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CO2HH
H
CH3
OC
O OH
HO
Highlights from the Synthesis of Gibberellins:a 30 Year Odyssey
A Friday Afternoon Seminar
6 February 2004
Jonathan R. Scheerer
01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM
H
H
CH3
OC
O OH
HO
CO2H
Highlights from the Synthesis of Gibberellins:
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
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)
Relvant Reviews:
02-gibberellin-outline.cdx 2/5/04 5:11 PM
CH3
O
HO
CO2H
H
H
OC
OH
A Brief History of Gibberellin Research:
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
1938 - Crystalline compound (mix of three gibberellins) isolated from fungal filtrate
1935 - First use of term "gibberellin" in scientific literature
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)
1828 - first reports of "bakanae" disease in rice plants (foolish seedling; stupid rice crop)
03-bakanae.cdx 2/5/04 5:19 PM
CO2H
H
CH3HO2C
CH3H
CO2H
H
H
CH3
OC
O
HO2CHO2C
H
OHO
R
A
B
C
D
C20 and C19 Gibberellins: Structure and Nomenclature
1
2
3 45
6
7
8910
11 12
13
14
19
20
1516 17
18
C20-Gibberellin Skeleton
GA12
ent-gibberell-16-ene-7,19-dioic acid
1
2
35
6
7
89
11 12
13
14
19
1516 17
18
C19-Gibberellin Skeleton
GA9
ent-norgibberell-16-ene-7,19-dioic acid 19,10-lactone
R = CO2H
05-gibberellin-structureB.cdx 2/5/04 5:13 PM
H3C
OHO
R
OH
OHH
CO2H
H
H
CH3
OC
O OH
HO
CO2HH
Me
OC
OH
OH
HOCO2H
H
Me
OC
OH
HO
Gibberellic Acid (GA3)
1
2
3
56
7
89
11 12
1314
19
1516 17
18
GA1
R = CO2H
Retail prices: $10 / g
Fermented from Gibberellia fujikuroi (a fungus) on ton scale
Widely investigated and applied for commercial uses
Bioactive at low concentrations ((sub-nanomolar common for applications)
Current yields: 15-30 g / L culture
GA3
Also bio-available in decent quantity:
GA4
07-gibberellin-GA3.cdx 2/5/04 8:55 PM
CO2HH
H
CH3
OC
O OH
HO
A Brief History of Gibberellins:
– Stimulate stem elongation by stimulating cell division elongation
– Stimulates flowering/budding in response to lengthening days
– Breaks seed dormancy in plants which require winter freezing
– 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
Representative Biological Functions of Gibberellins:
08-gibberellin-functions.cdx 2/5/04 5:15 PM
CO2HH
CH3HO2C
H3CH
HO2COH
HO Me H3C
H3C CH3
H
H
CHOH
CH3HO2C
H3CH
CO2HH
H
CH3
OC
O
Gibberellin Biosynthesis: Three Stages
mevalonic acid (MVA)
ent-kaur-16-ene
Stage A Stage B
GA12-aldehyde
C19-gibberellinsand C20-gibberellins
Stage C
10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM
HO2C
HO
OH
CH3
H3C
H3C CH3
H
H
OPP
H3C
H3C CH3
H
H
OPPIPPIsopentenylpyrophosphate
OPPOPP
OPP
FPP
OPP
IPP IPP
Gibberellin Biosynthesis: Stage A
ent-CCPent-copalylpyrophosphate
mevalonic acid (MVA)
ent-kaur-16-ene
Stage A
DMAPPDimethylallylpyrophosphate
GPP
GGPPgeranyl-geranylpyrophosphate
*
*
*
*
*
11-gibberellin-biosynthesis2 2/5/04 12:30 PM
H3C
H3C CH3
H
HH3C
H3C CH3
H
H
OPP
H4OPPHa
H
H5S
H5R
H4
H5R
H5S
Ha
H
H4
H5R
H5S
Ha
H
H
HaH
H5S
H5R
