Organic Synthesis from France 10/02/2010

Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Early French organic chemists (18th and 19th centuries): Albin Haller (1849–1925): Antoine-Laurent de Lavoisier (1743–1794): * semi-synthesis of camphor from camphoric acid and synthesis of menthol * law of conservation of mass * use of NaNH2 ("birth of strong bases chemistry") * recognized and named oxygen and hydrogen * abolished the phlogiston theory (see Seiple's GM 2010) Wurtz coupling (1855): * helped construct the metric system Na 2 + R W. heterocoupling * wrote the first extensive list of elements R1 X R2 X R1 * helped to reform chemical nomenclature THF, Et2O... Na R2 Wurtz-Fittig An appeal to delay the execution so that he could continue his experiments Ar X + R2 X Ar was cut short by the judge: "The Republic needs neither scientists nor THF, Et2O... chemists; the course of justice can not be delayed." (This quote may be more Ann. Chim. Phys. 1855, 96, 275 part of the legend than the reality) Lagrange's quote: "It took them only an instant to cut off his head, but France Müller modification: THF, -78°C, TPE (cat) to help Na solubilization may not produce another such head in a century." other modifications possible: different metal, sonication... Ph Ph Claude Berthollet (1748–1822): discovery of bleach Friedel-Crafts reaction (1877): Ph Ph Al, I2 Jean-Antoine Chaptal (1756–1832): TPE chaptalization (addition of sugar to unfermented wine to increase the Cl benzene I final alcohol level) Joseph Louis Gay-Lussac (1778–1850): " !!! * work in thermodynamics (Gay-Lussac's law) * discovery of boron, cyanogen and hydrogen cyanide Compt. Rend. 1877, 84, 1392 * developed a method for quantitative elemental analysis * named iodine, but also pipette and burette ! Combes quinoline synthesis (1888): R1 2 Eugène Chevreul (1786-1889): work on fatty acids, explanation of the O O 1. Δ R saponification process and isolation of oleic and stearic acid R + R R1 R3 2. H2SO4, Δ NH N R3 Joseph Bienaimé Caventou (1795–1877) with Pierre-Joseph 2 R2 Pelletier (1788–1842): alkaloids isolation: chlorophyll, emetine, Bull. Soc. Chim. Fr. 1883, 49, 89 strychnine, brucine, cinchonine, quinine and caffeine Notable French chemists from the 20th century outside the field of Louis Pasteur (1822–1895): Resolution of tartaric acid racemate ("racemic acid") organic synthesis field: (first experimental evidence of molecular chirality) Marie Curie (1867–1934): Nobel Prize in Chemistry (1911) for discovery of Elemental halogen isolation: the elements radium and polonium and the isolation and study of radium. (also Nobel Prize in Physics in 1903 !) * Br2 by Balard (1826) * I2 by Courtois (1811) Irène Joliot-Curie (1897-1956): Nobel Prize in Chemistry (1935) for their * F2 by Moissan (1886), Nobel Prize in 1906 for this and the invention of Frédéric Joliot-Curie (1900–1958) synthesis of new radioactive elements the electric furnace Georges Champetier (1905–1980): polymers, macromolecular chemistry

1 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Synthetic methods from the first half of the 20th century: Paul Sabatier (1854–1941):

The "organometallics school": * Nobel Prize in 1912 for hydrogenation catalyzed by metals (Ni...)

