Absolute Configuration Assignment from Optical Rotation Data by Means of Biphenyl Chiroptical Probes

A non-empirical approach for the assignment of the absolute configuration of chiral 2-alkyl-substituted carboxylic acids and primary amines by [α]_D measurements has been developed. The method requires the conversion of the chiral acids or amines into the corresponding 4,4′-disubstituted biphenylamides or biphenylazepines, respectively. In these derivatives a central-to-axial chirality transfer induces a preferred torsion in the biphenyl moiety revealed by the sign of the biphenyl A band in the ECD spectrum. By 4,4′-substitution on the biphenyl moiety a redshift of the A band is obtained, leading to an increase of its relative contribution to optical rotation. This allows to reliably establish a direct correlation between the [α]_D sign, the biphenyl twist and, then, the substrate absolute configuration. This approach thus constitutes a really practical and reliable method to assign the absolute configuration of chiral carboxylic acids and primary amines by simple and straightforward [α]_D measurement, readily obtainable by a routine instrumentation like the polarimeter.     

Tropos deoxycholic acid-derived biphenylphosphites: synthesis,stereochemical characterization and use as chiral ligands in the copper catalyzed conjugate addition of diethylzinc to acyclic enones

Three new deoxycholic acid-based 5,5′-substituted biphenylphosphites, 2–4, were synthesized and their stereochemical features were examined by CD and NMR spectroscopy, which allowed us to determine the sense of twist of the substituted biphenyl moiety as well as the extent of its prevalence in different solvents. Phosphites 1–4 were used as chiral ligands in the copper catalyzed conjugate addition of diethylzinc to acyclic enones, affording the alkylation products with ees up to 65%. The results obtained allowed a correlation between asymmetric induction and the sense of twist of the biphenylphosphite moiety of the chiral inducers.     

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 1. Chiroptical protocol for absolute configurational assignments of monoalcohols and primary monoamines.

A general microscale protocol for the determination of absolute configurations of primary amino groups or secondary hydroxyl groups linked to a single stereogenic center is described. The chiral substrates are linked to the achiral trifunctional bidentate carrier molecule (3-aminopropylamino)acetic acid (1, H(2)NCH(2)CH(2)CH(2)NHCH(2)COOH) and the resultant conjugates are then complexed with dimeric zinc porphyrin host 2 giving rise to 1:1 host/guest sandwiched complexes. These complexes exhibit exciton-coupled bisignate CD spectra due to stereodifferentiation leading to preferred porphyrin helicity. Since the chiral sense of twist between the two porphyrins in the complex is dictated by the stereogenic center of the substrate, the sign of the couplet determines the absolute configuration at this center. The twist of the porphyrin tweezer in the complex can be predicted from the relative steric sizes of the groups flanking the stereogenic center, such that the bulkier group protrudes from the complex sandwich. In certain alpha-hydroxy esters and alpha-amino esters, electronic factors and hydrogen bonding govern the preferred conformation of the complex, and hence the CD spectra.     

Chirality in liquid crystals. The remarkable phenylpropiolates

The biphenylyl esters of the 4-n-alkoxyphenylpropiolic acids are a unique family of liquid-crystalline materials. In particular, when the biphenyl moiety of the compounds carries a chiral end-group, many optically active mesophases are created which exhibit unusual structures and physical properties. For instance, when the chiral group attached to the biphenyl moiety is 1-methylheptyl then Abrikosov, twist grain boundary smectic A* and antiferroelectric smectic C* phases are observed. The wide variety of chiral phases and electrochiral properties exhibited by this family of materials makes them ideal candidates for exploring chirality in the liquid-crystalline state. These investigations allow us to contrast and compare chirality dependent phenomena in liquid crystals, thereby producing a broader view of the concept of chirality in organized fluids than is traditionally presented.     

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.     

