra. It is proposed that the species producing the Cotton effects are six-coordinate species of the type Mg (porphyrin) (amino acid)₂. For L-histidine and L-threonine CD spectra have shown that complexes of the opposite chirality can be obtained for different samples of magnesium protoporphyrin. For D- and L-proline such a change in sign of spectra was not found for the same magnesium porphyrin samples. Reasons for these observations are presented together with proposals regarding structural details of the six-coordinate complexes. It is also suggested that racemic samples of such amino acid-magnesium porphyrin mixtures could yield optical resolution of products on irradiation with circularly polarised light. Details of a study of this type are presented.     

Some applications of a chiral fluorometric reagent, (S)-TBMB carboxylic acid

Molecular design and applications of a fluorometric chiral agent, (S)-TBMB carboxylic acid, are briefly reviewed. The agent, possessing an asymmetric 1,3-benzodioxole skeleton, was designed as a novel class of chiral agent that functions also as a benzoate chromophore for exciton chirality CD methods. The utility of this agent has been demonstrated in an application to determine enantiomeric amino acids, acyl-sn-glycerols, glycosyl-sn-glycerols, and other chiral alcohols and amines.     

(alphaMe)Aun: a highly lipophilic, chiral, Calpha-tetrasubstituted alpha-amino acid. Incorporation into model peptides and preferred conformation.

Using a chemo-enzymatic approach we prepared the highly lipophilic, chiral, Calpha-methylated alpha-amino acid (alphaMe)Aun. Two series of terminally protected model peptides containing either D-(alphaMe)Aun in combination with Aib or L-(alphaMe)Aun in combination with Gly were synthesized using solution methods and fully characterized. A detailed solution conformational analysis, based on FT-IR absorption, 1H NMR and CD techniques, allowed us to determine the preferred conformation of this amino acid and the relationship between chirality at its alpha-carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that D-(alphaMe)Aun favors the formation of the left-handed 3(10)-helical conformation.     

Asymmetric autocatalysis and its application to chiral discrimination

Chiral pyrimidyl, quinolyl, and pyridyl alkanols act as asymmetric autocatalysts with significant amplification of enantiomeric excess (ee) in the enantioselective addition of diisopropylzinc to pyrimidine-5-, quinoline-3-, and pyridine-3-carbaldehydes, respectively. 2-Alkynyl-5-pyrimidyl alkanol with as low as 0.6% ee automultiplies during the consecutive asymmetric autocatalysis with increasing ee to as high as >99.5%. Asymmetric autocatalysis is applied to chiral discrimination of organic compounds. In the presence of methyl mandelate or 2-butanol with very low ee's (0.05-0.1%) as chiral initiators, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords pyrimidyl alkanol with higher ee's with the correlated absolute configurations to those of the chiral initiators. Chirality of amino acids (such as leucine) and helicenes with very low ee's are also discriminated by asymmetric autocatalysis, affording pyrimidyl alkanol with very high ee's. Asymmetric autocatalysis also discriminates the chirality of primary alcohols-alpha-d, monosubstituted [2.2]paracyclophanes and octahedral cobalt complex with achiral ligands of which the chirality is due to the topology of coordination of the achiral ligand. Even the chirality of inorganic crystals such as quartz and sodium chlorate is discriminated by asymmetric autocatalysis of pyrimidyl alkanol. Thus, asymmetric autocatalysis provides a unique method for the discrimination of chiral compounds and crystals.     