Barbier coupling reaction (1899): * Sabatier process: CO2 + 4 H2 –> CH4 + 2 H2O (cat. by Ni, Ru or Al2O3) could serve to produce fuel (CH4/O2) on Mars or drinkable water source in O 1. R3X + M OH space from human respiration, according to NASA 1 2 R1 R3 R R 2. work-up R2 *Sabatier principle: optimal interactions between the catalyst and the substrate have to be neither too strong (product not released after reaction) C R. Hebd. Seances Acad. Sci.. 1899, 128, 110 nor too weak (no binding, so no reaction). (see Volcano plot) * M can be Mg, Sm, Zn, Li... * When Mg is used, Barbier reaction is an in situ Grignard reaction. source: Karl * Yield may be improved by sonication and some reactions only work Kochloefl (2005). sonication, see JOC, 1998, 63, 5100. "Heterogeneous * In some cases, water can be used as solvent: green chemistry ! Catalysis and Solid Catalysts", Ullmann's Philippe Barbier was Victor Grignard's PhD supervisor... Encyclopedia of Industrial Chemistry. Grignard reaction (1900): Wiley-VCH Verlag O 1. R3MgX OH 1 2 R1 R3 R R 2. work-up R2

C R. Hebd. Seances Acad. Sci.. 1900, 130, 1322

* broad scope of substrate for addition of Grignard reagents: acid derivatives, nitriles, CO2 * can be used as strong Bronsted bases * can generate other organometallics like cuprates, organocerium (more Volcano plot for the decomposition of formic acid on transition metals nucleophilic), organocadmium (less nucleophilic) Grignard won the Nobel Prize in Chemistry in 1912 for this discovery Other noteworthy reactions: Blaise reaction (1901): Delépine amine synthesis (1895):

O O O N N 1. Zn, THF, reflux X HCl, EtOH 2 3 + R 1 + R CN 3 1 R X N N N N R NH X OR + R OR N N Δ 3 2. H3O X R2 R * alternative to Gabriel reaction Bull. Soc. Chim. Fr. 1895, 13, 352 C R. Hebd. Seances Acad. Sci.. 1900, 132, 478 * works better with activated halides: benzyl, allyl, α-haloketone... 2 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Darzens (1904) and aza-Darzens reactions: Prévost trans-hydroxylation (1933): I (1 eq) 1 3 2 OC(O)R OH 2 1 R R 1 3 1 3 X EWG O base R O R glycidic ester RCO2Ag (2 eq) R R base R R + for EWG=CO R 2 benzene 4 H2O 4 R1 R2 R3 R3 EWG R2 R4 R2 R R2 R R(O)CO HO Compt. Rend. Acad. Sci. 1904, 139, 1214 trans-diol Compt. Rend. 1933, 196, 1129 R4 X EWG NR4 base R2 N R1 Darzens aziridine Woodward-Brutcher modification + synthesis Me OH 1 2 3 3 R R R R EWG I (1 eq) 1 3 2 HO OH R R RCO Ag (1 eq) 1O O 3 base 1 3 J. Org. Chem. 1969, 34, 3600 2 R R R R 4 H O 4 R2 R4 AcOH/H2O R2 R 2 R2 R * EWG = CO2R, CN, SO2R, CONR2, C(=O), C(=NR) * base = NaOEt, NaH, LDA... cis-diol * X = Cl > Br or I J. Am. Chem. Soc. 1958, 80, 209 Synthesis of (–)-coriolin by Kuwajima using the Darzens reaction wrong epimer !!! OH I OTMS Br 1. LHMDS OTMS Br DBU OTMS 2 H Me H Me H Me O PhCO2Ag O 2. (CH2O)n O DMF O benzene, rt 24h 88% 88% then reflux 10h BzO H H H F 46 % OBz F OTMS OTMS OTMS OH O J. Org. Chem. 1999, 64, 1902 OTMS OTMS I OTMS cis-diol obtained with OsO4 (70 %) H Me 1. LDA H Me H Me O O 2. NIS O O Tiffeneau-Demjanov rearrangement (1937): 3. 72% H H H O H2N OH OTMS KO OK OTMS 1. HF pyr HNO2/H2O HO (CH2)n (CH2)n+1 H O , H Me O 2 2 n = 2-6 O NaHCO3 J. Org. Chem. 1999, 64, 2648 Compt. Rend. 1937, 205, 1411 (–)-coriolin H O OH 3 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Rapid overview of "French" organic chemistry from the Sonochemistry: last few decades: Methodology: Luche published the first paper that describes a synthetic application of ultrasound in Jean-Louis Luche (Université de Grenoble): organic synthesis: a Barbier coupling enhanced by sonication (1980). O Li, regular THF OH Luche reduction (1978): 1,2-reduction of enones Br + )))), 15 min CeCl •7H O (≥ 1 eq) 3 2 100 % !!! O NaBH4 (≥ 1 eq) OH J. Am. Chem. Soc. 1980, 102, 7926 R1 R2 ROH, T ≤ 0°C R1 R2 Sonication causes cavitation phenomenon: very small bubbles form in solution, grow and O OH collapse, liberating gas with very high local temperatures (up to 3000 K) and pressure. CeCl3•7H2O (≥ 1 eq) NaBH4 (≥ 1 eq) Cavitation-enhanced reactivity by cleaning the metal surface, improving mass transfer (inhomogeneous) and favoring SET ROH, T ≤ 0°C

