Total Syntheses of Strychnine
H
N
H
N
O
H
H
H
O
Song jin
2012-03-03
1
Strychnine
士的宁,番木鳖碱
CAS:57-24-9
H
N
H
N
O
H
H
H
O
＊ The most common source is from the seeds of the Strtchnos nux vomica tree.
＊ used as a pedticide, particularly for killing small vertebrates such as birds and rodents.
A highly toxic (LD50 = 0.16 mg/kg in rats, 1–2 mg/kg orally in humans)
＊ Strychnine has also served as an inspiration in several books, movies and TV series.
(e.g. Count of Monte Cristo )
＊ First isolated from Strychnos ignati:
Pelletier & Caventou, Ann. Chim. Phys. 1818, 8, 323.
2
H
Strychnine
N
H
N
O
H
H
H
O
＊ complex heptacyclic structure (24 skeletal atoms)
＊ 6 contiguous assymetric carbon centers
＊ 5 of those are included within one saturated six-membered ring
＊ 7-membered oxygen heterocyclic motif
＊ "Admittedly, by one whose special familiarity with the intricacies of its structure
and behavior might excuse a certain prejudice, but with six nuclear asymmetric
centers and seven rings constituted from only twenty-four skeletal atoms, the case
is a good one! "
---------(±)-strychnine fist sythesised by R. B. Woodward
in 1963, 0.00006% yield, 28 steps.
3
Syntheses of Strychnine
• R. B. Woodward - Harvard University (1954)
• Philip Magnus - University of Texas (1992)
• Gilbert Stork - Columbia University (1992)
• Larry E. Overman - University of California, Irvine (1993)
• Martin E. Kuehne - University of Vermont (1993)
• Viresh H. Rawal - The Ohio State University (1994)
• Josep Bonjoch & Joan Bosch - University of Barcelona (1999)
• Stephen F. Martin - University of Texas (1996-2001)
• Michael J. Eichberg & K. Peter C. Vollhardt - University of California,
Berkeley (2000)
• Graham J. Bodwell - Memorial University of Newfoundland (2002)
• Miwako Mori - Hokkaido University (2002)
• Masakatsu Shibasaki - University of Tokyo (2002)
• Tohru Fukuyama - University of Tokyo (2004)
• Albert Padwa - Emory University (2007)
• Christopher D. Vanderwal. – University of California (2011)
• David W.C. MacMillian – Princeton University (2011)
4
Retrosynthetic Analysis:
H
N
N
H
N
H
H
H
N
H H
HO
O
O
H
(-)-Strychnine
H
H
O
N
(1)
N
H H
(2)
(3)
CHO
H OH
Wieland–Gumlich aldehyde,
a natural product, CAS 466-85-3
(also named caracurine VII)
N
(1)
O
NR2
OBut
N
N
H H
M
OH
(2) M=SiMe3
(3) M=PdI
CHO
• (1) Larry E. Overman - University of California, Irvine (1993)
• (2) Christopher D. Vanderwal. – University of California (2011)
• (3) David W.C. MacMillian – Princeton University (2011)
5
The First Asymmetric Total Synthesis of
(-)-Strychnine
Larry E. Overman, J. Am. Chem. SOC. 1993, 115, 9293-9294
＊Strychnine's seven rings displayed on only 24 skeletal atoms still
represents a formidable challenge for total synthesis.
