Regiospecific, Enantiospecific Total Synthesis of the 12-Alkoxy- Substituted Indole Alkaloids, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and (-)-Fuchsiaefoline

Article abstract of DOI:10.1021/ol0362212

(Matrix presented) The enantiospecific synthesis of 7-methoxy-D-tryptophan was completed by combination of the Larock heteroannulation process with a Schoellkopf-based chiral auxiliary in good yield. This ester was then employed in the first total synthes

Full text of DOI:10.1021/ol0362212

ORGANIC
LETTERS
2004
Vol. 6, No. 2
249-252
Regiospecific, Enantiospecific Total
Synthesis of the 12-Alkoxy-Substituted
Indole Alkaloids,
(+)-12-Methoxy-N -methylvellosimine,
a
(+)-12-Methoxyaffinisine, and
(−)-Fuchsiaefoline
Hao Zhou, Xuebin Liao, and James M. Cook*
Department of Chemistry, UniVersity of Wisconsin-Milwaukee,
3210 N. Cramer Street, Milwaukee, Wisconsin 53211
capncook@uwm.edu
Received November 12, 2003
ABSTRACT
The enantiospecific synthesis of 7-methoxy-D-tryptophan was completed by combination of the Larock heteroannulation process with a Scho1llkopf-
based chiral auxiliary in good yield. This ester was then employed in the first total synthesis of (+)-12-methoxy-N -methylvellosimine, (+)-
a
12-methoxyaffinisine, and (−)-fuchsiaefoline in regiospecific, stereospecific fashion in excellent overall yield. The asymmetric Pictet−Spengler
reaction and enolate-driven palladium-catalyzed cross coupling processes served as key steps.
Sarpagine and ajmaline alkaloids have been isolated from
various species of Rauwolfia, which are broadly distributed
throughout Asia and Africa.1-9 These plants are widely used
in traditional Chinese medicine for the treatment of neuralgia,
migraine,7 and hypertension.3,5 Among these alkaloids, some
contain ring-A oxygenated functions at position 12, for
example, (+)-12-methoxy-Na-methyl-vellosimine, (+)-12-
methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-
ajmaline (see Figure 1). The bases (+)-12-methoxy-Na-
methylvellosimine and (+)-12-methoxyaffinisine have been
recently isolated from the bark of Rauwolfia bahiensis,10 the
structures of which were determined by detailed analysis of
the 1H NMR, 13C NMR, and two-dimensional NMR spectra.
However, the biological activity of these alkaloids has not
been reported. Ajmaline has been employed in the treatment
of cardiac arrhythmias for decades; however, no detailed data
on 12-methoxyajmaline has appeared. In this approach, a
regiospecific strategy was designed to incorporate the 12-
alkoxy group into ring-A of these alkaloids early in the route.
If successful, this would also provide an enantiospecific route
for the synthesis of many other 12-methoxy-substituted
sarpagine- and ajmaline-related indole alkaloids. On the basis
of previous work on the total synthesis of indole alkaloids
via the asymmetric Pictet-Spengler reaction,11 7-methoxy-
D-tryptophan was required as the chiral transfer agent and
starting material to synthesize these 12-methoxy-substituted
sarpagine and ajmaline alkaloids. Herein we report the first
(1) Chatterjee, A.; Bandyopadhyay, S. Ind. J. Chem. 1979, 18B, 87.
(2) Amer, M. M. A.; Court, W. E. Planta Med. 1980, Suppl., 8.
(3) Feng, X. Z.; Fu, F. Y. Acta Pharm. Sin. 1981, 16, 510.
(4) Sierra, P.; Novotny, L.; Samek, Z.; Budesinsky, M.; Dolejs, L.; Blaha,
K. Collect. Czech. Chem. Commun. 1982, 47, 2912.
(5) Lin, M.; Yang, B. Q.; Yu, D. Q. Acta Pharm. Sin. 1986, 21, 114.
(6) Banerji, J.; Das, B.; Chakrabarti, R.; Shoolery, J. N. Ind. J. Chem.
1987, 26B, 709.
(7) Ponglux, D.; Wongseriprpatana, S.; Subhadhirasakul, S.; Takayama,
H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S. J. Chem.
Soc., Perkin Trans. 1 1989, 5075.
(8) Arthur, H. R.; Johns, S. R.; Lamberton, J. A.; Loo, S. N. Aust. J.
Chem. 1968, 21, 1399.
(9) Braga, R. M.; Reis, F. A. M. Phytochemistry 1987, 26, 833.
10.1021/ol0362212 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