Effect of the dimeric H-bonded mesogens of chiral acids on the mesogenic and optical properties

A serial of chiral aromatic acid derivatives was systematically prepared to study the effect of dimeric H-bonded mesogens on liquid crystal (LC) and optical behaviours. The lateral fluoro-substituent and the chiral terminal chains were also studied for comparison. When the H-bonded mesogens changed from biphenyl or phenyl benzoate to naphthalene ring or benzene ring, the molecular length?width ratio reduced greatly, which thus led the temperature range of mesophases reduced and the phase transition decreased. The lateral fluoro-substituent, a shorter or meta-substituted terminal chain, could make the mesophase range narrowed or disappeared. Besides the chiral nematic (N*) phase, twist grain boundary C (TGBC*) phase was found in the double aromatic-ring acids with a chiral para-substituted octan-2-yloxyl group. Interestingly, the TGBC* phase could scatter away most incident light in any surface anchoring condition, and the light scattering performance exceeded any other phases of low-molecular-weight LCs known. The unusual H-boned material could be used for preparing reversible optical switches without using any polariser and any surface alignment treatment.     

Asymmetric induction by the cholestanic moiety on tropos species: synthesis and stereochemical characterization of bile acid-based biphenyl phosphites

Three different bile acid-derived biphenyl phosphites were synthesized, starting from cholic and deoxycholic acids and biphenol, and their stereochemical features were checked by CD and NMR spectroscopies. On the basis of the spectroscopic results, the capability of the cholestanic system to induce a prevalent sense of twist on the biphenyl moiety of the bile acid-derived phosphites as well as their tropos nature was inferred.     

Preparation and evaluation of new Pirkle type chiral stationary phases with long alkyl chains for the separation of amino acid enantiomers derivatized with NBD-F.

In order to improve the high-performance liquid chromatographic separation of alpha-amino acids derivatized with the fluorogenic reagent 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) on commercially available chiral stationary phases (CSPs) such as SUMICHIRAL OA-2500(S) (CSP 1) and OA-4700 (CSP 3), the preparation of two new CSPs (CSP 2 and CSP 4) having 11-aminoundecanoic acid between the aminopropyl silica gel support and the chiral moiety in CSP 1 and CSP 3 is described. CSP 2 and CSP 4 improved both the mutual and enantiomeric separation of NBD-amino acids compared with CSP 1 and CSP 3. Thus, 17 pairs of NBD-amino acid enantiomers and NBD-glycine were separated on CSP 2 except for six NBD-amino acids (D-Asn, D-Ser, D-Gln, L-Pro, L-Ser and Gly). CSP 2 and CSP 4 also showed better enantiomeric separation of NBD-amino acid esters and amides than CSP 1 and CSP 3. It was considered that the achiral long alkyl chains in the CSPs might form a hydrophobic space which assisted the stereoselective interaction of analytes with the chiral moiety by changing the environment around the chiral moiety. On CSP 1 and CSP 2, NBD-beta-amino acid was also enantiomerically separated.     

Diastereoselective synthesis of delta-aminoacids through domino Ireland-Claisen rearrangement and Michael addition

A novel domino reaction--stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition--is described. A protocol starting from Baylis-Hillman adducts 3a-f using chiral lithium amide affords optically active gamma-substituted delta-amino acids 4a-f with high diastereoselectivities and enantioselectivities. The acid can be isolated easily from large-scale reactions and transformed to 2,3-disubstituted piperidines 11 or 2-substituted nipecotic acid derivates 12.     

Click regulation of cyclodextrin primary face for the preparation of novel chiral stationary phases

In this study, a series of novel CD chiral stationary phases were fabricated by immobilization of mono‐6^A‐deoxy‐N₃‐cyclodextrin onto silica surfaces followed by click regulation of CD primary face with 4‐pentynoic acid (acidic moiety), 2‐propynylamine (alkaline moiety) and L‐propargylglycine (chiral amino acid moiety), respectively. Enantioseparations of various kinds of racemates including dansyl‐amino acids, chiral lactides and diketones were conducted in reversed phase modes on these chiral stationary phases, where nearly forty diketones and chiral lactides were firstly separated on cyclodextrin stationary phases. 4‐Pentynoic acid moiety can make the retention ability decline while amine moiety significantly enhanced the retention ability of the stationary phases. For most of the studied analytes, the chiral amino acid moiety had the most positive effects on both the retention time and the resolution. The inclusion complexation between chiral analytes and cyclodextrins were also investigated by fluorescence method.     

