Transcript (-)-Histrionicotoxin

Synthesis of Spirocyclic
Compounds
Yi He
• Introduction
• Synthetic methodologies
• Syntheses of spirocyclics in natural products
– Gelsemine
– Spirotryprostatin
– Histrionicotoxin
– Ginkgolide B
• Conclusion
Introduction
• “Spirocyclane” introduced by Baeyer in
1900
• Widely present in natural compounds
• Synthetic challenging
– Chiral quaternary carbon center
– Synthesis of two fused rings
Methodologies for Constructing
Spirocenters
•
•
•
•
•
Alkylations
Rearrangement reactions
Cycloadditions
Transition metal catalyzed reactions
Cleavage of bridged systems
Sannigrahi, M. Tetrahedron 1999, 55, 9007-9071.
Alkylation
X
n
n
m
m
Substitution
X
X
n
n
m
m
1,4 - Addition
Alkylation using Bis-acetal
MeO
MeO
OMe
H
H
H
TMSOTf
H
MeO
MeO
MeO
CH2OTs
OTs
MeO
MeO
Solvent
Yield%
A%
B%
CH3CN
77
71
29
52
26
74
H
H
OTs
A
H
MeO
H
O
THF
OTs
MeO
OTs
O
B
Tanaka, T.; Okuda, O; Murakami, K; Yoshino, H.; Mikamiyama, H;
Kanda, A; Iwata, C. Tetrahedron Lett. 1994, 35, 4125-4128.
Alkylation using Ynamine
R
R
O
Me
Ph N
n
O
MgBr, CH3CN, 70 ºC
H
60-70%
O
H
n
O
C
N Me
Ph
Ph
Me N R
R
n
O
+
n
O
Me N O
Ph
O
A
(±)-Acoradiene
B
n
R
A%
B%
2
CH3
85
15
1
CH3
80
20
1
i-Pr
100
0
Ficini, J.; Revial, G.; Genêt, J. P. Tetrahedron Lett. 1981, 22, 629-632.
Kaiser, R.; Naegeli, P. Tetrahedron Lett. 1972, 13, 2009-2012.
Michael Addition
Ph
Ph
N
N
O
CO2Me
EtO2C
N
Boc
O
O
a) DIEPA, CH3CN
b) H2, Pd/C, CH3OH
85% 2 steps
EtO2C
O
N
Boc
H
CO2Me
Ph
N
H
O
EtO2C
N
H
H
O
Manzamine A
Brands, K. M.; DiMichele, L. M. Tetrahedron Lett. 1998, 39, 1677-1680.
Rearrangement Reactions for
Spiroannulation
• Vinylcyclopropanol/Vinylcyclobutanol
rearrangement
• Pinacol-type rearrangement
• Sigmatropic rearrangement
Vinylcyclobutanol/Vinylcyclopropanol
Rearrangement
OR
OR
Lewis acid
n
n
OCH3
OCH3
m
m
OCH3
O
n
n = 1 or 2
m = 1 or 3
m
OCH3
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556-6558.
Trost, B. M.; Chen, D. W. D. J. Am. Chem. Soc. 1996, 118, 12541-12554.
Vinylcyclopropane Rearrangement
OTMS
O
1 eq. TMSOTf, 0.7 eq. pyr
OCH3
OCH3
-40 °C, 0.01M CH2Cl2, 85%
OCH3
85.2% de
O
H
OTMS
OCH3
O
CH3
favored
O
H
OTMS
O CH3
OCH3
H
disfavored
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556-6558.
Prins – Pinacol Rearrangement
Y
R
Y
slow
HO
XR
Y
fast
XR
HO
O
XR
XR
O
XR
XR
TMSO
TMSO
O
Prins-Pinacol Spiroannulation
OMe
t-Bu
OTMS
RuCl3•3H2O
TMSOTf, DTBMP
t-Bu
CH2Cl2, RT, 70%
MeO
O
NaIO4, CCl4
CH3CN, H2O
t-Bu
O
OMe
t-Bu
OMe
CH2Cl2, RT, 28%
O
OMe RuCl3•3H2O
TMSOTf, DTBMP
TMSO
MeO
O
t-Bu
O
NaIO4, CCl4
CH3CN, H2O
t-Bu
O
Me
DTBMP =
t-Bu
Minor, K. P; Overman, L. E. Tetrahedron 1997, 53, 8927-8940.
N
t-Bu
Mechanism for Regioselectivity
XR'
t-Bu
OR
H
t-Bu
X
fast
OR
t-Bu
R'
O
XR'
slow
XR'
XR'
t-Bu
RO
O
t-Bu
XR'
t-Bu
OR
X
t-Bu
OR
t-Bu
R'
XR'
H
O
slow
RO
t-Bu
XR'
t-Bu
XR'
O
Mechanism for Low Yield of AxiallyTethers Electrophile
R'
X
t-Bu
OR
XR'
t-Bu
OR
neither bond anti to the carbocation!
