H
OH
(-)-Vindoline
Me
N
OAc
CO2Me
Isolation: Gorman, M. et al. J . Am. Pharm. Assoc.,
Sci. Ed. 1959, 48, 256.
Structure: Gorman, M. et al. J. Am. Chem. Soc.
1962, 84, 1058-1059.
Crystal structure: Maurin, J. K. et al. Acta Cryst.
2004, C60, 377-380.
Biosynthesis: Scott, A. I. et al. J .Am. Chem. Soc.
1968, 90, 4144-4150.
CO2Me
N
OH
OAc
N
H
CO2Me
R
OH
N
R=Me, Vinblastine
R=CHO, Vincristine
MeO
N
H
MeO2C
N
CO2Me
[4+2]
CO2Me
Tabersonine
N
H
N
(-)-Vindoline
The above hypothesis was supported by the isolation of secodine from natural sources:
Battersby, A. R.; Bhatnagar, A. K. J. Chem. Soc., Chem. Commun. 1970, 193-194.
Dehydrosecodine
N
H
N
Biosynthetic hypothesis (Wenkert, E. J. Am. Chem. Soc. 1962, 84, 98-102)
For a review see: Potier, P. J. Nat. Prod. 1980, 43, 72-86.
(+)-Catharanthine
N
H
+
(-)-Vindoline
CO2Me
N
H
CO2Me
N
N
OH
OH
CO2Me
OAc
N
H
CO2Me
Me OH
N
O
N
CO2Me
N
C
D
Vindoline
OAc
N
H
CO2Me
Me OH
B
N
O
N
OH
CO2Me
OH
N
H
CO2Me
Me OH
N
H
Syntheses of Vindoline: 6 total (3 enantioselective)
4 formal
Through Danieli's 5-step sequence every synthesis of 16-MeO-tabersonine
can be extended to vindoline
Several syntheses of 16-MeO-tabersonine have been reported - the most
creative of them will be also discussed
Scope of presentation
Danieli, B.; Lesma, G.; Palmisano, G.; Riva, R. J. Chem. Soc., Chem. Commun. 1984, 909-911.
idem. J. Chem. Soc., Perkin Trans. 1 1987, 155-161.
A
E
Vindorosine
NaBH3CN,
40% HCHO,
pH 4.2, rt
anticipated
intermediate
N
(55% overall) MeO
(93%)
(PhSeO)2O,
PhH, 60 °C
16-MeO-Tabersonine
MeO
Similarly:
1. Raney-Ni, MeOH, rt
2. Ac2O, AcONa, rt
(78%)
mCPBA, K2CO3,
CH2Cl2, H2O, 0 °C
Tabersonine
N
H
N
N
Group Meeting
12/8/2004
Bruno Danieli (1984): Hemisynthesis of vindoline from 16-MeO-tabersonine
Vindoline
Vindoline bears no significant biological activities.
However, vinblastine, resulting from the coupling of (-)vindoline with (+)-catharanthine
and vincristine, the corresponding N-formyl alkaloid, display significant antitumor activity.
Currently vinblastine and vincristine are used for the treatment of leukemia and lymphoma.
Major alkaloid of Catharanthus roseus
MeO
N
Christos Mitsos
An avid hiker, hunter, skier and fisherman, died
of heart failure while hiking in Switzerland
A pioneer in organic photochemistry in the 50's
Determined the structure of 55 natural products
Completed the syntheses of 75 natural products
Worked on: organic photochemistry, natural product
characterization and natural product total synthesis
Passed his entire academic career in MIT (1951-1991)
Born in Baden, Switzerland. Diploma and DSc from
Eidgenoss-ische Technische Hoch-schule in Zurich
George H. Büchi (1921-1998)
Ac
O
BF 3.OEt2
N
H
Me
N
Ac
O
RO
RO
N
Me
N
O
O
RO
N
Ac
O
N
Me
+ RO
N
Me
Ac
O
N
Vindorosine
major
2%
N
N
Ac
O
OAc
N
H
CO2Me
Me OH
Benzylic cation formation
favored when para EDG
RO
R = Me : 9%
R = Ts : 89%
N
H
Me
Wagner-Meerwein
type rearrangement
BF3.OEt2
Ac
Intermediate
indolenium ion
N
Me
N
Ac
Effect of substituent on indole 6-position:
Büchi, G. et al. J. Am. Chem. Soc. 1971, 93, 3299-3300.
