Transcript The Phil Baran Special

1
The development of a novel
radical-mediated coupling of
indoles to enolates
Alex Bush
Early chemists describe the first dirt molecule
2
Regioselective challenges
X
N
H
N
N
N
H
H
X
N
N
N
H
3
C—C bond formation
H
R1
Br
R1
R2
Nucleophile Electrophile
R2
C C bond formed
R1
H
R2
No C C bond
4
Traditional solution: Grignard
reaction
-
O
+
MgBr
R2
N
PG
OH
N
PG
H O
MgBr
N
PG
R2
H
BrMg
O
H
H
O
O
H
N
PG
5
Traditional solution: Aldol reaction
O
R2
HN
O
O
strong
base
OH
O
R2
R3
H
HN
R2
HN
R3
strong
base
O
O
O
O
R2
R3
R3
R2
HN
N
O
OH
H
O
strong
base
R2
H
HN
R2
O
R3
R3
R2
HN
OH O
H
H
HN
R3
6
Modern solutions
R2
R
2
Br
Br
N
N
(HO)
(HO)22B
B
R
R22
Pd
Pd
N
N
R22
R
PG
PG
PG
PG
Br
Br
N
N
H
R2
Pd
NN
PG
PG
PG
PG
H
H
Ph
Ph
Pd
N
N
PG
PG
Stuart, D. R.; Fagnou, K. R., Science 2007, 316, 1172-1175.
Suzuki, A.; Brown, H.C., Organic Synthesis Via Boranes, Vol. 3, Suzuki Coupling, 2003.
N
N
PG
PG
7
Controlling chemical reactivities
• Multiple
Differentelectrophilic
nucleophilic
reactivites positions
O
O
NaOH
OH
HO
Br
N
H
OEt
O
HO
HO
O
OH
OH
NaOH
TBSO
Br
• Multiple Nucleophilic positions
TBSO
OH
• Multiple electrophilic positions
O
OH
N
H
HO
HO
O
OH
OEt
OH
O
8
Protecting groups decrease yield
O Protection
R
X
R
O
R
X
Decrease
in yield
O
O
R
Further
Chemistry
O
O
R
R
Deprotection
Product
Y
Decrease
in yield
Greene, T. W.; Wuts, P. G. M., Protective groups in organic synthesis, 3rd ed., (John Wiley & Sons, 1999).
9
Nature avoids protecting groups
• In nature
OH
OH
O
OH
HO
HO
Galactose
HO
HO
HO
HO
O
OH
Glucose
OH
Enzymes
HO
HO
OH
O
O
HO
HO
OH
O
OH
Lactose
• 1 step, 100 % yield
10
Synthesis needs protecting group
• In a lab
OH
OH
O
OH
HO
HO
Galactose
HO
HO
HO
HO
O
OH
Glucose
H
OH
OH
HO
HO
HO
HO
OH
O
HO
O
O
OOO
HO HO
HO
OH
HOO
HO
HO
OH
HO
O
HOHO
OHdimer
OH HO
HO

-1,4-Glucose
HO
OH
HO OH
HO
O
HO
OO HO
O
HO
O
-1,6-glucose
HO
HO OO O
HO Cellulose
HO
OH OH
HO
HO
O
HO
O
HO
HO
OH
O
HO
HO OH
Lactose
O
HO
OH
HO OH
HO -1,4-glucose
O
OHO
O
HO
HO
O
dimer
O
O
HO
OH
HO
HO O
HO OH O
HO
HO
OH
HO
OH
HO
HO
1,4--Galactose
dimer
O
OH
Glycogen 11
Applications of protecting groups
OH
O
OH
HO
OH
OH
HO
HO
HO
HO
2 preparative
steps
85 % yield
OAc
OAc
O
SPh
AcO
AcO
O
OH
OH
Enzymes
HO
100 %
HO
BnO
O
OAc
NIS
84 %
OMe
OH
O
O
HO
HO
O
OH
3 deprotection
steps
50 % yield
4 preparative
steps
50 % yield
HO
BnO
BnO
OH
AcO
OAc
BnO
O
O
AcO BnO
BnO
O
OCH3
12
Protecting groups in total synthesis
• Paeoniflorin
OBz H
OH
HO
HO
• (-)-Gilvocarcin V
O
O
O
O
OH
O
OH
H
OH
OH
OH
• 15 step total synthesis
• 3 protecting groups
• 17 step total synthesis
• 5 protecting groups
Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871
Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004
13
Hapalindole family
• Blue-green algae genus Hapalosiphon
• Antimycotic, antibacterial properties
• Natural production is very low, isolation difficult
Moore, R. E., et. al., J. Org. Chem. 1987, 52, 1036-1043
Stratmann, K., et. al., J. Am. Chem. Soc. 1994, 116, 9935-9942
14
Hapalindole family members
Cl
CN
H
SCN
CN
Cl
CN
H
H
H
H
N
H
N
H
hapalindole Q
fischerindole U
H
H
N
H
N
H
fischerindole I
fischerindole G
Cl
H
H
H
O
NC
H
NC
N
H
N
H
ambiguine H
hapalindole U
H
CN
N
H
welwitindolinone A
N
H
hapalindole family skeleton
Richter, J.M., et al., J. Am. Chem. Soc. 2007. In press.
