Research summary - 2011 updated

Julien BarbionDocteur en Chimie - Ingénieur Chimiste R&D ,[object Object]

Domicilié à Sannois (95 - Val d’Oise)

DEA - Université Cergy-Pontoise (Prof. J. Ardisson/DR A. Pancrazi) “Contribution à la Synthèse Totale du (+)-Discodermolide” ,[object Object], “Synthèse Totale du (+)-Altholactone” ,[object Object], “Contribution à la Synthèse Totale du Salinosporamide A, Nouvel Inhibiteur nM du Protéasome” (Programme ANR) ,[object Object], “Synthèse d’Hétérocycles Trifluorométhoxylés”

StudiesTowards the Total Syntheses of Bioactive Products Research Summary (last update 2011) I - (+)-Discodermolide II - (+)-Altholactone III - Salinosporamide A IV - OCF3-Heterocycles

(+)-Discodermolide(DEA, 2002-2003)Synthesis, 2004, 3017-3022.Angew. Chem., Int. Ed.2007, 46, 1917-1921.Chem. Eur. J. 2008, 14,11092-11112.

(+)-Discodermolide ,[object Object], (Discodermiadissoluta)  Low extraction yield (0.002%) ,[object Object],Cytotoxic IC50 = 2.5 nM Microtubule stabilisation Target = tubuline active in vivo ,[object Object],Polypropionate 13 chiral centres 3 double bonds (Z)

(+)-Discodermolide - Retrosynthesis

(+)-Discodermolide - Strategies

(+)-Altholactone(PhD, 2003-2006)defended in Aachen, the 10/27/2006 Chem. Eur. J. 2008, 14, 2842-2849.

(+)-Altholactone ,[object Object],(Goniothalamusgiganteus) Goniothalamusisknownas a sourceofnaturalproductspresentingbiologicalactivities  (5-hydroxy-5,6-dihydro-2H-pyran-2-one) ,[object Object],Cytotoxic IC50 = 0.7 µM Antitumoralandantibacterialproperties ,[object Object], 4 chiral centres in a row Bicycliccis-junction  Cycle 1: 5-hydroxy-5,6-dihydro-2H-pyran-2-one  Cycle 2: disubstitutedtetrahydrofurane

(+)-Altholactone - Retrosynthesis

(+)-Altholactone - Synthesis (1/2)ChiralityIntroduction

(+)-Altholactone - Synthesis (2/2)(18 steps, 13.7% overallyield)

Salinosporamide A(Research Scientist, 2006-2008)ANR Programʺstill underinvestigationʺ

Salinosporamide A ,[object Object], (marine bacteriumofthenewgenusSalinospora) ,[object Object], IC50 = 10 nM (in vitro) - Human coloncarcinoma Inhibition ofthe 20S proteasome ,[object Object], 5 chiral centres in a row cis-fusedc-lactam-b-lactone bicyclic ring structure 2 sidechains: cyclohexenylcarbinol and chloroethylchains

Salinosporamide A - SAR The b-lactone isrecognized as a keypharmacophor (itsforms a covalent adductwith the N-terminal Thr on proteasome 20S)

Salinosporamide A - Retrosynthesis

Salinosporamide ASynthesis ofthe Methyl Ketone TRIS = Tris(hydroxymethyl)aminomethane 99+%, 43€/500g (ACROS Organics)

Salinosporamide ASynthesis ofthe II-Carbamate Overallyield = 88% (over 4 steps) - Racemicversion of the II-carbamate

Salinosporamide AHoppe‘sAllylationwith a II-Carbamate (1/2)

Salinosporamide AHoppe‘sAllylationwith a II-Carbamate (2/2)

Salinosporamide AAttempts on Assymetricmethylation (1/2)

Salinosporamide AAttempts on Assymetricmethylation (2/2)

OCF3-Heterocycles(Research Scientist, 2009-2010)BayerCropScience, Lyonʺstill underinvestigationʺ(BCS-Patent in press)

Trifluoromethoxy Group - OCF3group is more & more important in agrochemical and pharmaceutical industries because of its unique properties. - OCF3isreferred as "pseudo- or super-halogen" (close to F or Cl):highlyelectron-withdrawing by induction (=3.7) slightlypositive mesomericeffect +M and hydrophobic R=+1.04compared to R(CF3)=+0.88 and R(OMe)=-0.02 ,[object Object]

Use of quitedrastic conditions and/or large excess of reagents

Research summary - 2011 updated

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Research summary - 2011 updated