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Synthesis of Gelsemine
Alexander J. L. Clemens
Burke Group
October 26, 2006
HNO
NMe
O
2
Genus Gelsemium
• G. rankini and G. sempervirens (Carolina Jasmine) native to southeastern U.S.
• G. elegans native to southeast Asia
• G sempervirens produces gelsemine (0.07% by weight)
Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350.Picture: http://www.e-referencedesk.com/resources/state-flower/south-carolina.html
3
Medicine and Homeopathy
• G. elegans traditional medicine in China and Japan
• G. elegans extract used as a clinical treatment for cancer
• G. sempervirens extracts sold as homeopathic treatment
Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350.Picture: http://www.naturallythinking.com/product/asp/ProdID/100091/CtgID/237/af/page.htm
4
Gelsemium Alkaloid Activity
•Around 20 alkaloids isolated from Gelsemium plants•Many Gelsemium alkaloids have antitumor, analgesic, anti-inflammatory, immunomodulating, and/or antiarrhythmic effects
a. Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. J. Nat. Prod. 2006, 69, 715-718. b. Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350. c. Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. J. Am. Chem. Soc. 1990, 112, 5220-5230.
N
NH
OH
H
HMeO
OMe
GelsemicineCytotoxic
N
NMe
O
H
H
H
KoumineAntitumor and Analgesic
HNO
NOMe
GelsemineNo known biological activity
5
A Synthetic Challenge
• Hexacycle with seven contiguous stereocenters on five rings
• Very little functionality• Four distinct synthetic challenges: [3.2.1] bicyclic
system, spirooxindole, pyrrolidine ring, and tetrahydropyran ring
NHO
N
MeO
*
**
*
*
*
*
NHO
N
MeO
*
**
*
*
*
*
NHO
N
MeO
NHO
N
MeO
NHO
N
MeO
6
Synthesis of Gelsemine
Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 4, 1-5.
Danishefsky (Columbia)Fukuyama (Tokyo)Overman (UC-Irvine)
Fukuyama (Tokyo)Speckamp (Amsterdam)Hart (Ohio State)Johnson (Leeds)
Crystal Structure
Isolation
200220001999
19961994
1959
1870
7
Gelsemine Construction
• [3.2.1] bicyclic core
• Pyrrolidine ring
• Spirooxindole
• Tetrahydropyran ring
NHO
N
MeO
8
[3.2.1] Construction Strategy
N
Me
electrophilic carbon
nucleophilic carbon
N
Me
N
Me
nucleophilic carbon
electrophilic carbon
divinylcyclopropanerearrangement
or
Speckamp, Johnson, Hart, and Overman Fukuyama and Danishefsky
Makes the pyrrolidine ring simultaneously
N
Me
electrophilic carbon
nucleophilic carbon
N
Me
N
Me
nucleophilic carbon
electrophilic carbon
divinylcyclopropanerearrangement
or
Speckamp, Johnson, Hart, and Overman Fukuyama and Danishefsky
Makes the pyrrolidine ring simultaneously
9
[3.2.1] by Speckamp
a. Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882-3884. b. Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.
N
NHO
MeO
HO
N OO
+
HO
N OO
HH
BF3OEt2, CH2Cl2, 10ūC
NO
OTIPS
MeN
O
Me O
Diels-Alder
PhMe, reflux
95%
TIPSO
N OEtO
H
Mannich
70%
MeMeMe
5 stepsH
10
Johnson’s Ring Closure
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, P. A. J. Chem. Soc., Chem. Commun. 1994, 763-764.
N
NHO
MeO
O
OTBS
N
O
MeON
O
MeBr
MeO
OTIPS
TFAreflux
O
NO
O
MeBr
OH
NO
O
MeBr74%
Mannich
4 steps
11
Overman’s Opening
Earley, W. G.; Jacobsem, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29(31), 3781-3784.
