Laurent Ferrié

Synthetic efforts toward the macrolactone core of Leucascandrolide A.

A chemoselective synthesis of 1, the macrocyclic core of leucascandrolide A, has been achieved by utilizing highly enantioselective allylmetalations, an enantioselective Noyori reduction of a propargylic ketone, and olefin metatheses as the key steps.

Acryloyl Chloride: An Excellent Substrate for Cross-Metathesis. A One-Pot Sequence for the Synthesis of Substituted α,β-Unsaturated Carbonyl Derivatives

A diverse set of functionalized alpha,beta-unsaturated carbonyl compounds were synthesized in good yield by utilizing a very simple one-pot process involving a cross-metathesis between acryloyl chloride and a terminal olefin followed by the addition of a nucleophile.

Efficient synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F.

The synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F was achieved by using a vinyloguous Mukaiyama aldol reaction on a chiral aldehyde with a silyloxyfuran and by using a C-glycosylation of a lactol derivative with an acetyl oxazolidinethione. From the available chiral acetonide-glyceraldehyde, all the stereogenic centers were perfectly induced along the synthesis. The C(1)-C(9) fragment was synthesized as a vinyl stannane at C(9) in 10 steps, with 16% yield.

Cycloadditions in heterocycle and alkaloid synthesis

Intramolecular cycloadditions of bicyclo[1.1.0]butylalkyl-amines represent a rich source of novel heterocyclic scaffolds. As a function of the side chain attached to the amine, formal ene- or [2 + 2] cycloaddition products can be obtained in moderate to high yields. By suitable further functionalizations, a library of 3-azatricyclo[5.1.1.01,5]-nonanes was prepared and interrogated in 450 biological assays. This discovery collection was found to generate high hit rates and yet the individual samples demonstrated sufficient selectivity to fulfill robust lead criteria. These applications of bicyclo[1.1.0]butanes demonstrate that new synthetic chemistry and novel architectures are promising starting points for the generation of high-value discovery libraries.

New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models

Parkinsons disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder.

Identification of a Novel 1,4,8-Triazaphenanthrene Derivative as a Neuroprotectant for Dopamine Neurons Vulnerable in Parkinson’s Disease

Parkinsons disease (PD) is a chronic degenerative disorder characterized by typical motor symptoms caused by the death of dopamine (DA) neurons in the midbrain and ensuing shortage of DA in the striatum, at the level of nerve terminals. No curative treatment is presently available for PD in clinical practice. In our search for neuroprotectants in PD, we generated new 1,4,8-triazaphenanthrenes by combining 6-endo-dig-cycloisomerization of propargylquinoxalines and Suzuki or Sonogashira cross-coupling reactions. Neuroprotection assessment of newly synthesized 1,4,8-triazaphenanthrenes in a PD cellular model resulted in the discovery of a new hit compound PPQ (5m). Neuroprotection by 5m was concentration-dependent and the result of a combined effect on intracellular calcium release channels and astroglial cells. Of interest, 5m also counteracted DA cell loss in a mouse model of PD, making this molecule a promising candidate for PD treatment.