Unusual Disordered Crystal Structure of a Racemate Exhibiting a Novel Enantiomeric Resolution: Preferential Enrichment

Simple recrystallization of racemic (±)-NC leads to preferential enrichment of one enantiomer in the mother liquor, which allows the efficient resolution of the two enantiomers. In the unique disordered crystal structure of the racemate, the two enantiomers form centrosymmetric dimers as the major component.     

Homochiral oligopeptides generated by induced "mirror symmetry breaking" lattice-controlled polymerizations in racemic crystals of phenylalanine N-carboxyanhydride

The formation of diastereoisomeric libraries of oligopeptides through the heterogeneous polymerization of racemic crystals of phenylalanine N-carboxyanhydride (PheNCA) is reported. The diastereoisomeric compositions of the oligopeptides formed on polymerization of (R,S) crystals incorporating the deuterium-tagged S enantiomer were determined by MALDI-TOF mass spectrometry. The racemic mixtures of the oligopeptides longer than pentamers are represented primarily by diastereoisomers of homochiral sequence and with peptides containing only one heterochiral repeating unit. A mechanism comprising the following three sequential steps to account for this unusual observation is proposed: 1) formation of dimers and trimers at a partially damaged liquid/solid interface, 2) chain propagation that takes place within the bulk of the crystal through a lattice-controlled "zipper-like" mechanism between homochiral molecules arranged in a head-to-tail motif to yield crystalline antiparallel beta-sheets of alternating oligopeptide chains of homochiral sequence of opposite handedness, and 3) enantiomeric cross-inhibition that results in chain termination. Induced desymmetrization of the racemic mixtures of the formed peptides was achieved by the polymerization of the mixed quasi-racemic crystals of (R)-PheNCA, ((S)-PheNCA), and (S)-ThieNCA (3-(2-thienyl)-alanine N-carboxyanhydride) of various compositions. These experiments resulted in the formation of nonracemic libraries of oligopeptides composed of homochiral chains of (R)-Phe and copolymers of randomly distributed (S)-Phe and (S)-Thie sequences. From these findings, we propose a stochastic model for the generation of libraries of nonracemic mixtures of oligopeptides from the polymerization of host (R,S)-PheNCA with racemic mixtures of other guest NCA amino acids dissolved in limited quantities in the crystal.     

A New Convenient Method for the Resolution of 1, 1''''-Binaphthalene-2, 2''''-diol Via a Phosphite Using (-)-Menthol as Resolving Agent

Optically active 1,1-binaphthalene-2, 2-diol has become a quite important chiral source in different fields of chirotechnology, especially in asymmetric synthesis1. Its synthesis and resolution has been extensively studied and various resolution methods have been reported2. Among the reported resolution methods, the following three, namely, via the formation of phosphoric acid derivatives3, boric acid derivatives4 and inclusion complexes5, are the most important. OHOH+_( )-1(-)-(S)-1(+)-(R)…     

Discovery of a solid solution of enantiomers in a racemate-forming system by seeding

A racemic liquid of opposite enantiomers usually crystallizes as a racemic compound (racemate), rarely as a conglomerate, and even more rarely as a solid solution. We discovered a Type II solid solution (mixed crystal) of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (enantiomorphs). Without seeding, the racemic liquid crystallized as a racemic compound. The crystal structure of this solid solution resembles that of the enantiomorph but has static disorder arising from the random substitution of enantiomers. This solid solution is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate (by 4- to 40-fold between 80 and 146 degrees C). The free energy of the solid solution continuously varies with the enantiomeric composition between those of the conglomerate and the racemates. The existence of the TZF solid solution explains the absence of eutectic melting between crystals of different enantiomeric compositions. The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility. Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways. The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.     

