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Literature Seminar#1 Literature Seminar (B4 part) January 17, 2012 Seiko KITAHARA (B4) Total synthesis of Laulimalide OH H O O 15 23 20 17 O O OH 1 H H O 3 5 9 1: Laulimalide (fijianolide B) Contents 1. Introduction 2. Previous Total Synthesis 2-1. Retrosynthetic Analysis 3. Trost's Total Synthesis -toward the atom economy- 3-1. What is "synthetic efficiency" ?? 3-2. Retrosynthetic Analysis 3-3. Total Synthesis Marine Sponge, 3-4. Asymmetric Direct Aldol Reaction Cacospongia mycofijiensis via a Dinuclear Zn Catalyst 3-5. Rh-Catalyzed Cycloisomerization 3-6. Ru-Catalyzed Alkene-Alkyne Coupling Barry M. Trost 1. Introduction OH OH H O H O 15 O OH 20 O 23 17 17 15 20 O O OH 1 H H On exposure to acid O O O 5 9 3 (within two hours) H H O 1: Laulimalide : intrinsically unstable isolaulimalide (fijianolide B) (fijianolide A) <Isolation> -From various marine sponges such as hyattela sp., Cacospongia mycofijiensis, f asciospongia rimosa a marine sponge in the genus Dactylospongia a nudibranch, Chromodoris lochi with its tetrahydrofuran containing isomer isolaulimalide <Structure> -Determined NMR analysis and X-ray crystallographic analysis Corley, D. G et al. J. Org. Chem. 1988, 53, 3644. Quinoa, E et al. J. Org. Chem. 1988, 53, 3642. -20-membered macrolide <Biological activity> -like Taxol (paclitaxel), induces microtubule polymerization and stabilization -unlike Taxol (paclitaxel), retains activity in multidrug resistant cell lines -binds to a different site than other known microtubule stabilzers suggesting new opportunities forchemotherapy ?? <Total synthesis> -Hot topic for over a decade (more than 10 reports !) due to its significant clinical potential its strict natural supply unique and complex molecular architecture Ghosh, A. K. et al. J. Am. Chem. Soc. 2000, 122, 11027. Ghosh, A. K. et al. J. Org. Chem. 2001, 66, 8973. Mulzer, J. et al. Angew. Chem., Int. Ed. 2001, 40, 3842. Paterson, I. et al. Org. Lett. 2001, 3, 3149. Enev, V. S. et al. J. Am. Chem. Soc. 2001, 123, 10764. Wender, P. A. et al. J. Am. Chem. Soc. 2002, 124, 4956. Crimmins, M. T. et al. J. Am. Chem. Soc. 2002, 124, 5958. Williams, D. R. et al. Tetrahedron Lett. 2002, 43, 4841. Nelson, S. G. et al. J. Am. Chem. Soc. 2002, 124, 13654. Ahmed, A. et al. J. Org. Chem. 2003, 68, 3026. Gallagher, B. M. et al. Med. Chem. Lett. 2004, 14, 475. Uenishi, J. et al. Angew. Chem., Int. Ed. 2005, 44, 2756. Gollner, A. et al. Chem.-Eur. J. 2009, 15, 5979. Trost, B. M. et al. J. Am. Chem. Soc. 2009, 131, 17089. 2. Previous Total Synthesis 2-1. Retrosynthetic Analysis Fragment union Fragment union asymmetric by Julia-Kocienski olefination by allyl transfer OH epoxidation OH Route4 Route3 H O H O 15 O 15 20 20 23 17 Route0 23 17 O O OH O O OH 1 H H 1 H H O Macrocyclization Route2 O 3 5 9 by Yamaguchi lactonaization 3 5 9 Route1 Macrocyclization 1: laulimalide by Still-Gennari reaction 2 Although more than 10 syntheses were reported, the retrosynthetic route was limited. (route0 the combination of route1-4) 3. Trost's Total Synthesis 3-1. What is "synthetic efficiency"?? Trost, B. M. et al. Science. 