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Joel Austin
MacMillan Group Meeting
January 9, 2002
Comparative syntheses of Gelsemine
! Historical context
! Approaches to Racemic Gelsemine
! Asymmetric Synthesis of Gelsemine
N O
HNO
Me
Historical Background of Gelsemine
! Isolated as an amorphous base from the roots of the Gelsemium Sempervirens
(Carolina or Yellow Jasmine) in 1870 by Wormley.
! Obtained in crystalline form by Gerrard in 1883.
! Molecular formula elucidated in 1910 by Moore.
! 80 years of largely inconclusive degradative studies still had not produced a
structure.
! Structure determined independently by the groups of Conroy and Wilson in
1959 via NMR and X-ray crystallography.
! Unique hexacyclic cage structure.
! Strychnine like activity, strong CNS stimulant as well as antihypertensive
activity.
N O
HNO
Me
Saxton, JE.; In The Alkaloids; Manske, R.H.F., Ed.; Academic Press: New York, 1965; Vol 8, pp 93-117Gerard, A. Pharm. J. 1883, 13, 641
Moore, C.W. J. Chem. Soc. 1911, 99, 1231Conroy, H.; Chakrabarti, J.K.; Tet. Lett. 1959, 6
Lovell, F.M.; Pepinsky, R.; Wilson, A.J.C. Tet. Lett. 1959, 1
Stork's approach to Gelsemine Core
! Key steps include mixed acetal radical cyclization and a sequential
transannular alkylation - Claisen rearrangement sequence.
! No further work on gelsemine is reported from the Stork lab beyond synthesis of
model core.
Stork, G.; Krafft, M.E.; Biller, S.A.;Tet. Lett. 1987, 28, 10, 1035-1038
O
O OH O
O OH
O
O O
H
O
O
O
OBOC
O
OEt
O
OEt
MeO2C
O
OEt
MeO2C
O
OEt
MeO2C BrHO
AIBN
i) LDA/ PhSeSePhii) mCPBA
DIBAL
1) DCC, DMAPOH
O
2) Hydrolysis / esterification
TMSOTfLDA / TMSCl
Radical Cyclization
Ireland Claisen
N O
HNO
Me
95% yield 93% yield 95% yield
95% yield
77% yield
67% yield96% yield
Stork's approach to Gelsemine CoreStereochemical Rationale
Stork, G.; Krafft, M.E.; Biller, S.A.;Tet. Lett. 1987, 28, 10, 1035-1038
O
O OH
O
O O
H
O
O
O
OBOCO
OEt
MeO2C
O
OEt
MeO2C Br
AIBNTMSOTf
LDA / TMSCl
HMeO2C
O
OTMS
H
O
O
O OTMSO
O O
H
N O
HNO
Me
! Mixed acetal radical cyclization
! Ireland Claisen
! Transannular Alkylation
H
OEtO
N O
HNO
Fleming's approach to Gelsemine Core
! Key steps are the use of a Diels-Alder to make bicycle core, bicycle
rearrangement, addition of an allylsilane to an acyliminium ion.
! No further work on gelsemine is reported from the Fleming lab after
considerable work to install the oxindole. Twenty steps. Me
EtO2CHN O
OEt
OEtHO
EtO2CHN OAc
HO
O
OAc
OH
OEtO2CHN
CO2Et
OTHP
O2N
OTHP
O2N
CO2Et
EtO2CHN O
OEt
OEt
OH
43% yield1) Al/Hg, MeOH
2) EtCO2CCl, Et3N
3) LiAlH4
4) AcCl, Et3N
5) PhH+ TsO-, EtOH
81% yield
OAc
OH
EtO2CHN
O2N
CO3H
85% yield
MgBr2
78% yield
1) PhNMe3Br3
2) DHP, H+
3) K2CO3, H2O
4) PyH+ TsO- EtOH
62% yield
1) PCC / Al2O3
2) MgBr
82% yield
Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944
N O
HNO
Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944Fleming, I; Moses, R.C.; Tercel, M.; Ziv, J. J. Chem. Soc. Perkin Trans 1 1991 617-626
Fleming's approach to Gelsemine Coreand approach to introduction of oxindole
Me
N O
O
EtO2CHN O
OEt
OEt
EtO2CHN O
OEt
OEt
Cl
EtO2CHN O
OEt
OEt
OH
EtO2C
X
NO
SOCl2
97% yield
(Me3Si)2CuLi
84% yield
(CH2O)3
HCO2H
! Devoped three new methods for introduction of oxindole moiety.
two of these go in very low yield. Third approach
works decently on adamantyl system but not as
well on model with ether bridge. No further work
is reported.