n n Al2O3 Ph Me J. Am. Chem. Soc. 1978, 100, 2226 PhCH2Br + PhCH3 no sonication effect 3h, 78 % * Ce catalyzes alkoxyborohydride formation and increases acidity of 3h, )))) 83 % the medium by coordinating to solvent * ROH : MeOH > EtOH or iPrOH Al2O3, KCN Ph Me * other lanthanide chlorides work (Eu, Yb, La..) but better yield with Ce PhCH2Br + PhCH3 ionic pathway 60 % * reduction generally done in less than 30 min "sonochemical * 1,2-selective, very little substrate dependence (e.g., sterics) switching" ! Al2O3, KCN * most functional groups are tolerated, H2O traces (up to 5 %), O2... PhCH2Br + PhCH3 PhCH2CN radical pathway * selective for conjugated or aryl ketones > ketones > aldehydes )))), 68 % Tetrahedron Lett. 1990, 31, 4125. (because aldehydes are acetalized by ROH) Tetrahedron 1986, 42, 2803. O HO Reviews on sonochemistry: Nature 2002, 418, 394 (general) CeCl3 Synthesis 1989, 11, 787 (Luche reviews about reactions improved by sonication) NaBH4 Luche also works on microwave activation: see Tetrahedron 1999, 51, 10851. 6CO2Me 6CO2Me EtOH, H2O - 15°C Marc and Sylvestre Julia (École Normale Supérieure): CHO CHO Julia-Lythgoe olefination (1973): Tetrahedron Lett. 1973, 49, 4833. J. Chem. Soc. Chem. Comm. 1978, 601 1, 2 [H] 1. n-BuLi SO Ar Na(Hg) 1 2 2. R CHO 1 MeOH 1 O OH OH Ar R R R S R R (E) O O 3. Ac2O OAc or SmI2 31 % 69 % LiAlH4 65 % 35 % NaBH4, CeCl3 4 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