1991. 254, 1471. Efficienct synthetic methods require to chemo-/regio-/diastereo-/enantio-selectivity atom economy = how much of the reactatns end up in the product An process that is both selective ant atom economical remains a challenge. Transition metal catalysis enable this ?? Cycloisomerizations offer opportunities for enhancing efficiency for construction of difficult medium and large rings converted to a unsaturation a ring unsaturation (with only a hydrogen shift) Trost used 3 atom economic reactions in total synthesis of laulimalide, and 2 of these is cycloisomerization 1. synthesis of syn-diol 2. synthesis of dihydropyran 3. synthesis of 1.4-diol Zn-cat. H Ru-cat. 3-2. Retrosynthetic Analysis Trost's retrosynthetic anlysis is based on the notion that laulimalide 1 could be formed from 1,4-diene 3. asymmetric OH epoxidation OPMB H O H O 15 O 15 20 20 23 17 23 17 O O OH O O OH 1 H H 1 H H O O 3 5 9 3 5 9 1: laulimalide 2 allylic transposition Ru-catalyzed alkene-alkyne OPMB OPMB coupling H H O 17 O 17 15 20 20 23 15 23 OH OH O O O O 1 H H 1 H H O O Still-Gennari 3 5 9 3 5 9 olef ination 4 3 Julia-Kocienski PMP olefination OPMB N O H H N N O 17 O H 17 20 S N 20 23 15 23 + O O 15 O O OMOM Ph O O OMOM 1 O 5 P 6 7 F CH CO 3 2 OCH2CF3 + H H H O HO H 3 O 9 9 5 9 O OBn OBn 8 9 10 3-3. Total Synthesis Trost, B. M. et al. J. Am. Chem. Soc. 2009, 131, 17087. <Synthesis of 6> N N 1) DEAD, PPh , Et2Zn, 10 mol% Pd(OAc)2, O 3 HO N OH 1-phenyl-1H-tetrazole-5-thiol (82%) S N 25 mol% PPh3, allyl acetate, Ph 11 2) CuI, propenylmagnesium bromide, 12 THF (62%, 76%brsm) THF (99%) N N MesN NMes N N H N 1) 15 mol% Mo7O24(NH4)6 4H2O, O N Cl O H O , EtOH (83%) S N Ru S N 2 2 O Ph Cl Ph O Ph PCy3 6 13 2) 3 mol% G2, CH2Cl2(0.015 M) (95%) G2 <Synthesis of 5> 1) H C=CHMgBr, CuI,THF (95%) S 2 H OH 2) MOMCl, i-Pr2EtN, N O + S CH2Cl2 (97%) O OMOM Et O 3) MeI, CaCO3, 14 15 9:1 MeCN/H2O (85%) 16 15 mol% (R,R)-I, Et Ph THF (53%, 10:1 dr) O O Ph Ph Zn Ph PMP Zn 1) p-MeOPhCH(OMe) , N O N 2 OH O 10-CSA, CH2Cl2 (81%) H 2) NaBH4, THF (86%) N Et O O OMOM 3) Dess-Martin periodinate, O OH OMOM CH2Cl2 Me 7 17 (R,R)-I 1) 6, LiHMDS, 3:1 DMF/HMPA 64% (64% over 2 steps) 2) DIBAL-H, CH2Cl2 (61%) OPMB OPMB H (CF CH O) P(O)CH CO H, H O 3 2 2 2 2 O 2,4,6-trichlorobenzenoylchloride, OH OMOM i-Pr2EtN, THF, O O OMOM O 18 then DMAP, PhH (99%) P 5 F3CH2CO OCH2CF3 12 13: Pd-catalyzed allylic etherification using Zn(II) alkoxides Kim, H. et al. Org. Lett. 2002, 4, 4369. -Generally, WIlliamson ether synthesis (SN2 type O-alkylation) is impractical. DMF O RX + R'O Na R R' SN2 Due to the strong basicity of Nu E2 Other products -Also in this case, allylation under basic or acidic condition were ineffective. N N N N N O HO base O N S N S N -SR ?? Ph Ph 12 Alternative approach: Pd-catalyzed allylic etherification The addition of O-nucleophile to