N
NHO
MeO
OTIPS
Me
OMe
O
+
OTIPS
Me CO2Me
OTIPS
NH2
1. ClCH2CN, cat. NBu4I iPr2NEt, THF 67ūC2. NBu4F, THF 0ūC
OH
N CN
90%
1. KH, [18]-crown-6, THF2. ClCO2Me, DTBMP -78ūC-r.t.3. KOH, MeOH, H2O r.t.
81%
N
H
O CO2Me
AlCl3, CH2Cl2, -78 ūC
76-83%
N
DTBMP
H
5 steps
12
Overman’s Aza-Cope
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.
N
NHO
MeO
N
H
KO
OH
N CN
1. KH, [18]-crown-6, THF2. ClCO2Me, DTBMP -78ūC-r.t.3. KOH, MeOH, H2O r.t.
81%
N
H
O CO2Me
OK
N
[3,3]
N
H
MeO2CO CO2Me
ClCO2Me
N
DTBMP
H
N
H
KO2CO CO2Me
1. ClCO2Me2. KOH
-CO2
13
Overman’s Ring Closure
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.
TFAreflux
OH
NMeO2C
Br
NO
HBr
MeO2CN
H
OMeO2C
O
NBrMeO2C
82%
Mannich
N
Br2, CH2Cl2, -78ūC
H H
N
NHO
MeO
14
Hart’s Radical Cyclization I
Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.
N
NHO
MeO
OTMS
OP
N
O
O H
H
Me
OH
Bu3SnH, AIBNPhH, reflux
O
O
BnO
N
CO2Et
OMe
O
O
BnO
N
CO2Et
OMe
AIBN =
61%
N
O
O
Me +
1. PhMe, reflux2. 2,2-dimethyl- 1,3-propanediol p-TsOH
NN CN
NC
Diels-Alder
O
O
BnO
N
CO2Et
OMe
SPh
7 stepsO
O
H
15
Fukuyama’s Beginning
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
N
NHO
MeO
OMe
O O
O
OEt OMe
O O
N2
Cu(acac)2 (cat.)CuSO4, PhH85 ūC
EEO
68%
3 steps
4 steps
MeO2C
O
OEE
MeO2C
O
OEE
MeO2C
OAc
O
OH
H H[Cu]H H
16
Divinylcyclopropane (1996)
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
oxindole, cat. piperidineMeOH, 23ūC
+
60% 4:1
89%exclusively Z
E Z4-iodooxindolecat. piperidineMeOH, 23ūC
desired product
MeO2C
OAc
O
OH
MeO2C
OAc
OH
NHO
MeO2C
OAc
OH
NH
O
MeO2C
OAc
OH
NH
O
I
MeO2C NH
O
I
O
H
H H H
H 2 steps
H H H
HH
N
NHO
MeO
17
Divinylcyclopropane (2000)
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.
N
NHO
MeO
N O
Cl
O O
Bn
+
SiMe2H
SiMe2H
Cl
ON
O O
Bn
OTES
CO2Me
O
MAD PhMe -20ūC
OTES
CO2Me
O
Diels-Alder
Et2AlCl CH2Cl2-78ūC
88%
MADMeO2C
O
OTES
H
MeO2C
O
H
NHO
I3 steps
65-78%one enantiomer
H H
Al
Me
O
tBu
tBu
tBu
O
tBu
tBu
tBuMAD =
5 steps
18
[3.2.1] and Spirooxindole
a. Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427. b. Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.