A one-pot Julia olefination (1991): Tetrahedron Lett. 1991, 32, 1175. Henri Kagan (Université Paris-XI, Orsay), introduction to future group meeting: 1. LDA Many contributions including: * Mild preparation of samarium (II) iodide ("Kagan's reagent") and Kagan-Molander N R 2. R1CHO 1 coupling (see Lewis' GM 2010) S R J. Am. Chem. Soc. 1980, 102, 2693 O R S O (E) * First general method for alkene asymmetric hydrogenation with a chiral ligand N Smiles OLi rearrangement SO HO OH O O S 2 R1 Li HOOC COOH 4 steps Ph P PPh O Li 2 2 R1 N R N O N (-) diop ((-)-2,3-O-Isopropylidene-2,3- (-) tartaric acid S O R dihydroxy-1,4-bis( diphenylphosphino O S O S S R S )butane) O O R1 S O HO HO O Li * conditions developed by Sylvestre Julia H2 N-acetyl-(R)- * more convenient, scalable NHAc RhCl[(-)-diop]PhH NHAc * no need for reducing agents tyrosine EtOH/PhH Julia-Kocienski (1998): use of PT sulfone as alkylating agent (same H COOH H COOH mechanism as BT sulfone) N R yield: 92 % N Synlett 1998, 26 O OH J. Am. Chem. Soc. 1972, 94, 6429 optical yield: 80 % SO2 N N * Rationalization of nonlinear effects in asymmetric synthesis and chiral N Ph Me amplification, Angew. Chem. Int. Engl. Ed 1998, 37, 2922 (see also Maimone's PT sulfone GM 2008) * Chiral sulfoxide syntheses: Bull. Soc. Chim. Fr. 1996, 133, 1108 Danishefsky's total synthesis of (±)-indolizomycin: tBuOOH i O J. Am. Chem. Soc. 1993, 115, 30 Julia-Lythgoe Ti(O Pr) , (R,R)-DET S 4 S e.e. ≥ 99 % HO OH Me RL RS RL RS Me EtOOC COOEt H2O (cat.), CH2Cl2, –20°C Tetrahedron Lett. 1989, 30, 3659 Marc Julia accomplished some nice total syntheses: O 1. R MgX SO , Et N S L O Syntheses of vitamin A, see Bull. Soc. Chim. Fr. 1973, 746 HO NHMe 2 3 PhMe, -40°C O NMe S CH Cl , 0°C 2. AlMe3 RL RS Synthesis of (±)-fredericamycin A, see Bull. Soc. Chim. Fr. 1993, 130, 447 Ph 2 2 Ph RSMgX crystallization, then e.e. ≥ 99 % diastereoisomer separation 5 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Alexandre Alexakis (Université Pierre et Marie Curie, Paris, then enantioselective 1,6-addition: University of Geneva): 1. 5 % Cu(OTf) enantioselective 1,4-addition: 2 yield up to 84 % O 10 % L O ee = 93-99 % rt, MeTHF, 14h + 1.4 R3 Zn R3 O CuX 2 mol % O 2 2. NH Cl (s), Ar L 4 mol % 1 4 1 * R 2 3. DBU (1.4 eq) R 2 + 1.4 R2 Al 1 n R 1 n R 3 yield up to 95 % R CH2Cl2 R solvent 2 * R ee up to 96 % Org. Lett., 2010, 12, 4335 R1 -30 °C, 18h R1 enantioselective 1,4- vs 1,6-addition: Angew. Chem. Int. Ed. 2005, 44, 1376

Tips to improve yield and ee of 1,4-addition (at least with organozincs):

* Solvent choice: acetonitrile gives low conversion, toluene is generally used, but Et2O, THF, EtOAc show better ee and solubilize substrate better * Cu(OTf)2 generally used, but Cu carboxylates are more efficient: Cu(OCOCF3)2 in THF, Cu(OAc)2•H2O in Et2O and copper thiophene- 2-carboxylate (CuTC) (the most efficient) in either toluene, Et2O, or EtOAc, Cu naphthenate soluble in most solvent and the cheapest reagent. Angew. Chem. Int. * Of course, ligand choice ! Ed. 2008, 47, 1

J. Am. Chem. Soc. 2002, 124, 5263 enantioselective organocatalyzed 1,4-addition on nitrostyrene: O [{Rh(cod)Cl}2] O L O 1 O Ph + ArAlMe2 yield ≥ 99 % R (3 eq) ee ≥ 99 % H NO solvent * Ar H 2 15 % R1 NO N N Org. Lett 2002, 4, Angew. Chem. Int. Ed. 2010, 49, 1 Ph 2 3611 ArLi or ArMgBr + Me2AlCl --> ArAlMe2 O Ph (HCl 15%), CHCl3 O O 2 NO2 3 % Cu(OTf)2 O R 4 % L 1 R1 + EtMgBr yield ≥ 99 % 2 R ee up to 96 % R (1.2 eq) Et2O, 0 or -30°C * 30 min