15
Hapalindole skeleton
O
O
N
H
N
H
• Preactivate substrates
• Direct coupling
Richter, J.M., et al., J. Am. Chem. Soc. 2007. In press.
16
Method 1: Preactivation
BrO
H
N
H
O
1) NaH,
TIPSCl
2) PyrH +Br367 %
Br
O
N
H
LDA,
Ac2O
100 %
Br
H
2 steps
42 %
Br
Bu3SnOMe,
Cl2Pd[(o-tol)3P]2
O
H
N
TIPS
OAc
51 %
Vaillancourt. V.; Albizati, K. F., J. Am. Chem. Soc. 1993, 115, 3499-3502
N
TIPS
17
Method 2: Direct coupling
O
O
H
N
H
N
H
base
O
O
[O]
N
N
18
Heterocoupling of aryl radicals
O
O
O
HO
K3[Fe(CN)6],
Na2CO3
OH
HO
HO
O
O
H 2O, 0 oC
OH
OH
OH
O
HO
O
HO
O
O
HO
O
OH
0.3 %
HO
HO
O
O
Barton, D.H.R.; Deflorin, A.M.; Edwards, O. E., J. Chem. Soc. 1956, 530-534.
O
O
19
Homocoupling of enolate radicals
O
2 R
1
OLi
LDA
R3
THF
R2
R3
2 R
1
R2
O
CuCl2
DMF
R1
OR
R33
R2
R1
R2
2
R3
R1
R3 O
Yields 7 to 95 %
R1, R2, R3 = alkyl, aryl
Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 4605-4606
Ito, Y.; Konoike, T.; Saegusa, T., J. Am. Chem. Soc. 1975, 97, 2912-2914
20
Heterocoupling of enolate radicals
O
O
LDA
O
O
R
R
CuCl2
3 eq
O
R
O
O
O
1 eq
1%
31-46 %
Heterocoupled Homocoupled
product
product
53-68 %
Heterocoupled
product
O
O
R = alkyl, aryl
R
R
R
R
O
O
Homocoupled
Products Not
Observed
Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T., J. Am. Chem. Soc. 1977, 99, 1487-1493
21
Heterocouple aryl & enolate
radicals
O
O
O
OH Na2CO3 HO
HO
O
N
H
HO
K3[Fe(CN)
[Fe(CN)66]]
O
N
N
OH
OH
OH
Same
Base
Same
Oxidant
O
HO
O
R2
O
O
N
H
OH R2
O
O
O
LDA
R1
R2
R1
R2
CuCl2
R1
R2
22
R1
R1
Optimizing the oxidant
O
LiHMDS
Oxidant
H
O
H
THF
N
H
H
-78 to 25 oC
N
H
Entry
Oxidant
Yield (%)
1
K3Fe(CN)6
0
2
Pb(OAc)4
Trace
3
CuCl2
25
4
Cu(II)-2-ethylhexanoate
53
Richter, J.M., et al., J. Am. Chem. Soc. 2007. In press.