N
Me
N
OH
N
N
NAc
O
O
O
N
H
Me CO2Me
N
H
Me
N
H
Me
N
Me
OH
N
H
CO2Me
Me OH
N
Ac2O
AcONa
MeO
N
H
Me
N
H
Me
N
NAc
N
Me
O
O
O
Al
O
hydride
attack
Cl
N
N
Me O O
Cl
'top' face flanked
by coordinated LA
55%
1. (MeO)2CO, NaH
2. 98% H2O2, t-BuOK,
t-BuOH, DME
49%
(±)-Vindoline
OAc
N
H
CO2Me
Me OH
N
reduction under other conditions resulted
in mixtures of epimeric alcohols
MeO
89%
BF3.OEt2
1. Me3O+BF4-,
DCM, NaHCO3
2. Acrylaldehyde,
MeONa, MeOH
3. MsCl, pyr
O
alkylation diastereoselectivity:
CD fused rings need to be cis
MeO
MeO
1. AlCl3, THF, -25 °C
2. Red-Al, -20 °C
53%
EtI, t-BuOK,
t-BuOH, DMF
79%
TsO
NAc
Group Meeting
12/8/2004
Ando, M.; Büchi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97, 6880-6881.
MeO
O
1. KOH, MeOH-H2O
2. Me2SO4, K2CO3,
acetone
74%
enolate hydroxylation: attack from the
opposite side of the ethyl group
MeO
MeO
TsO
TsO
1.
Cl
Et3N, EtOH
NH3Cl 2. AcCl, NaH, THF
George Büchi's total synthesis
Key step involves a Robinson-type annulation first employed in the synthesis of vindorosine:
Christos Mitsos
N
H
Me
MeO
NAc
OEt
O
MeO
(±)-Vindoline
62%
NaH, DMSO
70 °C
67%
N
H
O
N
Me
MeO
O
NAc
(±)-Vindoline
N2
N
Me
HCl
N
Me
MeO
NAc
O
92%
MeO
O
OMe
NH
Li/NH3
t-BuOH
N
Me
3:2 mixture of epimers
CO2Me
35% MeO
TFA
DCM
HO2C
O
Takano, S. et al. Heterocycles 1977, 6, 1699-1704.
Takano, S. et al. J. Chem. Soc., Chem. Comm. 1978, 943-944.
NH2
49%
60%
epimerization of the
Ac
'wrong' diasteromer
N
1. MeI, NaH, DMF
2. Li/NH3
N
O
H
Mixture of epimers
Et3O+BF4-,
ClCH2CH2Cl
single isomer
N
H
Me
NAc
1. AcCl, Et3N
2. KOH, EtOH
3. ClCO2Et, Et3N;
CH2N2
O
- No exchange of groups on phenol required
- Starting oxindole prepared from 4-amino-3-nitro-anisole in 6 steps (17% overall)
- Non-enantioselective synthesis
MeO
NAc O
Seiichi Takano (1977): Two syntheses of Büchi's ABCE intermediate
MeO
1st:
N
MeO
NAc O
O
O
Ban Y. et al. Tetrahedron Lett. 1978, 151-154.
N
H
MeO
NH2
O
1. O
NaOH, aq. MeOH
2. Acetylation
3. Acidic hydrolysis
Group Meeting
12/8/2004
N
Me
O
NAc
MeO
BF 3.OEt2
or H2SO4
N
H
N
N
Me
NAc
O
Li/NH3
t-BuOH
NAc
N
Me
N
O
H
Me
single isomer
MeO
CO2Et
MeO
100%
EtO
EtO2C
N
H H
N
ABCE tetracycle
52%
Ac2O-AcOH 3:2
reflux, 72 h
(±)-Vindoline
CO2Et
(±)-Aspidospermidine
CO2Et
NH
LAH
NAc
- Tandem 1,4-addition and Dieckmann-type condensation of the enamine
- No reaction in Ac2O or AcOH alone
- Non-enantioselective synthesis
3:2 mixture of epimers
MeO
N
Me
NH2
- Mechanistically interesting transformation
- Non-enantioselective route
- Similar transformations adopted by Langlois and Rapoport
in their total syntheses of vindoline (vide infra)
2nd:
MeO
O
O
Harley-Mason, J.; Kaplan, M. Chem. Comm. 1967, 915-916.
HO
N
H
N
H
N
Me
Precedent: Harley-Mason's synthesis of aspidospermidine
O
MeO
Mechanism: Diazoketone forms a cationic intermediate which attacks the indole double bond.
Rearrangement gives the ABCE tetracycle.
