Jean-Luc Vasse

Divergent access to cis and trans-2,3-disubstituted pyrrolidines from platform diastereoenriched homoallylic amines is described. Based on the allylmetalation of chiral imines, using an allylmetal containing a protected hydroxyethyl chain, homoallylic amines can be achieved in a highly diastereoselective manner by suitably adapting the reaction conditions and the chiral auxiliary to the C-substituent of the imine. Subsequent specific activation of either the hydroxyethyl or the vinylic chain promotes the C-N bond-forming cyclization, affording cis or trans pyrrolidines, which can be valued as precursors of polycyclic skeletons.

IspG (also known as GcpE) is a key [4Fe‐4S] metalloenzyme that catalyzes the penultimate step of the methylerythritol phosphate (MEP) pathway, a well‐established target for the development of new antimicrobials. This oxygen‐sensitive enzyme mediates the reductive dehydroxylation of 2‐ C ‐methyl‐ d ‐erythritol 2,4‐cyclodiphosphate (MEcPP) to ( E )‐4‐hydroxy‐3‐methylbut‐2‐en‐1‐yl diphosphate (HMBPP), requiring electron transfer proteins to deliver two electrons needed for catalysis. To probe the mechanism of IspG and access new mechanism‐based inhibitors, we synthesized a substrate analogue, monofluoromethyl‐ d ‐erythritol cyclodiphosphate, in which the natural methyl group of MEcPP is replaced by a CH ₂ F group. This analogue proved to be a potent inhibitor of IspG. This study also demonstrates that electron capture is a prerequisite for inhibition and that the inhibitor leads to fluoride release in the IspG‐catalyzed reaction. Together, these results provide further support for the involvement of a carbanionic intermediate in the IspG mechanism.

We report the synthesis of a cyclopropyl analogue of methyl-D-erytritol cyclopyrophosphate (MEcPP), designed as a fraudulent substrate likely to undergo the enzymatic process. This compound appears as an invaluable chemical tool to decipher the mechanism of IspG through analysis of metabolites deriving from the corresponding methylcyclopropyl cation or radical intermediate.

The synthesis of 2- and 6-substituted-3-aminopiperidines from Weinreb amides containing an allylamino fragment is reported. Involving the simultaneous hydrozirconation of the C═C and the C═O bonds, the cyclization was promoted by the BF₃-mediated generation of an iminium. Proven to be highly diastereoselective, the sequence can be applied to diversely substituted unsaturated Weinreb amides and valorized through the preparation of bicyclic heterocycles.

A straightforward synthetic route towards DAB-1 scaffolded dimeric iminosugars is described here, starting from readily available bis-glycosylamines. The method allows the integration of a variety of linkages (aryl, alkyl, polyethyleneglycol chains) between both iminosugars through the choice of the bis-amine used in the first step. Moreover, an additional substituent (allyl, ethynyl) may be inserted into the structure via nucleophilic addition of an organometallic reagent to the starting bis-glycosylamine. A symmetrical ethynyl-iminosugar proved susceptible to intramolecular Glaser coupling, affording the corresponding macrocyclic structure. Dimeric iminosugars were tested towards a series of commercial glycosidases to uncover potencies and selectivities when compared to DAB-1, their monomeric counterpart. Whereas a significant drop in inhibition potencies was observed towards glucosidases, some compounds displayed unexpected potent inhibition of β-galactosidase.

The use of unprotected carbohydrate-derived nitrones as partners in strain-promoted alkyne-nitrone cycloadditions was investigated as a new tool for bioconjugation. The observed second-order reactions displayed rate constants of 3.4 × 10^-4-5.8 × 10^-2 M^-1 s^-1, which is the common order of magnitude of reaction kinetics with other simple aliphatic or aromatic nitrones. Applicability of this method to aqueous media was demonstrated by performing a one-pot protocol, which combines sequential formation of the nitrone and cycloaddition with cyclooctyne in water.

Trifluoromethyl analogues of methylerythritol phosphate (MEP) and 2-C-methyl-erythritol 2,4-cyclodiphosphate (MEcPP), natural substrates of key enzymes from the MEP pathway, were prepared starting from d-glucose as the chiral template to secure absolute configurations. The obligate trifluoromethyl group was inserted with complete diastereoselectivity using the Ruppert-Prakash nucleophile. Target compounds were assayed against the corresponding enzymes showing that trifluoro-MEP did not disrupt IspD activity, whereas trifluoro-MEcPP induced 40% inhibition of IspG at 1 mM.

Access to 5-bromopentanal and 6-bromohexanal derivatives from Weinreb amides is described. The method relies on the sequential C-bromination/zircona-aminal hydrolysis of bis-C,O-zirconocenes, which are generated in situ from unsaturated Weinreb amides using Schwartz's reagent. Synthetic illustrations of such bromo-aldehydes, which can act as carbocycle and heterocycle precursors, are also presented.