N
NHO
MeO
90ūC, PhMe/MeCN (1:1)
ONH
O
CO2MeI
91-98%single isomer
ONH
O
CO2Me
Bu3SnH, AIBNPhMe, 95ūC
85%
MeO2C NH
O
I
O
H
MeO2C NH
O
I
O
H
MeO2C
O
H
NHO
I
and/or
H
H
H
19
Danishefsky’s [3.2.1]
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
N
NHO
MeO
OtBumCPBA
OtBu
OAl2O3 O
OtBu
NO2
(EtO)2(O)P
NaOMe, DMF, 0ÞC
OtBu
H
NO2
OtBu HNO2
O
OtBu
H
=
74%
H
20
[3.2.1] Bicyclic Synthesis
• Speckamp, Hart, Johnson, and Overman - create pyrrolidine ring at same time
• Fukuyama - simultaneous synthesis of a single isomer of spirooxindole
• Danishefsky - most limited; leaves olefins for further functionalization
21
Pyrrolidine Ring Installation
N
Me
N
Me
N
Me
nucleophilicnitrogen
Fukuyama Danishefsky
X
O
X
HN
Y
R'
Rnucleophilic/electrophiliccarbon coupling
N
Me
Speckamp, Hart, Johnson,and Overman
electrophiliccarbon
Mannich-like ring closing
N
Me
N
Me
N
Me
nucleophilicnitrogen
Fukuyama Danishefsky
X
O
X
HN
Y
R'
Rnucleophilic/electrophiliccarbon coupling
N
Me
Speckamp, Hart, Johnson,and Overman
electrophiliccarbon
Mannich-like ring closing
N
Me
N
Me
N
Me
nucleophilicnitrogen
Fukuyama Danishefsky
X
O
X
HN
Y
R'
Rnucleophilic/electrophiliccarbon coupling
N
Me
Speckamp, Hart, Johnson,and Overman
electrophiliccarbon
Mannich-like ring closing
22
Fukuyama (1996)
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
ONH
O
CO2Me
NOEtO2CHN
NMe OAc
O
Cl
NEtO2CHN
NMe OAc
O
O
AgOTf, Ag2CO3,CH2Cl2, 45ūC
NO
N
NMe OAc
O
OH
H2O
MOM
MOM
52%
CO2Et
H
MOM
11 steps
N
NHO
MeO
23
Fukuyama (2000)
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.
N
NHO
MeO
NH
CO2Me
OO
N
NtBuO2C
Me OH
O
NC N
NtBuO2C
NC
Me OH
OKHMDS, THF, -78ūC-0ūC
MOM MOM
68%
N
N
Me OK
O
NC
MOMOK
tBuO
7 steps
24
-Aminonitriles to Amides
Yokoshima, S.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Chem. Lett. 2002, 122-123.
R = alkyl, aromatic
R’ = alkyl
R” = alkyl, aromatic
Yields typically above 70%, often above 80%
R NR'
R"
CN mCPBA, Me2S, KOH(aq)CH3CN-H2O (4:1), 0ūC
R NR'
R"
O
mCPBA
R N R'
R"
CN-OHO
R N R'
R"
CN +OH
R N R'
R"
CNHO
-HCN
Polonovsky-typeelimination
25
Danishefsky’s Pyrrolidine
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
HNO2
O
H
OH
HNO2
O
O
EtO
cat.propionic acid,MeC(OEt)3, PhMe, reflux
HNO2
O
EtO
O
94%
HNO2
OH
OtBu
OH
1. MsCl, Et3N, CH2Cl2, -78ūC2. NaHMDS, THF, -78ūC
HNO2
O
OtBu4 steps
91%
Johnson-orthoester-Claisen Rearrangement
N
NHO
MeO
26
Oxetane Opening
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
N
NHO
MeO
HNO2
O
EtO
O HNO2
O
HN
MeO2CBF3•OEt2 CH2Cl2-78ÞC-12ÞC
HNO2
HO
NMeO2C
64%
HNO2
O
HN
MeO2C
BF3
2 steps
27
The Spirooxindole Moiety
NHO
N
Me
Intramolecular Heck ReactionSpeckamp and Overman
Eschenmoser-Claisen RearrangmentDanishefsky
Photo-induced Radical CyclizationJohnson
NMe
RHN
N
Me
N
Me
O
N
X
R
OH
NMe2
N
O
O
N
OMe
N
N
Me
R
OAc
AcN
O Br
R
O
Radical CyclizationHart
NHO
N
Me
Intramolecular Heck ReactionSpeckamp and Overman
Eschenmoser-Claisen RearrangmentDanishefsky
Photo-induced Radical CyclizationJohnson
NMe
RHN
N
Me
N
Me
O
N
X
R
OH
NMe2
N
O
O
N
OMe
N
N
Me
R
OAc
AcN
O Br
R
O
Radical CyclizationHart
NHO
N
Me
Intramolecular Heck ReactionSpeckamp and Overman
Eschenmoser-Claisen RearrangmentDanishefsky
Photo-induced Radical CyclizationJohnson
NMe
RHN
N
Me
N
Me
O
N
X
R
OH
NMe2
N
O
O
N
OMe
N
N
Me
R
OAc
AcN
O Br
R
O
Radical CyclizationHart
28
Hart’s Radical Cyclization II
Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.