Gibberellin Biosynthesis: ent-CCP to ent-kaurene
ent-kaur-16-eneent-CCPent-copalyl pyrophosphate
12-biosynthesis3.cdx 2/5/04 10:11 PM
CHOH
CH3HO2C
CH3HH3C
H3C CH3
H
H
H3C
CH3
H
H
OHHR
HS
H3C
CH3
H
H
O
HS
H3C
HO2C CH3
H
H
Ha
Hc
HbHd
H3C
HO2C CH3
H
H
Ha
OH
HbHd
HHO2C
CH3H
HbHd
O
Gibberellin Biosynthesis: Stage B
GA12-aldehydeent-kaur-16-ene
Stage B
ent-kaur-16-en-19-ol
ent-kaur-16-en-19-al
biosynthetic progenitorof all gibberellins
same biosynthesis for fungal or higher order plants
see next slide
13-biosynthesis4.cdx 2/5/04 10:35 PM
CHOH
CH3HO2C
CH3H
HO2C
OH
H
HH
H3C
H3C CH3
H
H
Fe4+Enz
O
HO2C
O
HH
H
Fe3+Enz
OH
HO2COHC
H
HO2C
O
HH
H
HO
Gibberellin Biosynthesis: Ring Contraction
GA12-aldehydeent-kaur-16-ene
Stage B
1,2-radical shift
radical trapping
14-biosynthesis5.cdx 2/5/04 12:37 PM
CHOH
CH3HO2C
CH3H
CO2HH
CH3HO2C
CH3H
CHOH
CH3HO2C
CH3H
HO
OH
CO2HH
CH3HO2C
CH3H
R
R
CO2HH
CH3HO2C
H
R
RHO
CO2HH
H
R
R
CO
O
Me
CO2HH
CH3HO2C
OHH
R
R
CO2HH
H
R
R
CO
O
Me
OH
CO2HH
OH
R
R
OC
MeCO2H
HCH3HO2C
H
R
RO
Gibberellin Biosynthesis: Stage C
GA12-aldehyde
and/or
GAn
early or late oxidations of C3, C13
-very complex-parallel pathways-organism dependent (fungal or higher order plants)-converge to common GA
many complex, as yet incompletely defined, oxidative processes
oxidative decarboxlyation
R = H, OH
15-biosynthesis6.cdx 2/5/04 12:40 PM
CO2HH
H
CH3
OC
O OH
HOCO2H
H
HOH
HO
HO
CH3HO2C
CO2HH
HOH
CH3–OOC
O
CO2HH
H
CH3
OC
O OH
HO
CO2HH
H
CH3
OC
O OH
HO
CO2HH
H
H3C
O OH
O
–O
CO2HH
H
CH3
CO
OH
HO
O
Rearrangements of Gibberellic Acid in Basic Media
GA3
Gibberellic Acid
0.01 N NaOH
retrogradealdol / aldol
Base
via
isolabletransformation can be effected by palladium
favored equatorial C3 configuration
16-GA3rearrangements.cdx 2/5/04 11:41 AM
CO2HH
H
CH3
OC
O OH
HO
H+
CO2HH
OH
HO
CH3HO2C
CO2H
OH
CH3
H
CO2H
OH
CH3
H
H+
H2NNH2
O
CO2H
CH3
CH3
H
H+
CH3
CO2H
OH
CH3
H
OH
HR
Rearrangements on Gibberellic Acid in Acidic Media
GA3
Gibberellic Acid
"...gibberellic acid has enjoyeda significant notoriety for instability and rearrangement. This view appears to be exagerated." L.Mander
(or H2NNH2)
Thermodynamicallymore stable C9 epimer
1,2 shift
Gibberellenic Acid
17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM
CO2MeH
Me
OC
O
AcO
CO2MeH
Me
OC
O
AcO
HO
OHH
HH
HH2B HB H
H
OH H
H
OH
CO2MeH
Me
OC
O
HO
HO
H
BH3
C11 oxidation: Bishydroboration
BH3•SMe2
H2O2, NaOAc
e.g. GA35
18-GA-C11oxidation.cdx 2/5/04 11:34 AM
CO2MeH
Me
OC
O H OAc
Br
OH
CO2MeH
Me
OC
O H OAc
Br
O
CO2MeH
Me
OC
OH
OH
OAc
Br OH
H
H
Br
H
O
H
OH
Br O
H
H
Pb4+
Br OH
H
Zn
CO2HH
Me
OC
OH
OH
OH
CO2HH
Me
OC
OH
OH
CO2HH
Me
OC
OH
OH
C12 oxidation of Gibberellin Skeleton
Pb(OAc)4, I2 Zn, HOAc
–1e–
GA31 GA70 GA69
19-GA-C12oxidation.cdx 2/5/04 11:32 AM
O
CO2MeH
Me
OC
O
MOMO
H
OH
OH
O
CO2MeH
Me
OC
O
MOMO
H OH
NaOMe
O
CO2MeH
Me
OC
O
MOMO
H OH
OTBS
CO2MeH
Me
OC
O
MOMO
H OAc
O
CO2MeH
Me
OC
O
MOMO
H OAc
OH
NaOMe
O
OH
OH
O
O
OH
HO
H
OH
O
HO H
C14 Hydroxylation of Gibberellin Skeleton
1) DMDO2) TBAF
acyloin rearrangement
dipole minimized?
