Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals

Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities

Automatic generation of 3D-printed reactionware for chemical synthesis digitization using ChemSCAD

We describe a system, ChemSCAD, for the creation of digital reactors based on the chemical operations, physical parameters, and synthetic sequence to produce a given target compound, to show that the system can translate the gram-scale batch synthesis of the antiviral compound Ribavirin (yield 43% over three steps), the narcolepsy drug Modafinil (yield 60% over three steps), and both batch and flow instances of the synthesis of the anticancer agent Lomustine (batch yield 65% over two steps) in purities greater than or equal to 96%. The syntheses of compounds developed using the ChemSCAD system, including reactor designs and analytical data, can be stored in a database repository, with the information necessary to critically evaluate and improve upon reactionware syntheses being easily shared and versioned

Digitizing Poly‑l‑lysine Dendrigrafts: From Experimental Data to Molecular Dynamics Simulations

Despite the growing use of poly-l-lysine dendrigrafts in biomedical applications, a deeper understanding of the molecular level properties of these macromolecules is missing. Herein, we report a simple methodology for the construction of three-dimensional structures of poly-l-lysine dendrigrafts and the subsequent investigation of their structural features using microsecond molecular dynamics simulations. This methodology relies on the encoding of the polymers’ experimental characterizations (i.e., composition, degrees of polymerization, branching ratios, charges) into alphanumeric strings that are readable by the Amber simulation package. Such an original approach opens avenues toward the in silico exploration of dendrigrafts and hyperbranched polymers

Multi-Technique Characterization of Poly-L-lysine Dendrigrafts-Cu(II) Complexes for Biocatalysis

Poly-L-lysine is a biocompatible polymer used for drug or gene delivery, for transport through cellular membranes, and as nanosized magnetic resonance imaging contrast agents. Cu(II)-poly-L-lysine complexes are of particular interest for their role in biocatalysis. In this study, poly-L-lysine dendrigrafts (DGLs) at different generations (G2, G3, and G4) are synthesized and characterized in absence and presence of Cu(II) by means of electron paramagnetic resonance (EPR), UV-Vis, potentiometric titration and circular dichroism (CD). The analysis is performed as a function of the [Cu(II)]/[Lys] (=R) molar ratio, pH and generation by identifying differently flexible complexes in different dendrimer regions. The amine sites in the lateral chains become increasingly involved with the increase of pH. The good agreement and complementarity of the results from the different techniques provide an integrate view of the structural and dynamic properties of Cu(II)-DGL complexes implementing their use as biocatalysts

Automatic Generation of 3D Printed Reactionware for Chemical Synthesis Digitization using ChemSCAD

Digital chemistry aims to define a hard link from the top abstraction layer in chemistry down to the synthesis, but this is difficult in traditional glassware since it is not possible to explicitly link the architecture with the unit operations. By 3D printing the synthesis modules in the precise order to affect the synthesis, it is possible to create digitally encoded reactors for chemical synthesis in ‘reactionware’. However, creation of these devices requires a specific skillset for CAD modelling which few synthetic chemists have. Herein, we describe an intuitive system, ChemSCAD, for the creation of digital reactor models based on the chemical operations, physical parameters and synthetic sequence to produce a given target compound. We demonstrate the ability of the ChemSCAD system to translate the gram-scale batch synthesis of the anti-viral compound Ribavirin (yield 43% over three steps), the narcolepsy drug Modafinil (yield 60% over three steps), and both batch and flow instances of the synthesis of the anti-cancer agent Lomustine (batch yield 65% over two steps) in purities ≥96%. The syntheses of compounds developed using the ChemSCAD system, including reactor designs and analytical data, can be stored in a single database repository where all the information necessary to critically evaluate, and improve upon, reactionware syntheses can be easily shared and versioned.</p

A Double Conformationally Restricted Dynamic Supramolecular System for the Substrate-Selective Epoxidation of Olefins-A Comparative Study on the Influence of Preorganization

A double conformationally restricted kinetically labile supramolecular catalytic system, the third generation, was designed and synthesized. We investigated the substrate selectivity of this system by performing competitive pairwise epoxidations of pyridyl-and phenyl-appended olefins. We compared the obtained substrate selectivities to previous less preorganized generations of this system. Five different substrate pairs were investigated, and the present double conformationally restricted system showed higher normalized substrate selectivities ( pyridyl versus phenyl) for two of the substrate pairs than the previous less conformationally restricted generations. As for the preorganization of the components of the system, the catalyst, and the receptor part, it was shown that for each substrate pair there was one generation that was better than the other to generate substrate-selective catalysis