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Tohru Fukuyama: Inspiring Nature Through TotalSynthesis
Chris RegensSED Group Meeting
Sept. 11, 2007
O O
O
OH
OH
OHHO H
NHHN
HO
H2N
O OMeH O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me
Tetrodotoxin Monensin
N
O
H
OH
H
N
Strychnine
O
HNO
N
Me
Gelsemine
Fukuyama's Graduate and Post Doc. Work With Kishi
N
NSS
O
O
Me
MeN
Me
HO
H
Cl
MeO
OMe
N NSS
O
O
MeH
HO
HO
O O
O
OH
OH
OHHO H
NHHN
HO
H2N
N NH
OMe
OCONH2O
O
MeO
Me
N NH
OMe
OCONH2O
O
H2N
Me
HNOH
Me
Me
HNOHO O
Me H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me8
7
9
1
26
12
X
Sporidesmin A: X = OH
Sporidesmin B: X = H
Gliotoxin Tetrodotoxin
Mitomycin A
Porfiromycin
Perhydrohistrionicotoxin HistrionicoxtinMonensin
J. Org. Chem. 1975, 40, 2009; 2011.
J. A.C.S. 1972, 94, 9217; 9219.
Tetrahedron Lett. 1970, 59, 5127; 5129.
J. A.C.S. 1977, 99, 8115.
Tetrahedron Lett. 1977, 4295.
J. A.C.S. 1973, 95, 6490; 6492; 6493.
J. A.C.S. 1976, 98, 6723.
Tetrahedron Lett. 1974, 1549; 1971,
4657; 1976, 3393.
J. A.C.S. 1979, 101, 259; 260; 262.
Three Different Forms of Tetrodotoxin
O O
O
OH
OH
OHHO H
NHHN
HO
H2NStructural Features:
-!Contains a unique dioxaadamantane skeleton with hydroxyl functionality-!Ortho-ester functional group-!Cyclic guanidine with a hemiaminal group
4,9-Anhydrotetrodotoxin
(anhydride form)
O OOH
O
OH
OHNH
HO H
HN
H2N
HO
Tetrodotoxin
(ortho-ester form)
O OOH
O
OH
OHNH
O H
HN
H2N
94 4
9 HOO
OH
O
OH
OHNH
HO
HN
H2N
HO 49
(lactone form)
(±)-Tetrodotoxin: Densely Functionalized 6-Membered Ring
O OOH
O
OH
OHNH
HO H
HN
H2N
HO 49 O O
OH
O
OH
OHH2N
HO H
OHC4 6
4a
5
9
7
HO
OHC
OH
OH
HO CO2H
HOOH
NH2
5
4
4a
67
8a
guanidine synthesis
ortho esterformation
Tetrodotoxin "tetrodoamine"
-General Retrosynthetic Analysis
- Key Challenges
- Construct a highly oxygenated and a densely functionalized cyclohexane skeleton - Construction of tetrasubstituted stereocenters C(6) and C(8a)- Introduction of the C(8a) amine - Prevent epimerization at C(9) and !-elimination of the hydroxyl group at C(5)- This is 1972 so, stereochemistry was determined through coupling constants and chemical derivativation
HOOH
OHOH
OHH2N
OHC4 6
4a
5
HOCO2H
8a
(±)-Tetrodotoxin: Beginning Diels Alder
O OOH
O
OH
OHNH
HO H
HN
H2N
HO 49
Tetrodotoxin
ortho esterformation
guanidine
O OOAc
O
OAc
OAcHN
H9
Ac
AcO
pyrolysis
4
O OOAc
O
OAc
OAcHN
H9
Ac
AcO
4
AcO10
4a
126
intramolecularcarboxylate addn.
oxocarbeniumion trapping
O
O NH
H
O
O
AcAcO OAc
O
H H12
10
44a
6
7
Baeyer-Villager
H
NHAcO
H
O
Ac
OAc
O
O
OAc
12
stereoselectivehydroxylation
H
NH
H
Ac
HO
O
O
129
9
MeH
epoxideopening
epoxidation
hydridereduction
HO
O
Me
N
Diels-Alder
OHMe
epoxidation
allylic oxidation
Ac
O
O
Me
N
HO
Me
(±)-Tetrodotoxin: How Does One Install the C(8a) Nitrogen?