23
Effects of the equivalents of indole
O
H
LiHMDS
Cu(II)-2-ethylhexanoate
H
O
THF
-78 to 25 oC
N
H
H
N
H
Entry
Equivalents of indole
Yield (%)
1
2
53
2
3
60
3
4
66
4
5
77
24
Variations of the nucleophile
O
2 eq. Nucleophile
LiHMDS,
THF
H
H
O
Cu
H
o
HN
-78 to 25 C
H
O
H
N
H
Entry
Nucleophile
Yield (%)
53
1
N
H
49
2
N
H
MeO
32
3
N
H
F
BnO
46
4
N
H
F
42
5
6
N
H
N
H
53 (dr > 20:1)
25
Electrophile scope
0.5 eq enolate
LiHMDS,
THF
N
H
Entry
1
2
3
Cu
o
-78 to 25 C
Electrophile
O
E
N
H
Yield (%)
53
H
O
30
H
Ph
O
51
H
O
O
4
H
O
34
26
Mechanism of reaction
O
O
base,
[O]
O
R
II
Cu L
N
H
R
N
N
H
O
O
CuIL
N
R
N
27
Hammett equation
O
O
OH
R
ko
H2O
O
O
25 ooC
H
H33O
O
R
• <
>0
k
log
= 
ko
EDG
R = EWG
O
OMe
NO
NH22
ko = rate constant of unsubstituted reaction
k = rate constant of substituted reaction
28
Hammett experiments
O
O
25 oC
OH
O
H2O
H3O
R
R
0.8
0.7
=1
0.6
O
OH
O
log
k
ko
O
Br
O
0.2
0.2
0.2
OH
0
O2N
OH
0.4
MeO
Cl
0.1 O
OH
-0.1
-0.2
-0.2
OH
F
0
0.2

0.4
0.6
0.8
29
Reaction constant 
O
OH
R
O
O
30 oC
O
HOEt
2O
H2O/EtOH R
R
OH
R
R
O
H3O
OEt
• -1
>
< -11< 1
•
•
> 1
O
O
-
+
OEt
OH
R
O
+
OEt
<-1
OEt
OH
R
OH
R
30
Reaction constant 
O
O
30 oC
OEt
O
HO
EtOH
H2O/EtOH
R
R
O
OEt
0
O
MeO
OEt
-0.5
Br
O
 = -2.50
-1
log
k
ko
OEt
-1.5
O
F
O
+
OEt
OH
OEt
Cl
-2
OEt
O
R
O2N
-2.5
-3
-0.2
0
0.2

0.4
0.6
0.8
31
Variations on 
Br
MeO
MeO
MeO

R

R
Swain, C.G.; Lupton, E.C. Jr. J. Am. Chem. Soc. 1968, 90, 4328-4337.
32
Kinetic studies
O
ko
H
O
H
H
N
H
N
H
O
k
H
O
H
R
H
N
H
R
N
H
33
Effect on the C-3 active centre
O
0.2
0
k
log
ko
MeO
O
N
H
-0.2
O
N
H
F
 = -0.61
N
H
Cl
-0.4
O
O
-0.6
Br
-0.8
-1
-0.8
-0.6
-0.4
-0.2
N
H
0
O2N
0.2
0.4
0.6
0.8
N
H
1
p+
34
C-3 in the transition state
 = -0.61
• Ionic
+
R
N
• Radical
O
O
CuIIL
CuIL
R
N
35
Effect on the N-1 active centre
O
0.2
BnO
O
N
H
0
N
H
-0.2
log
k
ko
-0.4
Cl
O
F
O
N
H
-0.6
Br
O
N
H
-0.8
O 2N
N
H
-1
-1.2
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
p+
36
N-1 in the transition state
O
0.2
BnO
N
H
0
O
Cl
-0.2
log
N
H
O
F
k -0.4
ko
O
R
O
N Br
H
-0.6
O
O 2N
N
H
-0.8
N
CuIL
N
H
-1
-1.2
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
p+
37
Mechanism of reaction
O
O
base,
[O]
O
R
II
Cu L
N
H
R
N
N
H
O
O
CuIL
N
R
N
38
Hapalindole family members
Cl
CN
H
SCN
CN
Cl
CN
H
H
H
H
N
H
N
H
hapalindole Q
fischerindole U
H
H
N
H
N
H
fischerindole I
fischerindole G
Cl
H
H
H
NC
H
NC
N
H
N
H
ambiguine H
hapalindole U
H
O
CN
N
H
welwitindolinone A
N
H
hapalindole family skeleton
Richter, J.M., et al., J. Am. Chem. Soc. 2007. In press.