Nonhanded chirality in octahedral metal complexes

Chiral molecules can either be handed (i.e., "shoes") or nonhanded ("potatoes"). The only chiral ligand partition for tetrahedral metal complexes (or for a tetrahedral carbon atom such as that found in amino acids and other chiral biological molecules) is the fully unsymmetrical degree 6 partition (1(4)), which leads to handed metal complexes of the type MABCD with a lowest-degree chirality polynomial consisting of the product of all six possible linear factors of the type (s(i)-s(j)) where 1 < or = i,j < or = 4. The lowest-degree chiral ligand partitions for octahedral metal complexes are the degree 6 partitions (31(3)) and (2(3)) leading to handed chiral metal complexes of the types fac-MA(3)BCD and cis-MA(2)B(2)C(2). The form of the lowest-degree chirality polynomial for the (31(3)) chiral ligand partition of the octahedron resembles that of the (1(4)) chiral ligand partition of the tetrahedron, likewise with four different ligands. However, the form of the lowest-degree chirality polynomial for the (2(3)) chiral ligand partition of the octahedron corresponds to the square of the chirality polynomial of the (1(3)) chiral ligand partition of the polarized triangle, which likewise has three different ligands. Ligand partitions for octahedral metal complexes such as (2(2)1(2)), (21(4)), and (1(6)), which are less symmetrical than the lowest-degree chiral ligand partitions (31(3)) and (2(3)), lead to chiral octahedral metal complexes which are nonhanded. In such complexes, pairs of enantiomers can be interconverted by simple ligand interchanges without ever going through an achiral intermediate.     

Design and studies of novel polyoxysterol-based porphyrin conjugates

New types of steroid-porphyrin conjugates derived from 20-hydroxyecdysone (20E) and 24-epibrassinolide (EBl) were synthesized. An exceptional regioselectivity in the reaction of both steroids with porphyrin boronic acids was found to give side-chain-conjugated boronic esters as sole products. UV-Vis-, fluorescence and NMR spectroscopy yielded similar data for all the studied compounds confirming the solvent driven supramolecular assembly with formation of J-aggregates. CD measurements of water diluted solutions showed a clear difference between 20E and EBl conjugates. The latter showed a strong supramolecular chirality, whereas 20E J-aggregates did not.     

Spectroscopic study of porphyrin self-assembly: Role of pH,time, and chiral template

In this study, we performed an ultraviolet-visible (UV-Vis) and circular dichroism (CD) spectroscopic analysis of the binary and ternary supramolecular structures formed by self-assembling the following three water-soluble porphyrins with and without a chiral template: the negatively charged, meso-Tetra(4-sulfonatophenyl) porphine (H₂TPPS⁴⁻); the positively charged meso-trans-(di(N-methyl-4-pyridyl)diphenyl) porphine (trans-DmPyDPP) and meso-cis-(di(N-methyl-4-pyridyl)diphenyl) porphine (cis-DmPyDPP). Polyglutamic acid (both L and D enantiomers) was selected as the chiral template due to its ability to change secondary structure with pH. The propensity for the porphyrins to show an induced CD in the presence of polyglutamic acid is demonstrated. The induced chirality of all supramolecular structures was found to depend on the pH of the solution, the chirality of the polymer, and the order of addition of the positively and negatively charged porphyrins (for ternary complexes). Of particular interest is that the interaction of H₂TPPS⁴⁻ with the chiral scaffold seems to undergo a dynamic rearrangement of the supramolecular structure as evident from the change in the CD spectrum over time. Moreover, experiments with ternary complexes suggest that the preferential interaction of trans-DmPyDPP with the random coil of the polymer shows promise as a sensor of protein secondary structure.     

External chirality-triggered helicity control promoted by introducing a beta-Ala residue into the N-terminus of chiral peptides

The noncovalent chiral domino effect (NCDE), defined as chiral interaction upon an N-terminus of a 3(10)-helical peptide, will provide a unique method for structural control of a peptide helix through the use of external chirality. On the other hand, the NCDE has not been considered to be effective for the helicity control of peptides strongly favoring a one-handed screw sense. We here aim to promote the NCDE on peptide helicity using two types of nonapeptides: H-beta-Ala-Delta(Z)Phe-Aib-Delta(Z)Phe-X-(Delta(Z)Phe-Aib)(2)-OCH(3) [Delta(Z)Phe = alpha,beta-didehydrophenylalanine, Aib = alpha-aminoisobutyric acid], where X as the single chirality is L-leucine (1) or L-phenylalanine (2). NMR, IR, and CD spectroscopy as well as energy calculation revealed that both peptides alone form a right-handed 3(10)-helix. The original CD amplitudes or signs in chloroform, irrespective of a strong screw-sense preference in the central chirality, responded sensitively to external chiral information. Namely added Boc-L-amino acid stabilized the original right-handed helix, while the corresponding d-isomer destabilized it or transformed it into a left-handed helix. These peptides were also shown to bind more favorably to an L-isomer from the racemate. Although similar helicity control was observed for analogous nonapeptides bearing an N-terminal Aib residue (Inai, Y.; et al. Biomacromolecules 2003, 4, 122), the present findings demonstrate that the N-terminal replacement by the beta-Ala residue significantly improves the previous NCDE to achieve more effective control of helicity. Semiempirical molecular orbital calculations on complexation of peptide 2 with Boc-(L or D)-Pro-OH reasonably explained the unique conformational change induced by external chirality.     