HO
O
Me
N
OH
O O
O
OH
OHNH
HO H
HN
H2N
HO 49
O
O
Me
N
Me
HO
SnCl3
CH3CN, rt
83%Me
6
4a8a
1. ClOSO2CH3, Et3N
2. H2O, 100 oC?
C13H15NO3
OH
(±)-Tetrodotoxin: Building the Tricycle
H
HN
O
O
Me
8a
Me O
H
HN
OH
O
Me
8a
Me O
5
H
HN
OH
O
Me
8a
Me O
5O
H
HN
H
Ac
Me
O
O
12
HO
H H
HN
H
Ac
Me
O
O
12
O
H
H
HN
H
Ac
Me
O
AcO12
H
5 54a4a
5
O
O
O O
O
OH
OHNH
HO H
HN
H2N
HO 49 OH
NaBH4
MeOH, 96%
m-CPBA, CSA
75%
CrO3.py
CH2Cl2, 90%
HO OH1. ,BF3.Et2O
2. Al(Oi-Pr)3
3. Ac2O, pyr. 95%
H
H
HN
H
Ac
Me
O
H12
H
5
O
OH
OAc
Dihedral angle = 90o
J = 0 Hz
H
7
8
Dihedral angle = 30o
J = 6 Hz
(±)-Tetrodotoxin: Finishing the 6-Memered Ring
H
HN
H
Ac
Me
O
OAc
12
H
5
O
O
87
O O
O
OH
OHNH
HO H
HN
H2N
HO 49 OH
1. SeO2, 180 oC
2. NaBH4, MeOH (100% 2 steps)
H
HN
H
Ac
O
OAc
12
H
5
O
O
87
OH
m-CPBA
90 oC, 95%
H
HN
H
Ac
O
OAc
12
H
5
O
O
8
OH
O
1. Ac2O, pyr.
2. CF3CO2H, H2O 70 oC3. Ac2O, pyr. (80% 3 steps)
H
HN
H
Ac
O
OAc
12
H
5
8
OAc
O
O
1. CH3C(OEt)3, EtOH, CSA
2. Ac2O, pyr.
H
HN
H
Ac
O
OAc
12
H
5
8
OAc
O
EtO
EtOCl
Cl
H
HN
H
Ac
O
OAc
H OAc
O
EtO,reflux
(±)-Tetrodotoxin: Installing the C(9) Hydroxyl Group
O O
O
OH
OHNH
HO H
HN
H2N
HO 49 OHm-CPBA
CH2Cl2, K2CO3
H
HN
H
Ac
O
OAc
H OAc
O
EtO
H
HN
H
Ac
O
OAc
H OAc
O
EtOO
AcOH, rt
(70% 3 steps)
H
HN
H
Ac
O
OAc
H OAc
O
EtO
HO
H
HN
H
Ac
O
OAc
H OAc
O
OHO
EtO
Me
O
H
HN
H
Ac
O
OAc
H OAc
OEtO
OO
OHMe
H
HN
H
Ac
O
OAc
H OAc
O
OO
Me
OEt
H
HN
H
Ac
O
OAc
H OAc
O
AcO
O
(±)-Tetrodotoxin: Key Step
H
HN
H
Ac
O
OAc
H OAc
O
AcO
O
O
O NH
H
O
OAc
AcAcO OAc
O
H H12
10
44a
6
7
O
O NH
O
OAc
AcAcO OAc
H
10
44a
6
7
OH
12
AcO
OO
AcHN O
OAc
AcO
OAc
H
10
44a
6
7
OH
12AcO
O
O
AcO
OH
OAc
O
AcO
HAcHN
H
OAc
O OOAc
O
OAc
OHHN
H9
Ac
AcO
4
AcO10
4a
126
O O
O
OH
OHNH
HO H
HN
H2N
HO 49 OHm-CPBA
100%
AcOK, AcOH
90 oC, 2 h.(quant)
(±)-Tetrodotoxin: Assembling the Cyclic Guanidine
O OOAc
O
OAc
OAcHN
H9
Ac
AcO
4
AcO10
4a
126
O OOAc
O
OAc
OAcHN
H9
Ac
AcO
4
10
4a6
EtS
NAc
SEt
O OOAc
O
OAc
OAcN
H9
AcO
AcHN
NHAcO O
OAc
O
OAc
OAcN
H9
AcO
H2N
NHAc
O OOAc
O
OAc
OHHN
H9
Ac
AcO
4
AcO10
4a
126
Ac2O
CSA (cat.)(quant)
290 - 300 oC
high vac.80%
Et3OBF4, Na2CO3
then AcOH/H2O92%
O OOAc
O
OAc
OAcH2N
H9
AcO
4
10
4a6
120 oC, 12h1.
