Efficient synthesis of isogranulatimide C, an analogue of the marine G2 checkpoint inhibitor alkaloid isogranulatimide

A three-step procedure to isogranulatimide C starting with the thermal condensation of 3-chloroindole with imidazole and proceeding in 41% yield is described.     

Efficient Pd‐Catalyzed Allene Synthesis from Alkynes and Aryl Bromides through an Intramolecular Base‐Assisted Deprotonation (iBAD) Mechanism

An optimized ligand‐controlled palladium‐catalyzed allene synthesis starting from alkynes and aryl bromides giving rise to allene products in a simple and direct manner is described. The methodology is performed in an inter‐ and intramolecular fashion with unprecedented scope and excellent yields. Based on mechanistic investigations and on DFT calculations, the role played by the carboxylic additive (i.e., PivOH) in controlling the selectivity of the reaction is discussed, allowing us to propose an intramolecular base‐assisted deprotonation (iBAD) mechanism for this process.     

Cytotoxic triterpenoid saponins from the roots of Cephalaria gigantea

Three new oleanane-type saponins, giganteosides L (1), M (2) and N (3) along with eight known ones were isolated from the roots of Cephalaria gigantea. Their structures were established as 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, respectively, by means of spectroscopic methods (1D and 2D NMR, HR-ESI-MS). Cytotoxic activity of monodesmosides was investigated in vitro using three cancer cell lines, namely, human non pigmented melanoma MEL-5 and human leukemia HL-60. Giganteosides D (4) and E (5) showed antiproliferative effect on human cell lines with IC(50) values in the range 3.15-7.5 microM.     

Diffusion coefficients of solids in supercritical carbon dioxide: Modelling of near critical behaviour

Most of the models proposed in literature for binary diffusion coefficients of solids in supercritical fluids are restricted to infinite dilution; this can be explained by the fact that most of experimental data are performed in the dilute range. However some industrial processes, such as supercritical fluid separation, operate at finite concentration for complex mixtures. In this case, the concentration dependence of diffusion coefficients must be considered, especially near the upper critical endpoint (UCEP) where a strong decrease of diffusion coefficients was experimentally observed. In order to represent this slowing down, a modified version of the Darken equation was proposed in literature for naphthalene in supercritical carbon dioxide. In this paper, the conditions of application of such a modelling are investigated. In particular, we focus on the order of magnitude of the solubility of the solid and on the vicinity of the critical endpoint. Various equations proposed in literature for the modelling of the infinite dilution diffusion coefficients of the solutes are also compared. Ten binary mixtures of solids with supercritical carbon dioxide were considered for this purpose.     

Synthesis and reactivity of furoquinolines bearing an external methylene-bond: access to reduced and spirocyclic structures

A family of furoquinolines were efficiently obtained through a tandem acetalization/cycloisomerization process catalyzed by (5 mol%) silver imidazolate polymer and triphenylphosphine, and diversity was brought by the use of 7 different alcohol groups. From these furoquinolines, 3 examples of reduced derivatives could be obtained (d.r. up to 94 : 6), 10 different spiroketal derivatives by hetero-Diels-Alder reaction (d.r. up to 20 : 1), 8 hetero-[5,5]-spirocycles by cycloaddition with dibromoformaldoxime (d.r. up to 86 : 14) and finally 6 hetero-[5,6]-spirocycles by [4 + 2] cycloaddition with ethyl 3-bromo-2-(hydroxyimino)propanoate (d.r. up to 90 : 10).     

Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A

Pinnatoxins belong to an emerging class of potent marine toxins of the cyclic imine group. Detailed studies of their biological effects have been impeded by unavailability of the complex natural product from natural sources. This work describes the development of a robust, scalable synthetic sequence relying on a convergent strategy that delivered a sufficient amount of the toxin for detailed biological studies and its commercialization for use by other research groups and regulatory agencies. A central transformation in the synthesis is the highly diastereoselective Ireland-Claisen rearrangement of a complex α,α-disubstituted allylic ester based on a unique mode for stereoselective enolization through a chirality match between the substrate and the lithium amide base. With synthetic pinnatoxin A, a detailed study has been performed that provides conclusive evidence for its mode of action as a potent inhibitor of nicotinic acetylcholine receptors selective for the human neuronal α7 subtype. The comprehensive electrophysiological, biochemical, and computational studies support the view that the spiroimine subunit of pinnatoxins is critical for blocking nicotinic acetylcholine receptor subtypes, as evidenced by analyzing the effect of a synthetic analogue of pinnatoxin A containing an open form of the imine ring. Our studies have paved the way for the production of certified standards to be used for mass-spectrometric determination of these toxins in marine matrices and for the development of tests to detect these toxins in contaminated shellfish.