Natural Products Chemistry: Koji Nakanishi

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Professor Koji NakanishiDavid LinMagicNotorious for his magic tricks at conferencesMy personal favorite is the magic bag trick, where aperson climbs into a bag which is tied up. After themagician performs his charm, the person appears frombehind a nearby curtain. Nakanishi has performed thistrick on Raymond Lemieux, Gilbert Stork, JackBaldwin, Ron Breslow, and others.Bioorganic Chemistry Studies into the bioactivity of the ginkgolides Synthesis and study of the activity of retinalchromophores Determining the cause of macular degeneration, theprimary form of blindness in the elderlySpectroscopic Methods in Structure Determination First discovered phenomenon of NOE in naturalproducts Development of exciton chirality method fordetermining absolute stereochemistryNatural Products Isolation and Characterization: Elucidated the structures of over 180 natural products Highlights include: the ginkgolides, brevetoxin A & B,the illudins, periplanone B, the taxcins, theecdysteroids“A Wandering Natural Products Chemist”Natural Products Chemistry: Koji Nakanishi Born 1925 in Hong Kong B.S., Nagoya University, 1947 Ph.D., Nagoya University, 1954 (Fujio Egami) Studied at Harvard (Louis Fieser), 1950-1952 Asst. Professor, Nagoya University, 1955-1958 Professor, Tsukuba University (Tokyo), 1958-1963 Professor, Tohoku University (Sendai), 1963-1969 Professor, Columbia University, 1969-present Married to Yasuko Two children, Keiko and JunBaran Group Meeting8/11/04

OHOOHOCO 2MeOHOHCOOHtaxicinOAcOAcOAcabscisic acidOHilludinOAcOantheridiogenHHHOBaran Group e AHOOHCO2Meperiplanone BOpristimerinOOginkgolide BOO HOHOOONONHOHOHHNOHHOHOHMeOHOHHHOneosaxitoxinH2NHO HO HOHOHOHOHOHOOOHDavid Lintunichrome BONHOHcabenegrinOH OOHHOOHNH2NHObrevetoxin BHMeOOHgrayanotoxin IOAc OHHOHOwarburganalOHCNatural Products Chemistry: Koji Nakanishi

Natural Products Chemistry: Koji NakanishiThe Exciton Chirality MethodBaran Group Meeting8/11/04David Lin

Serendipity: Typhoon hits Sendai, Japan and uprootsmany ginkgo trees. Nakanishi group members rushto Sendai to obtain material.Problem: Ginkgolide extracted from the root bark ofthe ginkgo tree, removal of which kills the tree.David LinSerendipity: Undergraduate contaminates sample ofLAH-reduced ginkgolide with acid and leaves it indrying oven while he goes off to play baseball.Sample goes to tar in oven. However,chromatography of the tar produces ginkgolidetriether derivative which provides more useful NMRdata and Problem: NMR spectra of ginkgolide not very helpfulin structure elucidation.Characterization of the Ginkgolides: Serendipity Rocks!Natural Products Chemistry: Koji NakanishiCharacterization of the Ginkgolides: Serendipity Rocks!Baran Group Meeting8/11/04

NOTE: For a comprehensive review of the biology andchemistry of the ginkgolides and the related bilobalides,see Nakanishi’s recent review: Angew. Chem. Intl. Ed.2004, 43, 1640.David LinEtO2C 350 nm100%hvO1.2:1 drOH2. i-Bu2AlH95% overall1. t-Bu2CuCNLi2CMe3OHC2Et3SiOOCO2EtCMe3OCuBr . SMe2HMPA, Et2O, THF82%MECHANISM?ZnCO2EtOOEt3SiOCMe3CO2Et2. n-BuLi, ClCO2EtTHF, -78 oC95% overallOTHF, -78 oC97%BrMg1. Et3SiCl, Et3NCH2Cl2CMe3ORATIONALIZE THE OBSERVEDDIASTEREOSELECTIVITY.CMe3O1. DEAD, Ph3P,p-NO2C6H4CO2H, PhCH32. NaOH, THF, H2O99%CMe3Et3SiOOHEtO2COCrimmins synthesis of ginkgolide B: J. Am. Chem. Soc. 1999, 121, 10249;J. Am. Chem. Soc. 2000, 122, 8453.Natural Products Chemistry: Koji Nakanishi The Discovery of NOEBaran Group Meeting8/11/04

