First Total Synthesis of (±)-Strychnofoline via a Highly Selective
Ring-Expansion Reaction
Andreas Lerchner and Erick M. Carreira*
Presented by Christopher T. Clark
JACS, 2002, 124, 14826-14827
Me
H
HO
N
H
H N
H
N
H
N
H
O
MeN
H
HO
H HN
N
H
HN
O
Isolation: Secondary metabolite from the leaves of Strychnos usambarensis by Angenot. Planta Med. Phytother.
1978, 12(2), 123-129
Biological activity: Displays antimitotic activity against cultures of mouse melanoma and Ehrlich tumor cells.
Angenot et al. Planta Med. 1982, 45, 123-126
Retrosynthetic Analysis of Strychnofoline
Me
H N
H
NHMe
H
Pictet-Spengler reaction
N
O
N-methyl-tryptamine
OTBDPS
H
N
N
Bn
ring expansion
O
O
BocN
OTBDPS
BocN
O
O
OTBDPS
H
BnN
O
Me
H
BnO
O
BnO
H
BnN
N
H
H
O
H
N
H HN
HN
O
BnO
HO
N
H
OMe
O
O
N
H
6-methoxyisatine
OTBDPS
O
N
Bn
conjugate addition
MeO2C
Cl
NH2
O
methyl propiolate benzylamine
acryloyl chloride
Methodolgy Towards Novel Ring Expansion
O
N
Bn
I
I-
5 mol % MgI2
THF
O
N
Bn
O
MgI
N
Bn
N
R'
R
N
H
1. MgI2 found to be best Lewis acid
2. Yields generally high
3. Reaction does not proceed without
metal salt
4. Diastereoselectivities from 1:1 to >98:2
5. Requires heating in a sealed tube
R
R'
H
R'
I
MgI
N
O
N
Bn
I
R
H
MgI
O
N
Bn
MgI
Disfavored due to
R-O interactions
I
N
R'
R'
N
R
O
N
Bn
Carreira et al. Angew. Chem. Int. Ed. 1999, 38, 3186-3189
R
O
N
Bn
Synthesis of Spiroindole Derivative
O
O
Me
O
N
H
O
NaH, BnBr
DMF
72%
Me
H2NNH2
EtOH; reflux
90%
O
O
N
Bn
Me
O
O
N
Bn
BBr3
CH2Cl2; 0o
92%
BrCH2CH2Br
NaH
DMF; 0o
86%
O
HO
N
Bn
BnBr, NaH
DMF
87%
O
BnO
N
Bn
O
TBDMSO
N
Bn
Imidazole
TBDMSCl
DMF; 0o
88%
O
HO
N
Bn
Mechanism of Wolff-Kischner Reduction
O
Me
H2N
O
N
Me
H2N
N
Bn
O
N
Bn
-N2
Me
O
O
N
Bn
Me
O
N
Bn
N
Me
OH
O
NH
O
O
NH2
NH
NH2
O
O
N
Bn
Synthesis of Imine Fragment
O
O
BnHN
BnNH2
MeO2C
O
Cl
OH
Cl
C
H
OMe
THF
OMe
BnHN
53% over two steps
O
O
LiBH4
OH
O
OMe
N
Bn
O
Pd/C, H2
EtOH
98%
OMe
O
N
Bn
N
Bn
Na/NH3
OH
O
TBDPSCl
OTBDPS
O
N
H
O
N
Boc
OTBDPS HOOH
N
Boc
N
Boc
LiHMDS
PhSeCl
THF; -78o
H
PhSe
O
OTBDPS
O
N
H
O
OTBDPS
Boc2O
EtOAc
80%
PhSe
O
OTBDPS
N
Boc
Synthesis of Imine Fragment, cont.
OTBDPS
O
N
Boc
CuBr SMe2
allyl MgCl
TMSCl
THF; -78o
75%
OTBDPS
O
DIBAL-H
THF; -78o
N
Boc
OTBDPS
HO
N
Boc
5:1 dr
inseparable
H2O
OTBDPS
OTBDPS
N
aqueous HCl
CH2Cl2; rt
75% over two
steps
N
TMS
O
Me
O
OTBDPS
TMSOTf, TEA
CH2Cl2; -20o
Me
Me
N
O
O
Mechanism of Deprotection
OTBDPS
Me
OTBDPS
Me3Si
Me
Me
Me
OTf
Me
N
Me
N
O
O
O
H2O
N
Me
-CO2
OTBDPS
H2O
OTBDPS
N
N
H2O
OTBDPS
N
Me
TMS
H
OTBDPS
N
H
O
TMS
HO
O
O
O
Bringing It Together: Synthesis of Spiro Alkaloid
H
OTBDPS
O
N
Bn
BnO
N
H
O
O
OTBDPS
H
BnN
N
BnN
OsO4, NMO
H2O, dioxane,
t-BuOH
H
NaIO4
H2O, dioxane
t-BuOH
H
OH
BnO
OH
N
OTBDPS
H
BnN
O
H
H
N
H
H
O
BnO
O
one diastereomer!
O
O
BnN
OTBDPS
H
O
I
BnO
N
BnO
O
O
H
1 eq. MgI2
THF, 80o
12 hr, 55%
H
H
OTBDPS
p-TsOH, CH(OMe)3
MeOH
80% over 3 steps
H MeO
OMe
BnO
N
H
BnN
O
H
OTBDPS
Synthesis of Spiroalkaloid, Cont.
H
H MeO
BnO
H
OTBDPS
N
H
OMe
TBAF
THF
OMe
BnO
H
N
OH
O
H
BnN
H
BnN
H MeO
O
O
IBX
O
I
OH
DMSO O
H
H
OMe
BnO
OMe
N
H
BnN
O
H
BnO
N
BnN
t-BuOK
Ph3PMeBr
THF
66% over
3 steps
10% aqueous HCl
acetone
94%
N-methyl tryptamine
H
O
AcOH
Toluene; 80o
H
1:1.5 dr
64% overall
H
H
H
OMe
H
BnO
OMe
N
O
H
BnN
O
Me
H N
H
BnO
H HN
N
H
BnN
O
Me
H N
H
BnO
H HN
N
O
H
BnN
O
Mechanism of the Pictet-Spengler Reaction
AcOH
H
H
AcOH
NHMe
O
BnO
H
N
H
BnO
H
BnN
N
H
O
OH
H
NMe
N
H
BnN
H
O
N
H
AcOH
Me
H N
H
H
BnO
H
BnO
H HN
N
N
BnN
O
Bn
NMe
H
N
O
N
H
H
Me
H N
BnO
N
BnN
O
H HN
Final Step: Strychnofoline
Me
H N
H
BnO
H HN
N
H
BnN
O
Na/NH3
THF, t-BuOH
–78 to –45o; 82%
Me
H N
H
HO
H HN
N
H
HN
O
Overall yield from lactam: 20 steps, 0.84%