2. Acetamide, 150 oC, 1h
(20% 2 steps)
NH3
MeOH/CH2Cl2
(quant)
(±)-Tetrodotoxin: Done!
O OOAc
O
OAc
OAcN
H9
AcO
H2N
NHAc
1. OsO4, THF, -20 oC
2. NaIO4, THF/H2O, 0 oC then ethylene glycol
O OOAc
O
OAc
OAcN
H
OHC9
OHCAcO
H2N
NHAc
NH4OH, MeOH, H2O
(25% 2 steps)
O O
O
OH
OHNH
HO H
HN
H2N
HO 49 OH
(±)-Tetrodotoxin
(±)-Tetrodotoxin: Conclusion
O O
OH
O
OH
OHNH
HO H
HN
H2N
HO
guanidine
intramolecularcarboxylate addn.
- 32 Steps- C(8a) and C(4a): diastereoselective Diels-Alder Reaction- C(8) and C(5) stereospecific, substrate controled hydride reductions- C(7) carboxylate attack onto epoxide
- Development of a novel way to synthesize a cyclic guanidine
10
8a
4a
5 7
8
(+)-Monensin: Historically Significant
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me8
7
9
1
26
12
Monensin
Properities:
- Ionophore: ability to complex inorganic cations for translocation thorugh a lipophilic interface.- Polyether antibiotic (terminate with a carboxylate and contains numerous cyclic ethers).- Isolated from Streptomyces cinamonensis-Displays anticoccidial activity, used to combat such infections in cattle and poultry.
Structure:
- 17 stereocenters, 6 contiguous of the 26 carbons- Contains only 3 elements O, H, C.- Monensin maintains a cyclic structure through H-bonding at C(1) and HO at C(26)- 2 THF rings 1 THP ring and a unique 1,6-dioxaspiro[4.5]decane
History:
- 5th polyether isolated, 1st characterized- Kishi reported the first synthesis (1979)
- The synthesis is noted for: - Convergency - The way it exploits acyclic conformational control elements allylic 1,3-strain, to achieve stereochemical control in acyclic systems
(+)-Monensin: Retrosynthesis
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me8
7
9
1
26
12
Monensin
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12
OHO
Me
OBn
Me
OMe
Me
CO2Me
7
5
1
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12MeCHO
Me
OBn
Me
OMe
Me
CO2Me
7
5
1
O
OMeMe
OMe
Me
OH
6
51
MeOO O O
H Et H
Me
H H
Me Me
OMe
OH129
Spiroketalization Aldol condensation
A
B
(+)-Monensin: Retrosynthesis of Fragment B
OMeMe
OMe
Me
OH
6
51
MeOO O O
H Et H
Me
H H
Me Me
OMe
OH129
A
B
MeOO O
H Et H
Me
HMe Me
129
OOP
O
O CCl3
MeOO OH
H Et H
Me
129
Me
Me
Bromoetherification
BromideDisplacement
Wittig reaction
2120
17
22
19
MeOO O
H Et H
Me
129 2017
OH
Hydroxy epoxide cyclization
Ring closure
OH
OMe
Et
H
MeO
16
18
13
(+)-Monensin: Retrosynthesis of Fragment A
O
MeMe
OMe
Me
OH
6
51
MeOO O O
H Et H
Me
H H
Me Me
OMe
OH129
A
B
O
MeMe
OMe
Me
OH
6
51
O
MeMe
OMe
O
51
O
MeMe
OEt5
1
O
O
CN1
Horner-Wadsworth-
Emmons
(+)-Monensin: Nice Johnson Ortho Claisen
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12Me
O
HO OH 1. PhCHO, CSA
2. LAH-AlCl3 (1:4) (93% 2 steps)
HO OBn
NCOMe
1. (S)-(+)-1-(1-naphthyl) ethyl isocyanate, Et3N
2. resolution3. LAH
HO OBnH
1. PCC
2. Et
MgBr
HO OBnH
EtCH3C(OEt)3
CH3CH2CO2H140 oC
OEtOH
OBn
[3,3]Johnson ortho ester
Claisen
Et
OBnH
EtO O
Et16
17
1617
1. LAH
2. PCC
Et
OBnH
O
16
17
(+)-Monensin: Expoxide Opening
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12Me
O
1617Et
OBnH
O
16
17
MeO MgBr1.
