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.     

Absolute stereochemical determination of 1,2-diols via complexation with dinaphthyl borinic acid

Rapid derivatization of chiral 1,2-diols with dinaphthyl borinic acid ( DBA ) leads to a cyclic boronate, enabling the absolute stereochemical prediction via exciton-coupled circular dichroic (ECCD) of the naphthyl groups. Aryl- and alkyl-substituted 1,2-diols derivatized with DBA yield a predictable ECCD, which is also in agreement with theoretical predictions derived from computationally minimized structures.     

Enantiodiscrimination of methamphetamine by circular dichroism using a porphyrin tweezer

Using exciton‐coupled circular dichroism (ECCD) spectroscopy, our lab was able to differentiate between the two enantiomers of methamphetamine using a commercially available porphyrin tweezer as an achiral host. The host–guest complex formed with (+)‐(S)‐methamphetamine produced a negative bisignate‐shaped ECCD spectrum, whereas the complex formed with (?)‐(R)‐methamphetamine produced a positive one. This sensitive technique could serve as an alternative method for the enantiodiscrimination of chiral methamphetamine, a commonly abused drug in the United States. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Derivatization,complexation, and absolute configurational assignment of chiral primary amines: application of exciton-coupled circular dichroism

We report here a sensitive method for the determination of the absolute configurations of primary amines using exciton-coupled circular dichroism (ECCD). The method works on a microgram scale by derivatization of chiral amines with quinoline chromophores. Complexation of the chiral ligands with metal ion fixes the geometry of the chromophores, resulting in a twist that is governed by the asymmetric carbon configuration and steric environment of the amine. The absolute configurations of the primary amines can be interpreted from the couplets of the ECCD spectra of the derivatized complexes. Crystal structures, 2D NMR studies, and semiempirical calculations provide structural evidence for our model.     

Configuration and racemization determination of cysteine residues in peptides by chiral derivatization and HPLC: application to oxytocin peptides.

An improved RP-HPLC method was developed for the determination of the configuration and stereochemical purity of cysteine residues in peptides. The method consists of oxidation of cysteine and cystine residues to cysteic acid, followed by hydrolysis and pre-column chiral derivatization with Val-Marfey's reagent.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

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.     

Chiral discrimination promoted by (1S,2S)-1-phenyl-2-amino-1,3-propanediol derivatives in the asymmetric Reformatsky reaction

Some 3-t-butyldimethylsilyloxy derivatives, synthesized from the cheap commercially available (1S,2S)-2-amino-1-phenyl-1,3-propanediol [(1S,2S)- 1 ], have been successfully employed as new chiral ligands in the asymmetric Reformatsky reaction on aldehydic substrates. The influence both of the substrate and of the ligand on the stereochemical pathway has been investigated by varying the structure of the carbonyl substrate and of the optically active aminodiols. © 1995 Wiley-Liss, Inc.     

Direct high-performance liquid chromatographic separation of penbutolol enantiomers on a cellulose tris-3,5-dimethylphenyl carbamate chiral stationary phase

Penbutolol is a β-adrenoceptor blocking agent, and it contains the clinically relevant (?)-S-enantiomer. It was reported that the (+)-R-enantiomer of penbutolol is pharmacologically 50 times less active than the (?)-S-isomer in β-sympatholysis and without intrinsic sympathomimetic activity and refractory period in the heart muscle. Furthermore, the (+)-R-enantiomer does possess mutagenic activity. A high-performance liquid chromatographic (HPLC) method is described for direct identification, stereochemical separation, and quantitation of (+)-R-enantiomer in the clinically used (?)-S-isomer. The method involves the use of cellulose tris-3,5-dimethylphenyl carbamate chiral stationary phase coated on silica gel (OD-Chiralcel column). The capacity factors (k′) for the first eluted enantiomer and stereochemical separation factor (α) obtained were 1.32 and 1.98, respectively. The maximum stereochemical resolution factor (R) was 5.05. The method could be applied for optical purity determination of (?)-(S)-penbutolol in pharmaceutical formulation to detect for the presence of the undesirable (+)-R-enantiomer.     