Induction and inhibition of preferential enrichment by controlling the mode of the polymorphic transition with seed crystals

Both induction and inhibition of "preferential enrichment", an unusual symmetry-breaking enantiomeric-resolution phenomenon observed upon simple recrystallization of a certain kind of racemic crystals from organic solvents, have been successfully achieved by controlling the mode of the polymorphic transition during crystallization with appropriate seed crystals. Such control of the polymorphic transition can be interpreted in terms of a novel phenomenon consisting of 1) the adsorption of prenucleation aggregates, 2) the heterogeneous nucleation and crystal growth of a metastable crystalline form, and 3) the subsequent polymorphic transition into the more stable form; these three processes occur on the same surface of a seed crystal. We refer to this phenomenon as an "epitaxial transition", which has been confirmed by means of in situ attenuated total reflection (ATR) FTIR spectroscopy in solution and the solid state, differential scanning calorimetry (DSC) measurements of the deposited crystals, and X-ray crystallographic analysis of the single crystals or the direct-space approach employing the Monte Carlo method with the Rietveld refinement for the structure solution from the powder X-ray diffraction data.     

CONTINUOUS OPTICAL RESOLUTION OF (p-IODOPHENYL)GLYCINOL

ABSTRACT

Enantiomeric enrichment of racemic (p-iodophenyl)glycinol was achieved with various optically active organic acids. The scalemic mixtures were further resolved by entrainment with racemic crystals of the starting material. The pure enantiomers were recovered from the mother liquor; the crystalline—almost racemic—base was recycled.     

A Novel Mechanism of Preferential Enrichment Phenomenon Observed for the Cocrystal of (RS)-2-{4-[(4-Chlorophenoxy)methyl]phenoxy}propionic Acid and Isonicotinamide

A new entry of chiral anti-hyperlipoproteinemia drug is reported, showing an excellent preferential enrichment (PE) phenomenon which is not caused by a polymorphic transition during crystallization, but is proposed to occur by a novel mechanism involving partially irregular stacking of R and S homochiral two-dimensional (2D) sheets with a large dipole moment, followed by selective redissolution of one homochiral 2D sheet into the mother liquor during crystallization. The cocrystal composed of (RS)-2-{4-[(4-chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA) and achiral isonicotinamide exhibited a substantial enrichment in the mother liquor up to 93 % ee by simply repeating recrystallization under nonequilibrium conditions using high supersaturation. Furthermore, the deposited crystals with low ee values obtained at the end of PE experiment were second harmonic generation (SHG)-positive, indicating the formation of homochiral domains in the deposited crystals, which reflects the proposed mechanism of PE.     

Planar chiral dianthranilide and dithiodianthranilide molecules: optical resolution, chiroptical spectra, and molecular self-assembly

Planar chiral dianthranilide (1) was resolved to enantiomers with use of (-)-(1S,4R)-camphanoyl chloride as a chiral derivatizing agent. The (+)-1 enantiomer was assigned the S absolute configuration from the X-ray crystal structure of its N,N'-dicamphanoyl derivative. Optical resolution of dithionodianthranilide (2) was accomplished by inclusion crystallization with (R,R)-1,2-diaminocyclohexane, and the X-ray structure of the corresponding adduct revealed the (-)-2stereoisomer has the R configuration. A slow boat-to-boat ring inversion (DeltaG(++) = 24.1 +/- 0.1 kcal mol(-1)) causes racemization of (+)-1 in solution as manifested by a gradual decrease of the CD spectrum whereas, (-)-2 is configurationally stable at these conditions. The analysis of the CD spectra of the title compounds showed that the n-pi* Cotton effect signs are determined by the helicity of the skewed benzamide and thiobenzamide chromophores. The solid-state structures of the racemic and homochiral forms of 1 and 2 show different self-assembly patterns: the racemate (+/-)-1 prefers the cyclic R(2)(2)(8) hydrogen bond motif, whereas the crystalline DMSO solvates of (+/-)-1 and (+)-1 consist of 1D homochiral hydrogen-bonded assemblies generated by the C(6) motif. In the case of dithionolactams (+/-)-2 and (-)-2 two types of 1D networks were observed: in the racemate they are generated by the centrosymmetric R(2)(2)(8) and R(2)(2)(12) hydrogen bond motifs, whereas the molecules in the homochiral crystals are connected solely with use of the strongly nonplanar R(2)(2)(8) motif.     

Novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents

A novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents is described. The key step is the kinetic lipase-catalyzed resolution of racemic mixtures of substituted propargylic alcohols. The efficiency of this new approach was tested in the preparation of the corresponding enantiomers of 1,11-hexadecandiol derivatives ((R)-5 and (S)-5). Two strategies were tested. In the first one, the racemic intermediate 1-octyn-3-ol (1) was resolved enzymatically and then elongated with 1-bromo-9,11-dioxadodecane. Alternatively, the racemic 1 can be elongated to the corresponding racemic 17,19-dioxa-7-eicosyn-6-ol (3) first and then resolved biocatalytically. Twelve commercially available lipases were screened for the kinetic resolution of these intermediates. Among them, Candida antarctica lipase (CAL-B) and Humicola lanuginosa lipase (HLL) were the best biocatalysts for the resolution of 1 (S enantiomer 90% ee, E = 35), and 3 (R enantiomer 90% ee, E = 34), respectively.     

Optical Resolution of 2-(3-Chloro-phenyl)-3,4a,5,6,7,7a-hexahydro-cyclopentapyrimidin-4-one with O,O′-Dibenzoyl-2R,3R-tartaric Acid in Water-Chloroform Two Phase Solvent System

Optical resolution of racemic 2-(3-chloro-phenyl)-3.4a. 5.6.7.7a-hexahydrocyclopentapyrimidin-4-one with O.O′-dibenzoyl-2R,3R-tartaric acid in an unusual solvent combination, in water-chloroform two phase solvent system was accomplished. During enantiomeric enrichment of the resulted raw base the optically active base can be recovered from the ethanolic mother liquor.     

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone

The stereoselective acetylation of meso-2,2-dimethyl-1,3-cyclohexanediol by vinyl acetate in the presence of three lipases gave the (1R,3S)-monoester in high enantiomeric excess (ee > or = 98%). The hydrolysis of the corresponding meso-diacetate in the presence of Candida antarctica lipase in phosphate buffer provided the opposite enantiomer. Optically active monoacetates were converted to both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile chiral building block.     

Homochiral drug design and development by racemization

One of the enantiomers of a racemic drug may be pharmacologically inactive or toxic or ballast and, hence, U.S. FDA and European agencies have issued certain guidelines for marketing of optically active (homochiral) drugs. However, some homochiral drug enantiomers racemize in to human body leading to the generation of other antipodes, which may be toxic or ballast to the human beings. In addition, racemization reduces the administrated dosage concentration when the optically active enantiomer is converted into its inactive form. Therefore, racemization studies of homochiral drugs are the important and urgent need of today. This article reviews in vitro and in vivo racemization of homochiral drugs. The racemization of some homochiral drugs is described considering the affect of different variables such as temperature, concentration of the drug, ionic concentration, pH, addition of cyclodextrins, formation of inclusion complexes, etc. Efforts have also been made to discuss the mechanisms of the racemization process. Attempts have been made to suggest safe dosages of such drugs.     

Enantioselective crystallization of histidine on chiral self-assembled films of cysteine

In this paper, the preparation and use of chiral surfaces derived from enantiomerically pure crystals of amino acids are described. For this purpose, a self-assembly process to grow thin chiral films of (+)-L- or (-)-D-cysteine on gold surfaces was chosen. These chiral films were utilized as crystallization catalysts in the crystallization of enantiomers from solutions. To demonstrate the chiral discrimination power of the chiral surfaces in crystallization processes, the crystallization of racemic histidine onto the chiral films was investigated. Our study demonstrates the potential application of chiral films to control chirality throughout crystallization, where one enantiomer crystallizes onto the chiral surfaces with relative high enantiomeric excess. In addition, crystallization of pure histidine enantiomers onto chiral films results in strong crystal morphology modification with preferred orientation.     

