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Gibberellins

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The document summarizes research on gibberellins, a class of plant hormones. It outlines the presentation topics, which include the history and discovery of gibberellins, their biosynthesis, the structure and reactivity of gibberellic acid, conversions between gibberellins, and approaches to total and partial synthesis. It then provides highlights on the history of gibberellin research from the initial discovery of the "bakanae" disease in rice to the isolation and structural elucidation of gibberellic acid. Biosynthesis occurs in three stages, and the structures and rearrangements of gibberellic acid under basic and acidic conditions are shown. Methods for oxidizing different carbons on the gibberellin

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Highlights from the Synthesis of Gibberellins: a 30 Year Odyssey O OH H OC HO H CH3 CO2H A Friday Afternoon Seminar 6 February 2004 Jonathan R. Scheerer 01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM
Highlights from the Synthesis of Gibberellins: O OH H OC HO H CO2H CH3 Outline of Presentation: I. Introduction to Gibberellins: History, Ubiquity, and Biology II. Biosynthesis III. Gibberellic Acid: Structure and Reactivity IV. Conversion of Gibberellic Acid into other Gibberellins V. Total Synthesis VI. Partial Synthesis / Stragedy Relvant Reviews: Mander, Chem. Rev. 1992, 573-612. Mander, Nat. Prod. Rep. 2003, 49-69. MacMillan, Nat. Prod. Rep. 1996, 229. Crozier, A. Ed. The Biochemistry and Physiology of Gibberellins. Praeger: New York, 1983. (vol 1 and 2) 02-gibberellin-outline.cdx 2/5/04 5:11 PM
A Brief History of Gibberellin Research: O OH H OC HO H CO2H CH3 1828 - first reports of "bakanae" disease in rice plants (foolish seedling; stupid rice crop) 1898 - first research paper, links disease to fungal infection 1912 - Kurosawa found that filtrates from infected dried rice seedlings also causes disease Concludes that bakanae is caused by discrete chemical 1935 - First use of term "gibberellin" in scientific literature 1938 - Crystalline compound (mix of three gibberellins) isolated from fungal filtrate 1945 - Research expands to U.S. and U.K. 1955 - compound isolated. termed "gibberellic acid" 1958 - correct structure proposed (stereochemical ambiguities remain) 1961 - structure verified by X-ray 1978 - First total synthesis (Corey) 03-bakanae.cdx 2/5/04 5:19 PM
C20 and C19 Gibberellins: Structure and Nomenclature 11 12 20 1 CH3 HC 13 2 9 10 8 14 A 17 HO2C 5 16 3 4 6 HO2C 15 D H H HO2C CH3 7 CO2H 19 18 GA12 C20-Gibberellin Skeleton ent-gibberell-16-ene-7,19-dioic acid 11 12 1 O H 13 2 9 8 14 OC 19 B 17 R 5 16 3 6 O 15 H O H CH3 7 CO2H R = CO2H 18 GA9 C19-Gibberellin Skeleton ent-norgibberell-16-ene-7,19-dioic acid 19,10-lactone 05-gibberellin-structureB.cdx 2/5/04 5:13 PM
Gibberellic Acid (GA3) 11 12 OH 1 O OH H H 13 2 9 8 14 H3C OC19 17 5 16 R 6 3 15 O HO H OH 7 CO2H GA3 O H R = CO2H CH3 18 Fermented from Gibberellia fujikuroi (a fungus) on ton scale Bioactive at low concentrations ((sub-nanomolar common for applications) Widely investigated and applied for commercial uses Retail prices: $10 / g Current yields: 15-30 g / L culture Also bio-available in decent quantity: O O OH H H OC OC HO H HO H Me CO2H Me CO2H GA4 GA1 07-gibberellin-GA3.cdx 2/5/04 8:55 PM
A Brief History of Gibberellins: O OH H OC HO H CH3 CO2H Representative Biological Functions of Gibberellins: – Stimulate stem elongation by stimulating cell division elongation – Breaks seed dormancy in plants which require winter freezing – Stimulates flowering/budding in response to lengthening days – Can induce seedless fruit development (parthenocarpic) – Can delay senescence (ripening) in leaves and fruit – Induces maleness (sex expression) in dioecious flowers – Other growth effects on fruit and budding 08-gibberellin-functions.cdx 2/5/04 5:15 PM
Gibberellin Biosynthesis: Three Stages H3C HO Me H 3C H H Stage A Stage B HO2C OH H H HO2C CH3 CHO mevalonic acid (MVA) H3C CH3 GA12-aldehyde ent-kaur-16-ene Stage C O H OC H3C H H CH3 CO2H H HO2C CH3 CO2H C19-gibberellins and C20-gibberellins 10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM
Gibberellin Biosynthesis: Stage A H 3C * H H 3C H HO CH3 HO2C Stage A * OPP * OH mevalonic acid (MVA) H * H ent-CCP H3C CH3 H3C CH3 ent-copalyl * ent-kaur-16-ene pyrophosphate OPP IPP OPP Isopentenyl GGPP pyrophosphate geranyl-geranyl pyrophosphate OPP IPP IPP OPP OPP DMAPP GPP FPP Dimethylallyl pyrophosphate 11-gibberellin-biosynthesis2 2/5/04 12:30 PM
Gibberellin Biosynthesis: ent-CCP to ent-kaurene H Ha H3C H H3C H OPP H H H5R H3C CH3 H3C CH3 H5S ent-CCP ent-kaur-16-ene ent-copalyl pyrophosphate Ha Ha H H H H H4 H5R H5R Ha H OPP H4 5S H5S H4 H5S H5R 12-biosynthesis3.cdx 2/5/04 10:11 PM
Gibberellin Biosynthesis: Stage B H3C H CH3 CH3 H H Stage B H H H O H3C CH3 HO2C CH3 CHO HO2C Hb Hd ent-kaur-16-ene GA12-aldehyde see next slide biosynthetic progenitor H3C H H3C H of all gibberellins same biosynthesis for OH fungal or higher order plants H HS H Hd CH3 ent-kaur-16-en-19-ol HO2C CH3 Ha Hb HR OH H3C H H3C H Hc H H Hd HS CH3 HO2C CH3 Ha Hb O ent-kaur-16-en-19-al 13-biosynthesis4.cdx 2/5/04 10:35 PM