2,3-Sigmatropic Rearrangement
SPh
Ph
CO2Et
S
Rh2(OAc)4
O
CO2Et
PhH, reflux
O
Ph
S
O
EtO2C
N2
PhS CO2Et
O
O
(+)-Acorenone
Kido, F.; Abiko, T.; Kato M. J. J. Chem. Soc. Perkin Trans. 1 1992, 229-233.
Cycloaddition
• [4+2]
+
n
n
X
X
• [3+2]
X
+
Y
• [2+2]
n
n
n
n
n
X
• [2+1]
n
X
Diels-Alder Approach to ShizukaAcoradienol
MeO2C
+
O O
O
CHCl3, 50 °C
O
m-CPBA
MeO2C
300 MPa, 57%
O O
O
MeO2C
xylene, reflux
45%
MeO2C
O
HO
Shizuka-acordienol
Hatsui, T.; Hashiguchi, T.; Takeshita. H. Chemistry Express 1993, 8, 581-584.
[2+1]Cycloaddition in the Total
Synthesis of (-)-Acorenone
N2
Cu powder
HCl
cyclohexane
CHCl3
O
O
O
(-)-Acorenone
Ruppert, J. F.; Avery, M. A.; White, J. D. J. Chem., Soc. Chem. Commun. 1976, 978.
Gelsemine
• Major alkaloid component
of Gelsemium
sempervirens
• Novel hexacyclic cage
structure
• Unique spiro-oxindole
center
O
N
Me
H
N
O
Retrosynthesis of Gelsemine by
Johnson
O
H
N
O
N
N
+
N
N
O
N
O
TMS
Me
OMe
Me
O
N
Me
O
O
N
Me
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P.
J. Chem. Soc., Chem. Commun. 1994, 763-766.
O
Johnson’s Total Synthesis of Gelsemine
N
N N
OMe
O
N
+
O
n-BuLi (2 equiv.)
N
N N
N
N
N
MeO
O
Me
TMS
+
O
OMe
N
O
Me
O
N
Me
major
MeO
minor
N
N
hv, CH3CN
Pyrex
+
O
N
OMe
O
N
O
O
Me
Me
1
:
O
2
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P.
J. Chem. Soc., Chem. Commun. 1994, 763-766.
Mechanism of Radical Cyclization
N
N
•
•
N
N•
OCH3
OCH3
O
O
N
N
O
N
O
N
O
Me
Me
OCH3
•
O
Me
rotation
MeO
N
O
OMe
N
N
•
•
O
N
O
N
Me
Me
MeO
O
N
Me
O
O
Unexpected Formation of Oxetane
•
Ph N
O
H
N
O
•
O
N
Me
H
N
CH2
O •
H
•
O
O
O
N
Me
N
Me
O
O
Retrosynthesis of Gelsemine by
Speckamp
O
H
N
O
OTf
N
SEM Br
O
N
N
O
Me
O
N
OTDS
OTDS
Me
Me
TIPSO
OH
H
O
N
Me
OH
O
OEt
N
CH3
+
O
O
N
CH3
Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N.
J. Chem. Soc., Chem. Commun. 1994, 767-768.
Speckamp’s Total Synthesis of Gelsemine
O
OTf
1) Pd(OAc)2, PPh3, Et3N
CO, 2-bromoaniline
DMF, RT, 24 h, 79%
O
N
SEM Br
O
2) NaH, SEMCl, THF
N
N
OTDS
Me
Pd2(dba)3, Et3N
PhCH3, refulx, 4h
60%
OTDS
Me
O
SEM
N
O
1) Bu4NF, THF, RT., 2 h
2) HgO, Tf2O, N,N-dimethylaniline
MeNO2, RT, 3 d, 60%, 3 steps
O
N
OTDS
3) NaBH4, NaOH, CH2Cl2, EtOH, 80%
4) Bu4NF, THF, 4 Å MS, reflux, 4 h, 90%;
Me
O
N
O
Me
de? 60:30
O
H
N
TDS = thexyldimethylsilyl
AlH3, THF, -65 - 0 °C
4 h, 50%
H
N
N
O
Me
Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N.
J. Chem. Soc., Chem. Commun. 1994, 767-768.
Retrosynthesis of Gelsemine by
Fukuyama
O
N
H
N
O
O
X
OH
CO2R
Me
Me
Me
X
X
O
NH
O
CO2R
H
N
X
RO2C
H
N
HN
N
O
H
N
RO2C
O
Fukuyama, T.; Liu G. Pure & Appl. Chem. 1997, 69(3), 501-505.