Ph3Al
X=CH2 91% yieldX=O 35% yield X
NO2
1) NaOMe2) AcCl
66% yield
ONC1) H2SO4
2) Na2CO3
69% yield
MeOHNOC1) t-BuOCl2) Zn(OAc)2
85% yield
OMe
Na / Hg
100% yield
HNO
NO2
Me3Si
! Key allylsilane construction of quaternary carbon.
85% yield
N O
HNO
Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944
Fleming's approach to Gelsemine CoreStereochemical Rationale
Me! Bicycle rearrangement.
EtO2CHN OAc
HO
O
OAc
OH
OEtO2CHN
MgBr2
78% yield
CO2Me
OH
OEtO2CHN
CO2Me
OH
EtO2CHNOH
NHCO2Et
CO2Me
O
35% yield
AlCl3
CO2Me
OH
EtO2CHN
Br
EtO2CHNCO2Me
HO
OMgBr2
44% yield 39% yield
HO Migration
Cl3AlO
N O
HNO
Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944
Fleming's approach to Gelsemine CoreStereochemical Rationale
Me! Pyran formation via intramolecular SN2
N O
O
EtO2CHN O
OEt
OEt
EtO2C
(CH2O)3
HCO2H
Me3Si
N O
O
EtO2C
Me3Si
EtO2CHN O
OEt
OEtHO
EtO2CHN OAc
HO
O
1) PhNMe3Br3
2) DHP, H+
3) K2CO3, H2O
4) PyH+ TsO- EtOH
62% yieldEtO2CHN OH
DHPO
O
! Allylsilane addition to acyliminium ion
Br
84% yield
N O
HNO
Johnson's synthesis of Gelsemine
! Key steps are the use of a photoinduced intramolecular cycloaddition, retro-
Claisen condensation, intramolecular Mannich, novel oxindole synthesis.
! Stops synthesis at racemic imino-ether of 21-oxogelsemine; this natural product
has previously been shown to be readily converted to gelsemine. 28 steps. Me
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764
O
TBDMSOOTMS
CO2Me
H
SePh
O
TBDMSOO
CO2Me
H
O
AcOO
H
OH
OH
MeO2C CO2Me
O
MeO2C CO2Me
Cl
MeO2C CO2Mepyridine h"
1) LiAlH4
2) AgOAc, I2, AcOH
73% yield 53% yield
44% yield
1) (i) RuCl3, NaIO4
(ii) CH2N2
2) K2CO3, MeOH3) TBDMSOTf, lutidine
PhSeSiMe3,ZnI2, PhMe
reflux
85% yield94% yield
OH
N O
HNO
Johnson's synthesis of Gelsemine
Me
N
O
H
O
MeTBDMSO
OH
H
CONHMe
CHO
O
H
TBDMSO
H
CONHMe
CO2Me
O
H
TBDMSO
HO
TBDMSOO
CO2Me
H
O
TBDMSOOTMS
CO2Me
H
O
TBDMSOOTMS
CO2Me
H
SePh
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764
N
OBr
OMe
H
O
MeTBDMSON
O
H
O
MeTBDMSO
mCPBA
92% yield
1) K2CO3, MeOH, THF
2) Me2SO, TFAA, –70°C
92% yield
86% yield95% yield
crude
97% yieldfrom hydroxy
lactam
88% yield
MeNH2, MeOHTHF
1) LiBH4
2) CrO3, pyridine
K2CO3, MeOH
TsOH, DCMBr2, MeOH
N O
HNO
Johnson's synthesis of Gelsemine
Me
65% yield
N O
NMeO
Me
O
N O
N
Me
OOMe
N O
Me
O
1:2
imino-ether of 21-oxogelsemine
MeON
NN
N O
Me
O
O
N
N
N
TMSOMe
N OMe
O
O
Br
N
OBr
OMe
H
O
MeON
OBr
OMe
H
O
MeTBDMSO
N
OBr
OMe
H
O
MeTIPSO
96% yield97% yield
74% yield70% yield
36% yield
1) TBAF2) Swern TIPSOTf, Et3N
TFA, reflux Bu3SnHbenzene
reflux
i) LDAii) nBuLiiii) then cage structure
h!