J. Am. Chem. Soc. 2006, 128, 8417 Only one equivalent of the alkylating agent !!

6 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Synthesis of an indefinitely stable singlet diradical: Christian Amatore (École Normale Supérieure): catalysis and mechanism (with Didier Bourissou, Université de Toulouse) Evidence that PPh3 can reduce Pd(II) into Pd(0) for Pd couplings (e.g. Heck): tBu Thanks to cyclic voltammetry and 31P NMR they propose a mechanism for Cl Cl 2 iPr PLi B reduction of Pd(II) 2 i i B B ( Pr)2P PH( Pr)2 t t 68 % B Pd(OAc)2 + 2 PPh3 ––> Pd(OAc)2(PPh3)2 Bu Bu fast tBu Science 2002, 295, 1880 Ph3P OAc 0 - + Pd ––> "Pd (PPh3)" + OAc + AcO–PPh3 This diradical may be used as radical scavengers and initiators... slow AcO PPh3 Yves Chauvin: Nobel Prize in Chemistry in 2005 for his mechanistic PPh3 is then oxidized to O=PPh3 (2 mechanisms proposed with or without H2O (Université de Lyon) studies in alkene metathesis Organometallics, 1992, 11, 3009 * Dimersol process: nickel-catalyzed dimerization of propylene into Guy Bertrand (Université de Toulouse, then UC Riverside): isohexenes used as additives in gasoline as octane number boosters or used as plasticizers starting material

Synthesis of cyclic (alkyl)-(amino)carbenes (CAACs) * Alphabutol process: titanium-catalyzed dimerization of ethylene into 1- butene used as co-monomer for polyethylene synthesis * more electron rich than NHC and steric N N interactions are different Supramolecular chemistry: * CAACs can be mademore or less bulky Jean-Marie Lehn (Collège de France): Nobel Prize in Chemistry in 1987 for the development of cryptands Angew. Chem. Int. Ed. 2005, 44, 5705 NHC N N

O O Synthesis of stable bent allenes: m 134.8° 97.5° 85° Me N O O m N Me N N O O N N N N N N n N N J. Am. Chem. Soc. 1975, 97, 6700 Ph Ph

Angew. Chem. Int. Ed. 2008, 47, 3206 Angew. Chem. Int. Ed. Angew. Chem. Int. Ed. One of the first cryptands... 2008, 47, 5411 2009, 48, 4792 May serve as very strong donor ligands, but also quite fun!

7 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Methodology applied to total synthesis: Jean-Pierre Sauvage (Université de Strasbourg): Lehn's first PhD student (cryptands), works on rotaxanes, catenanes, molecular motors... Guy Ourisson (Université de Strasbourg, deceased): One-step synthesis of squalene from farnesol under prebiotic conditions For a review, see Acc. Chem. Res. 1998, 31, 611 Wächtershäuser primitive reducing system hypothesis also see Ishihara's GM 2010 OH FeS + H2S

-FeS2 OH

A fullerene-stoppered rotaxane

André Collet (École Normale Supérieure de Lyon, deceased): Synthesis of cryptophanes – for a review, see:Tetrahedron 1987, 43, 5725 Yield of this reducing coupling: 2 % !!! (compare to vanTamelen- McMurry coupling for this reaction : 30–40 %) Angew. Chem. Int. Ed. 1995, 34, 1898

Olivier Baudoin (Université de Lyon):

Palladium-catalyzed β-arylation of carboxylic esters:

