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Accueil > Les équipes > Réactivité organométallique et catalyse pour la synthèse (ROCS) > Thèmes de recherche

Synthesis of Compounds of Synthetic or Pharmaceutical Interest

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The team is engaged in the synthesis of several targets of general synthetic interest by applying in-house developed methodologies as key steps. The research of the team in this area, classified by date, is exemplified here below by a concise description of the publications spanning the period 2007-2012.

Stereoselective Synthesis of syn-Β-Amino Propargylic Ethers : Application to the Asymmetric Syntheses of (+)-Β-Conhydrine and (–)-Balanol. The stereoselective synthesis of syn-Β-amino propargylic ethers by the addition of racemic lithio 3-(methoxymethoxy) allenylcuprates, and more particularly (cyano) and (mesityl)cuprates, to enantiopure chiral N-tert-butylsulfinylimines is reported. The scope and limitations of the reaction is studied. The usefulness of the methodology for the synthesis of compounds having a syn-1,2-amino alcohol unit is shown through the development of the asymmetric syntheses of (+)-Β-conhydrine and of an advanced intermediate of (–)-balanol. (+)-Β-Conhydrine was obtained in 6 steps and 33% yields from 5-chloropentanal, while the advanced intermediate of (–)-balanol was obtained in 7 steps and 35% yield from a know acetal.

Synthesis of (–)-Swainsonine and (–)-8-epi-Swainsonine by the Addition of Allenylmetals to Chiral α,β-Alkoxy Sulfinylimines. The asymmetric synthesis of (–)-swainsonine and (–)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,β-dialkoxy N-tert-butanesulfinylimines derived from D-erythronolactone. (–)-Swainsonine and (–)-8-epi-swainsonine were thus obtained in 15 steps and in 11% and 8% overall yield, respectively, from D-erythronolactone.

Org. Lett. 2011, 13, 6452-6455

Asymmetric Total Synthesis of (+)-6-epi-Castanospermine by the Stereoselective Formation of a syn,anti Acetylenic 2-Amino-1,3-diol Stereotriad. The asymmetric total synthesis of (+)-6-epi-castanospermine was described. In this synthesis the diastereoselective addition of a racemic allenylzinc reagent to an enantio-pure <-alkoxy-tert-butylsulfinylimine is the key step and is followed by the formation of a piperidine ring by ring-closing metathesis and subsequent syn-dihydroxylation of an alkene. We have then accomplished the total synthesis of (+)-6-epi-castanospermine in 8.5% overall yield from (S)-4-(tert-butyldiphenyl silyloxy)-3-(4-methoxybenzyloxy)butan-1-ol, readily available from cheap (S)-malic acid

Eur. J. Org. Chem. 2010, 2921-2926

New Cross-Coupling Based Synthesis of Carpanone. Carpanone has been stereoselectively synthesized in 55% yield and 6 steps from sesamol. Key step of the synthetic sequence is the direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II) catalyzed oxidative coupling yielded carpanone as a single diastereoisomer independently of the geometric configuration of the starting precursor. A new mechanism is proposed for this transformation.

Org. Lett. 2009, 11, 4378-4381

Expeditious Synthesis of a Common Intermediate of L-1-Deoxyallonojirimycin and L-1-Deoxymannojirimycin. The expeditious synthesis of a common intermediate of L-1-deoxyallonojirimycin (L-allo-DNJ) and L-1-deoxymannojirimycin (L-manno-DNJ) has been reported. This intermediate has been obtained in highly diastereo- and enantioselectivity with 38.4% overall yield in six steps involving the unprecedented ring-closing metathesis of a tert-butylsulfinyl allylamine as the key step.

J. Org. Chem. 2009, 74, 2238-2241

High-Yielding Synthesis of Sphingoid-Type Bases. An efficient methodology for the synthesis of sphingoid-type bases has been reported. It involves the stereoselective addition of a racemic 3-alkoxy allenylzinc to enantiopure N-tert-butylsulfinyl imines and a cross-metathesis reaction as the key steps. It has been successfully applied to the syntheses of sphinganine and naturally occurring bioactive related compounds, among which the hydrolysis product of clavaminol H and two spisulosines. All of these compounds have been prepared in six steps from N-tert-butylsulfinyl imines in high overall yields (>56%).