Ab initio: ∆5.7 kcal
Mander, Tetrahedron, 1998, 11637.
2 steps
20-GA-C14hydroxlation.cdx 2/5/04 11:29 AM
CO2MeH
Me
OC
O
O
HH
CO2MeH
OC
O
HO
HH
OH
CO2MeH
OH
HHO2C
O
HMe
NaOH
CO2MeH
OC
OH
H
O
O–
CO2MeH
OC
O
HO
HH
O
C18 Hydroxylation of Gibberellin Skeleton
Thomson, Mander, JCS Perkin I, 2000, 2893.
9 : 1 at C4
2 : 3 mixture of3α and 3β−OH
AllylOHDBU
RhCl(PPh3)3DABCO
21-GA-C18hydroxlation.cdx 2/5/04 11:25 AM
CO2MeH
H
CH3
OC
O OMOM
MOMO
CO2MeH
HOMOM
CH3HO2C
CO2MeH
HOMOM
CH3
ON2
Cu (powder)
PhH, 80˚C
CO2MeH
H
CH3
OC
OMOM
CO2MeH
H
CH3
OMOM
O
CO2MeH
HOMOM
CH3HO2C
CHO
OK OKO
OO
OK
O
Conversion of C19 Gibberellins into C20 Variants
Li/NH3
tBuOH
Li/NH3
tBuOH
KH, DMF; O2
C20 gibberellins: e.g. GA19
SOCl2;
CH2N2
Mander, Tet. Lett. 1985, 5725.22-GA-C19toC20.cdx 2/5/04 11:23 AM
CO2MeH
Me
CO
HOAcO
RO
CO2MeH
Me
CO
HOAcO
OPhO
S
Bu3SnH
SnR3
CO2MeH
Me
HOAc
O
OPhR3Sn-S
O
OCO2Me
H
Me
HOAc
O
OR3Sn-S H
O
O
CO2MeH
Me
HOAc
O
OR3Sn-S H
O
O
CO2MeH
Me
HOAc
O
H
O
O
O
Bu3SnH
Radical Cascade: Attempted Deoxygenation at C3
Barton, McCombie, JCS Perkin I, 1975, 1574.Mander,TL, 1996, 4255.*synthetic application: Sherburn,JACS, 2003, 12108.
equatorial (α)C3 hydroxyl removed without event
5-exo5-exo
23-GA-radicalcascade.cdx 2/5/04 11:15 AM
CO2MeH
HOH
CH3HO2CCO2Me
H
Me
OC
O
HO
HOH
CO2MeH
Me
OC
O
TsO
HOH
CO2MeH
Me
OC
OH
OHBr
Zn
CO2MeH
HOH
CH3HO2C
HO
HO
CO2MeH
Me
OC
O
HO
HOH
O
I
O
F3C
Zn
Dismantling and Reconstituting the A-Ring
Danheiser, Strategies and Tactics in Organic Synthesis. Ed. Lindberg 1984, 22-65.