Gibberellin Biosynthesis: Ring Contraction H3C H CH3 H Stage B H H H3C CH3 HO2C CH3 CHO ent-kaur-16-ene GA12-aldehyde OH H O H OHC HO2C H HO2C HO2C H H H H O 1,2-radical Enz Fe 4+ shift OH Enz Fe3+ H O HO HO2C radical trapping H H 14-biosynthesis5.cdx 2/5/04 12:37 PM
Gibberellin Biosynthesis: Stage C CH3 CH3 CH3 OH CH3 R H H and/or H H H HO H R H H CHO HO2C CH3 CO2H HO2C CH3 CHO HO2C CH3 CO2H HO2C CH3 early or late oxidations of C3, C13 R = H, OH GA12-aldehyde OH HO O R O R R H H H CO CO R R R H -very complex H H -parallel pathways CO2H CO2H HO2C CH3 CO2H Me Me -organism dependent (fungal or higher order plants) -converge to common GA O R O R OH R H H H GAn OC R H R R H H CO2H CO2H HO2C CH3 CO2H HO2C CH3 Me many complex, as yet incompletely oxidative decarboxlyation defined, oxidative processes 15-biosynthesis6.cdx 2/5/04 12:40 PM
Rearrangements of Gibberellic Acid in Basic Media O OH OH HO H H 0.01 N NaOH OC HO HO H H CO2H CH3 CO2H HO2C CH3 GA3 OH H O OH via H Gibberellic Acid O CO H HO CO2H H –OOC CH3 CH3 CO2H transformation can be isolable effected by palladium O OH O OH H Base H OC OC HO H HO H CH3 CO2H O OH CO2H –O H CH3 retrograde favored equatorial aldol / aldol O H C3 configuration H3C CO2H 16-GA3rearrangements.cdx 2/5/04 11:41 AM
Rearrangements on Gibberellic Acid in Acidic Media O OH OH H OC H+ HO H HO H CH3 CO2H CO2H (or H2NNH2) HO2C CH3 GA3 Gibberellic Acid Gibberellenic Acid H H H OH CH3 OH H+ O CH3 H+ H2NNH2 CO2H 1,2 shift CO2H CH3 CO2H CH3 CH3 Thermodynamically more stable C9 epimer H OH OH R "...gibberellic acid has enjoyed CH3 CO2H H a significant notoriety for instability and rearrangement. This view appears to be exagerated." L.Mander 17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM
C11 oxidation: Bishydroboration HO O O H BH3•SMe2 H OC OC AcO H2O2, NaOAc H AcO H OH H Me CO2Me CO2Me Me OH H 2B H HB H H OH BH3 H H HO O H OC HO H Me CO2Me e.g. GA35 18-GA-C11oxidation.cdx 2/5/04 11:34 AM
C12 oxidation of Gibberellin Skeleton OH O OH OH OAc OH OAc O OAc H OC Br Pb(OAc)4, I2 OC Br Zn, HOAc OC H H H Me CO2Me Me CO2Me Me CO2Me Zn Pb4+ Br OH Br O Br OH Br O OH H H H H H –1e– H H OH OH OH O O O OH H H H OC OC OC H H H Me CO2H Me CO2H Me CO2H GA70 GA69 GA31 19-GA-C12oxidation.cdx 2/5/04 11:32 AM
C14 Hydroxylation of Gibberellin Skeleton O O OH H OH H OC O OC O OH MOMO MOMO H H CO2Me Me CO2Me Me acyloin NaOMe rearrangement O O O OH H OH OH HO H OC O dipole MOMO minimized? NaOMe H Me CO2Me OH OH H 2 steps O HO O Ab initio: ∆5.7 kcal O OAc O OAc H H OC OTBS OC O MOMO H 1) DMDO MOMO H OH Me CO2Me 2) TBAF Me CO2Me 20-GA-C14hydroxlation.cdx 2/5/04 11:29 AM Mander, Tetrahedron, 1998, 11637.
C18 Hydroxylation of Gibberellin Skeleton O H O H H H OC OC O HO H H CO2Me CO2Me Me OH NaOH O H HO2C H RhCl(PPh3)3 O DABCO H H CO2Me Me 9 : 1 at C4 O H H OC O H H AllylOH HO H 2 : 3 mixture of OC DBU CO2Me 3α and 3β−OH O O H CO2Me O– Thomson, Mander, JCS Perkin I, 2000, 2893. 21-GA-C18hydroxlation.cdx 2/5/04 11:25 AM
Conversion of C19 Gibberellins into C20 Variants O OMOM OMOM H H Li/NH3 SOCl2; OC MOMO tBuOH CH2N2 H H CH3 CO2Me CO2Me HO2C CH3 OMOM OMOM H H Li/NH3 Cu (powder) H tBuOH H PhH, 80˚C CO2Me CO2Me CH3 O CH3 N2 O OMOM CHO OMOM H H KH, DMF; O2 OC OK OK OK H H O CO2Me CO2Me O CH3 HO2C CH3 O O C20 gibberellins: e.g. GA19 22-GA-C19toC20.cdx 2/5/04 11:23 AM Mander, Tet. Lett. 1985, 5725.
Radical Cascade: Attempted Deoxygenation at C3 O OAc H O CO H OAc Bu3SnH H RO H O Me CO2Me O H Me CO2Me O SnR3 O OAc H R3Sn-S O S H OAc equatorial (α) H CO C3 hydroxyl removed PhO O without event O H CO2Me O Me H Me CO2Me Bu3SnH O R3Sn-S OPh O R3Sn-S OAc H OAc H H O O O 5-exo O 5-exo H H Me CO2Me CO2Me O Me O Barton, McCombie, JCS Perkin I, 1975, 1574. Mander,TL, 1996, 4255. 23-GA-radicalcascade.cdx 2/5/04 11:15 AM *synthetic application: Sherburn,JACS, 2003, 12108.
Dismantling and Reconstituting the A-Ring O OH OH H H OC HO H H Me CO2Me methyl gibberellate CO2Me Corey-Carney Acid HO2C CH3 TsCl, pyr Zn Br O OH O OH H NaBr, H OC OC HMPA TsO H H 1) mCPBA Me CO2Me CO2Me 2) NaOH Me 76% I OH O HO H OH F3C O H 1) I2, NaHCO3 Zn OC 2) TFAA, pyr HO O H HO H CO2Me 90% 60% HO2C CH3 Me CO2Me Danheiser, Strategies and Tactics in Organic Synthesis. 24-GA3-coreytotal1.cdx 2/5/04 12:45 PM Ed. Lindberg 1984, 22-65.
Corey Synthesis of GA3: Hydronaphthalene Approach O O H 7 steps PhH, 80˚C OMe OMe 90% OMe O O HO O BnO HO o-allyl eugenol BnO H H 1) H2, Rh/C 1) DHP, TsOH K, TiCl3 2) Li, NH3 2) NaBH4 (50%) O O 3) PDC 3) MOMCl, iPr2NEt OMOM 4) LAH THPO CHO THPO 5) MsCl, NEt3 ; H2O BnO 50% from [4+2] adduct Oxidation Products: H H H H 1) Cl3CCO)2O, NEt3, DMSO OH OH OH OMEM O 2) MEMCl, iPr2NEt H H OH O THPO THPO O 60% "...quenching reactions involving OH O 50g of potassium can provide moments of great drama, as well as piquant stimulation COR R=H / OH O for the experimentalist." 25-GA3-coreytotal2.cdx 2/5/04 12:47 PM Corey, JACS, 1978, 8034.
