Transcript Total Synthesis of Gelsemine

Synthesis of Gelsemine
O
N
Me
H
N
O
Alexander J. L. Clemens
Burke Group
October 26, 2006
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
2
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
3
Gelsemium Alkaloid Activity
NMe
H
O
O
H
H
H
N
H
O
Koumine
Antitumor and Analgesic
H
N
MeO
N
OMe
H N
H
Gelsemicine
Cytotoxic
N
Me
O
Gelsemine
No known biological 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, 52205230.
4
A Synthetic Challenge
O
*
*
*
N
Me *
NH
*
*
*
O
• 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
5
Synthesis of Gelsemine
2002
2000
1999
Danishefsky (Columbia)
Fukuyama (Tokyo)
Overman (UC-Irvine)
1996
1994
Fukuyama (Tokyo)
Speckamp (Amsterdam)
Hart (Ohio State)
Johnson (Leeds)
1959
Crystal Structure
1870
Isolation
Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 4, 1-5.
6
Gelsemine Construction
• [3.2.1] bicyclic core
O
NH
• Pyrrolidine ring
• Spirooxindole
N
O
• Tetrahydropyran ring
Me
7
[3.2.1] Construction Strategy
nucleophilic
carbon
N
N
Me
Me
electrophilic
carbon
electrophilic
carbon
divinylcyclopropane
rearrangement
nucleophilic
carbon
or
N
Me
Makes the pyrrolidine ring simultaneously
Speckamp, Johnson, Hart, and Overman
Fukuyama and Danishefsky
8
O
[3.2.1] by Speckamp
HO
TIPSO
5 steps
HO
PhMe, reflux
+
O
N
Me
O
Diels-Alder
H
O
N
Me
O
H
H
H
O
N
Me
NH
O
OEt
N
Me
95%
BF3 OEt2, CH2Cl2, 10ūC
Mannich
O
O
N
Me
N
Me
OTIPS
O
70%
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.
9
O
Johnson’s Ring Closure
Me
4 steps
N
O
N
Mannich
O
Me
O
MeO
TFA
reflux
Br
O
OH
O
O
N
Me
Br
O
OTIPS
OTBS
O
N
Me
NH
O
N
Me
Br
O
74%
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, P. A. J. Chem. Soc., Chem. Commun. 1994, 763-764.
10
O
Overman’s Opening
OTIPS
O
+
OTIPS
OMe
AlCl3, CH2Cl2, -78 ūC
O
OTIPS
5 steps
NH2
CO2Me
Me
Me
N
Me
NH
76-83%
1. ClCH2CN, cat. NBu4I
iPr2NEt, THF 67ūC
2. NBu4F, THF 0ūC
1. KH, [18]-crown-6, THF
2. ClCO2Me, DTBMP -78ūC-r.t.
3. KOH, MeOH, H2O r.t.
OH
H
90%
N
CN
H
N
O
N
DTBMP
CO2Me
81%
Earley, W. G.; Jacobsem, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29(31), 3781-3784.
11
O
Overman’s Aza-Cope
1. KH, [18]-crown-6, THF
2. ClCO2Me, DTBMP -78ūC-r.t.
3. KOH, MeOH, H2O r.t.
OH
H
N
CN
N
Me
NH
O
H
N
O
CO2Me
81%
N
DTBMP
H
OK
1. ClCO2Me
ClCO
2Me
2. KOH
[3,3]
N
KO
-CO2
N
KO22CO
MeO
CO
HH
NN
CO
CO22Me
Me
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 29342936.
12
O
Overman’s Ring Closure
MeO2C
O
N
Br2, CH2Cl2, -78ūC
MeO2C
O
N
N
Me
NH
O
TFA
reflux
Mannich
H
Br
N
H
O
OH
MeO2C
N
Br
H
N
MeO2C Br
H
82%
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 29342936.
13
O
Hart’s Radical Cyclization I
1. PhMe, reflux
2. 2,2-dimethyl1,3-propanediol
p-TsOH
OTMS
O
O H
+
Me N
Me N
Diels-Alder
O
BnO
BnO
O
O
Me N
S O
Ph
CO2Et
Bu3SnH, AIBN
PhH, reflux
O
7 steps
O
O H
OP
O
N
Me
NH
OH
BnO
O
O
Me N
Me N
O
O
H
CO2Et
61%
CO2Et
AIBN = NC
O
O
N
N
CN
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.