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764Dutton, J.K.; Steel, R.W.; Tasker, A.S.; Popsavin, V.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 765-766
N O
HNO
Johnson's Synthesis of GelsemineStereochemical Rationale
" Photochemical [2+2]
Me
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764
O
AcOO
H
OH
OH
MeO2C CO2Me1) LiAlH4
2) AgOAc, I2, AcOH
44% yield
OH
MeO2C CO2Me
O
MeO2C CO2Me
h!
53% yield
" Pyran formation
O O
OH
O
OAc
CO2MeMeO2C
O
I
HO
HO
Me
O
OH
IO
HOOH
OO
Me
OH
OH
OO
O Me
N O
HNO
Johnson's Synthesis of GelsemineStereochemical Rationale
Me
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764
N
OBr
OMe
H
O
MeTBDMSO
N
O
H
O
MeTBDMSO 97% yieldfrom hydroxy
lactam
Br2, MeOH
! Methoxy bromination
N O
OTBDMS
HO
MeBr
MeOH
N O
OTBDMS
HO
Me
MeOBr
! Intramolecular Mannich cyclization
NO
Me
O
OTIPS
Br
N OMe
O
O
Br
N OMe
O
O
Br
N
OBr
OMe
H
O
MeTIPSO 74% yield
TFA, reflux
N O
HNO
Johnson's Synthesis of GelsemineStereochemical Rationale
Me
Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764
! Oxindole synthesis
N O
NMeO
Me
O
N O
N
Me
OOMe
N O
Me
O
1:2
MeON
NN
36% yield
h"
N O
Me
O
MeON
N O
Me
O
NMeO
N O
Me
O
MeON
NN
N2
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine
! Key steps are the use of a Diels-Alder, intramolecular Mannich, Overman
oxindole synthesis.
! Completes gelsemine in racemic form, enzymatic route to enantiopure starting
material is known. 19 steps.Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
(+) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061(-) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922
NMe
O OEt
H
TIPSO
H
NMe
O OEt
H
OHC
H
NMe
O OEt
HH
HO
NMe
HH
HO
O O
NMe
O O
OH
NMe
O OEt
H
TIPSO
95% yield
45% yieldfrom D–A
98% yield70% yield
toluenereflux NaBH4
EtOH, H+
TPAP / NMO
1) LDAPhSeCH2CHO
2) MsCl, Et3N
TIPSOTf, Et3N
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine
Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
(R) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061(S) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922
90% yieldN OTDS
NH
O
Me
OBr
N OTDS
Me
O
OTf
N OTDS
Me
O
O
N OH
Me
O
NCHO
Me
O
NMe
O OEt
H
TIPSO
N OTDS
NSEM
O
Me
OBr
70% yield 90% yield
45% yield
65% yield
BF3·OEt2 NaBH4
1) TDSCl, imidazole
2) CrO3
3,5-dimethylpyrazole
L-selectridethen Tf2NPh
Br
NH2
Pd(OAc)2, PPh3, Et3N,CO, DMF
70% yield
NAH, SEMCl
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine
Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
(R) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061(S) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922
50% yield
N O
HNO
Me
O
N O
HNO
Me
N O
SEMNO
Me
O
N OH
SEMNO
Me
O
N OTDS
SEMNO
Me
O
N OTDS
NSEM
O
Me
OBr
60% yieldover 2 steps
and 30% yield of epimer oxindole
50% yield
90% yield
Pd2(dba)3, Et3NPhMe
Overman conditions
TBAF
1) HgO, Tf2OPhNMe2, CH3NO2 2) NaBH4, NaOH
TBAFAlH3, THF
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine, Stereochemical Rationale
! Appendage of vinyl group
Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
NMe
O OEt
H
TIPSO
H
NMe
O OEt
H
TIPSO
70%yield
1) LDAPhSeCH2CHO
2) MsCl, Et3N
NH
OTIPSOEt
OLi
Se
O
NH
OTIPSOEt
O
Se OH
HH
NH
OTIPSOEt
O
Se OMs
H
Cl
NCHO
Me
O
NMe
O OEt
H
TIPSO
70% yield
BF3·OEt2
N
Me
O
OTIPS
! Intramolecular Mannich cyclization
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine, Stereochemical Rationale
! Overman Intramolecular Heck for Oxindole synthesis
Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
N OTDS
SEMNO
Me
O
N OTDS
NSEM
O
Me
OBr
Pd2(dba)3, Et3NPhMe
Overman conditions
N OTDS
NSEM
O
Me
OBr
N
SEMNO
Me
OPd
Br
L L
OTDSN
NSEMO
Me
O
PdBr
LOTDS
N Pd
SEMNO
Me
OTDS
LL
Br
N
SEMNO
Me
OTDSPd
L
L
BrH
PdL2
ox add
olefin coordination
migratory insertion
"-hydride elim
Et3N·HBr
N O
HNO
Hart's synthesis of Gelsemine
! Key steps are two free radical cyclization and an isomerization / cyclization.