Contraction of B-Ring; A-Ring Formation through Cycloaddition H H 1) OsO4, NMMO OHC 2) Pb(OAc)4 Bn2NH2+-TFA– OMEM OHC OMEM O 89% O 78% THPO THPO 1) Ph3PCH2 OHC H OMEM OMEM H OMEM H nBuLi; HMPA, 65˚ Cl O O 2) AcOH Cl Cl 57% HO THPO O O 72% OMEM OMEM H H 160˚C, PhH LiN(iPr)C6H11; H Me O Cl MeI H H O O O 70% O 55% 26-GA3-coreytotal3.cdx 2/5/04 12:51 PM Corey, JACS, 1978, 8034.
Gibberellic Acid Endgame: Corey OMEM 1) ZnBr OH H 2 H 2) KOH, Na2RuO4 Me H H 95% CO2H O HO2C Me O TsCl, NEt3; MeOH I O OH 1) mCPBA OH HO H H 2) NaOH OC HO H 3) I2, NaHCO3 H CO2Me CO2Me Me HO2C Me Corey-Carney Acid O OH 1) TFAA, pyr H 2) Zn OC 3) PrSLi HO H Me CO2H GA3 27-GA3-coreytotal4.cdx 2/5/04 12:53 PM Corey, JACS, 1978, 8034.
Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach O OMs O O 3 steps 7 steps O Me OBn OBn 67% 60% O KOtBu 93% H H O H O NaOH, O EtOH 3 steps O O O O O Me 46% 4 steps Me OH O O 6 steps 48% OMe H H H 1) EtOCHO, NaH 1) EtOCHO, NaH 2) KOtBu, MeI 2) RedAl O O OMEM OMEM OMEM 3) H+ 88% 4) Ph3PCH2 OH 39% 28-GA3-coreytotalrevised1.cdx 2/5/04 12:54 PM Corey, JACS, 1978, 8034.
Cope Rearrangement for B/C Ring Junction O CO2Me Br Br MeO2C Br Me 1) BuLi; + C2 isomer OTMS 2) DBU 2: 1 1) BF3•OEt2 Br 87% 2) TMSOTf, NEt3 160˚C 9 steps saved over original [3,3] DMSO, H2O 53% synthesis NaCl 71% H H H 1) nBu2CuLi 1) 9BBN; 2) MEMCl, iPr2NEt O NaOH, H2O2 O O O OMEM Br 2) PDC Br 65% 76% enantioselective variant has appeared R O O CHO CO2Me N B nBu H Ts Br Br CHO 10% mol Br 5 steps OTMS 99%ee Br Br 81% Corey, JACS, 1982, 6129. R = 3-indole Corey, JACS, 1994, 3611. 29-GA3-coreytotalrevised2.cdx 2/5/04 12:58 PM
Mander: Fluorene Approach MeO MeO 1) Li, NH3 PPA HO2C OMe 2) MeO OMe CO2H I CO2Me MeO 88% 36% CO2Me OCOCH2Cl O 1) HCN; NaOH O 2) (ClCH2CO)2O MeO N2 3) (ClCO)2; CH2N2 MeO CO2Me CO2Me 64% TFA 35% OCOCH2Cl 1) Na2CO3, MeOH OMOM 2) H+, (HOCH2)2 H O O MeO 3) MOMCl, iPr2NEt MeO O CO2Me 4) tBu(chx)NLi; CO2 CO2Me CO2H 5) H2, Pd/C 68% 30-GA3-mandertotal1.cdx 2/5/04 1:00 PM Mander, JACS. 1980, 6626.
Mander: A-Ring Assembly through Birch Reduction/Alkylation OMOM OMOM H H O 1) KOtBu, K, NH3; MeI O 2) CH3CHN2 MeO O O MeO CO2Me CO2H 66% MeO2C Me CO2Et 4 steps O OMOM OMOM H H O O KHCO3, KBr3 OC O 86% PhOCO O PhOCO Br CO2Et HO2C Me CO2Et Me H O H O Na, NH3; MeI MeO O MeO O CO2Me MeO2C Me CO2Me CO2H C7 ester controls alkylation Mander, JACS. 1980, 6626. 31-GA3-mandertotal2.cdx 2/5/04 1:03 PM Baker, Chem. Com. 1972, 951.
Mander: Gibberellic Acid O OMOM O OH H H 1) OsO4, NMMO O O 5 steps 2) PhCHO, H+ OC OC PhOCO O O Br CO2Et H Me Me CO2Me O OH O OH H 1) DBU Br H O O O 2) H2O, H+ OC NBS, hν PhHC OC O O PhOCO O H H CO2Me 3) TMSCl CO2Me Me Me 95% 90% O OTMS 1) Ph3PCH2, O OH H H ClCH2CH2OTMS OC O OC PhOCO H 2) K2CO3, MeOH HO H Me CO2Me 3) nPrSLi, HMPA CO2H GA3 Me 75% 31B-GA3-mandertotal3.cdx 2/6/04 10:12 AM Mander, JACS. 1980, 6626.
Mander: A-ring Aldol Approach (GA1) OCOCCl3 O OCOCCl3 OH 4 steps O TFA hv,MeOH O N2 O OMe 99% O 49% N2 O 80% O OH OH OH H O H O 1) (H2C=CHCH2)3Al O 1) (sia)2BH; O O 2) (EtCO)2O, DMAP NaOOH O O O CO2Me 78% 2) PDC Me CO2Me 3) LDA; Ph2Se2 CO2Me 1) KH, Et3NH-OAc 50% 89% 2) (sia)2BH; NaOOH 3) PDC O OH O OH O OH H O K2CO3, H H MeOH O OC 4 steps OC OC O O 1:1 at C3 HO O HO H H H Me CO2Me CO2Me CO2Me Me Me 60% GA1 32-GA3-mandertotal4.cdx 2/5/04 1:09 PM Mander, JACS. 1980, 6626.
Yamada: Intermolecular [4+2] Ring A Construction OMe OMe TMSO O 1) AlCl3 OMe 2) mCPBA H OC CN 2) NaOH O Me 49% H CN 3) Ac2O Me Me O O 10 steps CO2Me O Nakanishi, Chem. Com, 1969, 528. 57% SEMO SEMO 1) Na, NH3 SEMO H allene, H O H OMe H O H 2) AcOH, H2O hν 3) K2CO3, MeOH 69% H H H MOMOH2C Me CH2OMOM MOMOH2C Me CH2OMOM 80% MOMOH2C Me CH2OMOM O3, MeOH SEMO SEMO H 1) K, NH3 H OMOM H O H 86% 2) Swern CO2Me H 3) MOMCl, iPr2NEt H MOMOH2C Me CH2OMOM 4) Ph3PCH2 MOMOH2C Me CH2OMOM 53% 33-GA3-yamadatotal.cdx 2/5/04 2:48 PM Yamada, TL, 1989, 971.