14
O
Fukuyama’s Beginning
O
O
O
3 steps
O
O
OMe
OEt
OMe
N
Me
NH
N2
O
Cu(acac)2 (cat.)
CuSO4, PhH
85 ūC
EEO
OEE
[Cu]
MeO2C
OEE
OH
H
H
O
4 steps
H
O
MeO2C
MeO2C
H
OAc
O
68%
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
15
O
Divinylcyclopropane (1996)
OH
H
MeO2C
OH
H
OAc
oxindole, cat. piperidine
MeOH, 23ūC
O
N
Me
NH
O
OH
H
OAc
H
H
H
OAc O
+
MeO2C
MeO2C
NH
NH
4-iodooxindole
cat. piperidine
MeOH, 23ūC
E
O
60% 4:1
desired product
O
OH
2 steps
H
OAcO
H
MeO2C
NH
I
Z
H
H
MeO2C
O
NH
I
89%
exclusively Z
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
16
O
Divinylcyclopropane (2000)
O
O
N
Cl
SiMe2H
Et2AlCl
CH2Cl2
-78ūC
SiMe2H
O +
5 steps
N
Bn
O
MAD
PhMe
-20ūC
O
I
H
O
MAD
MeO2C
H
tBu
H
NH
O
one enantiomer
MeO2C
65-78%
MAD =
O
CO2Me
3 steps
H
CO2Me
O
O
88%
OTES
O
O
Bn
Diels-Alder
OTES
OTES
Cl
N
Me
NH
tBu Me tBu
Al
O
O
tBu
tBu
tBu
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.
17
O
[3.2.1] and Spirooxindole
N
Me
NH
O
O
O
O
H
H
I
O
MeO2C
and/or
90ūC, PhMe/
MeCN (1:1)
H
NH
MeO2C
I
H
NH
H
H
O
MeO2C
O
NH
I
O
O
NH
I
CO2Me
91-98%
single isomer
O
Bu3SnH, AIBN O
PhMe, 95ūC
NH
CO2Me
85%
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.
18
O
Danishefsky’s [3.2.1]
OtBu
OtBu
OtBu
mCPBA
Al2O3
O
O
O
=
H
NO2
OtBu H
OtBu
NaOMe, DMF,
0ÞC
O
OtBu
H
(EtO)2(O)P
N
Me
NH
NO2
NO2
H
74%
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
19
[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
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Pyrrolidine Ring Installation
Mannich-likering
ringclosing
closing
Mannich-like
Mannich-like
ring
closing
N
N
N
Me
Me
Me
O
O
YY
XX
H
H
N
N
Speckamp,Hart,
Hart,Johnson,
Johnson,
Speckamp,
Hart,
Johnson,
Overman
and
and Overman
Overman
nucleophilic
nucleophilic
nucleophilic
nitrogen
nitrogen
nitrogen
N
N
N
Me
Me
Me
R'
R'
R'
Me
Me
Me
nucleophilic/electrophilic
nucleophilic/electrophilic
carbon
carbon coupling
coupling
Fukuyama
Fukuyama
N
N
N
R
R
R
X
XX
electrophilic
electrophilic
electrophilic
carbon
carbon
carbon
N
N
N
Me
Me
Me
Danishefsky
Danishefsky
Danishefsky
21
O
Fukuyama (1996)
O
EtO2CHN
NH
O
11 steps
O
N
Me
O
MOM
AgOTf, Ag2CO3,
CH2Cl2, 45ūC
N
Cl
O
N
Me
NH
OAc
CO2Me
H
O
CO2Et
O
N
MOM
N
EtO2CHN
MOM
OH O
N
H2O
O
N
Me
OAc
N
Me
OAc
52%
Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.
22
O
Fukuyama (2000)
O
O
tBuO2C
NH
O
MOM
N
tBuO2C
KHMDS, THF,
-78ūC-0ūC
NC
7 steps
NC
CO2Me
N
Me
N
Me
O
NH
O
MOM
N
N
OH
Me
OH
68%
OK
O
tBuO
MOM
N
NC
N
Me
OK
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.