methyl gibberellate Corey-Carney Acid
TsCl, pyr
NaBr, HMPA
1) mCPBA2) NaOH
1) I2, NaHCO32) TFAA, pyr
76%
60%90%
24-GA3-coreytotal1.cdx 2/5/04 12:45 PM
THPO
H
O
OMEM
O
OMe
O
OMe
BnO
O
HO O
OMe
OH
HO
BnO
O
H
THPO
BnO
OMOM
O
H
THPO CHO
K, TiCl3
THPO
H
OH
OH
H
OOH
H
O
OH
H
O
OH
O
H
COR
Corey Synthesis of GA3: Hydronaphthalene Approach
Corey, JACS, 1978, 8034.
o-allyl eugenol
PhH, 80˚C
90%
1) DHP, TsOH2) NaBH4
3) MOMCl, iPr2NEt4) LAH5) MsCl, NEt3 ; H2O
1) H2, Rh/C2) Li, NH3
3) PDC
"...quenching reactions involving50g of potassium can provide momentsof great drama, as well as piquant stimulationfor the experimentalist."
(50%)
1) Cl3CCO)2O, NEt3, DMSO 2) MEMCl, iPr2NEt
R=H / OH
60%
50% from [4+2] adduct
7 steps
Oxidation Products:
25-GA3-coreytotal2.cdx 2/5/04 12:47 PM
O
H OMEMOHC
THPO
THPO
H
O
OMEM OHC
OHC
THPO
H
O
OMEM
H OMEM
HO
H OMEM
O
Cl
O
Bn2NH2+-TFA–
O
Cl Cl
O
HOMEM
OO
Cl
H
H
HOMEM
OO
Me
H
Contraction of B-Ring; A-Ring Formation through Cycloaddition
Corey, JACS, 1978, 8034.
1) OsO4, NMMO2) Pb(OAc)4
1) Ph3PCH2 HMPA, 65˚
2) AcOH
nBuLi;
160˚C, PhH LiN(iPr)C6H11;
MeI
89% 78%
57%
55% 70%
72%
26-GA3-coreytotal3.cdx 2/5/04 12:51 PM
HOMEM
OO
Me
H
1) ZnBr22) KOH, Na2RuO4
CO2MeH
HOH
MeHO2C
CO2HH
Me
OC
O
HO
HOH
CO2MeH
Me
OC
O
HO
HOH
HO
I
CO2HH
HOH
MeHO2C
Gibberellic Acid Endgame: Corey
Corey, JACS, 1978, 8034.
TsCl, NEt3; MeOH
Corey-Carney Acid
1) mCPBA2) NaOH
3) I2, NaHCO3
1) TFAA, pyr2) Zn
3) PrSLiGA3
95%
27-GA3-coreytotal4.cdx 2/5/04 12:53 PM
OBn
O
MeOBn
O
O
O
O
OMs
O
O
O
HO
O
H
OHMe
O
H
OMEM
O
O
O
H
O
Me
O
H
OMEM
OH
H
OMEM
O
OMe
Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach
Corey, JACS, 1978, 8034.
3 steps 7 steps
KOtBu
3 stepsNaOH, EtOH
6 steps
1) EtOCHO, NaH2) KOtBu, MeI
1) EtOCHO, NaH2) RedAl
3) H+
4) Ph3PCH2
67% 60%
93%
46% 4 steps
48%
88%
39%
28-GA3-coreytotalrevised1.cdx 2/5/04 12:54 PM
H
OMEM
O
Br
Br Br MeO2CMe
O
Br
CO2Me
OTMS
1) BF3•OEt22) TMSOTf, NEt3
H
BrO
H
BrO
O
Br Br CHO
Br
CHO
Br
Br
CO2Me
OTMS
OBN
O
TsH
nBu
R
Cope Rearrangement for B/C Ring Junction
Corey, JACS, 1982, 6129.Corey, JACS, 1994, 3611.