Yamada: Synthesis of Gibberellic Acid SEMO OMOM O OH H H H OC H HO H MOMOH2C Me CH2OMOM CO2H GA3 Me 8 steps OMOM H 6 steps (Corey et al) H HO2C Me CO2H MOM-protected 1) I2, NaHCO3 Corey-Carney Acid 91% 2) DBU OMOM O OMOM H H 1) MOMCl, iPr2NEt OC 2) LDA H H HO2C Me CO2MOM Me CO2H 99% 30% from tri-MOM-ether 34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM Yamada, TL, 1989, 971.
Synthesis of GA5 via Furan [4+2]: DeClercq OMe O OH MgI O Bu2CuLi O O Br then MeO2C MeO2C Br CO2Me 65% Br 3 steps 46% 50% OMEM OH H H OH O β-cyclodextrin O O 5 steps H2O, 65˚C EtO2C H OH EtO2C 81% CO2Et OH 96% MeO >95:5 kinetic PhH LiN(chx)iPr; product 80˚C 52% MeI OH O OMEM O OH H H H O OC 1) PPTS OC H H 2) NaClO2 CO2H CO2Et OH Me GA5 MeO thermodynamic 50% product 36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM DeClercq, Tet. Lett. 1986, 1731.
GA12 Synthesis from Dehydroabiatate: Tahara Me Me Me Me Me AlCl3 CrO3, HOAc H KOH H 39% O H MeO2C Me O MeO2C Me MeO2C Me (–)-methyl dehydroabietate Wenkert, JACS, 1958, 211. Me Me 1) H2, RuO2 Me OH H2, Pd/C 1) 1) CH2N2 2) H2CrO4 2) AcCl, AlCl3 2) H2SO4 3) Ph3PCH2 OH 3)mCPBA; H H CO2Me MeO2C Me CO2H 4) BH3/H2O2 CO2Me NaOH MeO2C Me MeO2C Me epimerization at C6 OH Me H Me Me H H H 1) H2CrO4 CuSO4, 2) SOCl2; O O hν H H H H CH2N2 H N2 MeO2C Me CO2Me MeO2C Me CO2Me MeO2C Me CO2Me 4 steps GA12 Tahara, JCS Perkin I, 1972, 320. 37-GA12-Tahara-total.cdx 2/5/04 3:00 PM Tahara, TL, 1976, 1515.
GA12 Formal Synthesis: Mori O O Me Me H 1) Ph3PCHOAr Me H 1) NBS, H2O 4 steps 2) H3O+ 2) DHP, H+ H H H O H O H H 3) Ph3PCH2 MeO2C Me MeO2C Me MeO2C Me 10-30% (±)- from synthesis of steviol Tet ,1966, 879. H H H 1) NaH Me H OTHP 1) Br2, HOAc Me O 2) LiCl, DMF 2) H3O+ Me H Br H 3) Ph3PCH2 O 3) H2CrO4 O H H H MeO2C Me MeO2C Me H O 10% Me O O Cross, Hanson, JCS, 1963, 2944. H Me Me H 1) NaBH4 1) KOH, tBuOH H 2) TsCl, pyr 2) H2CrO4 H H OTs H Me HO2C Me CO2H GA12 O O 38-GA12-Mori-total.cdx 2/5/04 3:03 PM Mori, Tet, 1976, 1497.
GA12 Formal Synthesis: Ihara H H 1) Bu3SnH, H H Me AIBN H Me Me Me Me SnR3 Me Me O 2) SiO2 Me O O O O O A:B O O 93% (1:18 mix) H H H Me H H 1) 200˚C 1) s-BuLi 5 steps H Me OTES 2) TBAF Me 88% OAc OAc O H O OTES 2) Ac2O 3:1 at C7 72% (4 steps) 10 steps 37% H Me H H Me H AcO H Me H O H HO2C Me CO2H MeO2C Me OTES Cross, Hanson, JCS, 1963, 2944. GA12 39-GA12-Ihara-formal.cdx 2/5/04 3:04 PM Ihara, JACS, 2001, 1856.
Stork D-ring Approach: Reductive Cyclization H H H O + O 1) H3O 1) K, NH3, O 2) NaBH4 (NH4)2SO4 O O O O OH O + 2) HOAc, H2O 3) (HOCH2)2 H 4) PDC Three Routes to Bicycle: H O O O O O O O O O O H H O O O O O O O O O O Br NC CN O O O O O O OEt MeO2C OEt MeO2C O OH Stork, JACS, 1979, 7107. 40-GA3-Stork-CDring.cdx 2/5/04 3:05 PM Stork, JACS, 1965, 1148.
Total Synthesis of Antheridic Acid: Corey I 1) Cu(II)L2 7 steps 2) Br2; DBU MeO NiBr2 2 N2 CO2Me TBSO TBSO EtAlCl2 H 51% overall 53% 80% O O O O O2N OH OH O2N H 1) MeCO3H 2) LiNEt2 H TBSO H TBSO H TBSO H 76% 57% O O O O O O 6 steps O 52% O O O H H H OC OC OC 1) TMSCl, LDA O 4 steps OH TBSO H TBSO H HO H CO2Me 2) Eschemoser's CO2Me CO2H 90% salt, MeI, iPr2NEt antheridic acid 60% original structure proposed as 3β−OH N-tBu =L OH 41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM Corey, Myers, JACS, 1985, 5574.
Proposed Biomimmetic Synthesis of Antheridic Acid Investigated C9,10-epoxygibberellin O OH A or B H AcO H Epoxide initiated AcO H CO2Me 1,2 bond migration AcO H HO2C CO2Me MeO2C MeO2C CO2H Desired Bond Migration could not beEffected A) Im2CO, H2O2 intramolecular delivery -2 B) mCPBA (krel < 10 ) intermolecular O H OC OH HO H CO2H antheridic acid original structure proposed as 3β−OH 42-anteridiogens2.cdx 2/5/04 3:33 PM Mander, JACS, 1987, 6839.
Conversion of GA7 into Antheridic Acid O H H O OC H OC HO H OH HO H CO2H CO2H GA7 antheridic acid 1) LiN(chx)iPr; original structure Et3NHCl proposed as 2) SeO2, tBuOOH 3β−OH 3) Me2BBr O I 4) LiOH O H O O H CO OC MOMO H MOMO H CO2Me CO2Me 1) DBU KH 2) H2, Rh O O ) Ph PCH 3 3 2 O O H H CO 4 steps OC MOMO H MOMO H CO2Me CO2Me 43-anteridiogens.cdx 2/5/04 3:35 PM Mander, JACS, 1987, 6839.