N
H
Fukuyama’s Total Synthesis of Gelesmine
O
OAc
CHO
CO2CH3
HO
2) DCC, DMSO
pyridium trifluoroacetate
Et3N, CH2Cl2, RT, 91%
O
CO2CH3
O
O
N
H3CO2C
CO2CH3
O
NH
I
H3CO2C
O
Me
O
O
H
N
NH
O
O
I
O
1) PhCH3/CH3CN, 1:1
90 ºC, 45 min, 98%
2) n-Bu3SnH, cat. AIBN
95 ºC, 1 h, 85%
NH
1) 4-iodooxindole
cat. piperidine
MeOH, RT, 89%
H
N
O
I
H3CO2C
Fukuyama, T.; Liu G. Pure & Appl. Chem. 1997, 69(3), 501-505.
NH
I
Spirotryprostatins
• Isolated from the
fermentation broth of
Aspergillus fumigatus
• Inhibits cell cycle at G2/M
phase
• Spiro-oxindole rings
O
O
HN
N
HN
N
N
N
H3CO
O
O
O
Spirotryprostatin A
O
Spirotryprostatin B
Cui. C. B.; Kakeya, H.; Osasa, H. Tetrahedron 1996, 51, 12651-12666.
Cui. C. B.; Kakeya, H. l.; Osasa, H. Tetrahedron 1997, 53, 59-72.
Danishefsky’s Pinacol-type
Rearrangement Approach
CO2CH3
N
H
Br
NBoc
H2O, AcOH
SPh
O
CO2CH3
H
SPh
O
HN
N
N
NBoc
SPh
NBoc
N
H O
H
O
HN
CO2CH3
NBS, THF
H3CO
O
Spirotryprostatin A
Edmonson, S. D.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1998, 37, 1138-1140.
Williams’ 1,3-Dipolar Cycloaddition
Approach
Ph
Ph
Ph
Ph
HN
OHC
O
O
Me
OMe
Me
4Å MS, PhCH3
O
N
Me
MeO
Ph
O
[1,3]-dipolar
cycloaddition
Me Ph
MeO
N
Me
O
82%
HN
CO2Et
Me O
EtO2C
HN
O
N
H
O
O
HN
N
N
O
Spirotryprostatin B
Sebahar, P. R.; Williams. R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667.
O
H
O
CO2Et
Overman’s Retrosynthesis of
Spirotryprostatin B
O
O
HN
3-allypalladium
capture
N
O
O
HN
N
HN
N
O
O
asymmetric
Heck cyclization
L2Pd
I
I
O
N
RN
HN
O
O
Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. Engl. 2000, 39, 4596-4599.
Overman’s Intramolecular Heck Approach
H
1) SEM-Cl, NaH
2) TBAF
O
I
N
N
H
OTBDPS
NH
O
3) Dess-Martin
4) A, t-BuOK
O
SEMN
N
O
SEM
O
O
N
N
HN
N
Me2AlCl
N
DIEPA (93%)
O
[Pd2(dba)3]•CHCl3
(otol)3P, KOAc
THF, 70 °C
(72%, B:C = 1:1)
I
O
O
O
B
O
O
SEMN
N
N
O
O
O
HN
Me2AlCl
DIEPA (93%)
H
N
N
N
A=
O
O
O
NH
PO(OMe)2
C
Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. Engl. 2000, 39, 4596-4599.
(-)-Histrionicotoxin
• Isolated from the skin of
frog Dendrobates
histrionicus
• Novel spiro-piperidine
structure
OH
H
N
(-)-Histrionicotoxin
Daly, J. W.; Karle, I.; Myer, C. W.; Tokuyama, T.; Walters, J. A.; Witkop, B.
Proc. Natl. Acad. Soc. U. S. A. 1971, 68, 1870.
Retrosynthesis of (-)-Histrionicotoxin by
Stork
HO
HN
CONH2
HO
Br
N
H
R
HO
CO2Me
O
OTBS
OTBS
O
+
O
R
H
H
Br
Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875-5876.
Stork’s Synthesis of (-)-Histrionicotoxin
CO2Me
OTBS
+
OTBS
O
LDA
O
1) O3, PPh3
2) (Ph3P+CH2I)I-, NaN(TMS)2
HMPA, THF, 52%
O
3) 5% HCl, THF
43%
H
Br
H
O
OH
O
1) Ph3P, CBr4, ether, 2h, 53%
2) NH4Cl, AlMe3, PhH, 40 °C, 18h
I
AcO
AcO
Br
3) Ac2O, Pry, DMAP, 70%
I
I
1) (CF3CO2)2IPh
CH3CN, H2O, 3 d
CONH2
I
HN
HO
HN
2) Et3N, ClCH2CH2Cl
65-70 °C, 2h, 31%
I
Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875-5876.
