Carbohydrate-Templated Syntheses of Trifluoromethyl-Substituted MEP Analogues for the Study of the Methylerythritol Phosphate Pathway.

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.

Protecting-group free synthesis of glycoconjugates displaying dual fungicidal and plant defense-eliciting activities.

A straightforward synthesis of carbohydrate templated isoxazolidines is described, by reaction of unprotected glycosylhydroxylamines (operating as 1,3-dipoles) with methyl acrylate using microwave activation. Rhamno- and erythro-isoxazolidines are recognized by plant cells, resulting in a strong ROS-production as a plant immune response, and exert a high antifungal activity against Botrytis cinerea.

Dual Activation of Unsaturated Amides with Schwartz's Reagent: A Diastereoselective Access to Cyclopentanols and N,O-Dimethylcyclopentylhydroxylamines.

The diastereoselective access to cyclopentanols and N,O-dimethylcyclopentylhydroxylamines from 4-pentenoic acid-derived Weinreb amides is described. Based on the concomitant generation of both the nucleophilic and the electrophilic poles by hydrozirconation of the amide and the C=C double bond, the cyclisation may be tuned towards cyclopentanols or N,O-dimethylcyclopentylhydroxylamines depending on the ring-closure promotor. An extension to cis 3-substituted N,O-dimethylcyclohexylhydroxylamines is also presented.

Irreversible Inhibition of IspG, a Target for the Development of New Antimicrobials, by a 2-Vinyl Analogue of its MEcPP Substrate.

IspG (also called GcpE) is an oxygen-sensitive [4Fe-4S] enzyme catalyzing the penultimate step of the methylerythritol phosphate (MEP) pathway, a validated target for drug development. It converts 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate (MEcPP) into (E)-4-hydroxy-3-methyl-but-2-enyl-1-diphosphate (HMBPP). The reaction, assimilated to a reductive dehydration, involves redox partners responsible for the formal transfer of two electrons to substrate MEcPP. The 2-vinyl analogue of MEcPP was designed to generate conjugated species during enzyme catalysis, with the aim of providing new reactive centers to be covalently trapped by neighboring amino acid residues. The synthesized substrate analogue displayed irreversible inhibition towards IspG. Furthermore, we have shown that electron transfer occurs prior to inhibition; this might designate conjugated intermediates as probable affinity tags through covalent interaction at the catalytic site. This is the first report of an irreversible inhibitor of the IspG metalloenzyme.

Access to 5-bromopentanal and 6-bromohexanal derivatives via the bromination/hydrolysis of C,O-bis-zirconocenes generated from unsaturated Weinreb amides.

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.

Broadening the reaction scope of unprotected aldoses via their corresponding nitrones: 1,3-dipolar cycloadditions with alkenes.

Condensation reactions of unprotected tetroses and pentoses with hydroxylamines afforded nitrones, which were easily converted to densely functionalized isoxazolidines in the presence of electron-poor alkenes. The 1,3-dipolar cycloaddition occurred with good facial discrimination of the chiral nitrone but under rather low endo/exo control. Stereochemistry of isomers was ascertained by chemical correlation with known derivatives from the literature. Microwave activation appeared as the most efficient reaction mode, affording the expected adducts within several minutes whereas hours were needed under standard heating. Alternatively, the transformation proved also possible under high pressure conditions by using a hand pump system, avoiding any energy source. Although water could not be used as the solvent, leading to hydrolysis of the nitrone substrate, a large variety of organic solvents proved efficient. The method has potential use in the preparation of non-ionic carbohydrate-based amphiphiles.

Homoallylic amines as efficient chiral inducing frameworks in the conjugate addition of amides to α,ß-unsaturated esters. An entry to enantio-enriched diversely substituted amines.

The diastereoselective conjugate addition of secondary homoallylamines, obtained in the enantioenriched form via allylmetallation of imines, to α,ß-unsaturated esters is reported. This method allows access to valuable building blocks as well as heterocyclic skeletons, providing tertiary amines bearing two chains integrating a stereogenic center adjacent to the nitrogen atom.

Synthesis of 1,3-disubstituted cyclohexenes from dienylethers via sequential hydrozirconation/deoxygenative cyclisation.

Access to 1,3-disubstituted cyclohexenes from zirconocenes containing a latent electrophilic allylic fragment is described. Requiring a specific conformation, 6-endo-trig cyclisation is based on the TMSOTf-mediated generation of a stabilized carbocation.

Regiospecific formation of sugar-derived ketonitrone towards unconventional C-branched pyrrolizidines and indolizidines.

The synthesis of unprecedented branched pyrrolizidines and indolizidines was accomplished via nitrone chemistry. The required ketonitrone, a known intermediate usually obtained as a mixture of regioisomers, was prepared in a pure form from d-arabinose by a sequence of oximation/reduction/oxidation steps. Nucleophilic vinylation or allylation followed by ring-closing metathesis of the corresponding N-allylpyrrolidines furnished the targeted iminosugars, which proved potent and selective inhibitors of alpha-glucosidase from rice (GH31 family).