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Gibberellins

  • 1. Highlights from the Synthesis of Gibberellins: a 30 Year Odyssey O OH H OC HO H CH3 CO2H A Friday Afternoon Seminar 6 February 2004 Jonathan R. Scheerer 01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM
  • 2. Highlights from the Synthesis of Gibberellins: O OH H OC HO H CO2H CH3 Outline of Presentation: I. Introduction to Gibberellins: History, Ubiquity, and Biology II. Biosynthesis III. Gibberellic Acid: Structure and Reactivity IV. Conversion of Gibberellic Acid into other Gibberellins V. Total Synthesis VI. Partial Synthesis / Stragedy Relvant Reviews: Mander, Chem. Rev. 1992, 573-612. Mander, Nat. Prod. Rep. 2003, 49-69. MacMillan, Nat. Prod. Rep. 1996, 229. Crozier, A. Ed. The Biochemistry and Physiology of Gibberellins. Praeger: New York, 1983. (vol 1 and 2) 02-gibberellin-outline.cdx 2/5/04 5:11 PM
  • 3. A Brief History of Gibberellin Research: O OH H OC HO H CO2H CH3 1828 - first reports of "bakanae" disease in rice plants (foolish seedling; stupid rice crop) 1898 - first research paper, links disease to fungal infection 1912 - Kurosawa found that filtrates from infected dried rice seedlings also causes disease Concludes that bakanae is caused by discrete chemical 1935 - First use of term "gibberellin" in scientific literature 1938 - Crystalline compound (mix of three gibberellins) isolated from fungal filtrate 1945 - Research expands to U.S. and U.K. 1955 - compound isolated. termed "gibberellic acid" 1958 - correct structure proposed (stereochemical ambiguities remain) 1961 - structure verified by X-ray 1978 - First total synthesis (Corey) 03-bakanae.cdx 2/5/04 5:19 PM
  • 4. C20 and C19 Gibberellins: Structure and Nomenclature 11 12 20 1 CH3 HC 13 2 9 10 8 14 A 17 HO2C 5 16 3 4 6 HO2C 15 D H H HO2C CH3 7 CO2H 19 18 GA12 C20-Gibberellin Skeleton ent-gibberell-16-ene-7,19-dioic acid 11 12 1 O H 13 2 9 8 14 OC 19 B 17 R 5 16 3 6 O 15 H O H CH3 7 CO2H R = CO2H 18 GA9 C19-Gibberellin Skeleton ent-norgibberell-16-ene-7,19-dioic acid 19,10-lactone 05-gibberellin-structureB.cdx 2/5/04 5:13 PM
  • 5. Gibberellic Acid (GA3) 11 12 OH 1 O OH H H 13 2 9 8 14 H3C OC19 17 5 16 R 6 3 15 O HO H OH 7 CO2H GA3 O H R = CO2H CH3 18 Fermented from Gibberellia fujikuroi (a fungus) on ton scale Bioactive at low concentrations ((sub-nanomolar common for applications) Widely investigated and applied for commercial uses Retail prices: $10 / g Current yields: 15-30 g / L culture Also bio-available in decent quantity: O O OH H H OC OC HO H HO H Me CO2H Me CO2H GA4 GA1 07-gibberellin-GA3.cdx 2/5/04 8:55 PM
  • 6. A Brief History of Gibberellins: O OH H OC HO H CH3 CO2H Representative Biological Functions of Gibberellins: – Stimulate stem elongation by stimulating cell division elongation – Breaks seed dormancy in plants which require winter freezing – Stimulates flowering/budding in response to lengthening days – Can induce seedless fruit development (parthenocarpic) – Can delay senescence (ripening) in leaves and fruit – Induces maleness (sex expression) in dioecious flowers – Other growth effects on fruit and budding 08-gibberellin-functions.cdx 2/5/04 5:15 PM
  • 7. Gibberellin Biosynthesis: Three Stages H3C HO Me H 3C H H Stage A Stage B HO2C OH H H HO2C CH3 CHO mevalonic acid (MVA) H3C CH3 GA12-aldehyde ent-kaur-16-ene Stage C O H OC H3C H H CH3 CO2H H HO2C CH3 CO2H C19-gibberellins and C20-gibberellins 10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM
  • 8. Gibberellin Biosynthesis: Stage A H 3C * H H 3C H HO CH3 HO2C Stage A * OPP * OH mevalonic acid (MVA) H * H ent-CCP H3C CH3 H3C CH3 ent-copalyl * ent-kaur-16-ene pyrophosphate OPP IPP OPP Isopentenyl GGPP pyrophosphate geranyl-geranyl pyrophosphate OPP IPP IPP OPP OPP DMAPP GPP FPP Dimethylallyl pyrophosphate 11-gibberellin-biosynthesis2 2/5/04 12:30 PM
  • 9. Gibberellin Biosynthesis: ent-CCP to ent-kaurene H Ha H3C H H3C H OPP H H H5R H3C CH3 H3C CH3 H5S ent-CCP ent-kaur-16-ene ent-copalyl pyrophosphate Ha Ha H H H H H4 H5R H5R Ha H OPP H4 5S H5S H4 H5S H5R 12-biosynthesis3.cdx 2/5/04 10:11 PM
  • 10. Gibberellin Biosynthesis: Stage B H3C H CH3 CH3 H H Stage B H H H O H3C CH3 HO2C CH3 CHO HO2C Hb Hd ent-kaur-16-ene GA12-aldehyde see next slide biosynthetic progenitor H3C H H3C H of all gibberellins same biosynthesis for OH fungal or higher order plants H HS H Hd CH3 ent-kaur-16-en-19-ol HO2C CH3 Ha Hb HR OH H3C H H3C H Hc H H Hd HS CH3 HO2C CH3 Ha Hb O ent-kaur-16-en-19-al 13-biosynthesis4.cdx 2/5/04 10:35 PM
  • 11. Gibberellin Biosynthesis: Ring Contraction H3C H CH3 H Stage B H H H3C CH3 HO2C CH3 CHO ent-kaur-16-ene GA12-aldehyde OH H O H OHC HO2C H HO2C HO2C H H H H O 1,2-radical Enz Fe 4+ shift OH Enz Fe3+ H O HO HO2C radical trapping H H 14-biosynthesis5.cdx 2/5/04 12:37 PM