23
-Aminonitriles to Amides
CN
R
N
R"
R'
mCPBA, Me2S, KOH(aq)
CH3CN-H2O (4:1), 0ūC
O
R
mCPBA
CN
R
N
R"
R'
-HCN
-OH
O
R
N R'
R" Polonovsky-type
elimination
CN
N R'
R"
+OH
R = alkyl, aromatic
R’ = alkyl
R” = alkyl, aromatic
HO CN
R
N R'
R"
Yields typically
above 70%, often
above 80%
Yokoshima, S.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Chem. Lett. 2002, 122-123.
24
O
Danishefsky’s Pyrrolidine
OtBu H
1. MsCl, Et3N,
CH2Cl2, -78ūC
OtBu H
2. NaHMDS, THF, -78ūC
NO2
OH
OH
NO2
4 steps H
O
H
N
Me
NH
O
NO2
O
91%
OH
cat.propionic acid,
MeC(OEt)3,
PhMe, reflux
O
H
NO2
O
H
NO2
EtO
EtO
O
Johnson-orthoester-Claisen Rearrangement
O
94%
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
25
O
Oxetane Opening
O
H
NO2
2 steps
MeO2C
H
NO2
HN
EtO
O
MeO2C
N
Me
NH
O
BF3•OEt2
CH2Cl2
-78ÞC-12ÞC
O
H
H
NO2
NO2
HN
N
O
BF3
MeO2C
HO
64%
Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.
26
The Spirooxindole Moiety
N
N
N
AcN
OMe
O Br
O
O
N
NH
O
O
Me
R
Me
Photo-induced Radical Cyclization
Johnson
RHN
OAc
N
Radical Cyclization
Hart
N
O
Me
R
N
R
N
Me
N
O
H
NMe2
Eschenmoser-Claisen Rearrangment
Danishefsky
X
Me
Intramolecular Heck Reaction
Speckamp and Overman
27
O
Hart’s Radical Cyclization II
BnO
O
O
Me
N
O
CO2Et
6 steps
AcN
BnO
Br Bu SnH, h, PhH
3
O
O
Me
N
OAc
C(OMe)Ph2
O
O
N
Me
O
N
Me
MeO
Ph
Ph
O
BnO
AcN
BnO
OAc
C(OMe)Ph2
O
Ac
N
O
BnO
N
Me
NH
OAc
40%
Ac
N
O
MeO Me
Ph
Ph
N
OAc
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.
28
O
Johnson’s Triazole Radical
O
N
Me
N
N
+
O
N
TMS
LDA, nBuLi
OMe Peterson
Olefination
h, MeCN
O
N
Me
O
65% combined yield
N
Me
MeO
O
O
N
N
O
N
Me
N
N N
OMe +
O
N
O
O
OMe
N
OMe
-N2
N
Me
N
N
O
NH
+
N
Me
O
O
N
Me
OMe
O
36% 1:2
Dutton, K. J.; Steel, R. W.; Tasker, A. S.; Popsavin, V.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 765-766.
29
O
Speckamp’s Heck Reaction
O
Br
O
N
Me
O
Pd2(dba)3, Et3N,
PhMe, reflux
N
SEM
SEM
N
O
OTDS
Pd Br N
SEM
dba
O
O
N
Me
OTDS
sterically blocks
lower face
O
N
Me
OTDS
O
OTDS
90% 2:1
TDS =
SEM =
O
N SEM
+
N
Me
N
Me
NH
O
Si
TMS
O
dba = Ph
Ph
•Overman’s protocol gives
9:1 selectivity
•Less selectivity due to
more steric bulk on
concave face
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.
30
O
Overman’s Trials
I
Pd2(dba)3, Et3N
PhMe, reflux
O
N
O
SEM
N
O
N SEM
+
SEM
Me N
Br
N
Me Br
N
Me
NH
N
Me Br
O
80-95% ~9:1
However:
O
SEM
N
O
SEM
N
X
N
Me Br
N
Me
OH
Madin, A.; O’Donnell, C. J.; Oh, T.; Old. D, W.; Overman, L. E.; Sharp, M. J. J.Am. Chem. Soc. 2005, 127, 1805418065.