Formal syntheses based on Büchi's route
Yoshio Ban (1978): Developed a synthesis of Büchi's ABCE tetracyclic intermediate
Christos Mitsos
N
H
MeO
N
H
N
Me
CN
N
MeO
N
Me
N
H
N
CO2Me
N
N
Me
CO2Me
N
N
(±)-Vindoline
KCN
DMF
O
Hg(OAc)2
or O2, Pt/C
MsO
-
20 steps
(0.00022%
overall)
Dihydro-MeO-tabersonine
MeO
BnO
N
H
Mixture of diastereomers
MeO
DL-Vincaminoridine
DL-epi-Vincaminoridine
MeO
MsCl
Et3N
OEt
1.Hydrolysis
2. CH2N2
3. Methylation
N
OBn
H
CO2Me
N
HO
N
H
+
O
- Simple and efficient route to 4-ring Aspidosperma alkaloids (Vincaminoridine)
- Transannular cyclization provides diastereoselectively the 5-ring vindoline skeleton
Dihydro-MeO-tabersonine: J. P. Kutney et al. J. Am. Chem. Soc. 1968, 90, 3891-3893.
Vindoline: J. P. Kutney et al. J. Am. Chem. Soc. 1978, 100, 4220-4224.
MeO
1. LAH
2. H2, Pd/C MeO
MeO
NH2
O
OSiMe3
N
Me
S
N
O
1. LAH, THF, -78 °C
2. Ac2O, pyr
MeO
MeS
N
Me
H
O
S
O
(±)-Vindoline
100%
Zn, aq. AcOH
MeO
+
N
O
-H+
N
70%
TsOH,
THF, ∆
OH
N
O
H
Me CO2Me
37%
N
O
N
H
Me CO2Me
N
PhCl, ∆
87.5%
CO2Me
Y. Langlois et al. J. Org. Chem. 1985, 50, 961-967.
52%
OH
N
O
H
Me CO2Me
O
N
1. NaBH3CN, TFA, MeOH
2. Raney Ni, acetone,
cyclohexene, ∆
3. (Me O)2 CO, Na H,
THF, ∆
MeO
69%
N
Me
N
Me
N
Group Meeting
12/8/2004
- Elegant synthesis based on Harley-Mason's transformation
- Requisite cationic intermediate formed through a Pummerer rearrangement
- Non-enantioselective synthesis
52%
N
O
MeO
1. EtI, LDA
THF, HMPA
2. CH3S(O)CH2Li,
MeO
THF, DMSO
88%
1. HCO2H, DCC
2. TFA, DCM
MeO
SMe
N
N
Me
N
Me
MeO2C
N
Me
OEt
TBAF (cat.), THF
2. mCPBA,
ClCH2CH2Cl
1.
MeO
MeO
MeO
MeO
NH2
Yves Langlois (1985): Third total synthesis of vindoline
Kutney's and Langlois' total syntheses
James B. Kutney (1968 and 1978): Second Total synthesis of vindoline
Christos Mitsos
CO2But
+
MeO
H
N
MeO
S
67%
TsOH,
THF, ∆
O
H+
N
Me
N
H
N
H
MeO2C
N
Racemization mechanism:
S
O
O
One enantiomer
N
Me
MeO
MeO
MeO
N
H
MeO2C
MeO
H
N
N
H
N
N
Me
S
N
OH
CO2Me
CO2H
(±)-Vindoline
1. MeI, KH, DMF
2. CH3S(O)CH2Li,
THF, DMSO
N
non-racemic
mixture of diastereomers
separated by chromatography
MeO
O
N
Me SMe
Langlois' intermediate
Racemic!
acid-catalyzed
retro-Mannich
N
81%
1. NaHCO3, MeCN
Br 2. 90% HCO2H
3. NaOMe
MeO
P. L. Feldman, H. Rapoport. J. Org. Chem. 1986, 51, 3882-3890.
80%
PhOPOCl2
from L-aspartic acid
(14% overall, >98%ee)
N
H
CO2Me
H
O
MeO
MeO
Cl
N
H
O
H
O
N
N
N
O
CO2Me
N
MeO
MeO2C
N
Me
Cl
H N
MeO
H O
MeO
MeO
O
N
H
MeO
N
H O
N
O
N
H
Me CO2Me
MeO2C
N
Me
75%
t-BuOCl, DCM;
then DBU
LDA, THF
19 steps, 3.6% overall
from L-aspartic acid
N
P. L. Feldman, H. Rapoport. J. Am. Chem. Soc. 1987, 109, 1603-1604.
85%
N
H
MeO
O
H
N
Ac
MeO2C
1. NaBH3CN, TFA, MeOH
2. aq. HCHO, NaBH3CN,
MeCN-AcOH
73%
NaOMe
MeOH
55%
KH, DMF; Ac2O
(-)-Vindoline
N
O
H
N
1. Rubottom oxidation
2. AlCl3, Red-Al
3. Acetylation
MeO
N
H
MeO2C
one diastereomer
MeO
MeO
Group Meeting
12/8/2004
2nd generation strategy: Exchange of roles between indole double bond and side chain.
