Stereoselective Crystallization of Chiral Pharmaceuticals Aided by Cellulose Derivatives through Helical Pattern Matching.

Stereoselective inhibition aided by "tailor-made" polymeric additives is an efficient approach to obtain enantiopure compounds through conglomerate crystallization. The chemical and configurational match between the side groups of polymers and the molecules of undesired enantiomer is considered to be a necessary condition for successful stereoseparation. Whereas in this contribution, we present an effective resolution of chiral pharmaceuticals by using cellulose acetates as the additives, which stereoselectively reside on the specific crystal faces of one enantiomer and inhibit its crystal nucleation and growth through helical pattern and supramolecular interaction complementarity. An investigation of nimodipine serves as a case study to highlight the novelty of this strategy wherein R-crystals exhibiting an impressive enantiomeric excess value of 97% can be attained by employing a mere 0.01 wt% cellulose acetate. Guaifenesin and phenyl lactic acid are also well-resolved by utilizing this methodology. Our work not only brings about a brand-new design strategy for "tailor-made" additives, but will also promote the further exploration of the endless potential for utilizing natural biomolecules in chiral recognition and resolution.

Tuning organic crystal chirality by the molar masses of tailored polymeric additives.

Hierarchically ordered chiral crystals have attracted intense research efforts for their huge potential in optical devices, asymmetric catalysis and pharmaceutical crystal engineering. Major barriers to the application have been the use of costly enantiomerically pure building blocks and the difficulty in precise control of chirality transfer from molecular to macroscopic level. Herein, we describe a strategy that offers not only the preferred formation of one enantiomorph from racemic solution but also the subsequent enantiomer-specific oriented attachment of this enantiomorph by balancing stereoselective and non-stereoselective interactions. It is demonstrated by on-demand switching the sign of fan-shaped crystal aggregates and the configuration of their components only by changing the molar mass of tailored polymeric additives. Owing to the simplicity and wide scope of application, this methodology opens an immediate opportunity for facile and efficient fabrication of one-handed macroscopic aggregates of homochiral organic crystals from racemic starting materials.

Noncovalently Functionalized Commodity Polymers as Tailor-Made Additives for Stereoselective Crystallization.

Stereoselective inhibition of the nucleation and crystal growth of one enantiomer aided by "tailor-made" polymeric additives is an efficient method to obtain enantiopure compounds. However, the conventional preparation of polymeric additives from chiral monomers are laborious and limited in structures, which impedes their rapid optimization and applicability. Herein, we report a "plug-and-play" strategy to facilitate synthesis by using commercially available achiral polymers as the platform to attach various chiral small molecules as the recognition side-chains through non-covalent interactions. A library of supramolecular polymers made up of two vinyl polymers and six small molecules were applied with seeds in the selective crystallization of seven racemates in different solvents. They showed good to excellent stereoselectivity in yielding crystals with high enantiomeric purities in conglomerates and racemic compound forming systems. This convenient, low-cost modular synthesis strategy of polymeric additives will allow for high-efficient, economical resolution of various racemates on different scales.

Enantiomer-selective magnetization of conglomerates for quantitative chiral separation.

Selective crystallization represents one of the most economical and convenient methods to provide large-scale optically pure chiral compounds. Although significant development has been achieved since Pasteur's separation of sodium ammonium tartrate in 1848, this method is still fundamentally low efficient (low transformation ratio or high labor). Herein, we describe an enantiomer-selective-magnetization strategy for quantitatively separating the crystals of conglomerates by using a kind of magnetic nano-splitters. These nano-splitters would be selectively wrapped into the S-crystals, leading to the formation of the crystals with different physical properties from that of R-crystals. As a result of efficient separation under magnetic field, high purity chiral compounds (99.2 ee% for R-crystals, 95.0 ee% for S-crystals) can be obtained in a simple one-step crystallization process with a high separation yield (95.1%). Moreover, the nano-splitters show expandability and excellent recyclability. We foresee their great potential in developing chiral separation methods used on different scales.

Self-Reporting Inhibitors: A Single Crystallization Process To Obtain Two Optically Pure Enantiomers.

Collection of two optically pure enantiomers in a single crystallization process can significantly increase the chiral separation efficiency but this is difficult to realize. Now a self-reporting strategy is presented for visualizing the crystallization process by a dyed self-assembled inhibitor made from the copolymers with tri(ethylene glycol)-grafting polymethylsiloxane as the main chain and poly(N6 -methacryloyl-l-lysine) as side chains. When applied with seeds together for the fractional crystallization of conglomerates, the inhibitors can label the formation of the secondary crystals and guide the complete separation process of two enantiomers with colorless crystals as the first product and red crystals as the second. This method leads to high optical purity of d/l-Asn⋅H2 O (99.9 % ee for d-crystals and 99.5 % for l-crystals) in a single crystallization process. It requires a small amount of additives and shows excellent recyclability.

Thermo-responsive recoverable polymeric inhibitors for the resolution of racemic amino acids.

Novel polymeric inhibitors with lower critical solution temperatures in water were prepared and used to mediate the crystallization of racemic asparagine monohydrate, leading to chiral separation with 88.6 ee%. They could be recollected by simply elevating the temperature with a high yield of around 95% and reused without compromising the stereoselectivity and stability.

A Star-Shaped Molecule with Low-Lying Lowest Unoccupied Molecular Orbital Level, n-Type Panchromatic Electrochromism, and Long-Term Stability.

An electron-deficient star-shaped molecule based on anthraquinone imide was synthesized and characterized. It showed high electron accommodating capacity and strong electron-withdrawing ability with a low-lying lowest unoccupied molecular orbital (LUMO) of -4.10 eV. In addition, it exhibited panchromatic electrochromism attributed to the simultaneous presence of π*-π* transitions and intervalence charge transfer (IV-CT) upon one-electron reduction, and revealed long-term stability in electron gain and loss due to the proper LUMO energy level and ordered intermolecular assembly.

Planar-to-Axial Chirality Transfer in the Polymerization of Phenylacetylenes.

A pair of enantiomerically pure planar chiral phenylacetylenes, R- and S-2'-ethynyl-1,10-dioxa[10]-paracyclophane, were prepared and polymerized under the catalysis of Rh(nbd)BPh4 and MoCl5, respectively. The resultant polymers had high cis-structure contents and took dominant cis-transoid helical conformations with an excess screw sense as revealed by 1H NMR, Raman, polarimetry, circular dichroism spectroscopy, and computational simulation, manifesting the effective guidance of the planar chirality of monomers to the growth of the polymer main chains. The rigid ansa-structure of monomer unit made the helical structure of polymer backbone stable toward grinding and thermal treatments. The stereoselective interactions between these chiral polymers and the enantiomers of racemic ethynyl-1,10-dioxa[10]-paracyclophane and cobalt(III) acetylacetonate were observed. This work demonstrated the first planar-to-axial chirality transfer in the polymerization of acetylenes and offered a new strategy to prepare chiral materials based on optically active helical polymers.

Electrochromism of a fused acceptor-donor-acceptor triad covering entire UV-vis and near-infrared regions.

A novel fused acceptor-donor-acceptor (A-D-A) type panchromatically electrochromic compound was synthesized. It exhibited intensive absorption bands covering entire UV-vis and near-infrared regions upon reduction to the radical anionic state, owing to the simultaneous presence of π*-π* transitions and intervalence charge transfer.