J. Org. Chem. 2009, 74, 6986-6992

Concise Synthesis of (2S,3R)-3-Hydroxy-2-phenylpiperidine, an Advanced Key Intermediate of Human Non-peptide NK-1 Receptor Antagonists. The rapid, high yielding synthesis of (2S,3R)-3-hydroxy-2-phenylpiperidine, a known advanced key intermediate of some non-peptide human NK-1 receptor antagonists (such as (+)-CP-99,994, (+)-CP-122,721 and (+)-LP-733,060) has been reported. This synthesis involves the stereoselective addition of racemic 3-(methoxymethoxy)allenylzinc bromide to enantiopure (RS,E)-N-2-benzylidene-2-methylpropane-2-sulfinamide and a ring-closing metathesis reaction as the key steps. Following this procedure, (2S,3R)-3-hydroxy-2-phenylpiperidine has been obtained in seven steps in 56% overall yield.

Synlett 2009, 3115-3118

N-Substituted Tetronamides as Ambident Nucleophilic Building Blocks for the Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins. Aza-analogs of podophyllotoxin were synthesized in two steps from N-substituted tetronamides. The acid-mediated benzhydrylation of N-substituted tetronamides with a suitably functionalized benzhydrol quantitatively afforded the cyclization precursors. The target pentacyclic 4-aza-2,3-didehydropodophyllotoxins were next obtained via an intramolecular copper-mediated Ullmann-type N-arylation.

Synlett 2008, 1475-1478

New Picropodophyllin Analogs via Palladium-Catalyzed Allylic Alkylation - Hiyama Cross-Coupling Sequences. Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-substituted γ-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could be achieved only with a substrate incorporating a suitably positioned silicon moiety which directs the ionization toward the desired η3-allylpalladium complex. The resulting 4-[dimethyl-(2-thienyl)silylvinyl]lactone could be subsequently engaged into Hiyama couplings with various iodoarenes, to give the corresponding 4-(α-styryl)-γ-lactones. The use of a specifically substituted iodoarene generated an advanced tetracyclic lactone intermediate incorporating rings A-D of lignans belonging to the podophyllotoxin family. Subsequent electrophilic aromatic substitution with a variety of electron rich arenes afforded the target picropodophyllin analogs.

J. Org. Chem. 2008, 73, 5795–5805

Asymmetric Synthesis of (–)-1-Hydroxyquinolizidinone, a Common Intermediate for the Syntheses of (–)-Homopumiliotoxin 223G and (–)-Epiquinamide. The short and efficient asymmetric synthesis of (–)-1-hydroxyquinolizidinone was achieved in seven steps and 25% overall yield from readily available 5-chloropentanal. It is a key intermediate in the formal syntheses of (–)-homopumilotoxin 223G and (–)-epiquinamide.

Org. Lett. 2007, 9, 4705-4708

New Access to Kainic Acid via Intramolecular Palladium-Catalyzed Allylic Alkylation. The formal synthesis of kainic acid was carried out in eleven steps. The key cyclization step was accomplished through an intramolecular palladium-catalyzed allylic alkylation of an allylic sulfone. Further functionalization of the resulting pyrrolidone featured, inter alia, a NHC-CuH mediated stereoconvergent conjugate reduction.

Synlett, 2007, 9, 1521-1524

Short and Efficient Asymmetric Synthesis of (–)-α-Conhydrine. The short and efficient synthesis of (–)-α-conhydrine was accomplished with 41% overall yield in seven steps and high diastereo- and enantioselectivity. The anti-stereochemistry of the two stereogenic centers has been confirmed by the single-crystal X-ray analysis of an intermediate.

J. Org. Chem. 2007, 72, 5358–5361

Hydroxylamine Oxygen as Nucleophile in Palladium(0) and Palladium(II)-Catalyzed Allylic Alkylation : A Novel Access to Isoxazolidines. In search for novel heterocyclization processes, the intramolecular Pd-mediated allylic alkylation of homoallyl hydroxylamines is described. Depending on both the reaction conditions and the substrates, cis or trans-3-substituted-5-vinyl isoxazolidines are preferentially obtained. The corresponding starting materials for the cyclization step are readily obtained through cross metathesis of the easily accessible unsubstituted homoallyl hydroxylamines.

Synlett, 2007, 944-948