1) BuLi;
2) DBU + C2 isomer2: 1
1) 9BBN; NaOH, H2O2
2) PDC
1) nBu2CuLi2) MEMCl, iPr2NEt
9 steps saved over originalsynthesis
5 steps
99%ee81%
R = 3-indole
10% mol
enantioselective variant has appeared
160˚CDMSO, H2ONaCl
[3,3]
87%
53%
71%
76%65%
29-GA3-coreytotalrevised2.cdx 2/5/04 12:58 PM
OMe
MeO
HO2CI
MeOCO2Me
OMe
MeO
CO2HCO2Me
MeO
O
CO2Me
MeO
CO2Me
MeO
OCOCH2ClO
N2
O
OCOCH2Cl
MeO
CO2Me
OMOM
MeO
CO2Me
H
CO2H
O
O
Mander: Fluorene Approach
Mander, JACS. 1980, 6626.
1) Li, NH3
2)
PPA
1) HCN; NaOH2) (ClCH2CO)2O
3) (ClCO)2; CH2N2
TFA
1) Na2CO3, MeOH2) H+, (HOCH2)2
3) MOMCl, iPr2NEt4) tBu(chx)NLi; CO2
5) H2, Pd/C
88% 36%
64%
35%
68%
30-GA3-mandertotal1.cdx 2/5/04 1:00 PM
OMOM
MeO
CO2Me
H
CO2H
O
OOMOM
MeO
H
CO2Et
O
O
MeMeO2C
OMOM
PhOCO
H
CO2Et
O
O
MeHO2C
OMOM
PhOCO
H
CO2Et
O
O
BrMe
O
OC
MeO
CO2H
H
CO2Me
O
O Na, NH3; MeI
MeO
H
CO2Me
O
O
MeMeO2C
Mander: A-Ring Assembly through Birch Reduction/Alkylation
1) KOtBu, K, NH3; MeI2) CH3CHN2
4 steps
KHCO3, KBr3
Mander, JACS. 1980, 6626.Baker, Chem. Com. 1972, 951.
C7 ester controls alkylation
66%
86%
31-GA3-mandertotal2.cdx 2/5/04 1:03 PM
CO2HH
Me
OC
O
HO
HOH
OMOM
PhOCO
H
CO2Et
O
O
BrMe
O
OC
OHH
CO2Me
O
O
HMe
O
OC
OHH
CO2Me
O
O
HMe
O
OC
O
PhHC
O
OHH
CO2Me
O
O
HMe
O
OC
PhOCO
Br1) DBU2) H2O, H+
3) TMSCl
OTMSH
CO2MeH
Me
O
OC
PhOCO
O
Mander: Gibberellic Acid
GA3
5 steps1) OsO4, NMMO2) PhCHO, H+
NBS, hν
95%
1) Ph3PCH2, ClCH2CH2OTMS
2) K2CO3, MeOH3) nPrSLi, HMPA
Mander, JACS. 1980, 6626.
90%
75%
31B-GA3-mandertotal3.cdx 2/6/04 10:12 AM
OHH
CO2Me
O
O
HMe
O
OC
O
OCOCCl3O
N2
OMe
O
OCOCCl3
O
OH
OO
O
N2
OH
CO2Me
O
OOH
CO2Me
O
OHOOH
CO2Me
O
OHO
Me
O
CO2MeH
Me
OC
O
HO
HOH
CO2MeH
Me
OC
O
HO
HOH
O
O
Mander: A-ring Aldol Approach (GA1)
GA1
TFA
4 steps
hv,MeOH
1) (H2C=CHCH2)3Al2) (EtCO)2O, DMAP
1) (sia)2BH; NaOOH 2) PDC3) LDA; Ph2Se2
K2CO3, MeOH
1:1 at C3
4 steps
Mander, JACS. 1980, 6626.