Generation of ϵ,ϵ-Difluorinated Metal-Pentadienyl Species through Lanthanide-Mediated C-F Activation.

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl3 has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds.

Cyclopent-2-enylaluminium as allylzinc precursor for the diastereoselective allylmetallation of non-racemic imines: applications to the synthesis of enantiomerically enriched heterocycles.

The generation of cyclopent-2-enylzinc from cyclopentadiene based on a titanium-catalyzed hydroalumination/transmetallation sequence is described. Applied to the allylmetallation of phenylglycinol-derived imines, this sequence leads to homoallylic amines with moderate to good stereoselectivities. The synthesis of disubstituted azetidines and piperidines illustrates the potential of the method.

Titanium-catalyzed hydroalumination of conjugated dienes: access to fulvene-derived allylaluminium reagents and their diastereoselective reactions with carbonyl compounds.

The described titanium-catalyzed hydroalumination of conjugated dienes opens up a new way to allylaluminium reagents. The reaction is carried out by using diisobutylaluminium hydride (DIBAL-H) and a catalytic amount of [Cp2TiCl2] (Cp = cyclopentadienyl). When applied to mono- and disubstitued pentafulvenes, this reaction proceeds in a highly endocyclic manner. The formed allylaluminium compounds react regio- and stereoselectively with both aldehydes and ketones to afford homoallylic alcohols that are suitable synthons for functionalized cyclopentanones. An extension of this methodology to simple dienes was also investigated. In the proposed mechanism, the initially formed bimetallic species (Ti/Al) are involved in the two possible catalytic cycles with a direct hydroalumination or/and a hydrotitanation followed by a titanium to aluminium transmetallation.

Kinetics of Strain-Promoted Alkyne-Nitrone Cycloadditions (SPANC) with Unprotected Carbohydrate Scaffolded Nitrones.

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.

Convergent Evolution of Diastereomeric Mixtures of 5-Methoxy-pentylzirconocenes toward Trans-1,2-substituted Cyclopentanes.

The access to 1,2- and 1,1,2-substituted trans cyclopentanes via a sequential hydrozirconation/TMSOTf-mediated cyclization applied to 5-methoxypent-1-enes is presented. Involving a transient carbocation, the reaction was shown to be diastereo-convergent. Possibly performed in a nonracemic version, the reaction proved compatible with a range of functional groups affording a large panel of cyclopentanes.

Asymmetric synthesis of proline-based conformationally constrained tryptophan mimetic.

The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substituted proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.

A direct stereoselective approach to trans-2,3-disubstituted piperidines: application in the synthesis of 2-Epi-CP-99,994 and (+)-epilupinine.

A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted piperidine skeleton which is present in a broad range of biologically active compounds.

Synthesis and glycosidase inhibition potency of all-trans substituted 1-C-perfluoroalkyl iminosugars.

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1',2')-dihydroxyethyl substituent of homoDMDP with -C4F9 proved detrimental for enzyme binding, introduction of a -C3F7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast.

Application of Elemental Lanthanides in the Selective C-F Activation of Trifluoromethylated Benzofulvenes Providing Access to Various Difluoroalkenes.

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the possibility of accessing unique fluorine-containing molecules, which are difficult to obtain by other synthetic pathways. Among various metals, which can undergo C-F activation, lanthanides (Ln) are good candidates as they form strong Ln-F bonds. Lanthanide metals are strong reducing agents with a redox potential Ln3+/Ln of approximately -2.3 V, which is comparable to the value of the Mg2+/Mg redox couple. In addition, lanthanide metals display a promising functional group tolerance and their reactivity can vary along the lanthanide series, making them suitable reagents for fine-tuning reaction conditions in organic and organometallic transformations. However, due to their oxophilicity, lanthanides react readily with oxygen and water and therefore require special conditions for storage, handling, preparation, and activation. These factors have limited a more widespread use in organic synthesis. We herein present how dysprosium metal - and by analogy all lanthanide metals - can be freshly prepared under anhydrous conditions using glovebox and Schlenk techniques. The freshly filed metal, in combination with aluminum chloride, initiates the selective C-F activation in trifluoromethylated benzofulvenes. The resulting reaction intermediates react with nitroalkenes to obtain a new family of difluoroalkenes.

Single or Synergistic Kinetic Resolutions of Chiral Allylalanes: Two Complementary Routes for the Asymmetric Synthesis of Syn Homoallylamines.

Two strategies based on kinetic resolution(s) of chiral alanes and providing enantioenriched syn homoallylamines are reported. The first implies a single kinetic resolution of the alane using camphor; the second requires two sequential kinetic resolutions using the synergistic combination of (-)-camphor/(R)-tert-butylsulfinamide-derived imines. This syn selectivity, specific to the use of allyaluminum, opens the way to the preparation of valuable building blocks as illustrated by the synthesis of (+)-epilupinamine.