Bulky melamine-based Zn-porphyrin tweezer as a CD probe of molecular chirality

The transfer of chirality from a guest molecule to an achiral host is the subject of significant interest especially when, upon chiral induction, the chiroptical response of the host/guest complex can effectively report the absolute configuration (AC) of the guest. For more than a decade, dimeric metalloporphyrin hosts (tweezers) have been successfully applied as chirality probes for determination of the AC for a wide variety of chiral synthetic compounds and natural products. The objective of this study is to investigate the utility of a new class of melamine-bridged Zn-porphyrin tweezers as sensitive AC reporters. A combined approach based on an experimental CD analysis and a theoretical prediction of the prevailing interporphyrin helicity demonstrates that these tweezers display favorable properties for chiral recognition. Herein, we discuss the application of the melamine-bridged tweezer to the chiral recognition of a diverse set of chiral guests, such as 1,2-diamines, α-amino-esters and amides, secondary alcohols, and 1,2-amino-alcohols. The bulky periphery and the presence of a rigid porphyrin linkage lead, in some cases, to a more enhanced CD sensitivity than that reported earlier with other tweezers.     

Transition metal complexes bearing atropisomeric saturated NHC ligands

From achiral imidazolinium salts, chiral transition metal complexes containing an N-heterocyclic carbene (NHC) ligand were prepared (metal = palladium, copper, silver, gold, rhodium). Axial chirality in these complexes results from the formation of the metal-carbene bond leading to the restriction of rotation of dissymmetric N-aryl substituents about the C–N bond. When these complexes exhibited a sufficient configurational stability, a resolution by chiral high-performance liquid chromatography (HPLC) on preparative scale enabled isolation of enantiomers with excellent enantiopurities (>99% ee) and good yields. A study of the enantiomerization barriers revealed the effect of the backbone nature as well as the type of transition metal on its values. Nevertheless, the evaluation of palladium-based complexes in asymmetric intramolecular α-arylation of amides demonstrated that the ability to induce an enantioselectivity cannot be correlated to the configurational stability of the precatalysts.     

Chirality Sensing With Stereodynamic Biphenolate Zinc Complexes

Two bidentate ligands consisting of a fluxional polyarylacetylene framework with terminal phenol groups were synthesized. Reaction with diethylzinc gives stereodynamic complexes that undergo distinct asymmetric transformation of the first kind upon binding of chiral amines and amino alcohols. The substrate‐to‐ligand chirality imprinting at the zinc coordination sphere results in characteristic circular dichroism signals that can be used for direct enantiomeric excess (ee) analysis. This chemosensing approach bears potential for high‐throughput ee screening with small sample amounts and reduced solvent waste compared to traditional high‐performance liquid chromatography methods. Chirality 27:700–707, 2015. © 2015 Wiley Periodicals, Inc.     

Metal-induced supramolecular chirality in optically active polymers of oxazoline-substituted N-phenylmaleimides

Polymerization of N-phenylmaleimide derivatives bearing a chiral oxazoline substituent at ortho-position on the phenyl group (namely, N-[o-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]maleimides, OPMI) was carried out with diethylzinc (Et2Zn) as an initiator. The resulting polymers exhibited a quite high specific rotation and a unique split-type circular dichroism. Furthermore, an induced Cotton effect was observed in the pi-pi* transition region of the chromophores upon complexation of these polymers with copper(II) salt in tetrahydrofuran solution, indicating the formation of chiral supramolecular aggregates. The induced supramolecular chirality was found to be dependent on the absolute configuration of monomer units, that is, the polymers with (R)-configurational oxazolinyl chromophores tended to form chiral aggregates with levorotatory handedness, while polymers obtained from the (S)-monomer offered dextrogyrate one upon the addition of Cu(II) salt.     