2. CrO3, H2SO4
H2O - (CH3)2CO
3. BCl3[31% from resolution]
Et
OHH
O
16
17
MeO
13
Aryl
O
Et
HHO[destabilized byallylic 1,3-strain]
1316
17 18
Aryl
O
Et
H
1316
17 18
OH
m-CPBA
NaHCO3OAryl
O
Et
OH
16
13
18
Hydroxyl directedepoxidation
1. p-TsCl, py
2. LAHOHAryl
O
Et
Me
16
13
18
CSA
O OH
Me
H Et HAryl
13 16
18
H
7:2 mixture of C(13) epimers
(+)-Monensin: SN2 Displacement with KO2
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12Me
O
1617
O OH
Me
H Et HAryl
13 16
18 OsO4, NaIO4
H2O-dioxane(36% 4 steps)
O O
Me
H Et HAryl
13 16
18
OH20
Me Me
Ph3P
DMSO78%
O OH
Me
H Et HAryl
13 16
18
20
Me Me
2124
26
O
Me
BrH !
!
C26-C22
C13-C16
17
20
O
Me
BrH !
!
C13-C16
17 20
C26-C22
NBS, CH3CN
57%
O O
Me
H Et HAryl
13 16
18
20
Me Me
Br21
22
KO2, 18-crown-6
46% O O
Me
H Et HAryl
13 16
18
20
Me Me
H21
22
OH
(+)-Monensin: Birch Reduction
O O
Me
H Et HAryl
13 16
18
20
Me Me
H21
22
OH
1. Cl3CCOCl, pyr2. OsO4, pyr., THF
3. PhCOCl, pyr., 4. CrO3, H2SO4, HO(CH3)2CO
Aryl O OH Et H
Me
HMe Me
13
OO
O
O CCl3
22
20 Ph
O
16
1. NaOMe, MeOH
2. (CH3O)3CH, MeOH, CSA (53% 6 steps)
O O OH Et H
Me
H H
Me Me
OMe
OH
MeO
Li, EtOH
NH3(l)
O O OH Et H
Me
H H
Me Me
OMe
OH
MeO
(+)-Monensin: One Last THF Ring To Go
O O OH Et H
Me
H H
Me Me
OMe
OH
MeO
1. (CH3O)3CH, MeOH CSA, CH2Cl2
2. O3,MeOH, -78 oC3. MgBr, CH2Cl2-H2O
O O OH Et H
Me
H H
Me Me
OMe
OH
OOHC O
Me
MeMgBr
Et2O
O O O
H
Et H
Me
H H
Me Me
OMe
OH
OOHC O
MeMg
L L
O O O
H
Et H
Me
H H
Me Me
OMeOH
OHO
Me
MeMe
OH
"Me"
Re face addtion
(+)-Monensin: Completing the Right Hand Portion
O O O
H
Et H
Me
H H
Me Me
OMeOH
OHO
Me
MeMe
OH
1. O3, MeOH -78 oC
2. conc. HCl MeOH(22% 7 steps)
O O OH Et H
Me
H H
Me Me
OMeOH
OOMe
MeLi, THF
-78 oC100%
O O O
H
Et H
Me
H H
Me Me
OMeOHMe
OHO Me
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12Me
O
(+)-Monensin: Resolution
OMeMe
OH
5
1
OMeMe
5
1
OBn
HO2C
MeMe
OMe
6
1
OBn
CHO
Me
OCHO1
Me
CO2Et
Me
Ph3P1.
2. LAH3. BnBr (95% 2 steps)
racemic
(E:Z 95:5), 70%
B2H6, THF0 oC; then
KOH, H2O2
85%(dr 8:1)
OMe
Me
51
OBn
H
BH3
OBn
!-face attack
1. KH, MeI
2. H2, 10% Pd-C MeOH (88% 2 steps)
OMeMe
OMe
5
1
OH
Ph
Me
NCO
(S)-(-)-!-methylbenzylisocyanate
1.