R2 R2 Cryptophanes can be used to make xenon biosensor (P.G Schultz with Cy2NLi (1.7 eq), N. Winssinger) J. Am. Chem. Soc. 2004, 126, 15287 H OR toluene Ar OR ArX + Ivan Huc (Institut Européen de Chimie et Biologie, Bordeaux): Dynamic O [Pd2(dba)3] (5 mol%), O synthesis of self-assembled helicates davephos (10 mol%) 1.6 eq yield up to 82 % * ArBr reacts better but Cl can be used as well * often electron donor groups are required at the ortho position (F, OMe...), and some heteroaromatic compounds can be inserted there as well (pyridine, thiophene...) * enantioselective versions exist: ee around 50 % * competitive with α-arylation since it generates the same intermediate: Ar Pd R2 H OR Angew. Chem. Int. Ed. 2010, 49, 7261 Nature Chem. 2010, 2, 684 O 8 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Asymmetric synthesis of atropisomeric biaryl compounds: Me OTBS Et 1. A, MgSO , Et Et Et OMOM MeO OTBS 4 MeO MOMO 2.5% Pd dba CH2Cl2, reflux N 2 3 H2N NH2 6% L* + MeO CHO 2. DMF, MeO I Ba(OH)2 160°C, 52 % B(pin) dioxane/H O B 2 ee = 40% 80°C, 1h, 66% OMe 1.5 eq 1. aq. HCl OMe 6 electro- 2. O π cyclization Cl3CO OCCl3 CH Cl , -78°C Me (–)-rhazinilam (isolation 2 2 Me electrocyclic Z artefact, cytotoxic) 98 % MeO MeO N opening N Ar Et O Et Et O MeO MeO Ar O ee = 40 % ee = 92 % HN HN Me OTBS N by recrystallization MeO (34 %) NH NaBH4, MeOH B (d. r. = 6:1) J. Org. Chem. 2003, 68, 4897 MeO (–)-rhazinilam analog, more active (68%) OMe Total synthesis of coralydine: OMe Me 1) TBAF, THF Me Me 2) HBF , PPh , DIAD, MeO Pd(OAc)2 / P(t-Bu)3 Me 4 3 N MeO K2CO3, DMF, 140 °C MeO THF, reflux CO2Me CO2Me (54 %) MeO H MeO Br (83 %) MeO OMe (±)-coralydine 2 steps from 1) NaOH, aq. MeOH, Angew. Chem. Int. Ed. 2009, 48, 179 OMe commercially reflux available material (62%) 2) (PhO)2P(O)N3, Nicolas Winssinger (Université OH O Et3N, toluene, reflux, de Strasbourg): Mitsunobu Me then aq. HCl, 80 °C MeO Synthesis of resorcinol O NH2 macrocycle analogs: olefin named reaction ? HO metathesis MeO A Cl J. Am. Chem. Soc. 2005, 127, 6999 O alkylation

9 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Total synthesis of deguelin and tephrosin: Chem. Eur. J. 2010, 16, 9767 Max Malacria (Université Pierre et Marie Curie Paris 6):

Early works were radical cyclizations, for a review, see: Chem. Rev. 1996, 96, 289

Recent example: cyclization of N-acylcyanamides: Total synthesis of luotonin A

O 1. PPh3, THF, H2O 2. BzCl, Et3N, CH2Cl2, N3 47% (2 steps) N N I 3. NaH, BrCN, THF, 41% N I N 4 steps from quinoline Bu6Sn2, PhMe, chlorocarbaldehyde reflux, sunlamp, in four steps (56% 43 % overall yield)

O Angew. Chem. Int. Ed. 2007, 46, 576 N N N luotonin A Co-catalyzed cyclizations and cycloadditions: E = CO2Me i) 5 mol % CpCo(CO)2, hυ, 80 °C, 8 h O ii) H E O TMS TMS TMS hυ, 136 °C, 15 min R OMe iii) 5 mol % dppe, O TMS Me decane, 175°C, 12h one-pot !!! formal yield= 42 %, R/S : 86/14 Conia-ene [4+2]

R TMS Δ TMS E [2+2+2] E O O TMS Synthesis of oligosaccharides as a mimic of HIV epitope: Me TMS Me Angew. Chem. Int. Ed. 2009, 48, 1 J. Org. Chem. 1996, 61, 2699

