Synthesis of the tricyclic core structure of vindoline

Article abstract of DOI:10.1016/j.tetlet.2003.11.115

An efficient synthesis of the core tricyclic structure (18) of vindoline has been achieved using the strategy, which features an intramolecular 1,3-dipolar cycloaddition of the azido dienone (12) to give aziridine (13) with complete region- and stereocontrol.

Full text of DOI:10.1016/j.tetlet.2003.11.115

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 919–921
Synthesis of the tricyclic core structure of vindolineq
Zihong Guo* and Arthur G. Schultz
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12180-3590, USA
Received 6 October 2003; revised 25 November 2003; accepted 25 November 2003
Abstract—An efficient synthesis of the core tricyclic structure (18) of vindoline has been achieved using the strategy, which features
an intramolecular 1,3-dipolar cycloaddition of the azido dienone (12) to give aziridine (13) with complete region- and stereocontrol.
Ó 2003 Elsevier Ltd. All rights reserved.
Vindoline (1), the major alkaloid component isolated
N
N
D
E
from the leaves of Vinca rosea Linn., is a highly func-
tionalized pentacyclic Aspidosperma alkaloid and of
important medicinal interest because of its biosynthetic
and synthetic role as a precursor of the carcinostateic
alkaloid drugs vinblastine and vincristine.1 Aspido-
sperma alkaloids are a family of over 200 members that
share in the molecular structures a common pentacyclic
framework with the C ring being of critical importance
due to the fact that the entire six stereocenters and most
functionalities of the molecule are located on it (1 in
Scheme 1). Individual members differ mainly in func-
tionality and stereochemistry. Over the past 40 years
there have been tremendous efforts for developing new
methodologies for the synthesis of these highly func-
tionalized alkaloids.2 Since then, a large number of
synthetic strategies for vindoline and other Aspido-
sperma alkaloids have been developed,3 and most of
them fall into one of the two major categories according
to the strategies used for the construction of the B ring
in the molecule (5 in Scheme 2). One involves the Fisher
indole synthesis, which is widely used in many Aspido-
sperma alkaloid syntheses to construct the B ring, leav-
ing major synthetic efforts to preparation of tricyclic
core 6.2;4 The other utilizes as building blocks indoles (7)
that contain suitable functionalities and substituents in
H
H
C
A
B
N
OAc
OH
CO2CH3
R
N
H
H
CH3
R2 R1
3, Aspidospermine (R1 = Ac, R2 = OCH3)
4, Aspidospermidine (R1 = R2 = H)
1, Vindoline (R = OCH3)
2, Vindorosine (R = H)
Scheme 1.
O
N
H
N
N
D
E
CO2Me
OMe
A
C
B
N
O
Z
O
8
5
6
N3
X
CO2Me
OMe
N
7
Y
O
Z
9
Scheme 2.
the side chains for conversion to the C, D, and/or E
rings.5 A more conceptually new strategy is reported
recently where
a tandem cyclization–cycloaddition
Keywords: Vindoline; Synthesis; 1,3-Dipolar cycloaddition; Birch
reduction–alkylation.
sequence has been used to assemble the C and E rings
with four of the stereocenters of vindoline being
installed in one step with a high degree of stereocontrol.6
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.115
* Corresponding author at present address: Suntory Pharmaceutical
Research Laboratories, 1 Kendall Square, Building 700, Cambridge,
MA 02139, USA. Tel.: +1-617-583-5349; fax: +1-617-621-0555;
e-mail: zihong.guo@sprlus.com
In this communication, we report an efficient synthesis
of the core tricyclic structure of vindoline by utilization
of the Birch reduction–alkylation to construct the C ring
and an intramolecular 1,3-dipolar cycloaddition to
Deceased January 20, 2000.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.115