Et3N, 50 oC2. resolution3. LAH
OMeMe
OMe
5
1
OH
enantiopure
(+)-Monensin: Hydroboration to Set C(5)-C(6) Stereocenters
OMeMe
OMe
Me
OH
6
51
HO2C
MeMe
OMe
6
1
OBn
CHO
Me
OMeMe
OMe
5
1
OH 1. PCC (88%)
2. CO2Me
Me
(MeO)2P(O)
3. LAH, (73% 2 steps)
H
Me
OH
Me
H OMe
Me
O
BH3
B2H6, THF, 0 oCthen H2O2
10% aq. KOH, THF, 25 oC
(dr 12:1) (80%)exclusive Z
!-face attack
OMeMe
OMe
Me
65
1
OH OH 1. MOMBr, PhNMe2
2. KH, BnBr (68% 2 steps)
(+)-Monensin: Completing the Left Hand Portion
HO2C
MeMe
OMe
6
1
OBn
CHO
Me
OMeMe
OMe
Me
65
1
OBn OMOM 1. O3, MeOH -78 oC
2. CH2N2
(55 % 2 steps)MeMe
OMe
Me
65
1
OBn OMOM
MeO
O1. HCl, MeOH
2. PCC, CH2Cl2
MeMe
OMe
Me
65
1
OBn O
MeO
O
H
(+)-Monensin: Building the Spiroketal
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12MeCHO
Me
OBn
Me
OMe
Me
CO2Me
7
5
1
O
i-Pr2NMgBr
THF, -78 oC
(21% yield; 92% yield)based on recovered ketone C5-C1
H Me
C OH
Nu
7
HO OMe H O
O
MeEt
HH Me
MeHO
HO
H
8
9
26
12
OHO
Me
OBn
Me
OMe
Me
CO2Me
7
5
(>8:1 mixture of C(7) epimers)
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2Me
Me8
7
9
1
26
121. H2, Pd-c MeOH-AcOH (100:5)
2. CSA, H2O, CH2Cl2-Et2O (3:1)
(+)-Monensin: Completing the Synthesis
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2Me
Me8
7
9
1
26
12 1N NaOH-MeOH (1:5)
60 oC(quant)
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
Me8
7
9
1
26
12
NaO
O
(+)-monensin sodium salt
(+)-Monensin: Conclusion
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me
Spiroketalization
Aldol condensation
- First Total Synthesis of (+)-Monensin in 1979- Cross-Aldol to bring together both left and right fragments- Beautiful illistration of ''stereospecific synthesis by induction or stereochemical communication'' by influence of preexisting stereocenters- Hydroboration to establish 4 of the 5 stereocenters- Demonstrated the importance of using allylic 1,3-strain as a controlling element
(+)-Gelsemine: Biological Activity?
O
HNO
N
Me
1
7
8
10
12
21
18
20
3
6
17
14
(+)-GelsemineO
NMe NH
O
17
18
2021
312
8
1017
6
14
5
- contains a [3.2.1] octane skeleton
- unique hexacyclic cage structure
- The C(20) and C(7) stereogenic centers are anchoring the spirooxindole the pyrrolidine moiety, and the very hindered tetrahydropyranyl ring on the concave face of the molecule
- isolated from gelsemium sempervirens- it has been known since 1870
- Biological activity?
" The degree of attention which has been lavished by many laboratorieson the total synthesis of gelsemine surely dod not arise from any documented information suggesting that this alkaloid might have valuable properties. Actually, reports concering any biological activity associated with gelsemine areat best sketchy and often anecdotal in style. Rather, the attratction to gelsemine as a target in total synthesis has been driven by its fascinating three-dimensional architecture.''
-Danishefsky
(+)-Gelsemine: Key Challenges in the Synthesis
O
HNO
N
Me
1
7
8
10
12
21
18
20
3
6
17
14
(+)-GelsemineO
NMe NH
O
17
18
2021
312
8
1017
6
14
5
- contains a [3.2.1] octane skeleton
- unique hexacyclic cage structure
- The C(20) and C(7) stereogenic centers are anchoring the spirooxindole the pyrrolidine moiety, and the very hindered tetrahydropyranyl ring on the concave face of the molecule
Challenges:
- Controlling the stereochemistry of the spiroindolinone system- Formation of the C(5) and C(6) bond
(+)-Gelsemine: Retrosynthesis
O
NMe NH
O
17
18
2021
312
8
1017
6
14
5
CO2R
X
NHO
O
H
HNO
CO2R
OH
NMe NR
O
O
intramolecularoxymercuration
intramolecular Michaeladditon
MeHN
Michaeladdition
RO2C
X
NHO
divinylcyclopropanerearrangement
RO2C
X
NHO
!"OC
Z
O
!"OC
ZZ
ClCl
CO!"
