Rapid deracemization through solvent cycling: proof-of-concept using a racemizable conglomerate clopidogrel precursor.

We demonstrate that a conglomerate-forming clopidogrel precursor undergoing solution phase racemization can be deracemized through cyclic solvent removal and re-addition. We establish that the combination of slow growth and fast dissolution of crystals is ideal for rapid deracemization, which we achieve by repurposing a Soxhlet apparatus to realize the slow removal and fast re-addition of solvent autonomously.

Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth.

Amplification of enantiomeric excesses (ee) is routinely observed during chiral crystallization of conglomerate crystals for which the enantiomers undergo racemization in solution. Although routes comprising a combination of crystal growth and dissolution are frequently used to obtain enantiopure molecules, crystal growth by itself has rather been considered as a source of enantiomeric erosion and discounted as a potential source of enantiomeric amplification. Counterintuitively, we here demonstrate striking enantiomeric amplification during crystal growth for clopidogrel and tert-leucine precursors. Based on a mechanistic framework, we identify that the interplay between racemization and crystal growth rates elicits this surprising effect. The asymmetric amplification of the solid-phase ee can be enhanced by increasing the mass of grown material relative to the product such that small amounts of seeds of only 60% ee already result in virtually exclusive growth of the majority phase. These results impact our understanding of asymmetric amplification mechanisms during crystallization and offer a tangible basis for practical production of enantiopure molecules.

Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions.

An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 °C, whereas deracemization is achieved by alternating crystal growth/dissolution steps with temperature cycling between 5-15 °C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.

Enantiospecific Solid Solution Formation Triggers the Propagation of Homochirality.

Propagation of homochirality plays a crucial role in the discussion on the origin of life. We investigated the role of structurally related enantiopure additives in chiral symmetry breaking during reactive crystallizations. We demonstrate that symmetry breaking can be driven towards the same absolute configuration as the additive if this additive forms an enantiospecific solid solution with the racemate. We observe two antagonistic processes: enantiospecific growth inhibition directs symmetry breaking to the opposite enantiomer following "the rule of reversal", and enantiospecific solid solution formation that favors homochiral outcome. During continuous grinding, contributions of solid solution formation override contributions of enantiospecific growth inhibition, directing the process towards the absolute configuration of the additive. Collectively, our findings offer a potential mechanism for the propagation of homochirality.

A chiral switch: balancing between equilibrium and non-equilibrium states.

Herein we introduce a "chiral switch" - a sequence of operations that alternate between equilibrium and non-equilibrium conditions to switch the absolute configuration of a chiral center. The generality and practical potential of the technique are demonstrated with three unnatural α-amino acid precursors.

A Viedma ripening route to an enantiopure building block for Levetiracetam and Brivaracetam.

A simple route to enantiomerically pure (S)-2-aminobutyramide - the chiral component of the anti-epileptic drugs Levetiracetam and Brivaracetam has been developed. This approach is based on the rational design and application of a Viedma ripening process. The practical potential of the process is demonstrated on a large scale.

The Strecker reaction coupled to Viedma ripening: a simple route to highly hindered enantiomerically pure amino acids.

The Strecker reaction is broadly used for the preparation of α-amino acids. However, control of enantioselectivity remains challenging. We here couple the Strecker reaction to Viedma ripening for the absolute asymmetric synthesis of highly sterically hindered α-amino acids. As proof-of-principle, the enantiomerically pure α-amino acids tert-leucine and α-(1-adamantyl)glycine were obtained.

Shape-preserving transformation of carbonate minerals into lead halide perovskite semiconductors based on ion exchange/insertion reactions.

Biological and bio-inspired mineralization processes yield a variety of three-dimensional structures with relevance for fields such as photonics, electronics and photovoltaics. However, these processes are only compatible with specific material compositions, often carbonate salts, thereby hampering widespread applications. Here we present a strategy to convert a wide range of metal carbonate structures into lead halide perovskite semiconductors with tunable bandgaps, while preserving the 3D shape. First, we introduce lead ions by cation exchange. Second, we use carbonate as a leaving group, facilitating anion exchange with halide, which is followed rapidly by methylammonium insertion to form the perovskite. As proof of principle, pre-programmed carbonate salt shapes such as vases, coral-like forms and helices are transformed into perovskites while preserving the morphology and crystallinity of the initial micro-architectures. This approach also readily converts calcium carbonate biominerals into semiconductors, furnishing biological and programmable synthetic shapes with the performance of artificial compositions such as perovskite-based semiconductors.

