Andreas Kirschning

Functionalized Polymers-Emerging Versatile Tools for Solution-Phase Chemistry and Automated Parallel Synthesis.

As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, industry searches for new technologies that allow for the automation of synthetic processes. Since the pioneering work by Merrifield polymeric supports have been identified to play a key role in this field however, polymer-assisted solution-phase synthesis which utilizes immobilized reagents and catalysts has only recently begun to flourish. Polymer-assisted solution-phase synthesis has various advantages over conventional solution-phase chemistry, such as the ease of separation of the supported species from a reaction mixture by filtration and washing, the opportunity to use an excess of the reagent to force the reaction to completion without causing workup problems, and the adaptability to continuous-flow processes. Various strategies for employing functionalized polymers stoichiometrically have been developed. Apart from reagents that are covalently or ionically attached to the polymeric backbone and which are released into solution in the presence of a suitable substrate, scavenger reagents play an increasingly important role in purifying reaction mixtures. Employing functionalized polymers in solution-phase synthesis has been shown to be extremely useful in automated parallel synthesis and multistep sequences. So far, compound libraries containing as many as 88 members have been generated by using several polymer-bound reagents one after another. Furthermore, it has been demonstrated that complex natural products like the alkaloids (+/-)-oxomaritidine and (+/-)-epimaritidine can be prepared by a sequence of five and six consecutive polymer-assisted steps, respectively, and the potent analgesic compound (+/-)-epibatidine in twelve linear steps ten of which are based on functionalized polymers. These developments reveal the great future prospects of polymer-assisted solution-phase synthesis.

Inductive Heating for Organic Synthesis by Using Functionalized Magnetic Nanoparticles Inside Microreactors

Interest in magnetic nanoparticles has increased considerably lately, with diverse applications as magnetic liquids, in catalysis, in biotechnology and biomedicine, and in magnetic resonance spectroscopy. A principal problem associated with naked metallic nanoparticles is their high chemical reactivity, in particular oxidation by air. This drawback can be overcome by coating the nanoparticles with SiO2, metal oxides, gold, or carbon. Several applications of these nanoparticles for quasi-homogeneous catalysis have been disclosed. These particles are typically removed after the reaction by exploiting their magnetic properties. An unexploited and very important feature of magnetic materials is the possibility of heating them in an electromagnetic field. It has been demonstrated that isolated magnetic nanoparticles show magnetic behavior different from that in the bulk. These magnetic nanoparticles when coated with a silica shell can show superparamagnetic behavior. The silica coating prevents the magnetic cores from coupling, thereby preserving their superparamagnetic properties. These composites do not have a residual magnetization and their magnetization curves are anhysteretic. However, the susceptibility of a superparamagnetic material is almost as high as that of a ferromagnetic material. The concept of magnetically induced hyperthermia is based on specific properties of the magnetic nanoparticles upon exposure to a constantly changing magnetic field. Surprisingly, this property of magnetic nanoparticles has so far not been applied in chemical synthesis, although organic chemists are constantly testing new technologies such as microwave irradiation, solid-phase synthesis, and new reactor designs in their work with the goal of performing syntheses and workups more efficiently. Herein we disclose the first application of heating magnetic silica-coated nanoparticles in an electromagnetic field. We demonstrate that these hot particles can be ideally used inside a microfluidic fixed-bed reactor for performing chemical syntheses including catalytic transformations. Thus, besides conventional and microwave heating, magnetic induction in an electromagnetic field is a third way to introduce thermal energy to a reactor. Superparamagnetic materials like nanoparticles 1 can be heated in mediumor high-frequency fields. As the technical setup for the middle-frequency field (25 kHz) is simpler (see Figure 1b,c), we investigated the electromagnetic induction of heat in magnetic nanoparticles in this frequency range. In principal, the processes can be operated in a cyclic or a continuous mode. The inductor can accommodate a flowthrough reactor (glass; 14 cm length, 9 mm internal diameter), which is filled with superparamagnetic material 1. The reactor can be operated up to a backup

Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogels for myocardial tissue engineering

Despite recent major advances including reprogramming and directed cardiac differentiation of human cells, therapeutic application of in vitro engineered myocardial tissue is still not feasible due to the inability to construct functional large vascularized contractile tissue patches based on clinically applicable and fully defined matrix components. Typical matrices with preformed porous 3D structure cannot be applied due to the obvious lack of migratory capacity of cardiomyocytes (CM). We have therefore developed a fully defined in situ hydrogelation system based on alginate (Alg) and hyaluronic acid (HyA), in which their aldehyde and hydrazide-derivatives enable covalent hydrazone cross-linking of polysaccharides in the presence of viable myocytes. By varying degrees of derivatization, concentrations and composition of blends in a modular system, mechanophysical properties of the resulting hydrogels are easily adjustable. The hydrogel allowed for the generation of contractile bioartificial cardiac tissue from CM-enriched neonatal rat heart cells, which resembles native myocardium. A combination of HyA and highly purified human collagen I led to significantly increased active contraction force compared to collagen, only. Therefore, our in situ cross-linking hydrogels represent a valuable toolbox for the fine-tuning of engineered cardiac tissues mechanical properties and improved functionality, facilitating clinical translation toward therapeutic heart muscle reconstruction.

A green catalyst for green chemistry: Synthesis and application of an olefin metathesis catalyst bearing a quaternary ammonium group

The novel catalyst 8, bearing a polar quaternary ammonium group, is very stable and can be easily prepared from commercially available reagents. Catalyst 8 can be efficiently used for olefin metathesis not only in traditional but also in aqueous media. Various ring closing-, cross- and enyne-metathesis reactions were conducted in water–methanol mixtures in air. The electron withdrawing quaternary ammonium group not only activates the catalyst chemically, but at the same time allows its efficient separation after reaction. Application of 8 leads to organic products of high purity, which exhibit very low ruthenium contamination levels (12–68 ppm) after filtering through a pad of silica gel.