31
O
Modified Heck Reaction
O
MOM
N
I
[Pd2(dba)3] CHCl3
Ag3PO4, Et3N,
THF, reflux
OMe
N
MeO2C Br
Pd insertion and
alkene complexation
N
MeO2C Br
O
N MOM
+
OMe
N
MeO2C Br
61-78% 1:11
dba
Pd
N MOM
syn addition
OMe
O
O
MOM
N
-Hydride
Elimination
N
MeO2C Br
N
Me
NH
N
MeO2C Br
OMe
O
Selective for the
wrong diastereomer!
MOM
THF
Pd dba
O dba
OMe
N
Madin, A.; O’Donnell, C. J.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38 (19), 2934-2936.
32
O
Heck Selectivity Rationale
O
MOM
N
N MOM
+
OMe
N
MeO2C Br
OMe
O
N
MeO2C Br
N
Me
NH
O
•Substituted enol ether
changes system tetrasubstituted and
electron-rich
61-78% 1:11
•Vinyl group
coordinates to Pd
vs.
O
SEM
N
N SEM
+
N
Me Br
N
Me Br
80-95% ~9:1
O
•Overman et al.
unable to optimize for
natural isomer requires correction
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 1805418065.
33
O
Aziridine Intermediate
N MOM
N MOM 3 steps
OMe
O
N
MeO2C Br
O
N
Me
NH
O
NaCN, DMSO, 150ūC
O
N
MeO2C Br
OEt
OEE
N MOM
1. MeOTf, DTBMP
CH2Cl2, 0ūC
2. NaCN, DMSO, 150ūC
N MOM
OH
OEE
N
O
99%
N
Me
DTBMP =
O
CN
99%
N
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.
34
O
Spirooxindole Correction
N
Me
NH
O
MOM
O
N MOM
N
DBU, PhMe, reflux
OH
N
Me
CN
N
Me
O
O
O
80%
N
N
aq. workup
DBU
N
Me
CN
O
H O DBUH
MOM
MOM
Rotation
and bond
N MOM formation
O
N
Me
CN
O
N
OH
N
Me
N
O
NH
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 29342936.
35
O
Danishefsky’s Original [2,3]
N
Me
NH
O
Ph
N
O 2N
3 steps
N
H
MeO2C
OH
PivO
HO
n-BuLi, THF
-78ūC to 25ūC
N
MeO2C
H
NH2
N
O
MeO2C
SnBu3
TIPSO not observed
TIPSO
Ph
O
N
Piv =
N
MeO2C
H
O
Li
TIPSO
[2,3] Still-Wittig rearrangement
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
36
O
Danishefsky’s Second [2,3]
CbzHN
N
MeO2C
H
NMe2
NHCbz
O
HC(OMe)2NMe2
m-xylene, reflux
N
MeO2C
PivO
O
Cbz
N
O
N
OH
N
Me
NH
MeO2C
PivO
PivO
neither product
observed
CbzHN
CbzHN
O
Piv =
H
N
H
MeO2C
PivO
O
NMe2
-H
N
H
MeO2C
BŸchi Rearrangement
O
NMe2
PivO
O
Cbz =
O
Ph
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
37
O
Danishefsky’s Tribulations
N
Me
NH
O
Me
O
tBuO
Me
N
Pd2(dba)3 CHCl3
tBuO
AgOTf, Et3N,
1,4-dioxane 120ūC
O
N
tBuO
N Me
+
O
I
50-70% 7:1
However:
tBuO
O
Me
N
tBuO
Me
N
O
X
O
Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.
38
O
[3,3] Rearrangement
Cbz
N
H
MeO2C
Me2N
NH
MeC(OMe)2NMe2
m-xylene
HN
N
Me
NH
O
Cbz
O
OH
N
MeO2C
PivO
PivO
H
Eschenmoser-Claisen Rearrangement
O
O
NMe2
HN
Cbz
N
O
Cbz
Piv =
silica gel
N
MeO2C
PivO
O
N
Cbz =
MeO2C
O
Ph
PivO
30-40%
Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.
