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

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

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

Crystal structure of 5-benzyl-8-bromo-2-meth-yl-1,3-oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one.

The title compound, C17H12BrN3O2, was unexpectedly isolated during an attempt to synthesize pyridodiazepinediones and identified as an oxazolonaphthyridinone derivative. The almost planar oxazolonaphthyridinone ring (r.m.s. deviation = 0.016 Å) makes a dihedral angle of 61.6 (2)° with the phenyl ring. In the crystal, columns of mol-ecules stacked along the a axis are formed by π-π inter-actions between the six-membered rings of the oxazolonaphthyridone moieties [centroid-to-centroid distances = 3.494 (2)-3.906 (3) Å], which further inter-act through C-H⋯π contacts with the phenyl rings

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

The zeamine antibiotics affect the integrity of bacterial membranes

The zeamines (zeamine, zeamine I, and zeamine II) constitute an unusual class of cationic polyamine-polyketide-nonribosomal peptide antibiotics produced by Serratia plymuthica RVH1. They exhibit potent bactericidal activity, killing a broad range of Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens. Examination of their specific mode of action and molecular target revealed that the zeamines affect the integrity of cell membranes. The zeamines provoke rapid release of carboxyfluorescein from unilamellar vesicles with different phospholipid compositions, demonstrating that they can interact directly with the lipid bilayer in the absence of a specific target. DNA, RNA, fatty acid, and protein biosynthetic processes ceased simultaneously at subinhibitory levels of the antibiotics, presumably as a direct consequence of membrane disruption. The zeamine antibiotics also facilitated the uptake of small molecules, such as 1-N-phenylnaphtylamine, indicating their ability to permeabilize the Gram-negative outer membrane (OM). The valine-linked polyketide moiety present in zeamine and zeamine I was found to increase the efficiency of this process. In contrast, translocation of the large hydrophilic fluorescent peptidoglycan binding protein PBDKZ-GFP was not facilitated, suggesting that the zeamines cause subtle perturbation of theOMrather than drastic alterations or defined pore formation. At zeamine concentrations above those required for growth inhibition, membrane lysis occurred as indicated by time-lapse microscopy. Together, these findings show that the bactericidal activity of the zeamines derives from generalized membrane permeabilization, which likely is initiated by electrostatic interactions with negatively charged membrane components

Stevioside and Steviol as Starting Materials in Organic Synthesis

Steviol glycosides, a collection of natural sweeteners extracted from the leaves of the Paraguayan shrub Stevia rebaudiana, have been drawing an increased amount of attention in the last decades. Very recently, the steviol glycosides were approved as a novel food additive in the European Union, which resulted in a growing interest by the general public. The structure of the steviol glycosides consists out of a diterpene ent-kaurene core, steviol, linked to one or more glucose units. Various benign medicinal properties have been assigned to the structure of stevioside, including antihypertensive and antihyperglycemic effects. These effects have encouraged many organic chemists to investigate the synthesis of possible analogues of the structure of both stevioside and its aglycon steviol. In previous work we discussed the known modifications of the structure of the ent-beyerane isosteviol, which is obtained via a Wagner-Meerwein rearrangement of steviol. In this review, we offer an organized overview of the available modifications of both stevioside and steviol. These modifications cover various fields in research, including medicinal chemistry, combinatorial chemistry or the synthesis of sweeteners with improved taste. For stevioside, the enzymatic transglycosylations are discussed, followed by all reported chemical transformations, which are not widespread in the literature. The possible microbiological transformations of stevioside and steviol are also discussed. These transformations have been carried out with various microorganisms or enzymes, resulting mainly in gibberellin-like structures or hydroxylated steviol analogues. An overview of all possible hydroxylations and their corresponding yields is provided. Compared to stevioside, the chemical modifications of steviol are more numerous. An overview, where each analogue is grouped according to the reactive site of steviol used, is provided. If possible, a comparison between the resulting yields of similar reactions is made. © 2012 Bentham Science Publishers.status: publishe

Isosteviol as a Starting Material in Organic Synthesis

In recent years the diterpene isosteviol, obtained via acid catalyzed rearrangement of stevioside, has gained growing interest by scientists. Its structural features and easy accessibility make isosteviol a useful starting material in organic synthesis. In this review, we group all existing modifications to the isosteviol moiety, ranging from biological transformation to rearrangements of the terpene skeleton. We will also discuss the known macrocycles based on isosteviol.status: publishe

Synthesis of N-Hydroxypyrazin-2(1H)-ones via Selective O-Debenzylation of 1-Benzyloxypyrazin-2(1H)-ones Using Flow Methodology

This paper describes the selective and reproducible debenzylation of benzyloxypyrazinones using flow chemistry to yield N-hydroxypyrazinones. Flow methodology enabled us to avoid overreduction of the compounds to pyrazin-2(1H)-ones.status: publishe

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