N
NHO
MeO
O
O
BnO
N
CO2Et
O
Me
BnO
N
C(OMe)Ph2
O
Me OAc
O
AcNBnO
NO
Me OAc
AcNO
Bu3SnH, h, PhHBr
MeO
PhPh
BnO
N
C(OMe)Ph2
O
MeOAc
O
AcN BnO
NO
Me OAc
AcNO
MeO
PhPh
40%
6 steps
29
Johnson’s Triazole Radical
Dutton, K. J.; Steel, R. W.; Tasker, A. S.; Popsavin, V.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 765-766.
N
NHO
MeO
O
NO
O
MeN
O
O
Me
OMeN
NN
h, MeCN
NO
O
Me
NMeO
36% 1:2
NO
O
Me
N
OMe
+
N
NN
TMS OMe
LDA, nBuLi
NO
O
Me
OMe
NN N
+
65% combined yield
+
PetersonOlefination
-N2N
O
O
Me
OMe
N
30
Speckamp’s Heck Reaction
Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33 (34), 4859-4862.
•Overman’s protocol gives 9:1 selectivity
•Less selectivity due to more steric bulk on concave face
N
NHO
MeO
NO
O
N
Pd2(dba)3, Et3N,PhMe, reflux
Me
Br
NO
OTDS
NO
+
NOTDS
N
O
90% 2:1Me Me
O
NO
OTDS
O
N
Me
SEM
sterically blockslower face
Pd Br
dba
SEM
OTDS
SEM =
TDS =
OTMS
Si
SEM
SEM
dba = Ph Ph
O
31
Overman’s Trials
Madin, A.; O’Donnell, C. J.; Oh, T.; Old. D, W.; Overman, L. E.; Sharp, M. J. J.Am. Chem. Soc. 2005, 127, 18054-18065.
N
NHO
MeO
O
NMe Br
NSEM
NMeBr
NOSEM
NMe Br
N
O
+
Pd2(dba)3, Et3NPhMe, reflux
80-95% ~9:1
However:
NMe Br
NOSEM
NMe
NO
OH
SEM
X
SEM
I
32
Modified Heck Reaction
Madin, A.; O’Donnell, C. J.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38 (19), 2934-2936.
N
NHO
MeO
NBr
OMe
ON
IMOM
MeO2CNBr
N
NBr
NO
O
MOM
MOM
+
MeO2CMeO2C
[Pd2(dba)3]CHCl3 Ag3PO4, Et3N, THF, reflux
OMeOMe
61-78% 1:11Pd insertion andalkene complexation
NBrMeO2C
-Hydride Elimination
syn addition
NBrMeO2C
N
OPd
OMe
N
O
MOMOMe
dbadba
dba
THFMOM
Selective for the wrong diastereomer!
Pd
33
Heck Selectivity Rationale
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054-18065.
•Substituted enol ether changes system - tetrasubstituted and electron-rich
•Vinyl group coordinates to Pd
•Overman et al. unable to optimize for natural isomer - requires correction
N
NHO
MeO
NBr
N
NBr
NO
O
MOM
MOM
+
MeO2CMeO2C
OMeOMe
61-78% 1:11
NMe Br
NOSEM
NMeBr
N
O
+
80-95% ~9:1
vs.