39
(+)-Ambiguine H
O
N
N
H
N
H
C
• Marine natural product from
Stigonemataceae family of
cyanobacteria
• Antifungal, antibacterial, antimycotic,
anticancer properties
Baran, P.S.; Maimone, T.J.; Richter, J.M. Nature 2007, 446, 404-408
40
Retrosynthetic analysis
N
N
N
H
N
H
C
O
C
N
H
Br
Br
O
N
H
O
NH
41
Terpene synthesis
1)
O
CO2Me
OMe
Cl
CCl3
Zn, sonication
2) NaOMe, 
OH
OH
61 %
1) DIBAL
2) MsCl,
pyridine
O
O
1) NaI, 
2) DBU, 
OMs
87 %
73 %
42
Indole-enolate coupling
LiHMDS
Cu
THF
Br
O
N
H
O
-78 to 25 oC
Br
Br
O
NH
N
Cu IL
O
Br
N
50 %
43
(+)-Ambiguine H tetracyclic core
O
NH
Br
[Pd(P(o-tol)3OAc)]2,
NaOCHO,
TBAB, Et3N
BrPd
DMF, 80 oC
O
O
NH
HO2CPd
O
N
H
65 %
N
H
44
(+)-Ambiguine H synthesis
1) NH4OAc,
NaCNBH3
O
N
H
HN
2) HCO2H,
CDMT
N
H
C
O
H
(COCl)2,
Et3N
N
H
O
N
C
60 %
(-)-hapalindole U
single diastereomer
N
N
H
C
H
O
Cl
O
45
Installing tert-prenyl group
tert-BuOCl;
prenyl-9-BBN
N
N
N
H
C
Cl
N
H
N
N Cl
Cl
B
N
N
N Cl
B
N Cl
B
46
(+)-Ambiguine H synthesis
N
N Cl
B
h
Et3N
N
N
N
N C
H
44 %
(+)-ambiguine H
single diastereomer
Cl
N H
B
N
H
Cl
B
47
Conclusion
O
N
H
O
N
H
N
N C
H
(+)-ambiguine H
3 % overall yield
8 steps from menthol
N
C
N
H
(-)-hapalindole U
8 % overall yield
6 steps from menthol
48
Regioselective challenges solved
X
N
H
N
N
O
R
H
LiHMDS
O
O
Cu
R
R
N
THF
-78 to 25 oC
N
N
H
25 to 77 %
49
Acknowledgements
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Dr. William Ogilvie
Dr. Alison Flynn
Mathieu Lemay
Julie Simard-Mercier
Thivisha Rajagopal
Philippa Payne
Katarina Vulic
Dan Carter
Michael H. Ho
N. Jojo Jiang
Dr. Benoît Liégault
Dr. Dan Black
Dr. Mohammed Asim
Dr. William Ogilvie’s Boat
Laura Evgin
50
(-)-fischerindole I synthesis
Cl
LiHMDS
Cu
O
N
H
-78oC to 25oC
O
Cl
62%
THF
NH
Montmorillonite K-10 Clay
Microwaves at 120oC
NH4OAc,
NaCNBH3,
3A MS
Cl
H2N
NH
O
Cl
NH
MeOH/THF,
sonication
24% over two steps
1) HCO2H, CDMT,
DMAP, NMM,
DCM, 23oC
2) COCl2, Et3N,
DCM, 0oC
C
N
DDQ, H2O,
THF, 0oC
Cl
N
C
NH
95%
11-epi-fischerindole G
Cl
NH
92%
(-)-fischerindole I
51
(+)-welwitindolinone A synthesis
C
N
XeF
C
N
XeF2, H2O,
MeCN, 23 oC
F
Cl
C
N
F
Cl
Cl
NH
F
NH
OH
NH
OH2
Cl
C
N
C N
Cl
NH
OH
O
N
H
44%
(+)welwitindolinone A
single diastereomer
52
C-6 substituted indoles
O
0.2
0
k
log
ko
MeO
O
N
H
-0.2
O
N
H
F
N
H
Cl
-0.4
O
O
-0.6
Br
-0.8
-1
-0.8
-0.6
-0.4
-0.2
N
H
0
O2N
0.2
0.4
0.6
0.8
N
H
1
p+
53