Swiss CAT+, a Data-driven Infrastructure for Accelerated Catalysts Discovery and Optimization.

The Catalysis Hub - Swiss CAT+ is a new infrastructure project funded by ETH-domain, co-headed by EPFL and ETHZ. It offers the scientific community a unique integrated technology platform combining automated and high-throughput experimentation with advanced computational data analysis to accelerate the discoveries in the field of sustainable catalytic technologies. Divided into two hubs of expertise, homogeneous catalysis at EPFL and heterogeneous catalysis at ETHZ, the platform is open to academic and private research groups. Following a multi-year investment plan, both hubs have acquired and developed several high-end robotic platforms devoted to the synthesis, characterization, and testing of large numbers of molecular and solid catalysts. The hardware is associated with a fully digitalized experimental workflow and a specific data management strategy to support closed-loop experimentation and advanced computational data analysis.

Allosteric modulation of a human odorant receptor.

Odor perception is first determined by how the myriad of environmental volatiles are detected at the periphery of the olfactory system. The combinatorial activation of dedicated odorant receptors generates enough encoding power for the discrimination of tens of thousands of odorants. Recent studies have revealed that odorant receptors undergo widespread inhibitory modulation of their activity when presented with mixtures of odorants, a property likely required to maintain discrimination and ensure sparsity of the code for complex mixtures. Here, we establish the role of human OR5AN1 in the detection of musks and identify distinct odorants capable of enhancing its activity in binary mixtures. Chemical and pharmacological characterization indicate that specific α-ß unsaturated aliphatic aldehydes act as positive allosteric modulators. Sensory experiments show decreased odor detection threshold in humans, suggesting that allosteric modulation of odorant receptors is perceptually relevant and likely adds another layer of complexity to how odors are encoded in the peripheral olfactory system.

Filterable Agents for Hyperpolarization of Water, Metabolites, and Proteins.

Hyperpolarization is generated by dissolution dynamic nuclear polarization (d-DNP) using a polymer-based polarizing agent dubbed FLAP (filterable labeled agents for polarization). It consists of a thermo-responsive poly(N-isopropylacrylamide), also known as pNiPAM-COOH, labeled with nitroxide radicals. The polymer powder is impregnated with an arbitrary solution of interest and frozen as is. Dissolution is followed by a simple filtration, leading to hyperpolarized solutions free from any contaminants. We demonstrated the use of FLAP to hyperpolarize partially deuterated water up to P((1) H)=6 % with a long relaxation T1 >36 s characteristic of high purity. Water hyperpolarization can be transferred to drugs, metabolites, or proteins that are waiting in an NMR spectrometer, either by exchange of labile protons or through intermolecular Overhauser effects. We also show that FLAPs are suitable polarizing agents for (13) C-labeled metabolites such as pyruvate, acetate, and alanine.

[4 + 2]-Annulations of aminocyclobutanes.

The first [4 + 2]-annulation between aminocyclobutanes and aldehydes to access tetrahydropyranyl amines is reported. With phthalimido cyclobutane dicarboxylates and aromatic aldehydes, tetrahydropyrans were obtained in 53-92% yield and 3:1-17:1 dr using scandium triflate or iron trichloride as catalyst. The use of thymine- or fluorouracil-substituted cyclobutanes gave direct access to six-membered ring nucleoside analogues. Finally, the [4 + 2]-annulation between aminocyclobutanes and enol ethers led to the corresponding cyclohexylamines.

Taming hypervalent bonds and strained rings for catalysis and synthesis.

Improving the synthesis of complex organic molecules is essential for progress in many fields such as medicine, agrochemicals or materials. Since 2007, our laboratory has been focusing on the development of non-classical bond disconnections based on the use of small, energy-loaded organic molecules: hypervalent iodine reagents and strained rings. In this overview article, we report our progress since 2011 in these areas. The use of cyclic hypervalent iodine reagents has been extended to the C2-selective alkynylation of indoles, the domino cyclization alkynylation of allenes, the alkynylation of thiols and the azidation of carbonyl compounds. Amino-substituted aminocyclopropanes and aminocyclobutanes were used in [3+2] and [4+2] annulations to access nitrogen-rich building blocks, including nucleoside analogues. The first example of dynamic kinetic [3+2] annulation of aminocyclopropanes with both enol ethers and aldehydes was also reported.

Synthesis of (carbo)nucleoside analogues by [3+2] annulation of aminocyclopropanes.

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine-, uracil-, and 5-fluorouracil-substituted diester donor-acceptor cyclopropanes and their use in the indium- and tin-catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.

Dynamic kinetic asymmetric [3 + 2] annulation reactions of aminocyclopropanes.

We report the first example of a dynamic kinetic asymmetric [3 + 2] annulation reaction of aminocyclopropanes with both enol ethers and aldehydes. Using a Cu catalyst and a commercially available bisoxazoline ligand, cyclopentyl- and tetrahydrofurylamines were obtained in 69-99% yield and up to a 98:2 enantiomeric ratio using the same reaction conditions. The method gives access to important enantio-enriched nitrogen building blocks for the synthesis of bioactive compounds.

Catalytic Friedel-Crafts reaction of aminocyclopropanes.

A Lewis acid catalyzed Friedel-Crafts reaction between donor-acceptor aminocyclopropanes and indoles and other electron-rich aromatic compounds is reported. Indole alkylation at the C3 position was generally obtained for a broad range of functional groups and substitution patterns. In the case of C3-substituted indoles, C2 alkylation was observed. The reaction gives a rapid access to gamma amino acid derivatives present in numerous bioactive molecules.

Catalytic enantiospecific [3+2] annulation of aminocyclopropanes with ketones.

An almost familiar ring: The first enantiospecific [3+2] annulation of donor-acceptor aminocyclopropanes with ketones is reported (see scheme; Phth=phthaloyl). The reaction is catalysed by tin(IV) chloride (5 mol %) at -78 °C and gives aminotetrahydrofurans bearing a quaternary C5 atom in high yield, diastereoselectivity and enantiospecificity (see scheme).

Iron-catalyzed [3 + 2] annulation of aminocyclopropanes with aldehydes: stereoselective synthesis of aminotetrahydrofurans.

The first method for the [3 + 2] annulation of donor-acceptor aminocyclopropanes with aldehydes is reported. The reaction is catalyzed by iron trichloride on alumina in yields up to 99% and with excellent cis selectivities (up to >20:1) and represents a stereoselective and atom economic access to valuable 2-aminotetrahydrofurans, which constitute the core of DNA and RNA.