(+)-Gelsemine: Rearrangement of exo Epoxide to Cyclopropane
N O
O
BnCl
O
+
HMe2Si Et2AlCl
-78 oC88%
Cl
X O
SiMe2H 1. Sm(OTf)3 (cat.). MeOH
2. H2O2, KF, KHCO3
THF/MeOH (53% 2 steps)
Cl
MeO O
OH
[VO(acac)2], t-BuOOH,
benzene, 100%
Cl
MeO O
OH
O
OTES
O
MeO2C
1. TESOTf, lutidine
2. t-BuOK, benzene (95% 2 steps)
MAD, PhMe
-20 oC65-78%
MAD =
TESO
CHO
CO2MeMe
t-Bu
t-Bu
O Al Me
t-Bu
t-Bu
O
Me
(+)-Gelsemine: Rearrangement of exo Epoxide to Cyclopropane
TESO
CHO
CO2Me
OTES
O
MeO2C
MAD, PhMe
-20 oC
65-78%
OTES
O
MeO2C
''Al''
OTES
O
MeO2C
''Al''
OTES
O
MeO2C
''Al''
H
OTES
O
MeO2C H TESO
CHO
CO2Me
(+)-Gelsemine: Installing the Oxoindole
HO
CHO
CO2Me
NH
O
cat.NH
,MeOH, rt
60%from racemic
synthesis
+
(E) (Z)(4:1)
OAc
HO CO2Me
OAc
NH
O HO CO2Me
OAc NHO
h!
+
(E) (Z)(1:1)HO CO2Me
OAc
NH
O HO CO2Me
OAc NHO
(+)-Gelsemine: 4-Iodooxindole Saves the Day
HO
CHO
CO2Me
NH
O
cat.NH
,MeOH, rt
89%from racemic
synthesis
+
(E) (Z)
OAc
HO CO2Me
OAc
NH
O HO CO2Me
OAc NHO
!
!
!
PM3 calculations suggest thatthe Z-isomer is more stable by 9.4 kcal/mol
(+)-Gelsemine: Divinylcyclopropane Rearrangement
TESO
CHO
CO2Me
NH
O
cat.NH
,MeOH, rt
99%
!
TESO CO2Me
NH
O
! 1. TBAF2. CrO3, H2SO4
3. PhMe/MeCN, reflux (72% 3 steps)
CO2Me
NH
O
!
O
mixture of cis andtrans isomers + A
O
MeO2C
NHO
!A
H
(+)-Gelsemine: How It Works.
CO2Me
NH
O
!
O
O
MeO2C
NHO
!H
Basic idea:
O
MeO2C
NH
H
O
! H
Two Michael Additions: Building the Pyrrolidine Ring
O
MeO2C
NHO
!
1. (EtO)2POCH2CO2t-Bu, n-BuLi, THF, 65 oC
2. MOMCl, t-BuOK3. n-Bu3SnH, AIBN (54% 3 steps) MeO2C
NO MOM
H CO2t-Bu
MeNH2, MeOH
100%
NO MOM
CO2t-Bu
CO2Me
MeN
H1. AllocCl, pyr. (cat.) DMAP
2. LiBH4, (cat.) LiEt3BH (88% 2 steps)
NO MOM
CO2t-Bu
MeN
Alloc
OH
1. [Pd(PPh3)4], pyrrolidine THF
2. ICH2CN, i-Pr2NEt, MeCN (78% 2 steps)
(+)-Gelsemine: Reduction and Protection
NO MOM
CO2t-Bu
MeN
Alloc
OH
1. [Pd(PPh3)4], pyrrolidine THF
2. ICH2CN, i-Pr2NEt, MeCN (78% 2 steps)
NO MOM
CO2t-Bu
MeN
OH
NC KHMDS, THF
-78 to 0 oC62%
NO MOM
CO2t-Bu
MeN
OH
NC 1. PhCOCl, pyr. (cat.) DMAP
2. HCO2H3. ClCO2Et, Et3N, then NaBH4, H2O (71% 3 steps)
NO MOM
MeN
OCOPh
NC
OH
(+)-Gelsemine: Oxidation of Cyanopyrrolidine and Oxymercuration
NO MOM
MeN
OCOPh
NC
OH
NO2
SeCN ,PBu3
THF, m-CPBAthen NEt3, 97%
NO MOM
MeN
OCOPh
NC1. m-CPBA, THF/H2O
2. K2CO3, MeOH
NO MOM
MeN
OH
O 1. Hg(OTf)2, PhNMe2
NaOH, MeNO2
then aq. NaCl (97%)
2. NaBH4, NaOH, BnNEt3Cl CH2Cl2/H2O (63%) O
NMe N
OMOM
O
(+)-Gelsemine: Completing the Synthesis
O
NMe N
OMOM
O
1. TMSCl, NaI, NEt3 MeOH (63%)
2. DIBAL-H (90%)
O
NMe NH
O
(+)-Gelsemine
(+)-Gelsemine: Conclusion
O
NMe NH
O
intramolecularoxymercuration
intramolecular Michaeladditon
divinylcyclopropanerearrangement
- 21 Steps, enantioselective synthesis- Reconized that the spiro-indoline was the most challenging and was able to control the stereochemistry by simple condnesation of 4-iodooxindole- The bicyclic [3.2.1] core was assembled through a divinylcyclopropane rearrangement
(-)-Strychnine: Structure and Prosperities
Biological Properities:
- LD50 10 mg, used as a pesticide for killing small vertebrates- Causes muscular convulsions and eventually death through asphyxia- Most bitter substances known. Its taste is detectable in concentrations as low as 1 ppm.