  • 12. Gibberellin Biosynthesis: Stage C CH3 CH3 CH3 OH CH3 R H H and/or H H H HO H R H H CHO HO2C CH3 CO2H HO2C CH3 CHO HO2C CH3 CO2H HO2C CH3 early or late oxidations of C3, C13 R = H, OH GA12-aldehyde OH HO O R O R R H H H CO CO R R R H -very complex H H -parallel pathways CO2H CO2H HO2C CH3 CO2H Me Me -organism dependent (fungal or higher order plants) -converge to common GA O R O R OH R H H H GAn OC R H R R H H CO2H CO2H HO2C CH3 CO2H HO2C CH3 Me many complex, as yet incompletely oxidative decarboxlyation defined, oxidative processes 15-biosynthesis6.cdx 2/5/04 12:40 PM
  • 13. Rearrangements of Gibberellic Acid in Basic Media O OH OH HO H H 0.01 N NaOH OC HO HO H H CO2H CH3 CO2H HO2C CH3 GA3 OH H O OH via H Gibberellic Acid O CO H HO CO2H H –OOC CH3 CH3 CO2H transformation can be isolable effected by palladium O OH O OH H Base H OC OC HO H HO H CH3 CO2H O OH CO2H –O H CH3 retrograde favored equatorial aldol / aldol O H C3 configuration H3C CO2H 16-GA3rearrangements.cdx 2/5/04 11:41 AM
  • 14. Rearrangements on Gibberellic Acid in Acidic Media O OH OH H OC H+ HO H HO H CH3 CO2H CO2H (or H2NNH2) HO2C CH3 GA3 Gibberellic Acid Gibberellenic Acid H H H OH CH3 OH H+ O CH3 H+ H2NNH2 CO2H 1,2 shift CO2H CH3 CO2H CH3 CH3 Thermodynamically more stable C9 epimer H OH OH R "...gibberellic acid has enjoyed CH3 CO2H H a significant notoriety for instability and rearrangement. This view appears to be exagerated." L.Mander 17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM
  • 15. C11 oxidation: Bishydroboration HO O O H BH3•SMe2 H OC OC AcO H2O2, NaOAc H AcO H OH H Me CO2Me CO2Me Me OH H 2B H HB H H OH BH3 H H HO O H OC HO H Me CO2Me e.g. GA35 18-GA-C11oxidation.cdx 2/5/04 11:34 AM
  • 16. C12 oxidation of Gibberellin Skeleton OH O OH OH OAc OH OAc O OAc H OC Br Pb(OAc)4, I2 OC Br Zn, HOAc OC H H H Me CO2Me Me CO2Me Me CO2Me Zn Pb4+ Br OH Br O Br OH Br O OH H H H H H –1e– H H OH OH OH O O O OH H H H OC OC OC H H H Me CO2H Me CO2H Me CO2H GA70 GA69 GA31 19-GA-C12oxidation.cdx 2/5/04 11:32 AM
  • 17. C14 Hydroxylation of Gibberellin Skeleton O O OH H OH H OC O OC O OH MOMO MOMO H H CO2Me Me CO2Me Me acyloin NaOMe rearrangement O O O OH H OH OH HO H OC O dipole MOMO minimized? NaOMe H Me CO2Me OH OH H 2 steps O HO O Ab initio: ∆5.7 kcal O OAc O OAc H H OC OTBS OC O MOMO H 1) DMDO MOMO H OH Me CO2Me 2) TBAF Me CO2Me 20-GA-C14hydroxlation.cdx 2/5/04 11:29 AM Mander, Tetrahedron, 1998, 11637.
  • 18. C18 Hydroxylation of Gibberellin Skeleton O H O H H H OC OC O HO H H CO2Me CO2Me Me OH NaOH O H HO2C H RhCl(PPh3)3 O DABCO H H CO2Me Me 9 : 1 at C4 O H H OC O H H AllylOH HO H 2 : 3 mixture of OC DBU CO2Me 3α and 3β−OH O O H CO2Me O– Thomson, Mander, JCS Perkin I, 2000, 2893. 21-GA-C18hydroxlation.cdx 2/5/04 11:25 AM
  • 19. Conversion of C19 Gibberellins into C20 Variants O OMOM OMOM H H Li/NH3 SOCl2; OC MOMO tBuOH CH2N2 H H CH3 CO2Me CO2Me HO2C CH3 OMOM OMOM H H Li/NH3 Cu (powder) H tBuOH H PhH, 80˚C CO2Me CO2Me CH3 O CH3 N2 O OMOM CHO OMOM H H KH, DMF; O2 OC OK OK OK H H O CO2Me CO2Me O CH3 HO2C CH3 O O C20 gibberellins: e.g. GA19 22-GA-C19toC20.cdx 2/5/04 11:23 AM Mander, Tet. Lett. 1985, 5725.
  • 20. Radical Cascade: Attempted Deoxygenation at C3 O OAc H O CO H OAc Bu3SnH H RO H O Me CO2Me O H Me CO2Me O SnR3 O OAc H R3Sn-S O S H OAc equatorial (α) H CO C3 hydroxyl removed PhO O without event O H CO2Me O Me H Me CO2Me Bu3SnH O R3Sn-S OPh O R3Sn-S OAc H OAc H H O O O 5-exo O 5-exo H H Me CO2Me CO2Me O Me O Barton, McCombie, JCS Perkin I, 1975, 1574. Mander,TL, 1996, 4255. 23-GA-radicalcascade.cdx 2/5/04 11:15 AM *synthetic application: Sherburn,JACS, 2003, 12108.
  • 21. Dismantling and Reconstituting the A-Ring O OH OH H H OC HO H H Me CO2Me methyl gibberellate CO2Me Corey-Carney Acid HO2C CH3 TsCl, pyr Zn Br O OH O OH H NaBr, H OC OC HMPA TsO H H 1) mCPBA Me CO2Me CO2Me 2) NaOH Me 76% I OH O HO H OH F3C O H 1) I2, NaHCO3 Zn OC 2) TFAA, pyr HO O H HO H CO2Me 90% 60% HO2C CH3 Me CO2Me Danheiser, Strategies and Tactics in Organic Synthesis. 24-GA3-coreytotal1.cdx 2/5/04 12:45 PM Ed. Lindberg 1984, 22-65.
  • 22. Corey Synthesis of GA3: Hydronaphthalene Approach O O H 7 steps PhH, 80˚C OMe OMe 90% OMe O O HO O BnO HO o-allyl eugenol BnO H H 1) H2, Rh/C 1) DHP, TsOH K, TiCl3 2) Li, NH3 2) NaBH4 (50%) O O 3) PDC 3) MOMCl, iPr2NEt OMOM 4) LAH THPO CHO THPO 5) MsCl, NEt3 ; H2O BnO 50% from [4+2] adduct Oxidation Products: H H H H 1) Cl3CCO)2O, NEt3, DMSO OH OH OH OMEM O 2) MEMCl, iPr2NEt H H OH O THPO THPO O 60% "...quenching reactions involving OH O 50g of potassium can provide moments of great drama, as well as piquant stimulation COR R=H / OH O for the experimentalist." 25-GA3-coreytotal2.cdx 2/5/04 12:47 PM Corey, JACS, 1978, 8034.