Instead of attacking a cationic intermediate, indole double bond
would be activated to nucleophilic attack by an anionic one.
Rapoport's total synthesis
Initial strategy: Enantioselective version of Langlois' total synthesis.
Ring D constructed first from L-aspartic acid and employed in the
enantioselective synthesis of Langlois' sulfoxide intermediate.
Henry Rapoport (1987): Enantioselective synthesis
Christos Mitsos
Cl
O
H
+
N
H
12%
N
H
MeO
CO2Me
N
CO2Me
N
N
H
MeO
N
OH
+
OH
[4+2]
81%
PPh3,
CCl4, MeCN
half-chair conformation
determines [4+2}
diastereoselectivity
CO2Me
N
CO2Me
N
Cl
OH
M. E. Kuehne et al. J. Org. Chem. 1987, 52, 347-353.
route similar
with Danieli's
(-)-Vindoline
OH
N
H
not isolated
hydroxysecodine
intermediate
N
H
MeO
CO2Me
52%
N
H
N
MeO
fragmentation
OH
CO2Me
MeO
CO2Me
H
N
H
NH
H3BO3,
MeOH, ∆
H
MsO
N
H
MsO
optimized Danieli's route
(51% in 4 steps)
65%
O S O
HN
NO2
O
CO2Me
N
N
H
O
MsO
N
H
N
CO2Me
OH
CO2Me
(-)-16-MeO-tabersonine
MeO
N
H
N
N
Boc CO2Me
T. Fukuyama et al. Synlett 2000, 883-886.
81%
1. PPh3, CCl4, MeCN
2. KOH, MeOH
3. MeI, t-BuOK, THF
OH
MsO
O
see also vinblastine's synthesis in 'Classics in Total Synthesis', Vol. 2.
OH
CO2Me
NH
89%
DEAD
PPh3, PhH
11 steps from
R-glyceraldehyde acetonide
O2N
(-)-Vindoline
15 steps from
from p-nitrophenol
N
Boc CO2Me
1. TFA, DCM, rt
2. pyrrolidine,
MeOH-MeCN,
rt, then reflux
MsO
+
OH
ArO2S
N
Group Meeting
12/8/2004
Tohru Fukuyama (2000): Second application of intramolecular [4+2]
Biomimetic syntheses
- Kuehne was the first to pursue a biomimetic synthesis of vindoline via an intramolecular
[4+2] cycloaddition of a secodine intermediate
- The diastereoselectivity of the key transformation is not great, but provides the vindoline
skeleton through an one-pot procedure from relatively simple SM
- Diastereoselectivity is based on the preference of the secodine intermediate to adopt a
conformation with the OH group in a pseudoequatorial position
- Kuehne completed the first enantioselective synthesis of (-)-vindoline, but also achieved
the synthesis of racemic and (+)-vindoline starting from RS- and R-epichlorohydrins
16-MeO-tabersonine
MeO
MeO
Et3N
∆
56% in 3 steps from
S-epichlorohydrin
HO
Martin E. Kuehne (1987): First enanntioselective synthesis of vindoline
Christos Mitsos
N
H
Ms
N
H
Ms
MeO
MeO
Intermediates:
N
H
Ms
OBn
N3
OH
OH
OBn
OBn
MeO
OBn
N
H
Ms
N
Ms
I
N
H
Me
NAc
N3
MeO
N
H
Ms
N
MeO
65%
NAc
O
OsO4 (1%), NMO,
acetone, H2O
OBn
OBn
N
H
O
NH
Boc
N
CO2Me
N
MeO
MeO
+
16-MeO-Tabersonine
MeO
MeO
96%
HCHO, TsOH,
PhH, reflux
97%
Ph3PCH3+Br-, n-BuLi
THF, -78 °C to rt
NHBoc
CN
O
N
67%
MeO
N
N
N
HO
NH
Boc
MeO
MeO
MeO
NHBoc
OH
MeO
N
O
O
N
Mannich
NHBoc
OH
ClCO2Me
LDA, THF
NH
Boc
H
OH N
NH
Boc
O
Intermediates' conformations
MeO
N
50%
KOH, MeOH
reflux
cationic
aza-Cope
NaOMe, MeOH
reflux
NH
Boc
OH N
NH
Boc
O
91%
O H CO2Me 1. n-BuLi (2 equiv)
N
THF, -78 to 0 °C
2. LiOH, MeOH, rt
Larry E. Overman (1983): Application of an aza-Cope - transannular Mannich cascade