Scheme 1a
Figure 1.
efficient approach for the synthesis of 7-methoxytrypto-
phans as well as the total synthesis of (+)-12-methoxy-
Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-
fuchsiaefoline.
a Reaction conditions: (1) 2% Pd(OAc)2, 2.5 equiv of K2CO3,
LiCl, DMF, 100 °C, 75%. (2) 2 N aq HCl, THF, 0 °C to room
temperature, 92%. (3) NaH, CH3I, DMF; 2 N aq HCl, THF, 0 °C
to room temperature, 90%.
The required 7-methoxy-D-tryptophan ethyl ester 6 was
prepared via the Larock heteroannulation12 process from
2-iodo-6-methoxyaniline 113 and the propargyl-substituted
Scho¨llkopf chiral auxiliary 214 in the presence of Pd (OAc)2,
K2CO3, and LiCl in DMF at 100 °C in 75% isolated yield.
The ratio of the desired indole 3 to the byproduct 4 was
determined on the basis of the integration of the proton at
C3 in the 1H NMR spectrum of the crude reaction mixture.
The ratio was optimized to 15:1 (3:4) when 2% catalyst was
employed rather than 5% catalyst [Pd(OAc)2]. The desired
indole 3 could be separated from the byproduct 4 by flash
chromatography. The annulation could be readily carried out
on both small (100 mg) and large scales (100 g) in good
yield. Hydrolysis of the Scho¨llkopf chiral auxiliary ac-
companied by concomitant loss of the indole-2-silyl group
with aqueous 2 N HCl in EtOH provided optically active
7-methoxy-D-tryptophan ethyl ester 5 in a single step in 92%
yield. The Na-methyl analogue 6 was obtained by methylation
of the indole Na-H function with MeI and NaH, followed by
removal of the Scho¨llkopf chiral auxiliary and TES group
in simple fashion (90% yield). In summary, the annulation
between 2-iodo-6-methoxyaniline 1 and the propargyl-
substituted Scho¨llkopf chiral auxiliary 2, followed by hy-
drolysis provided 7-methoxy-D-tryptophan ethyl ester in good
yield with excellent regioselectivity. Since the 2-iodo-6-
methoxyaniline 113 and the propargyl unit 214 could be readily
prepared on a large scale (>100 g), this provided an efficient
route to synthesize either 7-methoxy-D-tryptophan or 7-meth-
oxy-L-tryptophan with high diastereoselectivity.
With Na-methyl-7-methoxy-D-tryptophan ethyl ester 6 in
hand, the 12-methoxytetracyclic ketone 9 was prepared, as
shown in Scheme 2. The primary amine of 6 was converted
Scheme 2a
(10) Kato, L.; Braga, R. M.; Koch, I.; Kinoshita, L. S. Phytochemistry
2002, 60, 315.
a Reaction conditions: (1) 2 equiv of PhCHO, EtOH, 5 equiv of
Na2SO4, 0 °C, overnight; NaBH4, -5 °C, 2 h, 90%. (2) (a) 1.5
equiv of HCOCH2CH2CO2Me, 1 equiv of HOAc, CH2Cl2, 0 °C to
room temperature, overnight; (b) 1% TFA/CH2Cl2 (∼5 equiv TFA),
rt, 7 days, 92%. (3) NaH (60%, 3.2 equiv), MeOH (3.5 equiv),
toluene, reflux; 33% KOH, dioxane, reflux, 80%.
(11) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens, D.;
Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998.
(12) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(13) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
(14) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525.
250
Org. Lett., Vol. 6, No. 2, 2004