920
Z. Guo, A. G. Schultz / Tetrahedron Letters 45 (2004) 919–921
oxycarbonyl at C(6a) are in a syn position as shown in
Scheme 3.
I
CO2H
OH
a
CO2H
OH
With the C and D rings constructed, our attention was
turned to cleavage of the aziridine ring and installation
of a two-carbon chain to form the E ring as the next
step. Treatment of 13 with a methanolic HCl solution at
room temperature gave the chloride 14 as a single dia-
stereoisomer in quantitative yield, the stereochemistry of
which is as shown in 14 (Scheme 4). The high stereo-
selectivity might be a result of protonation of the
nitrogen, followed by an SN2 attack of a chloride anion,
resulting in ring opening of the aziridine ring. Reduction
of chloride 14 with zinc in acetic acid at room temper-
ature for 48 h afforded amine 15 in 75% isolated yield. It
was found that the direct reductive cleavage of the azi-
ridine ring in 13 with Zn/HOAc to 15 required long
reaction time and afforded low yields. Finally a one-step
reduction of 13 was achieved using Birch reduction
conditions to give 16, a diastereoisomer of 15. Treated
with acetic acid, 16 was isomerized to 15 exclusively.
Calculations using the MM2 force field were made to
predict the relative stereochemistry about the two pro-
tons at C(8) and C(8a). The stereochemistry of 15 and 16
was deduced with a comparison between the experi-
b
CO2Me
OMe
c
CO2Me
OMe
N3
92%
11
10
d 62%
N
CO2Me
H
e
6b
N3
3b
CO2Me
OMe
80%
O
O
OMe
13
12
Scheme 3. Reagents and conditions: (a) PhB(OH)2, (Ph3P)4Pd,
K2CO3, H2O, Tol., MeOH, reflux; (b) Me3SO4/K2CO3, acetone,
reflux; (c) Li/NH3/THF/t-BuOH, )78 °C, piperylene, I(CH2)3N3; (d)
PDC/t-BuO2H, PhH, Celite; (e) PhH, reflux, 2 days.
install the D ring of the alkaloid. Our disconnection of
vindoline is based upon the following considerations:
First, the B ring could result from an intramolecular
ring closure in 8 to avoid the low yielding and poor
regioselectivity of the Fisher indolization. Secondly, the
D ring is formed through an intramolecular azide–enone
1,3-dipolar cycloaddition of 9 with region- and stereo-
control; Lastly, the most important C ring (the tetra-
substituted cyclohexadienone ring in 9) is derived from
Birch reductive alkylation of the corresponding biaryl
substrate, followed by bis-allylic oxidation. An impor-
tant strategic element of the approach is an early
incorporation of the aromatic ring (ring A) in 8 as the
5-phenyl substituent in 10 (Scheme 3). The early
incorporation methodology has received attention from
several groups.7
1
mentally observed H–1H coupling constants, 11.0 and
2.7 Hz, and the calculated ones, 11.7 and 5.6 Hz,
respectively. This provided us with relatively high con-
fidence in the stereochemical assignment (Scheme 4).
Acylation of either 15 or 16 with bromoacetyl chloride
in THF in the presence of NaHCO3 for 30 min at 0 °C
furnished bromoamide 17 as a diastereomeric mixture in
90% yield after chromatography on silica gel. Finally, 17
was treated with t-BuOK in warm benzene for 48 h to
give the core tricyclic product 18 in 96% yield. The
assignment of the structure of tricyclic product 18 was
N
HN
8a
H
H
c
Our synthesis of the core tricycle of vindoline (equiva-
lent to the structure 8) starts with intramolecular 1,3-
dipolar cycloaddition of azido dienone 12, which is
prepared using a procedure that we described recently
(Scheme 3).8 Previous studies show that under photo-
chemical conditions (366 nm) 12 rearranges to a bicyclic
ketone product, while irradiation at 300 nm a tetrasub-
stituted phenol is formed.8 In refluxing benzene, how-
ever, 12 was converted to an aziridine product 13 in 80%
yield with complete region- and stereocontrol. The iso-
lation of aziridine 13 rather than a triazoline product
should be due to the triazoline instability in refluxing
benzene, which accelerates the extrusion of nitrogen in
the corresponding triazoline intermediate.9 The aziridine
8
CO2Me
OMe
H
O
CO2Me
OMe
91%
O
13
16
a
d
100%
HN
HN
8a
H
H
b
8
75%
Cl
O
CO2Me
OMe
H
O
CO2Me
OMe
14
15
e
90%
O
O
Br
N
H
N
1
f
H
structure of 13 was determined based upon its H and
13C NMR spectra along with a chemical ionization mass
spectrum. The molecular ion peak of 314 (Mþ+1, 100%)
for 13 was observed, ruling out the possible structure of
a triazoline product. Furthermore, a 2D NOESY
experiment showed interactions among the protons of
phenyl, C(6b), and carboxylic methyl ester, indicating
that the phenyl at C(3b), proton at C(6b), and meth-
CO2Me
OMe
96%
H
O
CO2Me
OMe
O
18
17
Scheme 4. Reagents and conditions: (a) HCl/MeOH (6 N, 1:1); (b) Zn,
HOAc, 72 h; (c) Li/NH3/THF, )78 °C; (d) acetic acid; (e) BrCH2COCl/
NaHCO3/THF; (f) t-BuOK/PhH, reflux, 48 h.