SEM
34
Aziridine Intermediate
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.
NBr
N
O
MOM
MeO2C
OMe
3 steps
NBr
N
O
MOM
MeO2C
O
OEt
OEE
NaCN, DMSO, 150ūC
N
N
O
MOM
OEE
1. MeOTf, DTBMP CH2Cl2, 0ūC2. NaCN, DMSO, 150ūC
N
N
O
MOM
OH
Me CN99%99% DTBMP =
N
N
NHO
MeO
35
Spirooxindole Correction
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.
N
N
O
MOM
OHDBU, PhMe, reflux
N
N
O
MOM
O
CNH
N
N
CNOH
O
N
N
O
O
NH
aq. workup
N
N
O
O
O
MOM
MOM
MOM
MeMe
Me
MeDBUH
80%N
N
DBU
MeCN
Rotationand bondformation
N
NHO
MeO
N
N
O
O
O
MOM
Me
80%
36
Danishefsky’s Original [2,3]
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
O2N
PivO
NMeO2C
OHH
TIPSO
NMeO2C
OH
SnBu3
N
Ph
n-BuLi, THF -78ūC to 25ūC
TIPSO
NMeO2C
HONH2
not observed
[2,3] Still-Wittig rearrangement
TIPSO
NMeO2C
OH
Li
N
Ph
Piv =
O
3 steps
N
NHO
MeO
37
Danishefsky’s Second [2,3]
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
N
NHO
MeO
CbzHN
PivO
NMeO2C
OHH
HC(OMe)2NMe2 m-xylene, reflux
PivO
NMeO2C
ONHCbz
NMe2
PivO
NMeO2C
NOCbz
neither productobserved
CbzHN
PivO
NMeO2C
OH NMe2
H
Bchi Rearrangement
Cbz =
O
O
Piv =
O
Ph
-H
CbzHN
PivO
NMeO2C
OH NMe2
38
Danishefsky’s Tribulations
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
N
NHO
MeO
tBuO NOMe
X
tBuO NOMe
O
However:
tBuO NOMe
tBuON
O
MetBuO N
I
O Me Pd2(dba)3CHCl3AgOTf, Et3N,1,4-dioxane 120ūC +
50-70% 7:1
39
[3,3] Rearrangement
Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.
NH
PivO
NMeO2C
OH
Cbz
MeC(OMe)2NMe2m-xylene
HN
PivO
NMeO2C
NMe2O
silica gel
PivO
NMeO2C
N
O
H N
O
H
HNMe2N Cbz
MeO2CPivO
30-40%
Eschenmoser-Claisen Rearrangement
Cbz =
O
O
Piv =
O
Ph
CbzCbz
N
NHO
MeO
40
Ring Contraction
Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.
N
NHO
MeO
PivO
NMeO2C
N
O
HO
NMeO2C
NO
O 1. TESOTf, Et3N, CH2Cl2 2. NaOMe, MeOH3. TPAP, NMO, CH2Cl2 4 mol. sieves
TESO
NMeO2C
NOCbz
1. DIBALH, CH2Cl2, -78 ūC2. TsOHH2O, CH2Cl2, reflux
1. OsO4, THF, -25ūC2. NaSO3
3. NaIO4, THF/H2O
HO
NMeO2C
N
40% (3 steps)9% (6 corrective steps)
50% (2 steps)
45%
CbzCbz
Cbz
41
Spirooxindole Synthesis N
NHO
MeO
Speckamp
Overman
Fukuyama
Danishefsky
Johnson
Hart
Yield90%
61-78%
91-98%
30-40%
36%
52%
d.r.*2:1
1:11
>99:1
>99:1
1:2
6.5:1
* d.r. reported desired:undesired
Method of Forming SpirooxindoleHeck reaction
Heck reaction
Divinylcyclopropane rearrangement
Eschenmoser-Claisen rearrangement
Radical cyclization
Radical cyclization
42
Tetrahydropyran Synthesis
NHO
N
MeO
NHO
N
MeOH
Activation of Alkene
NHO
N
MeOH
NuclephilicAlcohol
ElectrophilicCarbon
Hart and Overman
Speckamp, Johnson, Fukuyama, and Danishefsky
X
NHO
N
MeO
NHO
N
MeOH
Activation of Alkene
NHO
N
MeOH
NuclephilicAlcohol
ElectrophilicCarbon
Hart and Overman
Speckamp, Johnson, Fukuyama, and Danishefsky
X
43
Speckamp’s Oxymercuration
a. Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882-3884. b. Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.