Convenient synthesis of pi-acceptor chiral stationary phases for high-performance liquid chromatography from halogen-substituted 3,5-dinitrobenzoylamides

A convenient method for the "in column" synthesis of chiral stationary phases for high-performance liquid chromatography was elaborated. It involves preparation of chiral amides of 2-bromo- or 4-chloro-substituted 3,5-dinitrobenzoic acids followed by nucleophilic substitution of the halogen in the aromatic moiety with 3-aminopropyl groups of silanized silica gel at ambient temperature. A series of pi-donor compounds, such as amides and alkyl aryl carbinols, were chromatographed on the prepared chiral stationary phases. The results were compared with data reported for chiral separations of the same substrates on similar (R)-N-(3,5-dinitrobenzoyl)-alpha-phenylglycine-derived CSP. An example of indirect enantioseparation of racemic alpha-phenylethylamine was also described using (R)-2-(2-bromo-3,5-dinitrobenzoylamino)-2-phenylethanol as a chiral derivatizing reagent.     

联二萘酚衍生手性磷酸在亚胺不对称转移氢化反应中的应用研究进展

综述了BINOL衍生手性磷酸在亚胺不对称转移氢化反应中的应用研究进展。根据亚胺不对称转移氢化反应中三类不同的氢供体--Hantzsch酯类氢源、2-取代苯并噻唑啉类氢源及其他氢源,对BINOL衍生手性磷酸催化的亚胺不对称转移氢化反应进行了重点介绍。参考文献５３篇。     

Mesomorphic properties of troponoid esters and amides with cholest-5-ene-3β-carboxylic acid moiety

Troponoid esters and amides connected with cholest-5-ene-3β-carboxylic acid have been synthesized to characterize their mesomorphic properties and to compare them with those of the corresponding benzenoids. 5-Alkoxytroponyl esters and amides with a long alkoxy group exhibited a twist grain boundary A* phase, as well as chiral nematic and smectic A* (SmA*) phases. The corresponding benzenoid esters exhibit SmA* and blue phases and the benzenoid amides only a SmA* phase. The differences between the mesomorphic properties are discussed in terms of the structural features of the core.     

SmI(2)-promoted radical addition of nitrones to alpha,beta-unsaturated amides and esters: synthesis of gamma-amino acids via a nitrogen equivalent to the ketyl radical

[reaction: see text] Alkyl nitrones undergo radical addition reactions to a series of alpha,beta-unsaturated amides and esters when subjected to samarium diiodide via a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides access to a variety of functionalized gamma-amino acids. The methodology was extended to the asymmetric synthesis of 4-substituted gamma-amino acids, via the nitrone radical addition reaction to acrylates/amides possessing a chiral auxiliary.     

Stereochemistry of phenyl alpha-nitronyl nitroxide radicals

An extensive investigation of the conformations adopted by the family of phenyl alpha-nitronyl nitroxides has been carried out. A database containing 110 crystal structures was used in a statistical study of the solid-state geometries and conformations of these radicals. This study revealed that the favoured conformations involve a twisted distortion in the imidazolyl rings and a twist between the aromatic and heterocyclic rings in the molecules. As a consequence, these radicals show two types of preferred conformations in the solid state: the pseudo-anti enantiomeric pair and the pseudo-eclipsed pair, the latter type being the most statistically probable. A new chiral member of this group of radicals that bears a lactate moiety, (R)-1, and its corresponding racemic compound, (R,S)-1, have been prepared in order to study the influence of chiral induction from the stereogenic centre on the torsion angle between the aromatic and heterocyclic rings of the alpha-nitronyl nitroxides. The X-ray crystal structures of the enantiopure and racemic compounds, which both reveal chains of molecules sustained by strong O-H...O hydrogen bonds between the carboxylic acid group and the ON group of the radical in the solid, as well as their magnetic properties have been determined. Remarkably, the molecules with a given stereogenic centre have a single helical sense between their component rings, even in the racemic crystal. Chiral induction from the stereogenic centre to the radical unit has also been proved by CD spectroscopy in the solid state. The results of these experiments have been rationalised by ab initio calculations of the spectra.     