- Larry E. Overman.(1993)
Key Step: Domino aza-Cope/Mannich transform
H
[3,3]
HO
HO
Mannich
OHC
H
N
N
R
aza-Cope
N
R
N
N
R
O
H
H
H
O
3-formylpyrrolidine
J. Am. Chem. SOC. 1993, 115, 3966
J. Am. Chem. SOC. 1993, 115, 9293
J. Am. Chem. SOC. 1995, 117, 5776
6
Retrosynthetic Analysis:
H
N
N
H
N
H
N
H
H
N
H H
HO
O
O
H
(-)-Strychnine
N
H H
H
H
O
N
N
N
R
motif
Mannich
OBut
Cope
N
NR2
N
HO
HO
O
O
NR2
OBut
OBut
OBut
OHC
CHO
H OH
NR2
NR2
＊KEY: the cationic aza-Cope-Mannich reaction
OBut
CH2OTIPS
Epoxide
opening
H
N
HO
NR2
O
R2N
olefination
Me3Sn
CH2NHR epoxidation
carbonylative Stille
OBut
I
OBut
+ CO
+ R2N
7
Synthesis:
O
a)
OH
CH2Cl2, 23oC, 97%
AcO
H H
AcO
MeO
Cl , pyridine,
O
dr: 1:1
CO2Et
b) ButOCH2COCH2CO2Et, NaH,
1% Pd2(dba)3, 15%PPh3, THF, RT, 91%
OCO2Me
AcO
palladium-catalyzed displacement
of the allylic carbonate derivatives
c) NaBH3CN, 1.1eq TiCl4,
THF, -78oC, 98%
anti:syn = 20:1
H
H
CO2Et
CO2Et
+
AcO
OBut P.S. ZnBH , NaBH , NaBH +CeCl
4
4
4
3
syn: anti=1:1 to 3:1
OH
AcO
OH
OBut
OBut
(b)
(a)
a:b = 1:1
H
AcO
OH
OBut
H
CO2Et
AcO
CO2Et
OH
OBut
8
H
H
CO2Et
CO2Et
d) DCC, CuCl
benzene, 80oC
90%
syn dehydration
+
AcO
AcO
OH
OH
OBut
OBut
CO2Et
AcO
OBut
Bull. Soc. Chim. Fr., 1973, 1837.
H
AcO
H
N C N
CO2Et
H
+
OH
AcO
O
OBut
OBut
e) 5eq i-Bu2AlH, CH2Cl2
-78oC, 98%
CH2OTIPS
HO
f) 2eq TIPSCl, 2eq tetramethylguanidine
NMP, -10oC, 65%(bissilyl ether in 33%yield)
Selective protection of the primary alcohol
CO2Et
H NCy
OBut
O
+
CyHN
NHCy
NHCy
g) Jones oxidation,
acetone, -5oC
CH2OTIPS
O
OBut
careful treatment !!
J. Org. Chem. 1981, 46, 577-585
NH
tetramethylguanidine
N
N
NMP
N
O
9
CH2OTIPS
O
h) L-Selectride, PhNTf2,
THF, -78 to 0oC, 88%
CH2OTIPS
Me3Sn
i) Me6Sn2, 10%Pd(PPh3)4, LiCl,
THF, 60oC, 81%
OBut
H
B
Li
OBut
L-Selectride
Palladium-Catalyzed Coupling of Enol Triflates and Hexamethyldistannane.
see: J. Org. Chem. 1986, 51, 277
CH2OTIPS
conjugate addition of hydride
TfO
OBut
O
MeN
2.5%Pd2dba3,
22%Ph3As,
CO (50 PSI), LiCl,
NMP,70oC, 80%
NMe
N
1.shield both hydrogens of a primary amine
2.base stability
3.easily removed
Tetrahedron Lett. 1990, 31, 2109
CH2OTIPS
I
+
O
R2N
OBut
Stille carbonylative coupling
R2
ArI
+
Pd(0)
SnMe3
CO
ArPdI
ArCOPdI
R2
R1
the preparation of simple a,b-unsaturated amides, see:
Tetrahedron Lett. 1985, 26, 1109.
COAr
R1
10
CH2OTIPS
O
R2N
j) t-BuOOH, Triton-B (BnMe3NOH),
THF, -15oC,91%
k) PPh3=CH2, THF, 0 to 23 oC, 92%
TBAF, THF, -15oC, 100%
OBut
CH2OH
O
R2N
OBut
l) MsCl, i-Pr2NEt, CH2Cl2, -23oC;
LiCl, DMF, 23oC;
NH2COCF3, NaH, DMF, 23oC
OBut
CH2NHCOCF3
O
R2N
OBut
H
N
m) NaH, benzene,
100oC;
KOH. EtOH-H2O,
60oC, 62%
removal of the
triflouroacetyl group
N
n) (CH2O)n, Na2SO4,
MeCN, 80oC, 98%
HO
O
NR2
NR2
OBut
the key aza-Cope-Mannich
