A Robust and Scalable Continuous Flow Process for Glycerol Carbonate

We report a robust continuous flow procedure for the synthesis of glycerol carbonate (2‐GLC) from green reagents glycerol and dimethyl carbonate (DMC), mediated by an inexpensive polymer‐supported base catalyst using methanol as co‐solvent. High conversion and selectivity were obtained, while residence times were typically shorter than 10 minutes

trans-Chlorido[6-chloro-4-(4-methoxy­benz­yl)-3-oxo-3,4-dihydro­pyrazin-2-yl]­bis­(triphenyl­phosphine)palladium(II)

The title compound, [Pd(C12H10ClN2O2)Cl(C18H15P)2], is the inter­mediate of the reduction of a 3,5-dichloro­pyrazinone [Loosen, Tutonda, Khorasani, Compernolle & Hoornaert (1991 ▶). Tetra­hedron, 47, 9259–9268]. This species is formed by oxidative addition of coordinatively unsaturated Pd0 to the reactive 3-position of the heterocycle. The coordination around the Pd atom is square planar, with two trans PPh3 ligands. π–π inter­actions are observed between the centroid of the pyrazinone ring and planes of two adjacent phenyl rings, one from each PPh3 group (3.25 and 3.078 Å), stabilizing the inter­mediate structure. This could explain the reduced reactivity towards substitution of the Cl atom by the formate anion, resulting in poor yield of the reduced compound. 3-Substituted pyrazinones are important precursors in the synthesis of 5-amino­piperidinone-2-carboxyl­ate (APC) systems

2-(4-Meth­oxy­benz­yl)-4,6-diphenyl-2,5-diaza­bicyclo­[2.2.2]oct-5-en-3-one

In the crystal structure of the title compound, C26H24N2O2, weak inter­molecular C—H⋯π inter­actions involving the benzene of the p-methoxy benzyl group and one of the phenyl rings result in the formation of chains consisting of alternating enanti­omers. Weak C—H ⋯O inter­actions with the methoxy O atom lead to the formation of layers, which are inter­linked by further C—H⋯O inter­actions into a three-dimensional assembly

Alpha-helical destabilization of the Bcl-2-BH4-domain peptide abolishes its ability to inhibit the IP3 receptor

The anti-apoptotic Bcl-2 protein is the founding member and namesake of the Bcl-2-protein family. It has recently been demonstrated that Bcl-2, apart from its anti-apoptotic role at mitochondrial membranes, can also directly interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the primary Ca2+-release channel in the endoplasmic reticulum (ER). Bcl-2 can thereby reduce pro-apoptotic IP3R-mediated Ca2+ release from the ER. Moreover, the Bcl-2 homology domain 4 (Bcl-2-BH4) has been identified as essential and sufficient for this IP3R-mediated anti-apoptotic activity. In the present study, we investigated whether the reported inhibitory effect of a Bcl-2-BH4 peptide on the IP (3)R1 was related to the distinctive alpha-helical conformation of the BH4 domain peptide. We therefore designed a peptide with two glycine "hinges" replacing residues I14 and V15, of the wild-type Bcl-2-BH4 domain (Bcl-2-BH4-IV/GG). By comparing the structural and functional properties of the Bcl-2-BH4-IV/GG peptide with its native counterpart, we found that the variant contained reduced alpha-helicity, neither bound nor inhibited the IP (3)R1 channel, and in turn lost its anti-apoptotic effect. Similar results were obtained with other substitutions in Bcl-2-BH4 that destabilized the alpha-helix with concomitant loss of IP3R inhibition. These results provide new insights for the further development of Bcl-2-BH4-derived peptides as specific inhibitors of the IP3R with significant pharmacological implications

Introduction of Aryl Fluorosulfates into the Realm of Catellani Reaction Substrates

Application of activated phenol fluorosulfates as substrates in a Pd/NBE mediated sequential alkylation-arylation, commonly known as a Catellani reaction, is presented. These substrates provide a level of complementarity to the commonly used aryl halides and, in combination with a plethora of existing Catellani reaction variations, enable even wider application of this powerful synthetic tool.status: publishe

Electrochemistry and Photoredox Catalysis: A Comparative Evaluation in Organic Synthesis

This review provides an overview of synthetic transformations that have been performed by both electro- and photoredox catalysis. Both toolboxes are evaluated and compared in their ability to enable said transformations. Analogies and distinctions are formulated to obtain a better understanding in both research areas. This knowledge can be used to conceptualize new methodological strategies for either of both approaches starting from the other. It was attempted to extract key components that can be used as guidelines to refine, complement and innovate these two disciplines of organic synthesis.status: publishe

Ex situ gas generation for lab scale organic synthesis

Synthetic organic reactions involving gaseous reagents are frequently avoided in the research lab for practical and safety reasons. Nevertheless, reactive gases often represent convenient building blocks with high potential for atom economy. This review article aims at highlighting ex situ gas generation methods as safe and easily executable procedures for organic synthesis. Especially the advent of two-chamber type reactors has been responsible for the renewed interest in gas-liquid biphasic transformations. With the exemption of carbon monoxide, a discussion is provided on the scientific work from the last decade which employs ex situ generated gaseous reagents, generated on-demand and in a place other than the reaction mixture itself. Features of these protocols which are especially appealing to a laboratory bench-scale context will be underscored, with an emphasis on safety and synthetic diversity allowed by the gas-mediated reactions.status: Published onlin

Synthetic Protocol toward Fused Pyrazolone Derivatives via a Michael Addition and Reductive Ring Closing Strategy

A new class of pyrazolo[3,4-c]pyridine-3,7-dione and pyrazolo[3,4-d]azepine-3,7-dione scaffolds was synthesized via a Michael addition and reductive cyclization strategy. These fused heterocycles were accessed from simple starting materials such as nitroolefins and 3-ethoxycarbonyl-(methylene)pyrazoline-5-one. The pyrazolo-fused heterocycles were obtained in good overall yields.status: publishe

Towards novel tricyclic motifs: intramolecular C-H arylation as the key step in a formal (3+3) cyclocondensation strategy

Tricyclic scaffolds, structurally related to the well known benzodiazepine drug class, show diverse and strikingly different biological activities than their benzodiazepine counter parts. Interested by this scaffold hopping perspective, we previously developped a continuous flow method converting benzodiazepinediones to oxazoloquinolinones. Exploration of this synthetic route to the corresponding oxazolonaphthyridinone scaffolds met with limited success however, encouraging us to develop a different approach for pyridine based tricyclic motifs. In line with our interest in scaffold hopping, herein we describe a general, convergent (3+3) cyclocondensation approach giving access to [1,3]oxazolo[4,5-c]-1-naphthyridin-4(5H)-ones. The key synthetic steps in this approach are (1) the construction of an amide link connecting two peripheral heterocycles and (2) a palladium-catalysed intramolecular C-H arylation completing the tricyclic derivative.status: publishe

A Robust and Scalable Continuous Flow Process for Glycerol Carbonate

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim With glycerol being a bulk waste product, the interest in converting it to other value-added products is steadily increasing. A scalable continuous flow process was developed for the synthesis of glycerol carbonate (2-GLC) from glycerol and dimethyl carbonate on a hydroxide functional resin. High conversion and selectivity were obtained while the residence times were typically shorter than 10 min. Continuous production of 2-GLC was achieved in high throughput and with improved processing metrics, creating the foundations for a production level process.status: publishe