1) KH, Et3NH-OAc2) (sia)2BH; NaOOH3) PDC
99% 49% 80%
50%
78%
89%
60%
32-GA3-mandertotal4.cdx 2/5/04 1:09 PM
OMe
CN
CN
CO2Me
Me
OMe
O
O
O
Me
H
OMe
OHMe
TMSO
OC
O
OMe
H
SEMOH
CH2OMOMMeMOMOH2C
O
H
SEMOH
CH2OMOMMeMOMOH2C
HO
H
SEMOH
CH2OMOMMeMOMOH2C
H
O
H
SEMOH
CH2OMOMMeMOMOH2C
H
CO2Me
H
SEMOH
CH2OMOMMeMOMOH2C
HOMOM
Yamada: Intermolecular [4+2] Ring A Construction
Yamada, TL, 1989, 971.
allene, hν
1) K, NH32) Swern
3) MOMCl, iPr2NEt4) Ph3PCH2
O3, MeOH
2) NaOH3) Ac2O
1) AlCl32) mCPBA
10 steps
1) Na, NH32) AcOH, H2O
3) K2CO3, MeOH
49%
80%
69%
86%
53%
57% Nakanishi, Chem. Com, 1969, 528.
33-GA3-yamadatotal.cdx 2/5/04 2:48 PM
H
SEMO
H
CH2OMOMMeMOMOH2C
HOMOM
HCO2HMeHO2C
HOMOM
HCO2H
HOMOM
OC
O
Me
HCO2H
HOH
OC
O
Me
HO
HCO2MOMMeHO2C
HOMOM
Yamada: Synthesis of Gibberellic Acid
Yamada, TL, 1989, 971.
8 steps
1) I2, NaHCO32) DBU
6 steps (Corey et al)
GA3
MOM-protectedCorey-Carney Acid
1) MOMCl, iPr2NEt2) LDA
30% from tri-MOM-ether
91%
99%
34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM
CO2HH
Me
OC
OH
OH
OMe
CO2Me
O
MgI
Br
Br
O
MeO2C
O Br
OH
MeO2C
OBu2CuLi
OH
O
OH
EtO2C
OH
HOH
CO2Et
O
OH
HOH
CO2Et
O
HOMEM
EtO2C
O
MeO
H
H
OC
OH
OMEM
MeO
Synthesis of GA5 via Furan [4+2]: DeClercq
DeClercq, Tet. Lett. 1986, 1731.
GA5
β-cyclodextrinH2O, 65˚C
PhH80˚CLiN(chx)iPr;
MeI
1) PPTS
2) NaClO2
kineticproduct
thermodynamicproduct
then
5 steps
96%>95:5
81%
52%
50%
46%65%
3 steps50%
36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM
Me
MeMeO2C
H
HCO2Me
H
O
Me H
MeO2C Me
Me
MeMeO2CH
Me
Me
AlCl3
HCO2H
Me
MeO2C Me
OHCO2Me
Me
MeO2C MeHCO2Me
Me
MeO2C Me
OH
KOH
HCO2Me
Me
MeO2C Me
OH
H
H
1) CH2N2
2) H2SO4
1) H2, Pd/C2) AcCl, AlCl3
3) mCPBA; NaOH
Me
MeMeO2C O
O
H
HCO2Me
Me
MeO2C Me
H
H
O
N2
GA12 Synthesis from Dehydroabiatate: Tahara
Tahara, JCS Perkin I, 1972, 320.Tahara, TL, 1976, 1515.
(–)-methyl dehydroabietate
GA12
1) H2, RuO22) H2CrO4
3) Ph3PCH24) BH3/H2O2
CuSO4,hν
4 steps
CrO3, HOAc
1) H2CrO42) SOCl2;
CH2N2
39%
epimerization at C6
Wenkert, JACS, 1958, 211.
37-GA12-Tahara-total.cdx 2/5/04 3:00 PM
H
Me
MeMeO2CH
O
H
Me
MeMeO2CH O
H
H
Me
MeMeO2CH O
H
O
H
Me
MeMeO2CH O
H
H
Br
OTHP
H
Me
MeMeO2CH O
H
O
H
Me
H O
H
OO
Me
HCO2H
HMe H
HO2C Me
H
Me
H OTs
H
OO
Me
GA12 Formal Synthesis: Mori
Mori, Tet, 1976, 1497.
(±)- from synthesis ofsteviol Tet ,1966, 879.