rearrangement substrate
Mannich
Cope
N
X
N
O
HO
NR2
OBut
if NR2=NH2
N
N
[3, 3]
HO
OBut
OBut
OBut
NR2
NR2
N
11
N
O
NR2
N
o) LDA, NCCO2Me, THF, -78oC
p) 5% HCl-MeOH, reflux
q) Zn dust, 10% H2SO4-MeOH,
reflux
N
H
70%
OBut
N
80%
CO2Me OH
N
N
N
H+
N
H
N
O
OMe OH
ZnO
OMe OH
N
d) NaOMe, MeOH, RT
85%
Base-promoted epimerization
-ester to -ester
N
H H
N
H
ZnO
OMe OH
H
e) i-Bu2AlH, CH2Cl2,
-78oC
76%
CO2Me OH
N
H H
CO2Me OH
N
H
N
H H
HO
H
H
O
12
H
H
N
f) CH2(COOH)2, Ac2O,
NaOAc, HOAc, 110oC
H
N
H H
HO
H
H
N
65%
H
N
O
H
O
H
O
H
(-)-Strychnine
first asymmetric total synthesis
20 steps
~3% overall yield
Robinson, R; Saxton, J. E. J. Chem. Soc. 1952, 982
N
H+
H
H
N
H H
N
N
CH2(COOH)2
H
CHO
CH2OH
N
H H
heat
CH2OH
H
H
N
H
H
O
H
CH2OH
H
N
HOOC
N
H
H
N
CH2OH
O
O
N
H H
COOH
HOOC
N
H H
Ac2O
H
H
H
N
CH2OH
O
H
H
H
O
O
13
A synthesis of strychnine by a longest linear sequence
of six steps
Christopher D. Vanderwal. Chem. Sci., 2011, 2, 649–651
“strychnine can be considered a benchmark for the state-of-the art in alkaloid
synthesis strategy.”
Retrosynthetic Analysis:
H
N
N
H
N
H
N
H
H
N
H H
HO
O
O
H
(-)-Strychnine
H
H
N
H H
O
CHO
H OH
Wieland–Gumlich aldehyde,
a natural product
(also named caracurine VII)
OH
NH2
N
OH
N
H
N
H
N
N
SiMe3OH
CHO
N
H H
SiMe3OH
CHO
14
N
N
H
M
OH
CHO
Zincke aldehyde
5-aminopenta-2,4-dienals
NO2
Zincke Reaction
O2N
efficient for relatively electron-rich
secondary amines
N
N
H
+
Cl
N
H
M
OH
not tolerated
under basic condition
Condition of next step: KOtBu, THF, 80oC
NHR
N
H
limited stability of Zincke aldehydes
derived from primary amines
HN
N
H
removable under
palladium catalysis
Me, Bn, PMB, 2,4-DMB, TMSCH2CH2, and allyl
15
NO2
+
HN
O2N
N
H
N
aq NaOH
EtOH
N
Cl
N
H
CHO
NO2
+
HN
-HBr
O2N
N
H
N
Cl
N
H
H
N
NO2
N
O2N
N
N
H
N
NO2
N
H
N
O2N
CHO
Zincke aldehyde
5-aminopenta-2,4-dienals
16
O
O
O
N
N
KOtBu, THF,
N
H
N
H H
CHO
NH
an allyl scavenger
5%Pd(PPh3)4
80oC
64%
O
N
H H
CHO
CHO
poorly stable
H
O
O
O
NR2
+
O
prototropic
equilibrium
O
O
+
O
O
O
O
Pd(0)
NHR2
O
O
NHR2
O
O
O
NHR2
O
Pd
-allyl palladium(II) complex
17
NH
N
Br
SiMe3 OH
SiMe3 OH
N
H H
i-Pr2NEt3
CHO
N
H H
69%
H
H2C(COOH)2, Ac2O,
NaOAc, AcOH
NaHMDS
then CuBr SMe2
0 to 65oC
yield: 5-10%
Brook Rearrangement
N
H
N
H H
HO
CHO
H
H
O
N
H
N
60-80%
H
H
O
O
H
(-)-Strychnine
N
N
H H
SiMe3 OH NaHMDS
N
N
H H
CHO
N
transmetalation
N
H H
CHO
SiMe3 O
N
Brook Rearrangement
N
H H
CHO
OCu
intramolecular conjugate
addition
OSiMe3
CHO
N
N
H
H
N
H H
H
CHO
CH2OH
N
H H
HO
H
H
O
18
Collective synthesis of natural products by means of
organocascade catalysis
The shortest route to enantioenriched Strychnine
David W. C. MacMillan, Nature, 2011, 475, 183
shortest route; 12 steps; 6.4% overall yield.
