Benoit Folleas

FLUOROFORM : AN EFFICIENT PRECURSOR FOR THE TRIFLUOROMETHYLATION OF ALDEHYDES

Abstract Fluoroform is shown to be an efficient trifluoromethylating agent when deprotonated using standard reagents in DMF. The important role of DMF in that reaction was demonstrated.

Natural compounds: leads or ideas? Bioinspired molecules for drug discovery.

In this article, we compare drugs of natural origin to synthetic compounds and analyze the reasons why natural compounds occupy a place of choice in the current pharmacopoeia. The observations reported here support the design of synthetic compounds inspired from plant alkaloids and their biosynthetic pathway. Our reasoning leads to very efficient syntheses of compounds which complexity matches that of indolomonoterpenic alkaloids.

Highly Enantioselective Aza‐Diels–Alder Reaction of 1‐Azadienes with Enecarbamates Catalyzed by Chiral Phosphoric Acids

On demand: A highly enantio- and diastereoselective synthesis of 6-amino- trisubstituted tetrahydropyridine compounds has been developed through the inverse-electron-demand aza-Diels-Alder reaction of N-aryl α,β-unsaturated ketimines with enecarbamates (E)-1. Chiral phosphoric acid catalysts achieve simultaneous activation of both the 1-azadiene and dienophile partners.

New Radioligands for Describing the Molecular Pharmacology of MT1 and MT2 Melatonin Receptors

Melatonin receptors have been studied for several decades. The low expression of the receptors in tissues led the scientific community to find a substitute for the natural hormone melatonin, the agonist 2-[125I]-iodomelatonin. Using the agonist, several hundreds of studies were conducted, including the discovery of agonists and antagonists for the receptors and minute details about their molecular behavior. Recently, we attempted to expand the panel of radioligands available for studying the melatonin receptors by using the newly discovered compounds SD6, DIV880, and S70254. These compounds were characterized for their affinities to the hMT1 and hMT2 recombinant receptors and their functionality in the classical GTPγS system. SD6 is a full agonist, equilibrated between the receptor isoforms, whereas S70254 and DIV880 are only partial MT2 agonists, with Ki in the low nanomolar range while they have no affinity to MT1 receptors. These new tools will hopefully allow for additions to the current body of information on the native localization of the receptor isoforms in tissues.

Chiral α-amino phosphonates via rhodium-catalyzed asymmetric 1,4-addition reactions.

A new approach for the preparation of enantioenriched α-amino phosphonates and derivatives is described. Indeed, the rhodium-catalyzed asymmetric 1,4-addition of potassium organotrifluoroborates to dehydroaminophosphonates afforded α-amino phosphonates in good yields and high enantioselectivities (up to 96%) using Difluorphos as a chiral ligand.

A Sonogashira cross-coupling/5-exo-dig cyclization/ionic hydrogenation sequence: synthesis of 4-substituted 3-azabicyclo[3.1.0]hexan-2-ones from 2-iodocyclopropanecarboxamides.

A variety of 4-substituted 3-azabicyclo[3.1.0]hexan-2-ones have been prepared from 2-iodocyclopropanecarboxamides by a three-step sequence involving a copper-free Sonogashira coupling with terminal aryl- or heteroarylalkynes, followed by a 5-exo-dig cyclization and an ionic hydrogenation.

Efficient Synthesis of Substituted 3‐Azabicyclo[3.1.0]hexan‐2‐ones from 2‐Iodocyclopropanecarboxamides Using a Copper‐Free Sonogashira Coupling

The copper-free Sonogashira coupling between N-substituted cis- 2-iodocyclopropanecarboxamides and terminal aryl-, heteroaryl-alkynes or enynes, followed by 5-exo-dig cyclization of the nitrogen amide onto the carbon-carbon triple bond, provides a remarkably efficient access to a variety of substituted 4-methylene-3-azabicyclo[3.1.0]hexan-2-ones in excellent yields. Protonation of these latter enamides generates bicyclic N-acyliminium ions that can be involved in Pictet-Spengler cyclizations leading to new 3-azabicyclo[3.1.0]hexan-2-ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides.

Synthesis of Functionalized Alkylidenecyclopropanes by Ireland–Claisen Rearrangement of Cyclopropenylcarbinyl Esters

Glycolates or glycinates derived from diversely substituted secondary cyclopropenylcarbinols have been involved for the first time in an Ireland-Claisen rearrangement. This reaction allows an efficient and stereoselective access to highly functionalized alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid subunit, which in turn are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic alkene.

Synthesis of Alkylidene(gem-Difluorocyclopropanes) from Propargyl Glycolates by a One-Pot Difluorocyclopropenation/Ireland–Claisen Rearrangement Sequence

A one-pot difluorocyclopropenation/Ireland-Claisen rearrangement sequence applied to readily available propargyl glycolates was developed as a route toward functionalized alkylidene(gem-difluorocyclopropanes). This strategy conveniently avoids the isolation of the unstable 3,3-difluorocyclopropenylcarbinyl glycolates arising from the difluorocyclopropenation. The Ireland-Claisen rearrangement proceeds with high diastereoselectivity and chirality transfer to afford alkylidene(gem-difluorocyclopropanes) incorporating a quaternary stereocenter and a protected glycolic acid moiety, which are useful building blocks for the preparation of functionalized gem-difluorocyclopropanes.

[3,3]-Sigmatropic Rearrangement of Cyclopropenylcarbinyl Cyanates: Access to Alkylidene(aminocyclopropane) Derivatives

Cyclopropenylcarbinyl cyanates, generated in situ by dehydration of the corresponding carbamates, underwent an efficient and stereoselective [3,3]-sigmatropic rearrangement leading to the corresponding alkylidene(isocyanatocyclopropanes), which could be converted into various alkylidene(aminocyclopropane) derivatives in a one-pot manner. This transformation complements the repertoire of sigmatropic rearrangements involving cyclopropenylcarbinol derivatives and in particular, the previously reported Overman rearrangement of cyclopropenylcarbinyl trichloroacetimidates.