Z. Guo, A. G. Schultz / Tetrahedron Letters 45 (2004) 919–921
921
2. For the first syntheses of aspidospermine and vindoline, see:
Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872,
and Ando, M.; Buchi, G.; Ohnuma, T. J. Am. Chem. Soc.
1975, 97, 6880, respectively.
3. Saxon, J. E. Synthesis of the Aspidosperma Alkaloids. In
The Alkaloids; Cordell, J. A., Ed.; Academic: San Diego,
1998; Vol. 50, pp 343–376.
4. For examples, see: (a) Ban, Y.; Sato, Y.; Inoue, M.; Oishi,
T.; Terashima, M.; Yonemitsu, O.; Kanaoka, Y. Tetrahe-
dron Lett. 1965, 1, 2261; (b) Kuehne, M. E.; Bayha, C.
Tetrahedron Lett. 1968, 2639; (c) Stevens, R. V.; Fizpatrick,
J. M.; Kaplan, M.; Zimmerman, R. L. Chem. Commun.
1971, 857; (d) Meyers, A. I.; Berney, D. J. Org. Chem. 1989,
54, 4673.
Figure 1. X-ray structure of the core tricycle 18.
5. For examples, see: (a) Kutney, J. P.; Chan, K. K.; Failli, A.;
Fromson, J. M.; Gletsos, C.; Velson, V. R. J. Am. Chem.
Soc. 1968, 90, 3891; (b) Barton, J. E. D.; Harley-Mason, J.
Chem. Commun. 1965, 298; (c) Harley-Mason, J.; Kaplan,
M. Chem. Commun. 1967, 915; (d) Node, M.; Nagasawa,
H.; Fuji, K. J. Am. Chem. Soc. 1987, 109, 7901; (e) Schultz,
A. G.; Pettus, L. J. Org. Chem. 1997, 62, 6855; (f) Kuehne,
M. E.; Hafter, R. J. Org. Chem. 1978, 43, 3702; (g)
Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem.
Soc. 1983, 105, 4750; (h) Buchi, G.; Matsumoto, K. E.;
Nishimura, H. J. Am. Chem. Soc. 1971, 93, 3299; (i) Ando,
M.; Buchi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97,
6880. For the synthesis of vindorosine, see Ref. (h).
6. (a) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556; (b)
Padwa, A.; Price, A. T. J. Am. Chem. Soc. 1995, 60, 6258;
(c) However, relative little effort has been directed at an
asymmetric synthesis. See: Kuehne, M. E.; Podhorez, D. E.;
Mulamaba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52,
347; (d) Feldman, P. L.; Rapoport, H. J. Am. Chem. Soc.
1987, 109, 1603.
7. Recently three examples of this early incorporation in the
synthesis of the aspidosperma alkaloids have appeared. See:
(a) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R.
W.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966; (b)
Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1995, 117,
11017; (c) Toczko, M. A.; Heathcock, C. H. J. Org. Chem.
2000, 65, 2642.
8. Guo, Z.; Schultz, A. G.; Antoulinkis, E. G. Org. Lett. 2001,
3, 1177.
9. Schultz, A. G.; Dittami, J. P.; Myong, S. O.; Sha, C. K.
J. Am. Chem. Soc. 1983, 105, 1255; For a review, see:
Schultz, A. G. In Advances in Cycloaddition Chemistry;
Curran, D. P., Ed.; JAI: 1988.
1
made based upon the H and 13C NMR, IR, and mass
spectra and was further confirmed by X-ray crystallo-
graphic studies (Fig. 1).
The supplementary data is available online with the
paper in ScienceDirect. Experimental procedures and
analytical data for compounds 13, 14, 15, 17, and 18.
Acknowledgements
This work was supported by the National Institute of
Health (GM33061). We thank Dr. Fook S. Tham for the
X-ray structure determination of 18. Z.G. thanks Drs.
Agustin Casimiro-Garcia and Margarita Kirova for
helpful discussions and Dr. Carl Illig for proofreading
this manuscript.
References and notes
1. For reviews, see: (a) Verpoorte, R.; van der Heijden, R.;
Moreno, P. R. H. Biosynthesis of Terpenoid Indole
Alkaloids in Cantharaus roseus Cells. In The Alkaloids;
Cordell, G. A., Ed.; Academic: San Diego, 1997; Vol. 49, pp
221–299; (b) Kutchan, T. M. Molecular Genetics of Plant
Alkaloid Biosynthesis. In The Alkaloids; Cordell, G. A.,
Ed.; Academic: San Diego, 1998; Vol. 50, pp 257–316.