EtOrationalizing diastereoselectivity of the [2 2]:EtO2COOCMe3OCO2EtCMe3O3. EtOH, H2O, reflux4. PPTS, PhH, reflux63% over four steps1. HF/CH3CN2. MsCl, Et3NOOOCMe3ODavid LinHC(OMe)3p-TsOH95%overallMeOHPhSeCl, HCl,then NaIO4OOOOOO1:5.5 deH2O, acetone94%MECHANISM?OOOOO6 N HCl, acetoneOMeOHCMe3OH OMeCMe3ODMDO, thenp-TsOHOOHOHCMe3H OHOMeOHCMe3OH OMeONotice that a stereocenter has been inverted. This route wastaken to improve the diastereoselectivity of the [2 2]cycloaddition, which was poorer with the trans stereochemistry.Et3SiOONatural Products Chemistry: Koji Nakanishimechanism of Crimmins' homoenolate cyclopentenone formation:Baran Group Meeting8/11/04

OOOOOH2OCMe3OOPhONSO2PhOOOO HO66%OOOCMe3OO OMeEtOMeOHOHCMe3OOHOHCMe3H OHOOHNEt2, t-BuLi, THF O1.CMe3OOMe 2. (EtCO)2O, Et3NOHOHCMe3OOH2H OMeHOOOThis somewhat curious deoxygenation temporarily removes a hydroxyl whichproved troublesome in the upcoming ring-closing step.2. Bu3SnH, AIBN,60 oC78%ODMDOCMe3O1. CS2, MeI, DBU OOO OOOOLDAoOMe100%CSA88%MeOHTHF, -78 C HOOMeCMe3OOMeCMe3OO OMeEtOOHOOOVO(acac)2,t-BuOOHCH2Cl2, p-TsOH81%HOCO2MeOOHOOHOOOMeOHOOCMe3OOHOO HOOOHOOginkgolide BOHOCMe3HCMe3ODavid LinOMeOCMe3OHMeOH50%MeONa2. AcOH, MeNaOAc, Br2HO52%OOOOOMeCO 2MeCMe3 1. DMDOC6H5Cl85%PPTS, pyrOCMe3OOMeMeO2COOHere they racemize a troublesome stereocenter toachieve the poor 50% yield, but the undesireddiastereomer was easily recovered and recycled.HOOOOONatural Products Chemistry: Koji Nakanishimechanism for cyclobutane ring rupture:Baran Group Meeting8/11/04

OOHOHRR2R1HOα-OH: illudolβ-OH: epi-illudolOHOHOHilludeneOHOH OHCOOHIlludin BOIlludinic AcidOHO Highly toxic sesquiterpene first isolated from the bioluminescent mushroom tsuki-yo-take Possesses potent antitumor activity, probably by crosslinking DNA base pairs Subject of intense medicinal chemistry/SAR studiesOHOHIlludin AOR1, R2 H:Illudin CR1 OH, R2 H: Illudin C2R1 H, R2 OH: Illudin C3OIlludin M (R H)Illudin S (R OH)HODavid LinAc2OOOMeOOMeO O2. acetylation1. tBuOKAcOOOSSOOOAcOSOOOAcAcOHOOHOOO SHO SOOAcOOAcstereoselective; otherdiastereomer not observedOOSselective for ketone shown,and stereoselective as enzene, refluxO OCHOOOOAc OAcO OO SHOOOAcONa 2. acetylation3. dilute HCl1. NaBH4OEtNAMEREACTION?MECHANISM?AcOOOSOThe First Synthesis, Illudin M: Matsumoto et al (J. Am. Chem. Soc. 1968,90, 3280)Natural Products Chemistry: Koji NakanishiThe Illudins, Illudanes, and ProtoilludanesBaran Group Meeting8/11/04

-HI OO OSOSOOMeIH OSAcOOHOO SHAc2OSOOAcbaseAcOHMeOO OAcO2. HgCl2acetone-SOOHSSOIOMeOOMeilludin M (racemic)HOOMeSOAcO OOOHOOH OIMeOHSOI-H1. NaBH4the Pummerer rearrangement:OO %MECHANISM?NaO2SAr98%2:1 exo:endo OButX 2ArO75%5:3 deSwern87%Na(Hg)HOHOOOHHHOOendoOSO2ArOPhI CN-OTfDavid LinNote that stereoconfiguration at bridgehead carbonsultimately do not matter, so both isomers carried forward.OtOTfO- PhIArSO2NaPadwa et al, J. Org. Chem. 1997, 62, 1317.Natural Products Chemistry: Koji Nakanishimechanism of oxidative cyclization:Baran Group Meeting8/11/04