Retrosynthetic Analysis:
H
N
N
H
N
H
H
H
N
H H
HO
O
O
H
(-)-Strychnine
O
N
H H
H
H
O
NH
NHBoc
N
PMB
N
CHO
H OH
N
NH
CHO
SeMe
N
H
N
H H
CH2OH
N
H H
PdI OH
CH2OH
NHBoc
N
H
CHO
N
H
N
Boc
19
NHBoc
a) NaH, PMBCl, DMF, 0oC
N
H
N
Boc
b) SeO2, dioxane, H2O, 100oC
N
H
N
c) (EtO)2PO=CH2SeMe,
18-crown-6,
KHMDS, THF, -78oC to rt
N
CHO
PMB
63% for three steps
Boc
Me
O
N
cat:
NHBoc
N
PMB
SeMe
t-Bu
1-Nap
N
H
O
NBoc
CHO
20%cat+TBA
- 40oC to rt, tol
82%, 97%e.e.
KEY STEP 1 !
N
PMB
organocascade addition–cyclization
20
organocascade addition–cyclization:
Me
NHBoc
Boc
NH
t-Bu
SeMe
NR2
O
N
+
N
PMB
Boc
NH
1-Nap
N
PMB
NR2
N
PMB
SeMe
Boc
N
NR2
Boc
N
NR2
N
PMB
NR2
endo [4+2]
N
Path 1
Boc
NH

NBoc
H+
CHO
N
PMB
N
PMB
N
PMB
TM
c at +
HA
Boc
NH
NR2
NR2
evidence for path 2:
CHO
NBoc
Path 2
NBoc
N
PMB
N
PMB
N
PMB
***
CHO
NBoc
+
N
PMB
Me
NHBoc
N
PMB
SMe
O
N
+
t-Bu
Boc
NH
N
N-methyl-cat +
NR2
SMe
HA
TM
incapable of undergoing
iminium formation
Boc
NH
endo [4+2]
1-Nap
N
PMB
stoichiometric catalyst, at -78 oC,
quenched after 10 min with Et3N,
an 84% yield of *** was obtained.
NR2
H+
N
PMB
SMe
CHO
NBoc
SMe
N
PMB
21
J. Am. Chem. Soc. 2009. 131. 13606
NBoc
CHO
NBoc
d) (PPh3)3RhCl, tol,
PhCN, 120oC
N
PMB CO2Me
N
PMB
N
PMB
NBoc
N
PMB
f) 2 eq DIBAL-H, CH2Cl2,
then TFA, -78oC to rt
NBoc
e) COCl2, Et3N, tol, -45oC to rt,
then MeOH, -30oC to rt
-78oC
N
PMB
Cl
O
Cl
Cl
NBoc
N
PMB COOMe
O
g) DBU, K2CO3, DMF, rt
NH
to rt,
NBoc
N
Br
I
N
I
h) 6 eq DIBAL-H, CH2Cl2, -78oC
N
H
PMB
OAc
OAc
N
H
PMB CO2Me
61% for three steps
the enamine unsaturation
was reduced
I
N
H
PMB CO2Me
OH
N
i) 25%Pd(OAc)2, Bu4NCl,
NaHCO3, EtOAc, rt
H
N
OH
H
H
KEY STEP 2!
PMB
HO
O
cascade Jeffery–Heck
H
cyclization/lactol formation sequence
22
cascade Jeffery–Heck cyclization/lactol formation sequence:
in the absence of phosphine ligands.
AcO
+
Pd(OAc)2
Bu4NCl
+
R
Bu4NHCO3
NaHCO3
N
H
PMB
Bu4NOAc
OH
Pd(0)
I
N
N
H
PMB
OH
N
+
+
R
Pd
AcO OAc
Bu4NHCO3 + HPdOAc
N
AcO
R
H
+
Pd
OAc
HPdOAc
R
NaCl
H2CO3
+ Pd(0)
PdI OH
OH
N
N
H
PMB
HO
-hydride elimination
H
PdI OH
1. the allylic strain
H
2. formation of the
N-PMB-substituted enamine
N
N
H
N
H
PMB
H OH
OH
N
H OH
H
PMB
CHO
Wieland-Gumlich aldehyde
N
H
PMB
HO
H
H
O
23
N
N
j) PhSH, TFA, 45oC
H
N
H
PMB
HO
H
H
O
H
O
H
H
O
H
Wieland-Gumlich aldehyde
N
H
N
H
N
H H
HO
k) CH2(COOH)2, Ac2O,
NaOAc, HOAc, 120oC
H
O
H
(-)-Strychnine
shortest route
12 steps
6.4% overall yield
24