Enantioselective formal total synthesis of the Dendrobatidae frog toxin, (+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation

Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkyl-acetylenes (with Ph3SnH and Et3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman's pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

Asymmetric Total Synthesis of (+)-Inthomycin C Via O-Directed Free Radical Alkyne Hydrostannation with Phb>3b>SnH and Catalytic Etb>3b>B: Reinstatement of the Zeeck-Taylor (3R)-Structure for (+)-Inthomycin C

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (−)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (−)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama’s (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor’s original (3R)-stereostructure for (+)-inthomycin C is correct.<br/>

Synthesis of the C(7)-C(22)-Sector of (+)-Acutiphycin Via O-Directed Double Free Radical Alkyne Hydrostannation with Phb>3b>SnH/Etb>3b>B, Double I-Sn Exchange and Double Stille Coupling

<br/>Abstract Image<br/><br/>Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I–Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.<br/>

Preactivation of B lymphocytes does not enhance mouse mammary tumor virus infection.

We investigated whether mouse mammary tumor virus (MMTV) favors preactivated or naive B cells as targets for efficient infection. We have demonstrated previously that MMTV activates B cells upon infection. Here, we show that polyclonal activation of B cells leads instead to lower infection levels and attenuated superantigen-specific T-cell responses in vivo. This indicates that naive small resting B cells are the major targets of MMTV infection and that the activation induced by MMTV is sufficient to allow efficient infection.

Differential peptide binding to CD40 evokes counteractive responses.

The antigen-presenting cell-expressed CD40 is implied in the regulation of counteractive immune responses such as induction of pro-inflammatory and anti-inflammatory cytokines interleukin (IL)-12 and IL-10, respectively. The mechanism of this duality in CD40 function remains unknown. Here, we investigated whether such duality depends on ligand binding. Based on CD40 binding, we identifed two dodecameric peptides, peptide-7 and peptide-19, from the phage peptide library. Peptide-7 induces IL-10 and increases Leishmania donovani infection in macrophages, whereas peptide-19 induces IL-12 and reduces L. donovani infection. CD40-peptide interaction analyses by surface plasmon resonance and atomic force microscopy suggest that the functional differences are not associated with the studied interaction parameters. The molecular dynamic simulation of the CD40-peptides interaction suggests that these two peptides bind to two different places on CD40. Thus, we suggest for the first time that differential binding of the ligands imparts functional duality to CD40.

Cysteine-rich Domain 1 of CD40 Mediates Receptor Self-assembly.

The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self-assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a KD of 0.6 μm. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state.

Le bouquet présenté au Roy, le jour de sa feste, par le sieur J. B. D. L. R.

[Mazarinade. 1649]

[Le] général [de l'armée du salut William Bramwell] Booth [serrant la main de sa fille Mary B. Booth] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58688

500 cm3, Naas sur A.B.C. [critérium motocycliste de l'A.A.M.M., Association des anciens motocyclistes militaires à Auxerre, le 24 mai 1920] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59359

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1887 (SER2,T10).

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1888 (SER2,T13).

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1889 (SER2,T15).

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1888 (SER2,T14).

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1887/09/15 (NOUV SER,T11)-1887/12/15.

La Controverse et Le Contemporain : revue mensuelle religieuse, littéraire, politique et scientifique / dir. J.-B. Jaugey et Cazajeux

1888 (SER2,T12).