90%
1. (Me3Si)3SiH
AIBN, PhH
2. Acetylation
Group Meeting
12/8/2004
Syntheses of 16-MeO-Tabersonine
OSiMe3
NHMs
I
Vindoline
DEAD, PMe3, THF
MeO
J. A. Murphy et al. Org Lett 2002, 4, 443-445.
MeO
MeO
1. Na/NH3, i-PrOH
2. HCHO, NaBH3CN,
MeOH-DCM-H2O, pH 3
3. NaIO4, acetone, H2O
1. H2, Pd/c, EtOAc
2. o-O2N-Ph-SeCN,
Bu3P, THF
3. NaIO4, NaHCO3,
MeOH
74%
1. DDQ, DCM-H2O
2. MsCl, Et3N, DCM
3. NaN3, DMF
HO
OPMB
OBn
Diastereomer
(initial diastereomer
gave poor yields in
subsequent Mitsunobu)
Inversion
- Diastereoselectivity based on the necessity of the newly formed rings, B and E,
to be cis fused to existing C ring
- Absolute stereochemistry determined by cyclohexanol configuration
- Suitable for enantioselective synthesis of vindoline
MeO
NAc
NAc
(±)-Vindoline
N
Ms
OPMB
HO
OPMB
95/5 diastereoselectivity
relative stereochemistry
not determined yet!
9 steps
(35% overall)
MeO
I
CO2Et
CO2Et
John A. Murphy (2002): Construction of B and E rings through tandem radical cyclizations
Christos Mitsos
MeO
MeO
MeO
MeO
MeO
N
N
N
CO2Me
N
N
CO2Me
N
PhS
O
+
N
S
O
H
H
O
93%
PhMe
200 °C
86%
MeO
1. mCPBA, NaHCO3,
DCM-H2O, 5 °C
2. TFAA, DBMP, PhMe,
0 - 110 °C
70-75%
PhMe
reflux
76.5%
1. MeI, reflux
2. NaBH4, MeOH
89%
MeO
MeO
Balleau's reagent
THF, 0 °C
PhS
N
CO2Me
N
O
N
N
N
CO2Me
N
N
CO2Me
N
CO2Me
PhS
MeO
S
O
PhS
H
H
77%
POCl3, DMF,
0 °C to rt
84.5%
TsCl, i-Pr2NEt,
PhMe, reflux
95%
W-2 Raney-Ni
EtOAc
N
CO2Me
N
O
'indole-2,3-quinodimethane'
intermediate
MeO
no desulfurization conditions leaving
intact the double bond could be found
O
H
H
Cl
N
CO2Me
N
CO2Me
N
CO2Me
PhS
PhS
N
MeO2C
CHO
49%
1. NaClO2
2. CH2N2
3. NaOMe
N
H
CO2Me
(-)-16-MeO-Tabersonine
MeO
N
Group Meeting
12/8/2004
Fukuyama
Kuehne
Rapoport
Langlois
Kutney
Büchi
In brief:
O
H
Cl
HO2C
MeO
MeO
BnO
O
O
NH2
O
N
H
CO2H
N
Me
N
H
SM
NH2
NH2
21
8
22
13
29
18
Steps
13%
2.0%
< 3.6%
(last 3 steps not reported)
< 12%
(last step not reported)
< 0.00016%
(8 steps not reported)
< 2.8%
(last step not reported)
Yield
- CD rings formed via an IMDA of a 'quinodimethane' type indole derivative
- Alkene part attached to norbornyl moiety which acts as chiral auxiliary
- E ring formed via Pummerer rearrangement
- Chiral auxiliary removed with retro-DA
MeO
N
Magnus Indole-2,3-quinodimethane strategy
Philip Magnus (1988): Synthesis of 16-MeO-tabersonine via the Indole-quinodimethane strategy
Christos Mitsos