! Completes 21-oxogelsemine in racemic form. 23 steps.
Me
Kuzmich, D.; Wu, S.C.; Ha, D.C.; Lee, C.S.; Ramesh, S.; Atarahi, S.; Choi, J.K.; Hart, D.J. JACS 1994, 116, 6943-6944Atarahi, S.; Choi, J.K.; Ha, D.C.; Hart, D.J.; Kuzmich, D.; Lee, C.S.; Ramesh, S.; Wu, S.C. JACS 1997, 119, 6226-6241
MeN
H
R1
O
R217% yield
6 steps
O
O
BnO
R1 = CHO, R2 = OEt
2 steps
65% yield MeN
H
O
PhSO
O
BnO
CO2Et
N
BnO
Me
Ph2(MeO)C
free radical cyclization65% yield
functionalgroup manip
65% yield
N
BnO
Me
Ph2(MeO)C
OOAc
O AcN
Br
O O
NOAc
AcNOBnO
Me
O
Ph2(MeO)C
NOAc
AcNOBnO
Me
O
OHC
N O
AcNOBnO
Me
O
OH
Acylation ofisocyanate and
protection
Free Radical cyclization
Elimination /ozonolysis
79% yield 40% yield
Epimerizationand cyclization
90% yield 64% yield
4 stepsto 21-oxogelsemine
39% yield
N O
HNO
Speckamp and Hiemstra's synthesisof Gelsemine, Stereochemical Rationale
! Overman Intramolecular Heck for Oxindole synthesis
Me
Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166
N OTDS
SEMNO
Me
O
N OTDS
NSEM
O
Me
OBr
Pd2(dba)3, Et3NPhMe
Overman conditions
N OTDS
NSEM
O
Me
OBr
N
SEMNO
Me
OPd
Br
L L
OTDSN
NSEMO
Me
O
PdBr
LOTDS
N Pd
SEMNO
Me
OTDS
LL
Br
N
SEMNO
Me
OTDSPd
L
L
BrH
PdL2
ox add
olefin coordination
migratory insertion
"-hydride elim
Et3N·HBr
N O
HNO
Hart's synthesis of Gelsemine
! Key steps are two free radical cyclization and an isomerization / cyclization.
! Completes 21-oxogelsemine in racemic form. 23 steps.
Me
Kuzmich, D.; Wu, S.C.; Ha, D.C.; Lee, C.S.; Ramesh, S.; Atarahi, S.; Choi, J.K.; Hart, D.J. JACS 1994, 116, 6943-6944Atarahi, S.; Choi, J.K.; Ha, D.C.; Hart, D.J.; Kuzmich, D.; Lee, C.S.; Ramesh, S.; Wu, S.C. JACS 1997, 119, 6226-6241
MeN
H
R1
O
R217% yield
6 steps
O
O
BnO
R1 = CHO, R2 = OEt
2 steps
65% yield MeN
H
O
PhSO
O
BnO
CO2Et
N
BnO
Me
Ph2(MeO)C
free radical cyclization65% yield
functionalgroup manip
65% yield
N
BnO
Me
Ph2(MeO)C
OOAc
O AcN
Br
O O
NOAc
AcNOBnO
Me
O
Ph2(MeO)C
NOAc
AcNOBnO
Me
O
OHC
N O
AcNOBnO
Me
O
OH
Acylation ofisocyanate and
protection
Free Radical cyclization
Elimination /ozonolysis
79% yield 40% yield
Epimerizationand cyclization
90% yield 64% yield
4 stepsto 21-oxogelsemine
39% yield
N O
HNO
Overman's synthesis of Gelsemine
! Key steps are Aza-Cope rearrangment, Mannich cyclization, intramolecular
Heck, base promoted reorganization of oxindole. This synthesis is of note in that
the mannich cyclization was demonstrated well in advance of the other syntheses.