I
Retrosynthesis of (-)-Histrionicotoxin by
Holmes
N
N
H
R'
R
O
HO
R
N
O
R'
R
NH
OH
R'
Williams, G, M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.
J. Am. Chem. Soc. 1999, 121, 400-401.
Holmes’ Synthesis of (-)-Histrionicotoxin
O
O
NaN(TMS)2
1-chloro-1-nitrosocyclohexane
X
X
THF, then HCl (aq), 70%
(CH2)3OTBDPS
NHOH
(CH2)3OTBDPS
X = (+)-10,2-camphorsultam
CN
1) PHCH3, 80 °C, 6 h
2) styrene, 75 °C
85%, 2 steps
(CH2)3OTBDPS
X
O
BnO
N
O
N
O
Ph
Ph
TMS
PHCH3
BnO
sealed tube
BnO
N
O
N
CN
CN
N
O
O
1) Zn, AcOH, 30 min, 98%
2) K2CO3, MeOH, 94%
N
H
HO
Williams, G, M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.
J. Am. Chem. Soc. 1999, 121, 400-401.
TMS
Ginkgolide B
• Isolated from Ginkgo
biloba
• Complex structure
– Six ring in a confined space
– Eleven stereogenic
carbons
– Four contiguous quaternary
centers
– Ten oxygenated carbons
O
HO
O
HO
O
O
O
Me
HO
O
O
CMe3
Retrosynthesis of Ginkgolide B’s
Synthetic Intermediate by Corey
MeO
O
MeO
O
O
t-Bu
t-Bu
t-Bu
H
H
•
O
O
CO2H
OMe
MeO
O
OMe
t-Bu
O
O
Corey, E. J.; Kang, M.-C.; Desai, M. J.; Ghosh, A. K.; Houpis, I. N.
J. Am. Chem. Soc. 1988, 110, 648-651
Corey’s Total Synthesis of Ginkgolide B
OMe
1) t-Bu2Cu(CN)Li2, Et2O
-78 to -45 °C
2) TMSCl, Et3N, -45 to -10 °C
OMe
O
MeO
O
t-Bu
O
3) 1,3,5-trioxane TiCl4, CH2Cl2
-78 °C, 65% 3 steps;
1) LDA, DME, -78 to 0 °C
then PhNTf2, 0 to RT, 80%
2) A, Pd(PPh3)4, CuI, n-PrNH2
PhH, 16 °C, 84%;
MeO
MeO
O
1) (Cy-Hex)2BH, THF, 0 °C
2) AcOH, H2O2, pH 10
t-Bu
OO O
O
1) (COCl2)2, PhH
t-Bu
2) n-Bu3N, PhCH3
80% two steps
3) 1 N HCl, pH 3
4) pH 11, 4 h, pH 3
86% 4 steps
CO2H
Me
O
MeO
O
O
t-Bu
t-Bu
Me
H
O
O
HO
O
O
H
•
O
HO
HO
O
CMe3
O
O
A = Me
O
O
O
Corey, E. J.; Kang, M.-C.; Desai, M. J.; Ghosh, A. K.; Houpis, I. N.
J. Am. Chem. Soc. 1988, 110, 648-651
Retrosynthesis of Ginkgolide B’s
Synthetic Intermediate by Crimmins
Me O
HO
O
O
O CO Et
2
O
O OMe
O
O
CO2Et
O
OMe
CMe3
Et3SiO
CMe3
Et3SiO
CMe3
O
EtO2C
Et3SiO
CMe3
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.
Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc. 1999, 121, 10249-10250.
Crimmins’ Total Synthesis of Ginkgolide B
O
O
EtO2C
CO2Et
(EtO2CCH2CH2)2ZnCu
O
h, 366 nm
hexane. 100%
Et3SiO
CMe3
Et3SiO
CMe3
O
O CO Et
2
O
O
O
O
H
O
O
OH
dimethyldioxirane
O
O
OH
OH
H2O, p-TSA, 94%
Et3SiO
CMe3
CMe3
CMe3
O
O
1) MeOH, p-TSA
CH(OMe)3, 95%
2) CS2, MeI, DBU
O
O
3) Bu3SnH, AIBN
60 °C, 78% 2 steps
OMe
O
O
O
HO
HO
O
OMe
O
Me
CMe3
HO
O
CMe3
O
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.
Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc. 1999, 121. 10249-10250.
Conclusions
• Structure diversity of spirocyclic
compounds
• Various approaches to spirocenters
Thanks
• Kiessling Group Members