Design and synthesis of new alkyl‐based chiral phosphoric acid catalysts

Using chiral BINOL‐derived phosphoric acids (PA's) to activate substrates for enhanced reactivity is now regarded as a powerful strategy to control enantioselectivity in asymmetric synthesis. Generally, most substituents at the 3,3′‐positions of BINOL PA's are aryl derivatives. These derivatives are pivotal in attaining high selectivity. PA's with alkyl substituents in these positions have rarely been reported. Herein, we introduced alkyl‐based substituents at the 3,3′‐position of PA's. These new potential catalysts, if applied in reactions, may allow altered noncovalent interactions (as opposed to the typical aryl substituents in these positions) with substrates used in chiral PA‐catalyzed chemistry in the future.     

Effects of solvent on chiral and enantiomeric separation of Koga bases using derivatized amylose chiral stationary phase

The separation of R,R‐, S,S‐, and meso‐Koga bases on derivatized amylose chiral stationary phases (CSP) has been studied using different alcohol and alcohol‐hexane mixtures as eluant. Straight‐chain and branched alcohols with carbon numbers from one to four were investigated. The carbon number and geometry of the alcohol impacts the separation of Koga bases. The optimal separations were obtained using a mixture of methanol with linear or branched alcohol. Also, the elution order of meso‐ and R,R‐Koga base was switched as content of branched alcohol increases in cosolvent. The study of acidic and basic additive effects demonstrated that maintaining analytes in the free base state is crucial in order to achieve retention and separation. TEA alone or TEA and TFA mixture were used in the studies. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Excavations in drug chirality: 1. Cyclothiazide

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.     

Application of L-proline derivatives as chiral shift reagents for enantiomeric recognition of carboxylic acids

Four proline-derived chiral receptors 5-8 were readily synthesized starting from L-proline. The enantiomeric recognition ability of chiral receptors was examined with a series of carboxylic acids by (1) H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of guest molecules were determined by using Job plots and a nonlinear least-squares fitting method, respectively. The Job plots indicate that the hosts form 1:1 instantaneous complexes with all guests. The receptors exhibited different chiral recognition abilities toward the enantiomers of racemic guests. Among the chiral receptors used in this study, prolinamide 6 was found to be the best chiral shift reagent and is effective for the determination of the enantiomeric excess of chiral carboxylic acids.     

Circular dichroism detection in HPLC

A circular dichroism-based detection system presents several advantages in the HPLC analysis of chiral compounds because of the selective monitoring of optically active molecules. Its use allows reliable determination of enantiomeric excesses and elution order. To this end, the application of empirical, semiempirical, and nonempirical methods to get stereochemical information from the CD signal is reported. Furthermore, recording the CD spectra on line and evaluation of the dissymetry factor make the CD detection very powerful in characterizing the stereochemistry of chiral eluates.     

Asymmetric synthesis polymerization of meso oxiranes and thiiranes

The asymmetric synthesis polymerization or “enantiogenic” polymerization of some meso oxiranes, cis-dimethyloxirane (cis-DMO) and cyclohexene oxide (CHO), and thiiranes, cis-dimethylthiirane (cis-DMT) and cyclohexene sulfide (CHS), initiated with different chiral systems was examined. Strong differences in behaviour were observed between oxiranes and thiiranes depending on the initiator used. The initiators based on ZnEt₂ or CdMe₂ and a chiral diol give optically active polymers from meso thiiranes but fail to induce an asymmetric polymer synthesis with meso oxiranes. A new chiral initiator based on ZnEt₂ and (1S,2R)-ephedrine allowed us to prepare optically active poly CHOs, which can be fractionated into fractions exhibiting opposite optical activities. © 1992 Wiley-Liss, Inc.     

Benzoyl cellulose beads in the pure polymeric form as a new powerful sorbent for the chromatographic resolution of racemates

Cellulose-based stationary phases are known to be very efficient and versatile chiral sorbents for the chromatographic resolution of racemates. Except for microcrystalline cellulose triacetate (CTA I), basically all other cellulose-based phases have been prepared by coating of ca. 20% weight polymer on a wide pore silica gel used as a carrier. In this work we describe the preparation of benzoylcellulose (TBC) beads in the pure polymeric form (without inorganic carrier) from an emulsion of the organic polymer. The new material has been fully characterized and used as a chiral stationary phase for the resolution of various classes of racemic compounds such as benzylic alcohols or acetate derivatives of aliphatic alcohols and diols. The structural variety of the separated solutes as well as the irrational influence of the aromatic substituent in different classes of aryl compounds suggest that multiple interaction sites are involved in the complexation, making a prediction of the separation difficult. The benzoyl cellulose beads exhibit a very high loading capacity, which is particularly useful for preparative purposes as demonstrated for selected examples.     