Circularly Polarized Luminescence of Aluminum Complexes for Chiral Sensing of Amino Acid and Amino Alcohol

Determination of the absolute configuration (AC) of chiral molecules is a key issue in many fields related to chirality such as drug development, the asymmetric reaction screening, and the structure determination of natural compounds. Although various methods, such as X‐ray crystallography and NMR spectroscopy, are used to determine the AC, a simple and cheap alternative method is always anticipated. So far, electronic circular dichroism (ECD) spectroscopy has been widely used to ascertain the AC and enantiomeric excess (ee) values by applying appropriate organic probes. Here, circularly polarized luminescence (CPL) spectroscopy was applied to determine the AC and ee values of a series of amino acid and amino alcohol. The measurements were conducted by mixing the amino acids or amino alcohols with an achiral 1‐hydroxy‐2‐naphthaldehyde. Upon in situ formation of the Schiff base complexes, the system showed emission enhancement and CPL in the presence of Al³⁺, whose intensity and sign can be used to assign the chiral sense of the amino acids and amino alcohols. The authenticity of the method was further compared with the established CD spectroscopy, revealing that CPL spectra of formed Al³⁺ complex were effective to determine the AC of chiral species.     

A study of chiral recognition for NBD-derivatives on a Pirkle-type chiral stationary phase.

A chiral stationary phase (CSP 1) derived from an (S)-N-3,5-dinitrobenzoyl-1-naphthylglycine showed excellent enantiomeric separation for amino acid derivatives with a fluorogenic reagent, 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), in high-performance liquid chromatography (HPLC). We compared elution profiles (separation factor and elution order) of NBD-amino acids and their analogs on HPLC, to determine the diastereomeric complex between the chiral moiety of CSP 1 and NBD-amino acid, which is responsible for the chiral recognition. (1)H-NMR studies of a mixture of model compound of CSP 1 and NBD-Ala suggest that the diastereomeric complex is composed of two hydrogen bonding sites at the amino proton and oxygen atom, and a pi-pi interaction by the benzofurazan structure (2,1,3-benzoxadiazole) of NBD-amino acid. Furthermore CSP 1 was able to separate esters, amides and alpha-methyl amino acids derivatized with NBD-F.     

Induction of a preferred sense of twist in flexible diphenyls by carbohydrate scaffolds. Synthesis of two "naked" ellagitannin analogous.

The synthesis of "naked" ellagitannin analogues 1 and 2, having a preferred sense of twist of the diphenyl moiety, with a rhamnose and a glucose template, is reported. A clear induction in the chirality of the diphenyl moiety, mediated through a 10-membered ring via ester linkages, was observed. The chiral scaffold of glucose (diequatorial 2,3-hydroxyl groups) exerts a remarkable stronger atropdiastereoselective effect onto the diphenoyl group than the rhamnose ring (axial-equatorial 2,3-hydroxyl groups), according to the Schmidt-Haslam hypothesis.     

Construction of anomalously bent biphenyl structure using conformational properties of calix[4]amide

C_2v-symmetrical cyclic tetramers of aromatic amides were simply synthesized in moderate yield by condensation reaction of N,N′-dimethyl-1,3-phenylenediamine and isophthalic acid derivatives using dichlorotriphenylphosphorane. The calix[4]amides exist in 1,3-alternate structure with cis conformation of tertiary aromatic amides, which were shown to be a versatile scaffold leading to a bowl-shaped macrocyclic compound possessing a anomalously strained structure, a bent hinge angle between two aromatic ring planes of biphenyl moiety, via an intramolecular ligation reaction.     

Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine

Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.