N
O
N
O
H
H
7
H
3
4
(-)-Strychnine
Structure:
- Most celebrated member of the Strychnos alkaloids- Isolated from the seeds of the Strychnos nux vomica tree- Possess a complex polycyclic structure, assembled from 24 atoms- Unique heptacyclic framework as well as 6 contigous chiral centers with 5 of them in one unsaturated 6-membered ring
(-)-Strychnine: Key Step Using Nitrobenzenesulfonamide Chemistry
N
O
N
O
H
H
7
H
3
4
NH
O
N
H
HO
7
H
3
4
Wieland-Gumlich aldehyde
NH
MeO2C CO2Me
N
H7
H
3
4
Kuehne's intermediate
transannular cyclization
NH
CO2Me
N
7
H
3 O
H
Ns
Double Mistunobuvia nitrobenzene-
sulfonamide chemistry
NH
CO2Me
OH
7
H
3
H
HO
OMOM
Pd-mediatedcoupling
NH
CO2Me
CO2Me
TBSO
OTBS
O
+
(-)-Strychnine: Radical Cyclization of 2-Alkenylthioanilides
N
CSCl2, Na2CO3
THF-H2O, 0 oC
NaBH4, MeOH
0 oC
56%
HO
NCS
TBSO
NCS
CO2Me
CO2Me ,NaH
THF, 0 oC to rt
71%
TBSCl
imd.
CH2Cl298%
TBSO
NH
S
CO2Me
CO2Me
Bu3SnH
Et3B
PhMe, rt
TBSO
NH
SSnBu3
CO2Me
CO2Me
NH
HOTBS
SSnBu3R
NH
TBSO
CO2Me
CO2Me
Bu3SnH
-Bu3Sn
NH
HOTBS
SSnBu3R N
H
HOTBS
R
(-)-Strychnine: Preparation of Vinylepoxide
HO2C MeO2C MeO2C OH
Br
MeO2C OAc
Br
MeO2C OH
Br
OH
Br
HO TBSO
O
1. Na, liq. NH3-EtOH -78 oC
2. AcCl, MeOH, NaOMe rt
NBS, H2O, DMSO
rt (62% 3 steps)
Lipase AYS
vinyl acetate, 40 oC
DIBAL-H
0 oC
1. NaOMe, MeOH, rt
2. TBSCl, imd. (61% 2 steps)
+
46%, 99% ee 50%, 99% ee
(-)-Strychnine: Palladium-Mediated Coupling
TBSO
O
NH
CO2Me
CO2Me
TBSO
NH
TBSO
MeO2C
H
OTBS
OH
CO2Me
Pd2(dba)3 (5 mol%)
P(2-furyl)3 (5 mol%)PhMe, rt
86%
+
TBSO
ONH
CO2Me
CO2Me
TBSO
+H
Pd
LLTBSO
OHNH
CO2Me
CO2Me
TBSO
+
Pd
LL
NH
TBSO
MeO2C
H
OTBS
OH
CO2Me
NH
TBSO
MeO2C
H
OTBS
OH
CO2Me
''Pd''
(-)-Strychnine: Building the 9-Membered Ring
NH
TBSO
MeO2C
H
OTBS
OH
CO2Me
N
HO
H
OH
OMOM
CO2Me
1. MOMCl, i-Pr2NEt
2. LiI, collidine, 80 oC3. Boc2O, DMAP, MeCN4. NH4F.HF, DMF-NMP (72% 4 steps)
NsNH2, PPh3, DEAD
PhMe, rt, 95%
N
NsN
H
OH
OMOM
CO2Me
H
N
CO2Me
H
NNs
OMOM
Boc
BocBoc
(-)-Strychnine: Setting the Stage for Cross-Transannulation
N
CO2Me
H
NNs
OMOM
Boc
1. DBU, PhMe, 100 oC
2. aq. HCl, THF, 50 oC3. DMP, 0 oC (69% 3 steps)
N
CO2Me
H
NNs
O
Boc
1. TMSOTf, Et3N
2. m-CPBA, aq. NaHCO3-CH2Cl2 aq. HCl, MeOH, rt (66% 2 steps)
N
CO2Me
H
NNs
O
Boc
OH
Pb(OAc)4
MeOH-PhH0 oC
N
CO2Me
CO2MeH
NNs
Boc
O
PhSH, CsCO3, MeCN
N
CO2Me
CO2MeH
NH
Boc
O
(-)-Strychnine: Transannulation-How Does it Work?