• Fukuyama and Danishefsky used same oxymercuration/reduction conditions with similar yield
NO
OH
NO
NO
NO1. HgO, Tf2O, N,N-dimethylaniline, MeNO2 r.t.2. NaBH4, NaOH, CH2Cl2, EtOH
Me Me
48%
O
1. TBAF, THF, 4 mol. sieves, reflux2. AlH3, THF, -65ūC-0ūC
NO
NHO
Me
SEMSEM
45%
gelsemine
44
Johnson’s Alkene Activation
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 763-764.
N
NHO
MeO
O
CO2MeMeO2C 1. h, MeOH, cat. AcOH2. LiAlH4, THF OH
AgOAc, I2,AcOH
O
O
OAc
HO
OHI
HH
OAc
OHHO
HO OH
O
O
HO
OH
HO
O
IO
OH
HO
O
I
Anchimeric Assistance
44%
53%
45
Hart’s Hemiacetal
Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S. Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.
N
NHO
MeO
BnO
NO
Me OAc
AcNO
MeO
PhPh
BnO
NO
Me OAc
NHO
O
BnO
NO
Me O
NHO
6N HCl, DME, 48ÞC
NO
Me O
NHOBnO
NO
Me O
NHO
OH
TFA, Et3SiH, CH2Cl2
64%81%
21-Oxo-gelsemine
3 steps
1. TsOH, CH2Cl2, MeOH2. O3, CH2Cl2•MeOH, Me2S
59%
46
Overman’s Nitrile Trap
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.
DBU, PhMe, reflux
N
N
CNOH
O
N
N
O
O
NH
MOM MOM
Me MeN
N
O
MOM
OH
MeCN
N
N
O
OH
Me
N
N
O
O
O
MOM
Me
80%
1. conc. HCl, DME, 55ūC; (iPr)2NEt, MeOH, 55ūC2. DIBALH, PhMe 0ūC-r.t.3. Et3SiH, TFA, CH2Cl2, reflux
59% (3 steps)gelsemine
aq. workup
N
NHO
MeO
47
Synthetic Breakdown
• Most syntheses attacked more than one part at a time
• Danishefsky strategy: each section is made individually
• Overman’s biggest problem is Heck reaction selectivity
• Fukuyama’s 2000 synthesis only enantioselective route
Speckamp
Johnson
Hart
Fukuyama
Overman
Fukuyama
Danishefsky
Year1994
1994
1994
1996
1999
2000
2002
Steps19
29
23
32
26
31
36
Yield0.83%
0.58%
0.25%
0.67%
1.2%
0.86%
0.019%
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054-18065.
48
Synthetic Benefits
• Development and exploration of new reactions:– Stereoselective, quaternary Heck reaction (Overman)– Amides from -amino nitriles (Fukuyama)
• Despite similarities, syntheses demonstrate variety of strategies and reactions– Several distinct disconnection strategies– Many different types of reactions– Demonstrate power of sigmatropic rearrangements
49
Acknowledgements
• Prof. Steven D. Burke• Burke Group• Practice Talk Attendees
– Becca Splain – Katherine Traynor– Lauren Boyle – Maren Buck– Richard Grant – Chris Shaffer– Matt Windsor – Margie Mattmann
• Claire Poppe