Efficient crystallization-induced dynamic resolution of alpha-substituted carboxylic acids

Herein we present a novel route to enantiomerically enriched chiral alpha-substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR) of their diastereomeric salts with chiral amines. Thus, the racemic alpha-bromo acid 3 is converted reliably with (1R,2S)-2-amino-1,2-diphenylethanol in the presence of a catalytic amount of tetrabutylammonium bromide into its R-enantiomer 4 in 90% yield with 88% ee. Similarly, the racemic alpha-thiobenzoyl acid 5 could be resolved to 90% ee in 74% yield. Further enrichment to enantiomeric homogeneity could be achieved in both cases by crystallization. In a telescoped, two-step process, S-alpha-thiobenzoyl acid 6 (>or=99.6% ee) was prepared from the racemic bromide 3 in 63% yield. State-of-the-art parallel experimentation enabled rapid screening for suitable dynamic resolution conditions. Kinetic studies defined the influence of temperature, tetrabutylammonium bromide concentration, molarity, and solvent polarity on the resolution rate, product yield, and enantiomeric excess.     

Enantiomeric purity enrichment of (R)-tetrahydrothiophene-3-ol sulfonyl derivatives by crystallization

(R)-Tetrahydrothiophene-3-ol sulfonyl derivatives 3–19 were prepared by introduction of various sulfonyl groups at the hydroxyl group of (R)-tetrahydrothiophene-3-ol 1 with low enantiomeric purity (68–74% ee). Crystallization was applied to improve their enantiomeric purity. Improvement in enantiomeric purity depended on the introduced sulfonyl group. The enantiomeric purity of enantiomeric sulfonyl derivatives was improved to more than 90% ee by simple crystallization without using seed crystals. These products from crystallization provided not only higher %ee crystals but also a higher %ee mother liquor. The enantiomeric purity of diastereomeric sulfonyl derivatives was improved remarkably, and the product of the derivative 18 provided the mother liquor with 100% de. Crystallization of these sulfonyl derivatives showed a novel and interesting feature that mother liquors with high enantiomeric purity were obtained in many cases.     

Amplification of chirality as a pathway to biological homochirality

Amplification of enantiomeric enrichment is a key feature for the chemical evolution of biological homochirality from the origin of chirality. The aggregations of the enantiomers by diastereomeric interactions enable the modification of their enantiomeric excess during some chemical processes. Fluorine-containing chiral compounds possess large amplification effect via distillation, sublimation and achiral chromatography by self-disproportionation. Asymmetric amplifications in enantioselective catalysis occur by the differential formation and reactivity between homochiral and heterochiral aggregate in solution.We described the amplification of ee in asymmetric autocatalysis of 5-pyrimidyl alkanol in the reaction between diisopropylzinc and pyrimidine-5-carbaldehdye. During the reactions extremely low ee (ca. 0.00005% ee) can be amplified to achieve more than 99.5% ee. Since the proposed origins of chirality such as CPL, quartz, chiral organic crystals of achiral compounds and statistical fluctuation of ee can initiate the asymmetric autocatalysis with amplification of ee, the proposed origin of chirality can be linked with enantiopure organic compound in conjunction with amplification of ee by asymmetric autocatalysis. In addition, we described that the carbon isotopically chiral compound triggers the asymmetric autocatalysis of 5-pyrimiodyl alkanol to afford the enantioenriched product with the absolute configuration correlated with that of carbon isotope chirality, that is, isotope chirality including hydrogen isotopes can control the enantioselectivity of asymmetric addition of alkyl metal reagent to aldehyde.     

Chiral Amplification of Oligopeptides in the Polymerization of α‐Amino Acid N‐Carboxyanhydrides in Water

This article is concerned with the chiral amplification of oligopeptides formed in the polymerization of chiral, nonracemic mixtures of the N‐carboxyanhydride (NCA) of Leu and Glu in aqueous solution. Labeling (deuteration) of one enantiomer and reversed‐phase and normal‐phase high‐performance liquid chromatography mass spectrometry (RP‐ and NP‐HPLC/MS, respectively) were used to determine the product distribution, both with respect to oligopeptide chain length and stereoisomer distribution. Starting the polymerization with an enantiomeric excess (ee) of 20% of the L ‐enantiomer (L ‐amino acid/D ‐amino acid 6 : 4) leads to an ee of 73% at the level of the homochiral enantiomeric (Leu)₅, and of 71% at the level of the homochiral enantiomeric (Glu)₇. For the Leu system and in the presence of a solid support (quartz), the ee reached values of up to 100%. We argue that such amplification processes could be relevant for the chemical evolution towards single‐handedness.     