! Completes gelsemine in racemic form. 26 isolated intermediates. Me
Earley, W.G.; Jacobsen, E.J.; Meier, P.; Oh, T.; Overman, L.E. Tet. Lett. 1988, 29, 31, 3781-3784Madin, A.; Overman, L.E. Tet. Lett. 1992, 33, 34, 4859-4862
Madin, A.; O'Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Angew. Chem. Int. Ed. 1999, 38, 19, 2934-2936
i) KHMDS, Et3SiClii) (PhIO)n, BF3•OEt2iii) KHMDS, Comins' reagent
61% yield
OH
HN
CN
OK
N
N
H
OK
MeO2CN
H
O
X
MeO2CN
OH
Br
EtO2CN
MeO2CN
O
Br
OTf
OMe EtO2CN OMe
O
NMOM I
Br Br
EtO2CN
Br
NMOM
O
O
KH18-c-6ClCO2Me
X=H
X=Br
Br2
TFA
67% yieldover 2steps
81% yield
1) Carbonylation
2) Amidation / protection
74% yield
Heck
11:1
61-78% yield
N O
HNO
Overman's synthesis of Gelsemine
Me
Earley, W.G.; Jacobsen, E.J.; Meier, P.; Oh, T.; Overman, L.E. Tet. Lett. 1988, 29, 31, 3781-3784Madin, A.; Overman, L.E. Tet. Lett. 1992, 33, 34, 4859-4862
Madin, A.; O'Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Angew. Chem. Int. Ed. 1999, 38, 19, 2934-2936
EtO2CN
Br
NMOM
O
O
N
Me
NMOM
O
CN
OHN
Me
NMOM
O
CN
N
CN
HNO
MeO
N OHCN
MOMNO
Me
O
H
H
N O
MOMNO
MeO
N O
HNO
Me
N
NMOM
OOEE
1) HCl2) (iBu)3Al3) Ethyl vinyl ether4) NaCN, DMSO 150°C
59% yield
1) MeOTf, NaCN2) p-TSA
84% yield
80% yield
60% yield
DBU
1) HCl2) DIBAL3) Et3SiH, TFA
H
HNR3
N O
HNO
Overman's synthesis of Gelsemine
Me
Earley, W.G.; Jacobsen, E.J.; Meier, P.; Oh, T.; Overman, L.E. Tet. Lett. 1988, 29, 31, 3781-3784Madin, A.; Overman, L.E. Tet. Lett. 1992, 33, 34, 4859-4862
Madin, A.; O'Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Angew. Chem. Int. Ed. 1999, 38, 19, 2934-2936
HN
Br
NMOM
O
N
NMOM
OOEE
NaCN, DMSO 150°C
EtO2CN OMe
O
NMOM I
Br
EtO2CN
Br
NMOM
O
O
11:1
61-78%yield
OEE HN
NMOM
OOEE
CN
! Aziridine formation
! New Heck conditions
HN
Br
NMOM
OOEE
CN
N
NMOM
Me
OTDS
OOMe
PdL
L
[Pd2(dba)3] CHCl3, Ag3PO4
Et3N
N O
HNO
Fukuyama's synthesis of (+)-Gelsemine
! Key steps are an epoxide rearrangment and a divinylcyclopropane
rearrangement.
! Completes gelsemine enantioselectively. Shorter endgame than racemic
synthesis. 21 steps. Me
Fukuyama, T.; Liu, G. JACS 1996, 118, 7426-7427Fukuyama, T.; Liu, G. Pure & Appl. Chem. 1997, 69, 3, 501-505
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075
88% yield
N O
Bn
OO
Cl
SiMe2H SiMe2H
Cl
OX X=Aux
X= OMeSm(OTf)3
MeOH
Et2AlCl
–78°C
H2O2
53% yield
99% yield
OH
Cl
CO2Me
OH
Cl
CO2Me
O
Et3SiO
CO2Me
OSiEt3
O
CHO
Et3SiO
CO2Me
NHI
O
100% yield
95% yield65-78% yield99% yield
VO(acac)2
t-BuOOH
a) TESOTflutidine
b) t-BuOK
CO2Me
MAD, PhMe4-I-oxindolepiperidine
Single Isomer
N O
HNO
Fukuyama's synthesis of (+) Gelsemine
Me
100% yield
Et3SiO
CO2Me
NHI
O
CO2Me
NHI
O
O
NH
O
I
O
MeO2C
NMOM
O
MeO2C
HCO2tBu
MOMN
O
H
CO2tBu
MeHN
CO2MeH H
MOMN
O
H
CO2tBu
AllocN
Me OH
Fukuyama, T.; Liu, G. JACS 1996, 118, 7426-7427Fukuyama, T.; Liu, G. Pure & Appl. Chem. 1997, 69, 3, 501-505