OSO2ArOORhOOOOHSO2ArOendotBuHHere Padwa intercepts a knownintermediate from another HOODavid LinHOHOOHilludin-M30%OOOOHOHOundesired n of the Padwa synthesis: Kinder and Bair, J. Org. Chem. 1994,59, 6965.HOONatural Products Chemistry: Koji NakanishiPadwa's Rh(II)-catalyzed 1,3-dipolar cycloaddition:TfO-Omechanism of cyclization:Baran Group Meeting8/11/04

BrNOEtOH, 40oCHOEt2O-78 oC -- rt58%SO2NHClANBOHEtOH, H2O82%ONAHBr2. MsCl, Et3NCH2Cl2, -78 oC;DBU, rt73%1. Ra-Ni, H2, B(OH)3,MeOH/H2O72%THF, -78 oC68%t-BuLi, 3 eq2. DBU, 80 C58%o1. PPh3, I2, imid.benzene, rt82%BrOOHHHODMF, 3 eqCH2Cl2, rt, 72 Et3SiOPOBr3 , 2.5 eqOHOilludin-COHOHONBOOOOEtO OEtMeO2CAcOOMeO2COhvOEtOEtOOOstepsEtO OEtAcOPhCHO, KOHNaBH4Ac2O/pyr HOO3KOHEtOH, 40oC1.2.3.4.5.2. 20% HClO41. BrOOHMgBr2. Ac2O/pyr1. Bi2O32. H2/Pd-C1. NaHDavid LinOHilludol2. O33. Ag2O, then CH2N24. MsCl/pyr1.OHIlludol: Matsumoto et al (TL 1969, 3913; TL 1971, 3521):Natural Products Chemistry: Koji NakanishiFunk's synthesis of illudin-C (Org. Lett. 2001, 3, 2611):Baran Group Meeting8/11/04

OBnOEtO[4 2]OEt3. LDA, PhSeCl4. H2O21. LDA, CO22. CH2N2O3. BnBr, NaHOHHMatsumotointermediateEtO OEtEtO OEtMeO2CMECHANISM?3. CrO3, pyridineOEtOEt1. 3A mol sieves2. LiBEt3HOTMSEtO2CCO2EtOEtEtOOTMS99%LDA,TMSCl63%[2 2]1. LiAlH42. Li, NH2Et, ClPO(NR2)270-75% 20:1 deCO2EtOEtEtOOEtOEtCO2EtOTMSCO2Etsteps1. CpCo(CO)2toluene, hv, 110 oCOHOHOH2. ludolIlludol: Vollhardt (J. Am. Chem. Soc. 1991, 113, 381):Natural Products Chemistry: Koji NakanishiIlludol: Semmelhack (J. Am. Chem. Soc. 1982, 104, 747):Baran Group Meeting8/11/04OSiMetBuDavid Lin

OHstepsNAMEREACTION?mCPBATHF, 70 oCKH, 18-crown-6OEEOOTMSOEEO-Operiplanone BOOMe3SiCl, -78 oCO63%MgBrHOHHKH, 18-crown-672%hv, Et2OOO2:1 de60 oC75%anionic oxy-Cope rearrangementHHHPeriplanone B: S.L. Schreiber (J. Am. Chem. Soc. 1984, 106, 4038):OEEOOEEOTMSOEEOHOOstepsOperiplanone BOO[2 2] electrocyclic ring openingHhv, benzene82%175 oC, toluene77%Natural Products Chemistry: Koji NakanishiPeriplanone B: W.C. Still (J. Am. Chem. Soc. 1979, 101, 2493.Baran Group Meeting8/11/04David Lin

Natural Products Chemistry: Koji NakanishiAdditional References Circular Dichroism: Principles and Applications. 2nd Ed.Berova, N., K. Nakanishi, R.W. Woody, eds. New York:Wiley-VCH, 2000. Nakanishi, K. A Wandering Natural Products Chemist.J.I. Seeman, ed. Washington, D.C.: American ChemicalSociety, 1991. Nicoloau, K.C., E.J. Sorensen. Classics in TotalSynthesis. New York: VCH Publishers, 1996. A complete list of Nakanishi’s publications may be foundat his group’s s/nakanishi/Baran Group Meeting8/11/04David Lin

Natural Products Chemistry: Koji Nakanishi Baran Group Meeting 8/11/04 David Lin Professor Koji Nakanishi Born 1925 in Hong Kong B.S., Nagoya University, 1947 Ph.D., Nagoya University, 1954 (Fujio Egami) Studied at Harvard (Louis Fieser), 1950-1952 Asst. Professor, Nagoya University, 1955-1958 Professor, Tsukuba University (Tokyo), 1958-1963 Professor, Tohoku University .

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