Absolute stereochemistry assignment of N-phosphorylimine-derived aza-Diels-Alder adducts with TDDFT CD calculations

N-phosphorylimines undergo Lewis acid-catalyzed Diels-Alder reactions with Danishefsky's diene. Application of the chiral catalyst zinc(II)-(S)-BINOL results in good-to-low asymmetric induction but poor chemical conversion. However, the absolute stereochemistry of novel aza-Diels-Alder cycloadducts, such as diethyl 4-oxo-2-phenyl-3,4-dihydropyridin-1(2H)-ylphosphonate, can be determined using circular dichroism (CD). Comparison between experimental and TDDFT-calculated CD spectrum shows that use of the (S)-catalyst results in predominant formation of the (6R) cycloadducts.     

A periodic system of chiral structures in molecular biology

A systemic regularity of molecular biology is considered: the tendency towards alternating of the sense of chirality of intramolecular structural levels of DNA and proteins, namely, D–L–D–L for DNA and L–D–L–D for proteins, is observable starting from the level of asymmetric carbon in deoxyribose and amino acids. Helicity is a special case of chirality. In intermolecular interactions, the sense of chirality of the highest intramolecular structural level directly involved in the interaction prevails in each of the participants. The interaction of molecules of the same nature (protein–protein, DNA–RNA, tRNA–mRNA, and ribozymes) mainly occurs in the case of the same sense of chirality, either L–L or D–D, and for molecules of different types (DNA–protein, tRNA–amino acids, and enzyme–substrate), in the case of different senses of chirality, either D–L or L–D. An alternating sense of the chiral hierarchy of conjugated levels of macromolecular structures in proteins and nucleic acids is of general biological importance: it determines the discreteness of levels, serves as a tool of folding, and provides a structural basis for “preferred collective” (or “macroscopic mechanical”) degrees of freedom in the design of macromolecular machines, as well as being one of the mechanisms of blockwise/saltatory development of the evolutionary process. A new fundamental concept is proposed: the homochirality of primary structures of DNA and proteins determines the amount of the entropic component of the free energy, which is used in the processes of folding and molecular rearrangements.     

Asymmetric epoxidation of unfunctionalized alkenes catalyzed by sugar moiety-modified chiral salen-Mn(III) complexes

Several chiral Schiff-base ligands with sugar moieties at C-3 (3′) or C-5 (5′) of salicylaldehyde were synthesized from reaction of salicylaldehyde derivatives with diamine. These ligands coordinated with Mn(III) to afford the corresponding chiral salen-Mn(III) complexes characterized by FT-IR, MS, and elementary analysis. These complexes were used as catalysts for the asymmetric epoxidation of unfunctionalized alkenes. Only weak enantioselectivity is induced by the chiral sugar moieties at C-3 (3′) or C-5 (5′) in the case of absence of chirality in the diimine bridge moiety. It was also shown that the sugars at C-5 (5′) having the same rotation direction of polarized light as the diimine bridge in the catalyst could enhance the chiral induction in the asymmetric epoxidation, but the sugars with the opposite rotation direction would reduce the chiral induction.     

Preferred solution conformation of peptides rich in the lipophilic, chiral, C(alpha)-methylated alpha-amino acid (alpha Me)Aoc.

The lipophilic, chiral, C(alpha)-methylated alpha-amino acid L-(alphaMe)Aoc (2-methyl-2-amino-octanoic acid) was prepared using a chemo-enzymatic approach. Two series of terminally protected model peptides, from dimer through to hexamer, containing L-(alphaMe)Aoc in combination with either Gly or Aib, were synthesized by solution methods and were fully characterized. A solution conformational analysis, based on FT-IR absorption, 1H-NMR and circular dichroism (CD) techniques, was performed with the aim at determining the preferred conformation of this novel amino acid and the relationship between chirality at its alpha-carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that L-(alphaMe)Aoc favours the formation of the right-handed 3(10)-helical conformation.