  • 23. Contraction of B-Ring; A-Ring Formation through Cycloaddition H H 1) OsO4, NMMO OHC 2) Pb(OAc)4 Bn2NH2+-TFA– OMEM OHC OMEM O 89% O 78% THPO THPO 1) Ph3PCH2 OHC H OMEM OMEM H OMEM H nBuLi; HMPA, 65˚ Cl O O 2) AcOH Cl Cl 57% HO THPO O O 72% OMEM OMEM H H 160˚C, PhH LiN(iPr)C6H11; H Me O Cl MeI H H O O O 70% O 55% 26-GA3-coreytotal3.cdx 2/5/04 12:51 PM Corey, JACS, 1978, 8034.
  • 24. Gibberellic Acid Endgame: Corey OMEM 1) ZnBr OH H 2 H 2) KOH, Na2RuO4 Me H H 95% CO2H O HO2C Me O TsCl, NEt3; MeOH I O OH 1) mCPBA OH HO H H 2) NaOH OC HO H 3) I2, NaHCO3 H CO2Me CO2Me Me HO2C Me Corey-Carney Acid O OH 1) TFAA, pyr H 2) Zn OC 3) PrSLi HO H Me CO2H GA3 27-GA3-coreytotal4.cdx 2/5/04 12:53 PM Corey, JACS, 1978, 8034.
  • 25. Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach O OMs O O 3 steps 7 steps O Me OBn OBn 67% 60% O KOtBu 93% H H O H O NaOH, O EtOH 3 steps O O O O O Me 46% 4 steps Me OH O O 6 steps 48% OMe H H H 1) EtOCHO, NaH 1) EtOCHO, NaH 2) KOtBu, MeI 2) RedAl O O OMEM OMEM OMEM 3) H+ 88% 4) Ph3PCH2 OH 39% 28-GA3-coreytotalrevised1.cdx 2/5/04 12:54 PM Corey, JACS, 1978, 8034.
  • 26. Cope Rearrangement for B/C Ring Junction O CO2Me Br Br MeO2C Br Me 1) BuLi; + C2 isomer OTMS 2) DBU 2: 1 1) BF3•OEt2 Br 87% 2) TMSOTf, NEt3 160˚C 9 steps saved over original [3,3] DMSO, H2O 53% synthesis NaCl 71% H H H 1) nBu2CuLi 1) 9BBN; 2) MEMCl, iPr2NEt O NaOH, H2O2 O O O OMEM Br 2) PDC Br 65% 76% enantioselective variant has appeared R O O CHO CO2Me N B nBu H Ts Br Br CHO 10% mol Br 5 steps OTMS 99%ee Br Br 81% Corey, JACS, 1982, 6129. R = 3-indole Corey, JACS, 1994, 3611. 29-GA3-coreytotalrevised2.cdx 2/5/04 12:58 PM
  • 27. Mander: Fluorene Approach MeO MeO 1) Li, NH3 PPA HO2C OMe 2) MeO OMe CO2H I CO2Me MeO 88% 36% CO2Me OCOCH2Cl O 1) HCN; NaOH O 2) (ClCH2CO)2O MeO N2 3) (ClCO)2; CH2N2 MeO CO2Me CO2Me 64% TFA 35% OCOCH2Cl 1) Na2CO3, MeOH OMOM 2) H+, (HOCH2)2 H O O MeO 3) MOMCl, iPr2NEt MeO O CO2Me 4) tBu(chx)NLi; CO2 CO2Me CO2H 5) H2, Pd/C 68% 30-GA3-mandertotal1.cdx 2/5/04 1:00 PM Mander, JACS. 1980, 6626.
  • 28. Mander: A-Ring Assembly through Birch Reduction/Alkylation OMOM OMOM H H O 1) KOtBu, K, NH3; MeI O 2) CH3CHN2 MeO O O MeO CO2Me CO2H 66% MeO2C Me CO2Et 4 steps O OMOM OMOM H H O O KHCO3, KBr3 OC O 86% PhOCO O PhOCO Br CO2Et HO2C Me CO2Et Me H O H O Na, NH3; MeI MeO O MeO O CO2Me MeO2C Me CO2Me CO2H C7 ester controls alkylation Mander, JACS. 1980, 6626. 31-GA3-mandertotal2.cdx 2/5/04 1:03 PM Baker, Chem. Com. 1972, 951.
  • 29. Mander: Gibberellic Acid O OMOM O OH H H 1) OsO4, NMMO O O 5 steps 2) PhCHO, H+ OC OC PhOCO O O Br CO2Et H Me Me CO2Me O OH O OH H 1) DBU Br H O O O 2) H2O, H+ OC NBS, hν PhHC OC O O PhOCO O H H CO2Me 3) TMSCl CO2Me Me Me 95% 90% O OTMS 1) Ph3PCH2, O OH H H ClCH2CH2OTMS OC O OC PhOCO H 2) K2CO3, MeOH HO H Me CO2Me 3) nPrSLi, HMPA CO2H GA3 Me 75% 31B-GA3-mandertotal3.cdx 2/6/04 10:12 AM Mander, JACS. 1980, 6626.
  • 30. Mander: A-ring Aldol Approach (GA1) OCOCCl3 O OCOCCl3 OH 4 steps O TFA hv,MeOH O N2 O OMe 99% O 49% N2 O 80% O OH OH OH H O H O 1) (H2C=CHCH2)3Al O 1) (sia)2BH; O O 2) (EtCO)2O, DMAP NaOOH O O O CO2Me 78% 2) PDC Me CO2Me 3) LDA; Ph2Se2 CO2Me 1) KH, Et3NH-OAc 50% 89% 2) (sia)2BH; NaOOH 3) PDC O OH O OH O OH H O K2CO3, H H MeOH O OC 4 steps OC OC O O 1:1 at C3 HO O HO H H H Me CO2Me CO2Me CO2Me Me Me 60% GA1 32-GA3-mandertotal4.cdx 2/5/04 1:09 PM Mander, JACS. 1980, 6626.
  • 31. Yamada: Intermolecular [4+2] Ring A Construction OMe OMe TMSO O 1) AlCl3 OMe 2) mCPBA H OC CN 2) NaOH O Me 49% H CN 3) Ac2O Me Me O O 10 steps CO2Me O Nakanishi, Chem. Com, 1969, 528. 57% SEMO SEMO 1) Na, NH3 SEMO H allene, H O H OMe H O H 2) AcOH, H2O hν 3) K2CO3, MeOH 69% H H H MOMOH2C Me CH2OMOM MOMOH2C Me CH2OMOM 80% MOMOH2C Me CH2OMOM O3, MeOH SEMO SEMO H 1) K, NH3 H OMOM H O H 86% 2) Swern CO2Me H 3) MOMCl, iPr2NEt H MOMOH2C Me CH2OMOM 4) Ph3PCH2 MOMOH2C Me CH2OMOM 53% 33-GA3-yamadatotal.cdx 2/5/04 2:48 PM Yamada, TL, 1989, 971.
