Hydrogenation of fluorinated molecules: an overview.

The review aims at providing an overview on the developments made in hydrogenation reactions of molecules having various fluorinated groups (F, CF3, CF2H, CF2Rf). Indeed, the hydrogenation of fluorine-containing molecules is a straightforward and atom-economical way to access challenging (chiral) fluorinated scaffolds. This promising field is still in its infancy and milestones are expected in the coming years. To illustrate that, the review will highlight the major contributions made in that field and will be organized by fluorinated groups.

Diastereoselective alkylation of 2,3,4,6-Di-O-isopropylidene-2-keto-L-gulonic amides. Application to the asymmetric synthesis of 1-substituted-1,2,3,4-tetrahydroisoquinolines and 1-substituted-1,2,3,4,-tetrahydro-beta-carbolines.

The diastereoselective alkylation of amides 3a,b and 7a,b derived from gulonic acid is described. Substituted compounds are obtained in good yield and high diastereoselectivity. A mechanistic investigation establishes that the diastereoselectivity did not arise from an initial asymmetric deprotonation. The stereochemistry is then determined during the alkylation step.

Synthesis of alpha-substituted beta-amidophosphines by diastereoselective alkylation. A new access to chiral ligands for asymmetric catalysis.

Chiral beta-amidophosphine boranes 7a-f can be diastereoselectively alkylated, using O-protected amino-alcohols as chiral inducers, to furnish alpha-substituted beta-amidophosphine boranes 8a-f and 9-12 with up to 72% diastereoisomeric excess. Selective deprotection afforded optically pure carboxylic derivative 13 which is a key intermediate for the synthesis of various potential chiral ligands for asymmetric catalysis.

Effect of oxysterol derivatives on the time course development of hepatocarcinoma in transgenic mice.

Among their biological properties, several oxysterols display a stronger toxicity towards tumor cells than towards normal cells. Water-soluble phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29), that were proved to retain a specific antitumoral activity in vitro, have been recently developed, allowing in vivo studies. They have been assayed on transgenic mice expressing the Large T antigen of SV40 in their liver and developing systematically hepatocarcinoma within 8 months. We show that JB69 and XA29 administered intraperitoneally into transgenic mice, before the onset of adenoma, may prevent or delay the tumor development. Consequently, oxysterol derivatives might constitute new efficient prodrugs against naturally occurring tumors.

Antitumor activity of oxysterols. Effect of two water-soluble monophosphoric acid diesters of 7 beta-hydroxycholesterol on mastocytoma P815 in vivo.

Oxysterols, a family of naturally occurring products, have been shown to possess several biological activities. In particular, they are more toxic towards tumor cells than towards normal cells. In addition, they markedly modify immune cell responses. To carry out in vivo studies, we have synthesized phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29). These water-soluble prodrugs have a similar toxicity to their parent compound under in vitro conditions. When administered intraperitoneally to mice bearing the P815 mastocytoma, they induced significant increases in life span. The results depend on the administration protocol. Under appropriate conditions, 20 to 40% of treated mice recover completely. This, together with their immunological effect, suggests that these oxysterols should be considered to be agents for immunochemotherapeutic investigations. By their ability to inhibit HMG CoA reductase, they may prevent the biosynthesis of prenyl groups whose coupling to oncogenes is responsible for the biological activity expression of the latter. Several indications are compatible with an effect on the cell membrane. Our recent studies have shown Protein Kinase C to be a target of oxysterols. On the basis of results obtained by our group and by others, we believe that oxysterols may form a new class of antitumor agents.