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Highlights from the Synthesis of Gibberellins:                                               a 30 Year Odyssey            ...
Highlights from the Synthesis of Gibberellins:                                                          O                 ...
A Brief History of Gibberellin Research:                                      O              OH                           ...
C20 and C19 Gibberellins: Structure and Nomenclature                                                    11      12        ...
Gibberellic Acid (GA3)                                                11      12                                          ...
A Brief History of Gibberellins:                                    O                   OH                                ...
Gibberellin Biosynthesis: Three Stages                                                                                    ...
Gibberellin Biosynthesis: Stage A                                                           H 3C                          ...
Gibberellin Biosynthesis: ent-CCP to ent-kaurene                                                                          ...
Gibberellin Biosynthesis: Stage B                      H3C     H                                     CH3                  ...
Gibberellin Biosynthesis: Ring Contraction                      H3C         H                                             ...
Gibberellin Biosynthesis: Stage C             CH3                                     CH3                               CH...
Rearrangements of Gibberellic Acid in Basic Media                        O                                                ...
Rearrangements on Gibberellic Acid in Acidic Media                             O                  OH                      ...
C11 oxidation: Bishydroboration                                                                                 HO        ...
C12 oxidation of Gibberellin Skeleton                              OH                                                    O...
C14 Hydroxylation of Gibberellin Skeleton                                   O                                             ...
C18 Hydroxylation of Gibberellin Skeleton                               O                  H                              ...
Conversion of C19 Gibberellins into C20 Variants                           O            OMOM                              ...
Radical Cascade: Attempted Deoxygenation at C3                      O                     OAc                             ...
Dismantling and Reconstituting the A-Ring                      O                  OH                                      ...
Corey Synthesis of GA3: Hydronaphthalene Approach                                                       O                 ...
Contraction of B-Ring; A-Ring Formation through Cycloaddition                     H                                       ...
Gibberellic Acid Endgame: Corey                                           OMEM 1) ZnBr                                    ...
Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach                                            ...
Cope Rearrangement for B/C Ring Junction                                                                                  ...
Mander: Fluorene Approach             MeO                                                            MeO                  ...
Mander: A-Ring Assembly through Birch Reduction/Alkylation                                         OMOM                   ...
Mander: Gibberellic Acid                         O                 OMOM                           O             OH        ...
Mander: A-ring Aldol Approach (GA1)                        OCOCCl3                          O                             ...
Yamada: Intermolecular [4+2] Ring A Construction                              OMe                                         ...
Yamada: Synthesis of Gibberellic Acid                    SEMO                                          OMOM               ...
Synthesis of GA5 via Furan [4+2]: DeClercq                    OMe        O                                                ...
GA12 Synthesis from Dehydroabiatate: Tahara                                Me                                     Me      ...
GA12 Formal Synthesis: Mori                                   O                                       O                  M...
GA12 Formal Synthesis: Ihara                                                                                              ...
Stork D-ring Approach: Reductive Cyclization                  H                                                     H     ...
Total Synthesis of Antheridic Acid: Corey                        I                                                        ...
Proposed Biomimmetic Synthesis of Antheridic Acid Investigated                                                C9,10-epoxyg...
Conversion of GA7 into Antheridic Acid                           O             H                                 H        ...
Gibberellins
Gibberellins
Gibberellins
Gibberellins
Gibberellins
Gibberellins
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Gibberellins

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Gibberellins

  1. 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. Scheerer01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM
  2. 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. 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. 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-lactone05-gibberellin-structureB.cdx 2/5/04 5:13 PM
  5. 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 GA107-gibberellin-GA3.cdx 2/5/04 8:55 PM
  6. 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 budding08-gibberellin-functions.cdx 2/5/04 5:15 PM
  7. 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-gibberellins10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM
  8. 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 pyrophosphate11-gibberellin-biosynthesis2 2/5/04 12:30 PM
  9. 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 H5R12-biosynthesis3.cdx 2/5/04 10:11 PM
  10. 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-al13-biosynthesis4.cdx 2/5/04 10:35 PM
  11. 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 H14-biosynthesis5.cdx 2/5/04 12:37 PM
  12. 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 processes15-biosynthesis6.cdx 2/5/04 12:40 PM
  13. 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 CO2H16-GA3rearrangements.cdx 2/5/04 11:41 AM
  14. 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.Mander17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM
  15. 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. GA3518-GA-C11oxidation.cdx 2/5/04 11:34 AM
  16. 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 GA3119-GA-C12oxidation.cdx 2/5/04 11:32 AM
  17. 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 CO2Me20-GA-C14hydroxlation.cdx 2/5/04 11:29 AM Mander, Tetrahedron, 1998, 11637.
  18. 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. 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. GA1922-GA-C19toC20.cdx 2/5/04 11:23 AM Mander, Tet. Lett. 1985, 5725.
  20. 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. 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. 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. 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. 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 GA327-GA3-coreytotal4.cdx 2/5/04 12:53 PM Corey, JACS, 1978, 8034.
  25. 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. 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. 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. 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. 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. 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% GA132-GA3-mandertotal4.cdx 2/5/04 1:09 PM Mander, JACS. 1980, 6626.
  31. 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. 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-ether34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM Yamada, TL, 1989, 971.
  33. 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% product36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM DeClercq, Tet. Lett. 1986, 1731.
  34. 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. 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 O38-GA12-Mori-total.cdx 2/5/04 3:03 PM Mori, Tet, 1976, 1497.
  36. 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. GA1239-GA12-Ihara-formal.cdx 2/5/04 3:04 PM Ihara, JACS, 2001, 1856.
  37. 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. 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) Eschemosers CO2Me CO2H 90% salt, MeI, iPr2NEt antheridic acid 60% original structure proposed as 3β−OH N-tBu =L OH41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM Corey, Myers, JACS, 1985, 5574.
  39. 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−OH42-anteridiogens2.cdx 2/5/04 3:33 PM Mander, JACS, 1987, 6839.
  40. 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 CO2Me43-anteridiogens.cdx 2/5/04 3:35 PM Mander, JACS, 1987, 6839.

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