  • 32. Yamada: Synthesis of Gibberellic Acid SEMO OMOM O OH H H H OC H HO H MOMOH2C Me CH2OMOM CO2H GA3 Me 8 steps OMOM H 6 steps (Corey et al) H HO2C Me CO2H MOM-protected 1) I2, NaHCO3 Corey-Carney Acid 91% 2) DBU OMOM O OMOM H H 1) MOMCl, iPr2NEt OC 2) LDA H H HO2C Me CO2MOM Me CO2H 99% 30% from tri-MOM-ether 34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM Yamada, TL, 1989, 971.
  • 33. Synthesis of GA5 via Furan [4+2]: DeClercq OMe O OH MgI O Bu2CuLi O O Br then MeO2C MeO2C Br CO2Me 65% Br 3 steps 46% 50% OMEM OH H H OH O β-cyclodextrin O O 5 steps H2O, 65˚C EtO2C H OH EtO2C 81% CO2Et OH 96% MeO >95:5 kinetic PhH LiN(chx)iPr; product 80˚C 52% MeI OH O OMEM O OH H H H O OC 1) PPTS OC H H 2) NaClO2 CO2H CO2Et OH Me GA5 MeO thermodynamic 50% product 36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM DeClercq, Tet. Lett. 1986, 1731.
  • 34. GA12 Synthesis from Dehydroabiatate: Tahara Me Me Me Me Me AlCl3 CrO3, HOAc H KOH H 39% O H MeO2C Me O MeO2C Me MeO2C Me (–)-methyl dehydroabietate Wenkert, JACS, 1958, 211. Me Me 1) H2, RuO2 Me OH H2, Pd/C 1) 1) CH2N2 2) H2CrO4 2) AcCl, AlCl3 2) H2SO4 3) Ph3PCH2 OH 3)mCPBA; H H CO2Me MeO2C Me CO2H 4) BH3/H2O2 CO2Me NaOH MeO2C Me MeO2C Me epimerization at C6 OH Me H Me Me H H H 1) H2CrO4 CuSO4, 2) SOCl2; O O hν H H H H CH2N2 H N2 MeO2C Me CO2Me MeO2C Me CO2Me MeO2C Me CO2Me 4 steps GA12 Tahara, JCS Perkin I, 1972, 320. 37-GA12-Tahara-total.cdx 2/5/04 3:00 PM Tahara, TL, 1976, 1515.
  • 35. GA12 Formal Synthesis: Mori O O Me Me H 1) Ph3PCHOAr Me H 1) NBS, H2O 4 steps 2) H3O+ 2) DHP, H+ H H H O H O H H 3) Ph3PCH2 MeO2C Me MeO2C Me MeO2C Me 10-30% (±)- from synthesis of steviol Tet ,1966, 879. H H H 1) NaH Me H OTHP 1) Br2, HOAc Me O 2) LiCl, DMF 2) H3O+ Me H Br H 3) Ph3PCH2 O 3) H2CrO4 O H H H MeO2C Me MeO2C Me H O 10% Me O O Cross, Hanson, JCS, 1963, 2944. H Me Me H 1) NaBH4 1) KOH, tBuOH H 2) TsCl, pyr 2) H2CrO4 H H OTs H Me HO2C Me CO2H GA12 O O 38-GA12-Mori-total.cdx 2/5/04 3:03 PM Mori, Tet, 1976, 1497.
  • 36. GA12 Formal Synthesis: Ihara H H 1) Bu3SnH, H H Me AIBN H Me Me Me Me SnR3 Me Me O 2) SiO2 Me O O O O O A:B O O 93% (1:18 mix) H H H Me H H 1) 200˚C 1) s-BuLi 5 steps H Me OTES 2) TBAF Me 88% OAc OAc O H O OTES 2) Ac2O 3:1 at C7 72% (4 steps) 10 steps 37% H Me H H Me H AcO H Me H O H HO2C Me CO2H MeO2C Me OTES Cross, Hanson, JCS, 1963, 2944. GA12 39-GA12-Ihara-formal.cdx 2/5/04 3:04 PM Ihara, JACS, 2001, 1856.
  • 37. Stork D-ring Approach: Reductive Cyclization H H H O + O 1) H3O 1) K, NH3, O 2) NaBH4 (NH4)2SO4 O O O O OH O + 2) HOAc, H2O 3) (HOCH2)2 H 4) PDC Three Routes to Bicycle: H O O O O O O O O O O H H O O O O O O O O O O Br NC CN O O O O O O OEt MeO2C OEt MeO2C O OH Stork, JACS, 1979, 7107. 40-GA3-Stork-CDring.cdx 2/5/04 3:05 PM Stork, JACS, 1965, 1148.
  • 38. Total Synthesis of Antheridic Acid: Corey I 1) Cu(II)L2 7 steps 2) Br2; DBU MeO NiBr2 2 N2 CO2Me TBSO TBSO EtAlCl2 H 51% overall 53% 80% O O O O O2N OH OH O2N H 1) MeCO3H 2) LiNEt2 H TBSO H TBSO H TBSO H 76% 57% O O O O O O 6 steps O 52% O O O H H H OC OC OC 1) TMSCl, LDA O 4 steps OH TBSO H TBSO H HO H CO2Me 2) Eschemoser's CO2Me CO2H 90% salt, MeI, iPr2NEt antheridic acid 60% original structure proposed as 3β−OH N-tBu =L OH 41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM Corey, Myers, JACS, 1985, 5574.
  • 39. Proposed Biomimmetic Synthesis of Antheridic Acid Investigated C9,10-epoxygibberellin O OH A or B H AcO H Epoxide initiated AcO H CO2Me 1,2 bond migration AcO H HO2C CO2Me MeO2C MeO2C CO2H Desired Bond Migration could not beEffected A) Im2CO, H2O2 intramolecular delivery -2 B) mCPBA (krel < 10 ) intermolecular O H OC OH HO H CO2H antheridic acid original structure proposed as 3β−OH 42-anteridiogens2.cdx 2/5/04 3:33 PM Mander, JACS, 1987, 6839.
  • 40. Conversion of GA7 into Antheridic Acid O H H O OC H OC HO H OH HO H CO2H CO2H GA7 antheridic acid 1) LiN(chx)iPr; original structure Et3NHCl proposed as 2) SeO2, tBuOOH 3β−OH 3) Me2BBr O I 4) LiOH O H O O H CO OC MOMO H MOMO H CO2Me CO2Me 1) DBU KH 2) H2, Rh O O ) Ph PCH 3 3 2 O O H H CO 4 steps OC MOMO H MOMO H CO2Me CO2Me 43-anteridiogens.cdx 2/5/04 3:35 PM Mander, JACS, 1987, 6839.