NH
CO2Me
N
CO2MeH
PhSH, CsCO3, MeCN
then TFA, Me2S, CH2Cl250 oC (84% 2 steps)
NH
CO2Me
N
CO2MeH
N
CO2Me
CO2MeH
NH
Boc
O NH
CO2Me
N
CO2MeH
NH
CO2Me
N
CO2MeHNH
CO2Me
N
CO2MeH
HO
(-)-Strychnine: Completing the Synthesis
NH
CO2Me
N
CO2MeH
1. NaBH3CN, AcOH, 10 oC
2. NaOMe, MeOH-THF, rt
N
O
N
O
H
H
H
NH
O
N
H
HO
H
Wieland-Gumlich aldehyde
DIBAL-H, BF3.OEt2
CH2Cl2, -78 oC93%
NH
CO2Me
N
HOH
NH
CO2Me
N
HOH
DIBAL-H, -98 oC
CH2Cl2
(-)-Strychine
CH2(CO2H)2, NaOAc
Ac2O, AcOH, 110 oC(42 %, 4 steps)
(-)-Strychnine: Conclusion
N
O
N
O
H
H
H
Double Mistunobuvia nitrobenzene-
sulfonamide chemistry
- Utilized their own chemistry nitrobenzenesulfonamide Mitsunobu reaction radical cyclizations of 2-alkenylthioanilides- Double Mitsunobu nice way to build the 9-membered ring - Cross-Transannulation beautiful cascade to pentacyclic core
Conclusion
N
O
N
O
H
H
H
Double Mistunobuvia nitrobenzene-
sulfonamide chemistry
O
NMe NH
O
intramolecularoxymercuration
intramolecular Michaeladditon
divinylcyclopropanerearrangement
O OMe H O
O
OH
HO MeEt
HH Me
MeHO
HO
HMe
OMe
Me
CO2H
Me
Spiroketalization
Aldol condensation
O OOH
O
OH
OHNH
HO H
HN
H2N
HO
guanidine
intramolecularcarboxylate addn.
Bibliography(±)-Tetrodotoxin:
(1). Y. Kishi, M. Aratani, T. Fukuyama, F. Nakatsubo, T. Goto, S. Inoue, H. Tanino,
S. Sugiura, H. Kakoi, J. Am. Chem. Soc. 1972, 94, 9217 – 9219;
(2). Y. Kishi, T. Fukuyama, M. Aratani, F. Nakatsubo, T. Goto, S. Inoue, H. Tanino,
S. Sugiura, H. Kakoi, J. Am. Chem. Soc. 1972, 94, 9219 – 9221.
(3). T. Goto, Y. Kishi, S. Takahashi, Y. Hirata, Tetrahedron 1965, 21, 2059 – 2088;
(+)-Monensin:
(1). Kishi, Y. Aldrichimica Acta 1980, 13, 23.
(2). Fukuyama, T.; Vranesic, B.; Negri, D.P.; Kishi, Y. Tetrahedron Lett. 1978, 2741.
(3). Johnson, M.R.; Nakata, T.; Kishi, Y. ibid. 1979, 4343.
(4). Johnson, M.R.; Nakata, T.; Kishi, Y. ibid. 1979, 4347
(5). Hasan, I.; Kishi, Y. ibid. 1980, 21, 4229.
(6). Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y.
J. Am. Chem. Soc. 1978, 100, 2933.
(7). Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101,
259..
(8). Fukuyama, T.; Wang, C.-L.J.; Kishi, Y. ibid. 1979, 101, 260.
(9). Fukuyama, T.; Akasaka, K.; Karanewsky, D.S.; Wang, C.-L. J.; Schmid, G.;
Kishi, Y. ibid. 1979, 101, 262.
(10). Class i cs in Total Synthesis, Targets, Strategies, Methods. Nicolaou, K.C.;
Sorensen, E.J. VCH-Publishers, Inc. New York, 1996.
(+)-Gelsemine:
(1). Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39,
4073.
(-)-Strychnine:
(1). Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