10 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

Org. Lett. 2002, 4, 1027 Stereoselective Michael addition on chiral bis-sulfoxides: O named reaction ? O O O O 1. TFAA, pyr p-tol OAr p-tol S S (2 eq) S S 2. LiOH, H2O2 11 p-tol p-tol 50 % LDA, THF HO2C CO2H 11 -78°C, 79% 11 (+)roccellic acid Angew. Chem. Int. Ed. 2003, 42, 5342 O OAr

+ – 1. Me2S(O)CH3 I O O 2. NaH O O p-tol p-tol S S DMSO S S p-tol p-tol R R enantioselective synthesis of polyalkylated cyclopropane derivatives Angew. Chem. Int. Ed. 2008, 47, 6865

Sir Derek Barton: he was the director of the Institut de Chimie des Substances Naturelles (ICSN - Gif Sur-Yvette) from 1978 to 1986.

Gif chemistry: biomimetic hydroxylation of alkane catalyzed by Fe.

OH O Pt-catalyzed cycloisomerization: FeL(NCMe)2 (1 eq), R=Me H2O2 (10 eq) (1000 eq) + 1) PtCl2 (10 mol%) toluene, rt, 3h for a review, see Acc. Chem. Res. 1992, 25, 504 and also Voica's GM 2009 2) SiO2 55% (2 steps) RO Samir Zard (École Polytechnique): O R=p-NO2-C6H4C(O) 1) PtCl2 (10 mol%) works mostly on radical chemistry, like Barton radical decarboxylation, xanthates... toluene, rt, 18h, 85% Org. Lett. 2004, 6, 3771–3774. 2) K2CO3, MeOH 56% O 11 Baran Group Meeting Q. Michaudel Organic Synthesis from France 10/02/2010

H Barton-Zard pyrrole synthesis: Key steps: radical cascade, Pauson-Khand R1 R2 R1 N Me O base H H Bu SnH, ACCN N + R O Ph 3 NC R2 N O R N PhMe, 110°C O O O O O2N O H O 71% R1 R2 O Me Me R (-)-dendrobine J. Am. Chem. Soc. 1999, 121, 6072 N O B N See also the synthesis of (±)-aspidospermidine O R1 O R1 O R1 BH+ H Org. Lett. 2006, 8, 831 R2 R2 R2 H R R R "Thus, in one clean sweep, the side chain we NO NO N N NO N 2 N 2 had painstakingly attached was cut off and we H C 2 H were returned to our starting point." (±)-aspidospermidine Tetrahedron 1990, 46, 7587

Useful synthesis of pyrroles with an ester at the α-position Janine Cossy (École Supérieure de Physique et Chimie Industrielles de la ville de Paris): Some total synthesis using radical chemistry: Heck-Suzuki-Miyaura domino reactions involving ynamides: 3

Org. Lett. 2004, 6 , 2511

N H H H H Enantioselective reduction of cyclic aminoketones with carrots: N Org. Lett. 2009, 11, 1245 (±)-matrine

Angew. Chem. Int. Ed. 1998, 37, 1128

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Sequential enantioselective allyltitanations and metathesis: To conclude, a quote from Albert Camus (French Nobel Prize for Literature in 1957): metathesis O metathesis OH OH O "The struggle itself...is enough to fill a man's heart. One must imagine Sisyphus happy." The Myth of Sisyphus (+)-strictifolione enantioselective Are chemists the modern Sisyphus ??? allyltitanations

Org. Lett. 2003 5, 1995

Pierre Potier (Institut de Chimie des Substances Naturelles, deceased):

First semi-synthesis of Taxol from yew leaves: "Meanwhile, we had access to some yew trees, Taxus baccata L. (European species), which had to be felled to make way for a new road across the campus at Gif." Discovery of Docetaxel (Taxotere), commercialized by Sanofi-Aventis: this patent provides one of the most important fundings for CNRS !

Acc. Chem. Res. 1993, 26, 160