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Synthesis of Strychnine by R. B. Woodward et al.(1954)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.. J. Am. Chem. Soc., 1954, 76, 4749.
Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis, Targets, Strategies, Methods; Wiley-VCH: New York, 1996; pp 21-40.
Presenter: Kiyoto Tanemura
Strychnine
N
N
O
O
H
HH
H
• Synthetic challenge• Seven fused rings• Six chiral centers
• Validation of certain step in strychnine biosynthesis
Background• First isolation of strychnine
from Strychnos ignatii1• Strychnos species recognized
as poisonous• Structure of strychnine
elucidated• chemical degradation2
• X-ray crystallography3
[1] note: Original paper not found. Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.[2] (a) Robinson, R. Experientia 1946, 2, 28. (b) Briggs, L. H.; Openshaw, H. T.; Robinson, R. J. Chem. Soc., 1946, 903.[3] Peerdeman, A. F. Acta Cryst., 1956, 9, 824.
Strychnos ignatii (image from rarebooks.org)
Retrosynthetic analysis
isostrychnine I
N
N
O
O
H
HH
HN
N
O
H
HH
ON
N
O
HH
OH
Prelog, V.; Battegay, J.; Taylor, W. I. Helv. Chim. Acta 1948, 31, 2244.
Retrosynthetic analysis
HN NH2 O OMe
OMe
OMe
OMe
NH
+
N
N
O
HH
OHN
HN
O
O
HO
N
N
O
Ac
OMeO
OMeO
H
NH
NSO2Ar
OEtO
H
CO2MeCO2Me N
H
NCO2Et
OMe
OMe
100 %
HN NH2 O OMe
OMe
OMe
OMe
NH
+H3PO4 CH2O, Me2NH,
92 %H2O-dioxane, AcOH
N
N
O
O
H
HH
HN
N
O
O
H
HH
H
70. %
HN NH2 O OMe
OMe
OMe
OMe
NH
+H3PO4 CH2O, Me2NH,
92 %H2O-dioxane, AcOH
OMe
OMe
NH
NMe21. MeI2. NaCN, DMF
97 %OMe
OMe
NH
CNLiAlH4
THF, reflux, 85%
OMe
OMe
NH
NMe21. MeI2. NaCN, DMF
97 %OMe
OMe
NH
CNLiAlH4
THF, reflux, 85%
OMe
OMe
NH benzene, 92%
NH2 EtO
OH
OOMe
OMe
NH
N OEt
O
p-TsCl, pyridine
64 %
OMe
OMe
NH benzene, 92%
NH2 EtO
OH
OOMe
OMe
NH
N OEt
O
p-TsCl, pyridine
64 %
N
N
O
O
H
HH
H
22 %N
N
O
O
H
HH
H
OMe
OMe
NH benzene, 92%
NH2 EtO
OH
OOMe
OMe
NH
N OEt
O
p-TsCl, pyridine
64 % N
NTs
OEt
O 1. NaBH4, EtOH2. Ac2O, pyridine
84 % N
NTs
OEt
OO3, AcOH
H2O, 29 %OMe
OMe
OMe
OMe
H
Ac
5 %
N
NTs
OEt
O 1. NaBH4, EtOH2. Ac2O, pyridine
84 % N
NTs
OEt
OO3, AcOH
H2O, 29 %OMe
OMe
OMe
OMe
H
AcN
NTs
OEt
O
CO2MeCO2Me
MeOH, HCl
heat, 75 % N
NTs
OEt
O HI, red phosphorus
heat, 72 %
O
CO2MeAc
N
N
O
O
H
HH
H
N
N
O
O
H
HH
H4 %
N
NTs
OEt
O
CO2MeCO2Me
MeOH, HCl
heat, 75 % N
NTs
OEt
O HI, red phosphorus
heat, 72 %
O
CO2MeAc
2 %N
N
O
O
H
HH
H
N
NTs
OEt
O
CO2MeCO2Me
MeOH, HCl
heat, 75 % N
NTs
OEt
O HI, red phosphorus
heat, 72 %
O
CO2MeAc
N
NH
OH
O
O
CO2H
2. CH2N2, MeOH
79 %
1. Ac2O, pyridine
N
NAc
OMe
O
O
CO2Me N
NAc
OMe
O
O
CO2Me
NaOMe
MeOH, heat
N
N
O
O
H
HH
H2 %
N
NAc
OMe
O
O
CO2Me
N
NAc
OMe
O
O
CO2Me
NaOMe88%
N
NAc
O
OH
CO2Me
1 %N
N
O
O
H
HH
H
N
NAc
O
OH
CO2Me
TsCl, pyridine
95 %N
NAc
O
OTs
CO2MeN
NAc
O
OTs
CO2Me
NaSCH2Ph
MeOH, 25 °C, 77 % N
NAc
O
SCH2Ph
CO2Me
Raney Ni
EtOH, heat, 84 %
N
NAc
O
OTs
CO2Me
NaSCH2Ph
MeOH, 25 °C, 77 % N
NAc
O
SCH2Ph
CO2Me
Raney Ni
EtOH, heat, 84 % N
NAc
O
CO2Me73 %
N
NAc
O
CO2Me
H2, Pd/C
H2O/MeOH, heat, 87 %KOH
N
NAc
O
CO2Me73 %
N
NAc
O
CO2Me
H2, Pd/C
H2O/MeOH, heat, 87 %KOH
0.3 %N
N
O
O
H
HH
H
N
NAc
O
CO2Me73 %
N
NAc
O
CO2Me
H2, Pd/C
H2O/MeOH, heat, 87 %KOH
N
NAc
O
CO2H N
NAc
O
CO2Me
CH2N2
Et2O
Ac2O, pyridine
reflux, 42 %N
NAc
O
CO2H N
NAc
O
CO2Me
CH2N2
Et2O
Ac2O, pyridine
reflux, 42 %
N
NAc
O OAc
HCl, AcOH
H2O, reflux N
NH
O O
SeO2
EtOHN
NAc
O OAc
HCl, AcOH
H2O, reflux N
NH
O O
SeO2
EtOH
N
N
O
O
H
HH
H
N
NAc
O OAc
HCl, AcOH
H2O, reflux N
NH
O O
SeO2
EtOH
N
NH
O O
H
O N
NH
O O
H
O N
N
OH
O
O
0.3 %
0.006 %N
N
O
O
H
HH
H
N
N
OH
O
O
1. NaCCH, THF, 53 %2. H2, Lindlar, 86 %
N
N
OH
O
OH
LiAlH4
Et2O, reflux, 30 %
N
N
OH OHH
1.HBr, AcOH, 120 °C2. H2SO4, H2O, reflux
13 % N
N
OHH
HO
N
N
O
O
H
HH
HN
N
O
O
H
HH
H
N
N
OHH
HO
KOHEtOH N
N
O
O
H
HH
H
0.006 %
Strychnine
N
N
O
O
H
HH
H
• 30 steps• 0.006 % total yield
Later Syntheses: Diels-Alder route3 % yield, 12 steps
Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
CO2Me
N
N CO2Me
MeO2C
benzene, 185 °C, 4 h CO2Me
N
N CO2Me
MeO2C
Later Syntheses: Collective total synthesis/organocascade catalysis• 6 % yield, 12 steps
Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183.
–40 °C to Rt, tolueneNPMB
NHBoc
SeMeCHO
N
NH
O
t-Bu
1-Nap
20 mol %
NPMB
CHONBoc
+
82 %, 97 % e.e.
1 equiv
Strychnine
N
N
O
O
H
HH
H
• 30 steps• 0.006 % total yield