Difluorenyl carbo-Benzenes: Synthesis, Electronic Structure, and Two-Photon Absorption Properties of Hydrocarbon Quadrupolar Chromophores.

The synthesis, crystal and electronic structures, and one- and two-photon absorption properties of two quadrupolar fluorenyl-substituted tetraphenyl carbo-benzenes are described. These all-hydrocarbon chromophores, differing in the nature of the linkers between the fluorenyl substituents and the carbo-benzene core (C-C bonds for 3 a, C-C=C-C expanders for 3 b), exhibit quasi-superimposable one-photon absorption (1PA) spectra but different two-photon absorption (2PA) cross-sections σ2PA. Z-scan measurements (under NIR femtosecond excitation) indeed showed that the C≡C expansion results in an approximately twofold increase in the σ2PA value, from 336 to 656 GM (1 GM = 10(-50) cm(4) s molecule(-1) photon(-1)) at λ = 800 nm. The first excited states of Au and Ag symmetry accounting for 1PA and 2PA, respectively, were calculated at the TDDFT level of theory and used for sum-over-state estimations of σ2PA(λi), in which λi = 2 hc/Ei, h is Planck's constant, c is the speed of light, and Ei is the energy of the 2PA-allowed transition. The calculated σ2PA values of 227 GM at 687 nm for 3 a and 349 GM at 708 nm for 3 b are in agreement with the Z-scan results.

Carbo-cyclohexadienes vs. carbo-benzenes: structure and conjugative properties.

Ideally Cs-/C2v-symmetric chromophores, constituted by two electro-active groups conjugated through the carbo-mer of the cyclohexa-1,3-diene core, are selectively prepared by the SnCl2-mediated reduction of tailored hexaoxy-[6]pericyclynes: in the latter substrates, one of the 1,4-dioxybut-2-yne edges is "chemically locked" by two CF3 substituents preventing complete reduction to the corresponding aromatic carbo-benzenic core, which is expected to be more "π-insulating" between the electro-active ends. The bis-trifluoromethylated carbo-cyclohexadiene products are also shown to be significantly stabilized with respect to their bis-phenylated analogues. Their structural (crystal X-ray diffraction analyses), spectroscopical (NMR and UV-vis spectra), physio-optical (dichromism in solution) and electrochemical (cyclic voltammograms) properties are compared on the basis of the electron-donating/electron-withdrawing nature of the substituents. These properties are also compared with those of their aromatic carbo-benzene and flexible carbo-n-butadiene counterparts.

Enhanced π-frustration in carbo-benzenic chromophores.

The synthesis, structure, and absorption spectra of highly π-frustrated carbo-benzenes with indolic enamine substituents more or less directly conjugated to the C18 macro-aromatic core are described, and their peculiar reactivity is analyzed.

1-Ethyl-2-phenyl-3-[2-(tri-methyl-sil-yl)ethyn-yl]-1H-indole.

The title compound, C21H23NSi, was synthesized by Sonogashira-type reaction of 1-ethyl-3-iodo-2-phenyl-1H-indole with tri-methyl-silyl-acetyl-ene. The indole ring system is nearly planar [maximum atomic deviation = 0.0244 (15) Å] and is oriented at a dihedral angle of 51.48 (4)° with respect to the phenyl ring. The supramolecular aggregation is completed by weak C-H⋯π inter-actions of the methylene and phenyl groups with the benzene and pyrrole rings of the indole ring system. The methyl groups of the tri-methyl-silyl unit are equally disordered over two sets of sites.

Highly π electron-rich macro-aromatics: bis(p-aminophenyl)-carbo-benzenes and their DBA acyclic references.

A series of stable quadrupolar bis(p-aminophenyl)-carbo-benzenes, featuring both donor-donor-donor π-frustration and central macro-aromaticity, is described and compared to the acyclic dibutatrienylacetylene (DBA) reference series.