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075
72% yield54% yield
94% yield
i) TBAFii) CrO3, H2SO4
ii) Tol/ACN Heat
i) Wittigii) MOMCliii)nBu3SnH, AIBN
MeNH2
MeOH
A) AllocClB) LiBEt3H
N O
HNO
Fukuyama's synthesis of (+)-Gelsemine
Me
61% yield
MOMN
O
H
CO2tBu
AllocN
Me OH
MOMN
O
H
CO2tBu
N
Me OH
NC
N OH
MOMNOt-BuO2C
Me
NC
N OCOPh
MOMNO
Me
NC
OH
N OX
MOMNO
Me
O
X=COPh
X=H N O
MOMNO
Me
O
N O
HNO
Me
Fukuyama, T.; Liu, G. JACS 1996, 118, 7426-7427Fukuyama, T.; Liu, G. Pure & Appl. Chem. 1997, 69, 3, 501-505
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075
78% yield
62% yield
97% yield
57% yield96% yield
a) [Pd(Ph3)4]pyrrolidine
b) ICH2CNiPr2NEt
KHMDS
1) PhCOCl
2) Hydrolysisreduction71% yield
o-NO2PhSeCN,mCPBA, Et3N
K2CO3
MeOH
Hg(OTf)2
PhNMe2, NaOH
1) TMSCl, NaI2) DIBAL
N O
HNO
Fukuyama's synthesis of (+)-Gelsemine
! Divinyl cyclopropane rearrangement.
Me
Meinwald, J.; Labana, S.S.; Chadha, M.S. JACS, 1963, 85, 582Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075
CO2Me
NHI
O
O
NH
O
I
O
MeO2C
O
MeO2C H
HNO
I
H
O
MeO2C
HNO
I
N O
HNO
Fukuyama's synthesis of (+)-Gelsemine
! Rearrangement analogous to one previously reported by Meinwald.
Me
Meinwald, J.; Labana, S.S.; Chadha, M.S. JACS, 1963, 85, 582Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075
Et3SiO
CO2Me
OSiEt3
O
CHO
Et3SiO
CO2Me
NHI
O
65-78%yield
99%yield
CO2Me
MAD, PhMe
4-I-oxindolepiperidine
OSiEt3
O
CO2Me
MAD
OSiEt3
OMAD
CO2Me
OSiEt3
O
CO2Me H Et3SiO
CO2Me
CHO
! Condensation by oxindole, Iodine at 4 position helps with olefin geometry.
Et3SiO
CO2Me
CHO
Et3SiO
CO2Me
NHI
O
HO
Et3SiO
CO2Me
NH
I
O
HO
OSiEt3
CO2Me H
OMAD
N O
HNO
Danishefsky's synthesis of Gelsemine
! Key step is a divinylcyclopropane rearrangement, new oxindole synthesis from
an Eschenmosr Amide acetal Claisen.
! Completes gelsemine in racemic form. Not completely published. ? steps.
Me
Ng, F.; Chiu, P.; Danishefsky, S.J. Tet. Lett 1998, 39, 767-770Lin, H.; Ng, F.W.; Danishefsky, S.J. Tet. Lett fast 2002
t-BuO
HNO2
N
H
MeO2COPiv
N
MeO2COPiv
CbzHN
OHN
MeO2COPiv
NCbz
O
N
MeO2COH
NCbz
N
CbzNO
EtO2COTESN
MeO2COPiv
ONMe2
CbzN
N
MeO2COPiv
NMe2
CbzN
O
rearrangement
then unknownelaboration
5 step process
NO224%yield
CH3C(OMe)2NMe2
30-40%yield24%yield
2 steps
Dihydroxylationprotection andoxidation sequence(5 steps)
18%yield
Conclusion
! Lots of synthetic work on this molecule with two basic premises dominating:
cyclisation onto an iminium and rearrangements to build core.
! Oxindole synthesis at end is problematic but solved.
! This molecule is SCREAMING for a faster synthesis along a novel strategy.
N O
HNO
Me
![Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine [
J. Am. Chem. Soc.
2002
,
124
, 9812−9824]](https://img.pdfslide.us/doc/110x75/5750a30b1a28abcf0c9fb9fd/explorations-in-organic-chemistry-leading-to-the-total-synthesis-of-gelsemine-58a857fa50e8c.jpg)