diastereomer 8b. Dieckmann cyclization of the trans diester
8b was followed by base-mediated hydrolysis/decarboxyl-
ation to provide optically pure ketone 9 in a one-pot process.
The tetracyclic ketone 9 was then converted into 12-
methoxy-Na-methylvellosimine, 12-methoxyaffinisine, and
fuchsiaefoline, as illustrated in Scheme 3. The Nb-benzyl
group of 9 was removed via catalytic hydrogenation, and
this was followed by alkylation with (Z)-1-bromo-2-iodo-
2-butene to provide ketone 11. When this ketone 11 was
subjected to the conditions of the enolate-driven palladium-
catalyzed intramolecular cyclization,16-22 the pentacyclic
ketone 12 was obtained in 80% yield. Establishment of the
C(19)-C(20) (E)-ethylidene function had been achieved in
stereospecific fashion. The ketone 12 was then converted
into 12-methoxy-Na-methylvellosimine 13 via a Wittig
reaction followed by hydrolysis, a process developed earlier
to prepare sarpagine alkaloids.19 The data from the 1H NMR
and 13C NMR spectra of 13 were identical to those reported
by Kato and co-workers (see Table 1);10 however, the optical
Scheme 3a
Table 1. 13C NMR of Indole Alkaloids 13, 14, and 16
synthetic
lit.
synthetic
lit.
synthetic lit.
carbon
13
value10
14
value10
16
value9
2
134.2
49.3
134.5
49.3
135.7
49.4
135.8
49.4
125.6
58.2
125.6
58.4
3
5
50.4
50.4
54.2
54.2
62.5
62.3
6
27.2
27.2
27.0
27.0
24.4
24.4
7
103.3
126.6
111.1
119.3
102.5
147.5
129.2
32.3
103.3
126.7
111.1
119.4
102.6
147.6
129.2
32.3
103.8
126.5
111.0
119.1
102.3
147.5
129.3
32.7
103.8
126.6
111.1
119.2
102.5
147.5
129.4
32.9
98.8
99.0
8
127.6
110.6
120.8
103.8
180.0
127.4
30.4
127.5
110.6
120.6
103.8
147.7
127.4
30.6
9
10
11
12
13
14
15
16
17
18
19
20
21
26.5
26.5
27.4
27.5
27.3
27.2
54.8
54.6
44.1
44.3
47.6
47.6
202.7
12.6
202.6
12.6
64.9
65.0
12.7
12.7
a Reaction conditions: (1) 10% Pd/C, EtOH/HCl, 7 h, 92%.. (2)
1.2 equiv of (Z)-1-bromo-2-iodo-2-butene, THF, 6.5 equiv of
K2CO3, reflux, 24 h, 90%. (3) 5% Pd(OAc)2, 20% PPh3, 1 equiv
of Bu4NBr, 4 equiv of K2CO3, DMF/H2O (9:1), 65 °C, 12 h, 80%.
(4) 8 equiv of MeOCH2PPh3Cl, 8.8 equiv of KOtBu, benzene, rt,
24 h; 2 N aq HCl/THF, 55 °C, 6 h, 90%. (5) 2 equiv of NaBH4/
EtOH, 0 °C to room temperature, 95%. (6) KOH, I2, EtOH, 85%.
(7) MeI/THF, 0 °C; AgCl, EtOH, rt, 81%.
12.7
12.8
121.5
133.0
65.0
121.2
132.8
64.9
116.9
139.3
56.1
117.0
139.3
56.0
116.7
139.5
56.2
116.7
139.7
56.2
170.0
33.6
169.9
33.4
Na-CH3
32.4
32.5
32.3
32.4
-O-CH3
55.3
55.4
55.3
55.4
55.5
55.4
N+-CH3
47.0
46.9
CO2CH2CH3
CO2CH2CH3
62.0
61.9
14.0
13.9
into the required Nb-benzyl ester 7 by reductive amination
in high yield. The Pictet-Spengler condensation between
the aldehyde and the Nb-benzylamine 7 was carried out in
the presence of acetic acid in CH2Cl2 to afford a mixture (at
C-1) of cis-8a and trans-8b diesters in nearly quantitative
yield in a ratio of 1:2. When TFA/CH2Cl2 was employed in
this step in place of HOAc/CH2Cl2, decomposition of much
of the 7-methoxytryptophan 7 was observed. In keeping with
the mechanistic studies on the carbocation-mediated cis/trans
isomerization,15 when the Pictet-Spengler reaction was
completed, 5 equiv of TFA was added to the reaction mixture
to epimerize the cis diastereomer 8a into the desired trans
rotation of synthetic 13 was different from the reported value.
For this reason, the aldehyde 13 was reduced with NaBH4
to provide 12-methoxyaffinisine 14 (95% yield), the optical
(15) (a) Cox, E. D.; Hamker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.;
Deng, L.; Bennett, D. W.; Cook, J. M.; Watson, W. H.; Krawiec, M. J.
Org. Chem. 1997, 62, 44. (b) Zhang, L. H.; Trudell, M. L.; Hollinshead, S.
P.; Cook, J. M. J. Am. Chem. Soc. 1989, 111, 8263. (c) Zhang, L. H.; Cook,
J. M. Heterocycles 1988, 27, 2795. (d) Zhang, L. H.; Gupta, A. G.; Cook,
J. M. J. Org. Chem. 1989, 54, 4708.
(16) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454.
(17) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.
(18) Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 7219.
Org. Lett., Vol. 6, No. 2, 2004
251