Inductive Heating with Magnetic Materials inside Flow Reactors

Superparamagnetic nanoparticles coated with silica gel or alternatively steel beads are new fixed-bed materials for flow reactors that efficiently heat reaction mixtures in an inductive field under flow conditions. The scope and limitations of these novel heating materials are investigated in comparison with conventional and microwave heating. The results suggest that inductive heating can be compared to microwave heating with respect to rate acceleration. It is also demonstrated that a very large diversity of different reactions can be performed under flow conditions by using inductively heated flow reactors. These include transfer hydrogenations, heterocyclic condensations, pericyclic reactions, organometallic reactions, multicomponent reactions, reductive cyclizations, homogeneous and heterogeneous transition-metal catalysis. Silica-coated iron oxide nanoparticles are stable under many chemical conditions and the silica shell could be utilized for further functionalization with Pd nanoparticles, rendering catalytically active heatable iron oxide particles.

Hypervalent Iodine and Carbohydrates – A New Liaison

Synthetic applications of hypervalent iodine reagents in the oxidation state +3 in relation to unsaturated carbohydrates are reviewed. By using the Koser reagent or its bis(azido) derivative, fully protected glycals are oxidatively deblocked in the allylic position. The reaction furnishes carbohydrate-derived 2,3-dihydro-4H-pyranones, which serve as starting materials for the preparation of C-saccharides, glycosyl stannanes or thromboxane A2-analogues. Alternatively, iodine(III) reagents can be used to oxidize halide anions. The halogen-ate complexes thus generated behave like synthetic equivalents of acyl hypobromite and iodite, respectively, or halogen azides, which can all add to alkenes, including glycals, under very mild conditions.

PASSflow Syntheses Using Functionalized Monolithic Polymer/Glass Composites in Flow‐Through Microreactors

: A chemistapos;s wish finally becomes reality: microreactors for every synthetic laboratory! By precipitation polymerization various polymers are introduced into the irregular pore system of a porous glass rod. By embedding these rods into a housing, followed by functionalization and immobilization of reagents onto the polymer phase, versatile microreactors are obtained. With this apparatus, chemical transformations in solution can be performed, for example, a steroid derivatization.

Total synthesis approaches to natural product derivatives based on the combination of chemical synthesis and metabolic engineering

Secondary metabolites are an extremely diverse and important group of natural products with industrial and biomedical implications. Advances in metabolic engineering of both native and heterologous secondary metabolite producing organisms have allowed the directed synthesis of desired novel products by exploiting their biosynthetic potentials. Metabolic engineering utilises knowledge of cellular metabolism to alter biosynthetic pathways. An important technique that combines chemical synthesis with metabolic engineering is mutasynthesis (mutational biosynthesis; MBS), which advanced from precursor-directed biosynthesis (PDB). Both techniques are based on the cellular uptake of modified biosynthetic intermediates and their incorporation into complex secondary metabolites. Mutasynthesis utilises genetically engineered organisms in conjunction with feeding of chemically modified intermediates. From a synthetic chemists point of view the concept of mutasynthesis is highly attractive, as the method combines chemical expertise with Natures synthetic machinery and thus can be exploited to rapidly create small libraries of secondary metabolites. However, in each case, the method has to be critically compared with semi- and total synthesis in terms of practicability and efficiency. Recent developments in metabolic engineering promise to further broaden the scope of outsourcing chemically demanding steps to biological systems.

Molecular Basis of Elansolid Biosynthesis: Evidence for an Unprecedented Quinone Methide Initiated Intramolecular Diels–Alder Cycloaddition/Macrolactonization

Elansolids A1/A2 (1) and B1–B3 (2–4) and the structurally unusual and highly reactive elansolid A3 (5) are new metabolites from the gliding bacterium Chitinophaga sancti (formerly Flexibacter spec. ; Scheme 1). While elansolid A2 (1*) shows antibiotic activity against Gram-positive bacteria in the range of 0.2 to 64 mgmL 1 and cytotoxicity against L929 mouse fibroblast cells with an IC50 value of 12 mgmL , the atropisomer elansolid A1 (1) is significantly less active. 3] The elansolids feature a bicyclo[4.3.0]nonane core which in the case of elansolids A1/A2 is part of a 19-membered macrolactone. Elansolid B1 is the corresponding seco acid of elansolids A1/A2, while the elansolids B2 and B3 are workup artifacts that result from nucleophilic addition of methanol and NH3, respectively, to

Applications of Immobilized Catalysts in Continuous Flow Processes

As part of the dramatic changes associated with automation in pharmaceutical and agrochemical research laboratories, the search for new technologies has become a major topic in the chemical community. Commonly, high-throughput chemistry is still carried out in batches whereas flow-through processes are rather restricted to production processes, despite the fact that the latter concept allows facile automation, reproducibility, safety, and process reliability. Indeed, methods and technologies are missing that allow rapid transfer from the research level to process development. Continuous flow processes are considered as a universal lever to overcome these restrictions and only recently, joint efforts between synthetic and polymer chemists and chemical engineers have resulted in the first continuous flow devices and microreactors which allow rapid preparation of compounds with minimum workup. Importantly, more and more developments combine the use of immobilized reagents and catalysts with the concept of structured continuous flow reactors. Consequently, the present article focuses on this new research field, which is located at the interface of continuous flow processes and solid-phase-bound catalysts.