Stereoelective polymerization of tert-butyl thiirane

The polymerization in bulk of racemic tert-butyl thiirane with a chiral initiator resulting from the reaction between diethylzinc and (? )3,3-dimethyl-1,2-butanediol produces an optically active polymer by preferential consumption of R enantiomer. The unreacted monomer is enriched in S enantiomer. The relative rate r of consumption of R enantiomer versus S enantiomer is as high as 2.8. Obtained polymer could be separated into two crystalline fractions: an optically active fraction, formed from regular sequences of R type enantiomeric units, and an optically inactive fraction which corresponds to a racemate. Experimental results are consistent with a stereospecific mechanism of addition, the two enantiomers being chosen by two different type of sites. The stereoelective process is due to an unequal number of these two types of sites.     

Heterocomplexation of a chiral dipeptide and quantitative enantiomeric enrichment of nonracemic 1,1'-bi-2-naphthol

Heterocomplexation of a chiral host to a racemic guest has been discovered. A cyclic dipeptide generated from (S)-proline alkyl ester undergoes an achiroselective complexation to both the enantiomers of racemic BINOL in benzene to yield a crystalline heterocomplex bearing the solvent molecules. However, complexation crystallization does not occur between the diptide and either enantiomer of BINOL under similar conditions. The difference in complexation behavior has been successfully applied in the enantiomeric enrichment of nonracemic BINOLs, and almost quantitative separation of the excess enantiomer from racemic BINOL was achieved.     

Structures formed by the chiral assembly of racemic mixtures of enantiomers: iodination products of elaidic and oleic acids

The self-assembled monolayer structure of the products of elaidic acid iodination (the racemic mixture of 9,10-(9S,10R)-diiodooctadecanoic acid and 9,10-(9R,10S)-diiodooctadecanoic acid) and the products of oleic acid iodination (the racemic mixture of 9,10-(9R,10R)-diiodooctadecanoic acid and 9,10-(9S,10S)-diiodooctadecanoic acid) are studied by high-resolution scanning tunneling microscopy. For the iodination products of elaidic acid, the separation of enantiomers into distinct chiral domains during the formation of the 2-D crystal on the highly ordered pyrolytic graphite (HOPG) surface is not observed. Instead, within the diiodooctadecanoic acid SAM, each row of molecules is composed of opposite racemates. The two opposite racemates pack alternately inside a row, using different faces to adsorb on the surface. The unit cell is composed of a pair of opposite racemates, forming a heterochiral structure. For the iodination products of oleic acid, the racemic mixture is observed to exhibit quasi-phase separation during the formation of the 2-D crystal on the HOPG surface. Each row is composed of homochiral acid molecules, either the 9,10-(9R,10R)-diiodooctadecanoic acid (R) or the 9,10-(9S,10S)-diiodooctadecanoic acid (S). The R row and the S row pack alternately, with a unit cell composed of four molecules. Two of the molecules in the unit cell are the 9,10-(9R,10R)-diiodooctadecanoic acid (R) molecules; two are the 9,10-(9S,10S)-diiodooctadecanoic acid (S) molecules. In the unit cell, the two molecules that have the same chirality pack antiparallel inside the homochiral row, using different faces to adsorb on the surface. These results suggest that several different types of chiral assembly are possible. Enantiomers with opposite chirality exhibit many chiral assembly patterns, forming heterochiral structures on the surface in addition to separation to form macroscopic chiral domains. By using different conformations, similar enantiomers with opposite chirality will display many chiral assembly patterns to form heterochiral structures on the surface.