39
O
Ring Contraction
N
Me
NH
O
O
N
Cbz
1. DIBALH, CH2Cl2, -78 ūC
2. TsOH H2O, CH2Cl2, reflux
N
Cbz
N
N
MeO2C
MeO2C
HO
PivO
O
1. OsO4, THF, -25ūC
2. NaSO3
3. NaIO4, THF/H2O
O
1. TESOTf, Et3N, CH2Cl2
Cbz 2. NaOMe, MeOH
N
3. TPAP, NMO, CH2Cl2
4Ÿ mol. sieves
N
50% (2 steps)
O
Cbz
N
N
MeO2C
MeO2C
HO
45%
TESO
40% (3 steps)
9% (6 corrective steps)
Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.
40
O
Spirooxindole Synthesis
Yield
90%
d.r.*
2:1
Method of Forming Spirooxindole
Heck reaction
Overman
61-78%
1:11
Heck reaction
Fukuyama
91-98%
>99:1
Divinylcyclopropane rearrangement
Danishefsky
30-40%
>99:1
Eschenmoser-Claisen rearrangement
Johnson
36%
1:2
Radical cyclization
Hart
52%
6.5:1
Radical cyclization
Speckamp
N
Me
NH
O
* d.r. reported desired:undesired
41
Tetrahydropyran Synthesis
O
O
NH
N
OH
NH
N
Activation of Alkene
OH
Me
Me
Speckamp, Johnson,
Fukuyama, and Danishefsky
X
Nuclephilic
Alcohol
Electrophilic
Carbon
Hart and Overman
O
NH
N
O
Me
42
Speckamp’s Oxymercuration
SEM
O
N
SEM
1. HgO, Tf2O, N,N-dimethylaniline,
MeNO2 r.t.
2. NaBH4, NaOH, CH2Cl2, EtOH
O
N
O
O
N
Me
N
Me
OH
O
48%
O
NH
1. TBAF, THF, 4Ÿ mol. sieves, reflux
2. AlH3, THF, -65ūC-0ūC
N
Me
O
45%
gelsemine
• Fukuyama and Danishefsky used same
oxymercuration/reduction conditions with similar yield
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.
43
O
Johnson’s Alkene Activation
N
Me
MeO2C
1. h, MeOH, cat. AcOH
2. LiAlH4, THF
CO2Me
O
O
NH
O
AgOAc, I2,
AcOH
H
HO
OH
53%
O
HO
H
O
H
OAc
H
I
OH
O
O
HO
OAc
O
I
OH
O
HO
O
H
OH
O
HO
O
I
44%
Anchimeric Assistance
Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 763-764.
44
O
Hart’s Hemiacetal
Ac
N
O
BnO
O
MeO Me
Ph
Ph
N
Me
O
O
BnO
NH
OH
64%
O
NH
O
N
O
59%
3 steps
O
O
OAc
NH
TFA, Et3SiH, CH2Cl2
Me
NH
6N HCl, DME, 48ÞC
OAc
O
N
O
O
N
BnO
O
BnO
1. TsOH, CH2Cl2, MeOH
2. O3, CH2Cl2•MeOH, Me2S
N
Me
NH
Me
O
Me
N
O
21-Oxo-gelsemine
81%
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.
45
O
Overman’s Nitrile Trap
N
Me
O
MOM
MOM
O
NH
O
N
N
N MOM DBU, PhMe, reflux
OH
N
Me
CN
N
Me
O
CN
OH
N
Me
O
NH
MOM
O
N
aq. workup
N
Me
O
O
80%
1. conc. HCl, DME, 55ūC;
(iPr)2NEt, MeOH, 55ūC
2. DIBALH, PhMe 0ūC-r.t.
3. Et3SiH, TFA, CH2Cl2, reflux
O
N
Me
H
N
O
59% (3 steps)
gelsemine
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 29342936.
46
Synthetic Breakdown
Speckamp
Year
1994
Johnson
1994
29
0.58%
Hart
1994
23
0.25%
Fukuyama
1996
32
0.67%
Overman
1999
26
1.2%
Fukuyama
2000
31
0.86%
Danishefsky 2002
36
0.019%
Steps Yield
19
0.83%
• 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
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.
47
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
48
Acknowledgements
• Prof. Steven D. Burke
• Burke Group
• Practice Talk Attendees
–
–
–
–
Becca Splain
Lauren Boyle
Richard Grant
Matt Windsor
– Katherine Traynor
– Maren Buck
– Chris Shaffer
– Margie Mattmann
• Claire Poppe
49