4 steps1) Ph3PCHOAr2) H3O+
3) Ph3PCH2
1) Br2, HOAc2) LiCl, DMF
3) Ph3PCH2
GA12
1) NaBH42) TsCl, pyr
1) KOH, tBuOH2) H2CrO4
Cross, Hanson, JCS, 1963, 2944.
1) NaH2) H3O+
3) H2CrO4
1) NBS, H2O2) DHP, H+
10-30%
10%
38-GA12-Mori-total.cdx 2/5/04 3:03 PM
H
Me
H
H
OAc
O
H
Me
H O
H
MeO2C Me
HCO2H
HMe H
HO2C Me
OO
Me
Me
H
H
OO
Me
MeH
OO
Me
MeH
H
H
MeO
H
H
OAc
OTES
Me OTES
OO
Me
Me
H
SnR3
AcOH
Me
OTES
GA12 Formal Synthesis: Ihara
Ihara, JACS, 2001, 1856.
GA12Cross, Hanson, JCS, 1963, 2944.
1) 200˚C
2) TBAF
1) Bu3SnH, AIBN 2) SiO2
93% (1:18 mix)A : B
1) s-BuLi
2) Ac2O
5 steps
10 steps
3:1 at C7 72% (4 steps)
88%
37%
39-GA12-Ihara-formal.cdx 2/5/04 3:04 PM
H
OH
O
H
O
O
O
HO
OO
O
O
O
O
O
O
O
O
O
H
O
O
O OEt OEtOH
O
MeO2C O
O
MeO2C
HO
OO
O
OO
O
O
O
Br NC
H
CN
O
OO
O
Stork D-ring Approach: Reductive Cyclization
Stork, JACS, 1979, 7107.Stork, JACS, 1965, 1148.
1) K, NH3, (NH4)2SO4
2) HOAc, H2O
1) H3O+
2) NaBH4
3) (HOCH2)2 H+
4) PDC
Three Routes to Bicycle:
40-GA3-Stork-CDring.cdx 2/5/04 3:05 PM
CO2HH
OC
O
HOOH
H
O
TBSOH
O
HTBSO
O O
H
EtAlCl2
HTBSO
O O
OH
H
OH
H
TBSO
O2N
O O
H
O
H
TBSO
O
OC
CO2Me
MeO
CO2Me
I
O
TBSO
O
N2
CO2MeH
OC
O
O
H
TBSO
NiBr2
O2N
OH
N-tBu
Total Synthesis of Antheridic Acid: Corey
Corey, Myers, JACS, 1985, 5574.
antheridic acidoriginal structure proposed as 3β−OH
1) Cu(II)L22) Br2; DBU
1) MeCO3H2) LiNEt2
7 steps
2
6 steps
1) TMSCl, LDA
2) Eschemoser's salt, MeI, iPr2NEt
4 steps
= L
51% overall 53% 80%
57%76%
52%
60%
90%
41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM
CO2MeHAcO
MeO2C
O
CO2HH
OC
O
HOOH
H
CO2HH
OH
H
AcO
MeO2CCO2MeHAcO
HO2C
Proposed Biomimmetic Synthesis of Antheridic Acid Investigated
Epoxide initiated1,2 bond migration
Mander, JACS, 1987, 6839.
C9,10-epoxygibberellin
antheridic acidoriginal structure proposed as3β−OH
Desired Bond Migration could not beEffected
A or B
A) Im2CO, H2O2 intramolecular deliveryB) mCPBA (krel < 10-2) intermolecular
42-anteridiogens2.cdx 2/5/04 3:33 PM
CO2HH
OC
O
HO
HH
CO2HH
OC
O
HOOH
H
O
CO2MeH
CO
MOMO
HOI
CO2MeH
CO
MOMO
H
O
O
CO2MeH
OC
O
MOMO
O
H
CO2MeH
OC
O
MOMO
O
H
KH 1) DBU2) H2, Rh3) Ph3PCH2
Conversion of GA7 into Antheridic Acid
Mander, JACS, 1987, 6839.