Recent advances in methods of direct optical resolution

Very great advances have been made in the field of direct optical resolution of organic compounds by chromatographic techniques. Chiral capillary gas chromatography now permits a determination of the enantiomeric composition of a few nanograms of a compound present in a mixture of many others. Coupled with high resolution mass spectrometry the technique will additionally permit structural elucidation; of great interest in pheromone research and related areas. Analytical separations of enantiomers are now also carried out by high-performance liquid chromatography (HPLC) methods based on a variety of principles. Basically, two main types are used, differing as to whether the mobile phase has to be a chiral medium or not. Two-dimensional HPLC, whereby compounds separated on a non-chiral column are progressively and automatically transferred to a chiral column for optical resolution, has been used successsfully for chiral amino acid separations. Many different chiral sorbents for preparative LC and HPLC resolutions have been prepared; some of these are now used in columns capable of producing pure enantiomers from a given racemate at a rate of the order of one gram/hour in continuous, automatic HPLC procedures. Apart from all important applications of these results of optical resolution technology, an increased knowledge of the underlying chiral recognition phenomena responsible for enantioselection has also been achieved.     

Core-modified porphyrins. Part 6: Effects of lipophilicity and core structures on physicochemical and biological properties in vitro

Thiaporphyrins 2-8 were prepared as analogues of 5,20-diphenyl-10,15-bis[4-(carboxymethyleneoxy)-phenyl]-21,23- dithiaporphyrin (1) to examine the effect of structural modifications: substituent changes in meso aryl groups of dithiaporphyrins with one water-solubilizing group (2-5), dihydroxylation of a pyrrole double bond and reduction to dihydroxychlorins (6 and 7), and the removal of two meso aryl groups to give unsubstituted meso positions (8). The impact of these structural modifications was measured in both physicochemical (UV spectra, generation of singlet oxygen, lipophilicity, and aggregate formation) and biological properties (dark toxicity and phototoxicity, cellular uptake, and subcellular localization). Mono-functionalized porphyrins had much higher lipophilicity than di-functionalized porphyrin 1 and, consequently, formed more aggregates in aqueous media. The formation of aggregates might lower the efficiency of lipophilic porphyrins as photosensitizers. Interestingly, dihydroxylation of a core pyrrole group in the dithiaporphyrin core did not affect either the absorption spectrum or the efficiency for generating singlet oxygen. The phototoxicity of dihydroxydithiachlorins mainly depended on their intracellular uptake. The potent phototoxicity of 6, IC(50)=0.18muM, was attributed to the extraordinarily high uptake. The intracellular uptake of 6 was about 7.6 times higher than 1. In contrast, thiaporphyrin 8 with only two meso aryl groups was less effective as a photosensitizer, perhaps due to poorer uptake and a lower quantum yield for the generation of singlet oxygen.     

Determination of enantiomerization barriers by dynamic and stopped-flow chromatographic methods

In recent years, dynamic chromatography and stopped-flow chromatographic techniques have become versatile tools for the determination of enantiomerization and isomerization barriers. Increasing demands for the stereochemical safety of chiral drugs contributed to the rapid development of new techniques. New computer-aided evaluation systems allow the on-line determination of interconversion barriers from the experimental chromatograms. Both dynamic chromatography and stopped-flow chromatography have been applied to the entire range of chromatographic methods (GC, SFC, HPLC, CE).     

Chromatographic optical resolution on trans-1,2-diaminocyclohexane derivatives: Theory and applications

An overall view on some new chiral stationary phases based on (trans)-1,2-diaminocyclohexane is illustrated. The selected chiral moiety, derivatized with different aroyl groups, has been linked to a silica matrix in order to give chiral stationary phases (CSPs) enabling them to be used efficiently in the normal and reverse phase, both for analytical and preparative purposes. In addition new polymeric CSPs have been prepared by using the same selector, suitably modified, as monomer. The new chiral stationary phases have been characterised by physicochemical methods and used for the resolution of various racemic compounds classes such as α-aryloxyacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, tertiaryphosphine oxides, benzodiazepines etc. without prederivatization or as amines, amino acids, amino alcohols, nonsteroidal antiinflammatory agents in a derivatized form. The separated solutes structural variety suggests that multiple interaction sites are involved in the recognition process: some thermodynamic data relative to the CSPs—selectands interactions are also illustrated. © 1992 Wiley-Liss, Inc.