Pierre Vogel

Chemoselective C-H bond activation: ligand and solvent free iron-catalyzed oxidative C-C cross-coupling of tertiary amines with terminal alkynes. Reaction scope and mechanism.

FeCl(2) catalyzes the oxidative C-C cross-coupling of tertiary amines with terminal alkynes into propargylamines using (t-BuO)(2) as oxidant. The reaction can be applied to aromatic and aliphatic amines and alkynes without solvent. High chemoselectivity for aminomethyl groups is due to a steric factor.

Rational design of indoleamine 2,3-dioxygenase inhibitors

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

Iron‐Catalyzed Desulfinylative CC Cross‐Coupling Reactions of Sulfonyl Chlorides with Grignard Reagents

Reference LGSA-ARTICLE-2008-006doi:10.1002/anie.200704858View record in Web of Science Record created on 2008-03-21, modified on 2017-05-12

Derivatives of 7-oxabicyclo[2.2.1]heptane in nature and as useful synthetic intermediates

Keywords: Diels-alder-reaction ; opening metathesis polymerization ; acid-catalyzed ; hydrolysis ; lithium aluminum-hydride ; soybean cyst nematode ; diastereoselective bis-hydroxylation ; thromboxane-a2 receptor ; antagonists ; enantioselective total synthesis ; wagner-meerwein ; rearrangements ; platelet-activating-factor Note: Univ Lausanne, Chim Sect, BCH, CH-1015 Lausanne, Switzerland. Ecole Super Phys & Chim Ind, Dept Chim Organ, F-75005 Paris 5, France. Univ Complutense Madrid, Fac Quim, Dept Quim Organ 1, E-28040 Madrid, Spain. Reference LGSA-ARTICLE-1999-014doi:10.1016/S0040-4020(99)00845-5 Record created on 2005-11-09, modified on 2017-05-12

Glycosidase Inhibitors as Potential HIV Entry Inhibitors

A few alpha-L-fucosidase inhibitors and alpha-D-glucosidase inhibitors have shown in vitro anti-HIV activities, that have been attributed to their ability to inhibit HIV entry. The mechanism of action of inhibitors such as 1-deoxynojirimycin (1) is not clearly established. One possible hypothesis is that the glycosidase inhibition affects the final conformation of the glycoproteins involved in the virus/cell recognition and fusion phenomena. This hypothesis is presented critically and the mechanisms of some glycoprotein biosynthesis are out-lined. Up to now, very few glycosidase inhibitors have been assayed for their potential as HIV entry inhibitors. Further assaying should be done and larger collections of glycosidase inhibitors should be prepared. To help investigations in that perspective, the inhibitory activities of alpha-glucosidase and alpha-L-fucosidase inhibitors have been summarized.

Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.

The first synthesis of substituted azepanes mimicking monosaccharides: a new class of potent glycosidase inhibitors

The synthesis of the first examples of seven-membered ring iminoalditols, molecules displaying an extra hydroxymethyl substituent on their seven-membered ring compared to the previously reported polyhydroxylated azepanes, has been achieved from d-arabinose in 10 steps using RCM of a protected N-allyl-aminohexenitol as a key step. While the (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxy-azepane 10, a seven-membered ring analogue of fagomine, is a weak inhibitor of glycosidases, the (2R,3R,4R,5S,6S)-2-hydroxymethyl-3,4,5,6-tetrahydroxy-azepane 9 selectively inhibits green coffee bean alpha-galactosidase in the low micromolar range (Ki = 2.2 muM) despite a D-gluco relative configuration.

Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered clinical trials. However, a significant number of the reported compounds contain problematic functional groups, suggesting that enzyme inhibition could be the result of undesirable side reactions instead of selective binding to IDO1. Here, we describe issues in the employed experimental protocols, review and classify reported IDO1 inhibitors, and suggest different approaches for confirming viable inhibitor scaffolds.

(1S,2S,7R,8aS)- and (1S,2S,7S,8aS)-trihydroxyoctahydroindolizine: Two new glycosidase inhibitors by nitrone cycloaddition strategy

Abstract The two new epimeric (1 S ,2 S ,7 R ,8a S )- and (1 S ,2 S ,7 S ,8a S )-1,2,7-trihydroxyoctahydroindolizines 4 and 5 have been synthesized via methylenecyclopropane-nitrone cycloaddition-rearrangement methodology employing an enantiomerically pure l -tartaric acid derived nitrone 7b . Highly stereoselective reductions of the intermediate indolizidinone 10b and final deprotection furnished the two title indolizidinetriols 4 and 5 , the inhibiting abilities of which toward 24 commercially available glycosidases were tested. Both 4 and 5 are good competitive inhibitors of amyloglucosidases with K i values of ca. 6 and 75 μM, respectively. Compared with (+)-lentiginosine 3, 4 and 5 are less powerful inhibitors but, in contrast to 3 , the (7 R )-hydroxy analogue 4 possesses a weak inhibiting activity toward α- l -fucosidase from bovine epididymis. A model to rationalize the structure-activity relationship of (+)-lentiginosine and the two new 7-hydroxylentiginosines toward glucoamylases is proposed on the basis of their structural comparison with known inhibitors and with the natural enzymes substrate amylose.

New Chiral Auxiliaries and New Optically Pure Ketene Equivalents Derived from Tartaric-Acids - Improved Synthesis of (-)-7-Oxabicyclo[2.2.1]Hept-5-En-2-One

Abstract Condensation of di-O-acetyl( R,R )- and ( S,S )- tartaric anhydride with acetals of N-alkylaminoacetaldehyde gave new chiral auxiliaries (1 R ,5 S ,7 R )- and (1 S ,5 R ,7 S )-3-alkyl-2-oxo-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carbpxu;oc (RADO(alkyl)-X and SADO(alkyl)-X) derivatives, respectively. The latter could be used to generate the corresponding 1-cyanovinyl esters that add to furan to give readily crystallizable, optically pure Diels-Alder adducts. The method was illustrated by application to the synthesis of (−)-(1 S ,4 S )-7-oxabicyclo[2.2.1]-hept-5-en-2-one.