antheridic acidoriginal structure proposed as3β−OH
GA7
4 steps
1) LiN(chx)iPr; Et3NHCl 2) SeO2, tBuOOH3) Me2BBr4) LiOH
43-anteridiogens.cdx 2/5/04 3:35 PM
CO2MeH
OC
O
HO2C
O
H
COCHN2
OMe
O
H
OMe
O
O
O
Me
O
H
OMe
OO
O H
H
OH
OC
O
BnO2C
N2
HO
CO2HH
OC
O
H
CO2MeH
OC
O
O
H
AcO
CO2HH
OC
O
H
OH
Synthesis of Antheridiogens: Mander
Mander, JACS, 1997, 3828.
antheridic acid
Cu(acac)2
1) hν, MeOH2) PDC
3) H2, Pd
18h, rtadded in situ
GA103GA104
Formalsynthesis
75%5 steps
1) PhI(OAc)2, I22) HSnBu33) Zn, CH2Br2 TiCl4
1) PhI(OAc)2, I22) Hg(OAc)2 HOAc75%
31%
70%
71%
44-antheridiogens4-Mander.cdx 2/5/04 3:36 PM
HO
O
H
H
OH
O
O
O
OH
Me
O
OO
OH
H
OH
O
H
SMe
OH
OOMeO2C
H
O
O SMe
O
MeO2C CO2Me
HOH
NaOMe
H
O
MeO2C
Br
CO2Me
H
CO2Me
OH
MeO2C
Aldol C/D Ring Strategies Not Discussed
Ireland, JOC, 1966, 2530. (toward kaurenes)
Takano, Ogasawara, Chem. Com., 1981, 635.
Hg(II)OH2SO4
HCl,acetone
tBuMgCl 14 steps
Takano, Ogasawara, Chem. Com., 1981, 637.
House, JOC, 1973, 1398.
Ziegler, JOC, 1971, 3707. (model system)
Zn,HOAc
45-cd-ring stragedy.cdx 2/5/04 3:43 PM
CO2Me
H
H
O
O
O
CO2H
O
1) NaOMe
2) HClMeO2C
H
CO2Me
CO2Me
CO2H
H
O
O
H
O
Acylation C/D Ring Strategies Not Discussed
Baker, Chem. Com., 1971, 180.
PPA
Jammaer, Tet., 1975, 2293.
BF3
AcOHLowenthal, JCS Perkin I, 1976, 944.
46-cd-ring stragedy2.cdx 2/5/04 3:44 PM
H
OO
OTs
CHO
O
SPh
OMs
HO
H
O
SPh
O
HSPh
DBU
CHO
H
OO
HN
O
H
CO2Me
O
MeO
SMe
MeO
O
MeS O
TFAA
O
MeS O
O
O
TFAA
SnCl4O
SMeO
Alkylation C/D Ring Strategies Not Discussed
Trost, JOC, 1978, 1031.
Barco, Tet., 1989, 3935.
Mander, Synthesis, 1981, 620.
1) PhSCH2Li2) TsOH
6 steps
Nagata, JACS, 1972, 4654.
GA15
47-cd-ring stragedy3.cdx 2/5/04 3:46 PM
OHCN
Cl
HMe
OHH
H
PCl5
HOH
HOMs
Me
MeO
CO2H
ArOH
Me
O
HO2C
Ar
H3O+
O
Cl CN
O
ClCN
H BF3•OEt2
O
HOH
O
H O HOH
OH
H OH
Rearrangement C/D Ring Strategies Not Discussed
Ziegler, Tet., 1977, 373.
Yamada, Synthesis, 1977, 581.
Monti, JOC, 1978, 4062.
Cross, MacMillan, JCS, 1958, 2520.
H2O, acetone, 2,6-Lutidine
Zn, HOAcMori, Tet., 1972, 3217.
poor conversion
48-cd-ring stragedy4.cdx 2/5/04 3:57 PM
H HOH
O
HOH
A Summary of General C/D Ring Strategies
I) Reductive Ring Closure
II) Alkylation / Acylation
III) Aldol
IV) Carbenoid
V) Rearrangement / Fragmentation
"The problem of the synthesis of gibberellic acid has provided the impetus for the development of many new synthetic methods . . . " Corey
49-cd-ring summary.cdx 2/5/04 3:58 PM
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