an 3-allylmetal intermediate Mild & Stereoselective MISMATCH ! modulating the apparent "hardness" of RO = Hard RO aliphatic alcohols: Can the Zinc effect lead to "softening" ?? poor nucleophilicity Zn(II)-bound alkoxides possess weakened basicity Soft R' strong hardness while reatining sufficient nucleophilicity !! -allylpalladium the zinc effect in biochemistry: the Zn enzyme LADH Kimura, E. et al. J. Am. Chem. Soc. 1992, 114, 10134. Parkin, G. et al. Chem. Commun. 2000, 1971. II Zn-containing The pKa of alcohols(normally ~16) liver alcohol dehydogenases (LADH) can be reduced by about 9 units upon coordination to ZnII ?? Nucleophilicity is reatined. LADH catalyze the hydride transfer from alcohol to NAD. + deprotonation hydride transfer 13 6: oxidation of the sulfide into the corresponding sulfone using H2O2 and Mo(VI)catalyst -Altough sulfoxides and sulfones are important in synthetic oranic chemistry, only a few reports are available for selective oxidation of sulfides to sulfoxides and sulfones The oxidation of sulfides to sulfoxides with H2O2 Kaczorowska, K. et al. Tetrahedron. 2005, 61, 8315. Several disadvantages of sulfide oxidation: H2O2 is the most attractive oxidant : selectivesulfide oxidation long reaction times relative mild conditions inconvenient reaction conditions an ideal waste-avoiding oxidant: water is only byproduct ! expensive oxidants only a small excess of H2O2 undesired reactions at other FGs high yield low yield liquid-phase reactions good solubility in water and many organic solvents Moreover,aqueousH2O2 has further advantages: safty in storage, operation, and transportion commercially available reatively cheap However, H2O2 alone has possibility of an over-oxidation reaction. The oxidation of sulfides to sulfoxides with H2O2 & catalyst Controlled oxidation of sulfides to sulfoxides and sulfones Chiral oxidation is possible ! Mo(VI) catalyst/H2O2 system at room temperature Jeyakumar, K. et al. Tetrahedron. Lett. 2006, 47, 4573. Jeyakumar, K. et al. Catalysis. communications. 2009, 10, 1948. MoO2Cl2/H2O2 system New system used in this time R R commercially available (NH4)6Mo7O24 4H2O is cheap air stable Substrate Scope of (NH4)6Mo7O24 4H2O/H2O2 System -Both systems provide excellent yield with short time. -In both systems, various sensitive functional groups are tolerated such as alkyl, allyl, vinyl, propargyl, alcohol, ketone, ester, and remarkably oxime ! <Synthesis of 10> CO Me O 2 methylpropilate, O CuI, MeLi, THF, Pd(OH)2,H2, O n-BuLi, BF3 Et2O, then AcOH, PhH (94%) EtOAc (97%) O O THF (93%) HO OBn OBn OH 19 OBn 20 21 22 DIBAL-H,CH2Cl2, then Dowex 50W 8a), MeOH (99%) HO MeO 1) TEMPO, NaOCl, MeO AcOH, H SO , KBr, NaCO , O 2 4 O 3 O H2O (82%) CH2Cl2/H2O (97%) 2) ethynylmagnesium bromide, OBn OBn THF (77%) OH 3) NaH, BnBr, DMF (96%) 25 24 23 dimethyl-1-diazo-2- oxopropylphosphonate, K2CO3, MeOH (57%, 69% brsm) a) Dowex: -One of the more common ion-exchange resins.
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