syntheses of stenine - department of...
TRANSCRIPT
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Syntheses of Stenine
James Partridge August 24th, 2012
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Stemona alkaloids
• First reported in 1967 • Found in extracts of Stemonaceous plants • Used in traditional Chinese medicine • Insecticidal, anthelmintic, antitussive, and
neurochemical effects.
N
O
O
H
(-) Stenine
N
O
O
H
O O
H
H
Tuberostemonine
N
O
O
Neostenine
H
H
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Stenine
• 4 fused rings • 7 contiguous stereocenters • B ring
– Fused to 3 other rings – Every carbon in B ring is a
stereocenter – Most methodologies centered
around construction of B ring
N
O
O
HA
B
C
D
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1st total synthesis, 1990
Chen, C.; and Hart, D. J. J. Org. Chem, 1990, 55, 6236
O
OEt2AlCl
CHCl3, 85°
67%
Name of Reaction?
O
O
H
exo
or endo?
NH2NH2
MeOH, 87%O
H
NHNH2
OH
1)K2CO3, MeI2) AcCl100% over 2 steps
O
H
NHNMe2
OAc
Mesitylene, !
Then MeOH
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Curtius/ Hoffman Rearangement
O
H
NHNMe2
OAc
Mesitylene, !
Then MeOH NH
H
OAc
O O
!
HNMe2
O
H
N
OAc
N
H
OAc
C
O
MeOH
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Hart Stenine Synthesis, 1990
NH
H
OAc
O O
1) 9BBN2) NaBO3 94% NH
H
OAc
O O
OH
MsCl, NEt3
NH
H
OAc
O O
OMs
MeLi, THF
94% over 2 steps
N
H
OH
OO
H2Cr2O7N
H
OH
OOO
Name of reaction?
1) I2
2) DBUN
H
OO
OO
91%
Name of reaction?
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Stenine Total Synthesis
N
H
OO
OO
1) NaBH4 100%
2) TBDMSCl N
H
TBDMSOO
OHO
O N
O
xylene, !93%
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Eschenmoser Claisen
N
H
TBDMSOO
OHO
O N
O
xylene, !93%
N
H
TBDMSO
OO
O
N
N
O
N
H
OTBDMS
OO
O
-MeOH
-MeOH
N
N
H
OTBDMS
OO
O
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Hart Stenine Synthesis, 1990
N
H
OO
OO
1) NaBH4 100%
2) TBDMSCl N
H
TBDMSOO
OHO
O N
O
xylene, !93%
N
H
TBDMSO
OO
O
N
I2, THF, H2O
N
H
OH
OO
O
O
75%I
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Hart Stenine Synthesis, 1990
Sn(Bu)3
AIBN, PhH, !, 83% N
H
OH
OO
O
O 1) LDA
2) MeI N
H
OH
OO
O
O
N
H
OH
OO
O
O
I
1) DMSO, (ClCO)2, NEt3
2) Ph3PO
OEt
N
H
OO
O
O
O
EtO
91%
Red Al, CuBr
N
H
OO
O
O
O
EtO
85%
TMS-I
Tol. !
N
H
O
O
O
85%
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Hart 1990 endgame • Racemic synthesis, • 25 steps • 5% overall yield • Established end game
N
H
O
O
O
1)OsO4, NaIO42) SiO2 SOCl2SH SH
N
H
O
O
O
S
S
Lawessons Reagent
N
H
O
O
S
S
S
Raney-Ni
84%
N
H
O
O
(+/-) Stenine
75%
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Padwa Furan Synthesis N
OOAc
SMe
MeS R
N
O
RSS BF4
MeS
N
OOAc
SMe
S R
Me
Me
N
O
AcO
MeS
R
SMe2
H
N
O
AcO
MeS
R
HOAc
Ginn, J. D., and Padwa, A. Org. Lett. 2002, 4, 1515
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Padwa Stenine synthesis
N
OOAc
SMe
CO2Me
O
MeS
SS BF4
N
MeO2C
O
O
MeS
H
80%
N
O
CO2Me
O
Furan
Formation
MeS
N
O
CO2Me
O
MeSDA H
N
O CO2Me
O
MeS
H
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Wipf Stenine synthesis, 1995
• HINT!!!!!!!!
PhI(OAc)2
MeOH, NaHCO3HOHN
CO2H
O
OBnO N
CO2H
OOBn
OH
H
PhI(OAc)2
MeOH, NaHCO3HOHN
O
OBnO N
OOBn
OH
H
O
OH
O
OMe
Wipf, P.; Kim, Y.; and Goldstein, D.M. J. Am Chem. Soc.1995, 117, 11106
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Swing and a Wipf! PhI(OAc)2
MeOH, NaHCO3HOHN
CO2H
O
OBnO N
CO2H
OOBn
OH
H
+I
O
O
O
O
HOHN
O
OBn
O
OH
HO
O
OHN
O
OBn
O
OH
IO
O
O
NH
O
BnO
OO
MeOH
O
NH
OBnO
O
OH
MeO
O N
OOBn
OH
H
O
OMe
dr= 98:2
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Aube Synthesis, 2008 OBn
O
N3MeAlCl2
N
O
OBn
H
+
OBn
H
N
O
43%24%
Frankowski, K. J.; Golden, J.E.; Zeng, Y.; Lei, Y.; and Jeffrey Aubé (Badass) J. Am. Chem. Soc. 2008 130, 6018
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N
O
OBn
H
+
OBn
H
N
O
43%24%
9 17
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Zhang synthesis, 2012
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Synthesis of Starting Materials
O3, MeOH
Then Ac2O, NEt3
O
O O
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Ozonolysis O O
O
O OO
O O
O
MeOH
O OOH
O
O3, MeOH
Then Ac2O, NEt3
O
O O
O
OO
O OO
O
OH
O
O H
O
O
O
O
O
+
O
O O
NEt3
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Always End on a Good Note