rotation of which was in excellent agreement with the
employed to synthesize 7-substituted indoles in moderate
yield.26 Hoveyda et al. have also reported a recent synthesis
of a 7-hydroxytryptophan.27 The strategy reported here can
be employed for the synthesis of either the 7-alkoxy-D- or
7-alkoxy-L-tryptophan on a large scale.14 The first regio-
specific, enantiospecific total synthesis of (+)-12-methoxy-
Na-methylvellosimine in a concise manner was reported here.
The synthesis of (+)-12-methoxy-Na-methyl-vellosimine 13,
(+)-12-methoxy-affinisine 14, and (-)-fuchsiaefoline 16 was
accomplished (from D-tryptophan 6) in seven, eight, and nine
reaction vessels, respectively. The asymmetric Pictet-
Spengler reaction and an enolate-driven palladium-mediated
cross-coupling reaction are two pivotal steps employed to
establish the correct stereochemistry in these natural products.
The total synthesis of 12-methoxyajmaline and other indole
alkaloids (from 7-methoxytryptophan) will be reported in due
course.
reported value ([R]26 ) 3.3, lit.10 3.0). In addition, the
D
signals in the 1H NMR and 13C NMR spectra were identical
to the reported values (see Table 1).10 The aldehyde function
of intermediate 13 was then oxidized to the ethyl ester 15
with I2 and KOH in EtOH, following the work of Yamada
et al.,23 a process employed earlier in our laboratory to
prepare sarpagine alkaloids.24 Subsequent quaternization of
the Nb nitrogen function in ester 15 with MeI provided the
Nb-methiodide salt, which was then converted into the
chloride 16 on treatment with AgCl in EtOH.25 The 1H NMR
spectrum, 13C spectrum and optical rotation of 16 were in
good agreement with those of the reported values (see
Scheme 3 and Table 1).
In summary, 7-methoxy-D-tryptophan 5 was prepared via
combination of the Larock heteroannulation with 2-iodo-6-
methoxyaniline and the propargyl-substituted Scho¨llkopf
chiral auxiliary in good yield. To the best of our knowledge,
this is the first synthesis of an optically pure 7-alkoxy-
tryptophan, although the Bartoli indole synthesis has been
Acknowledgment. We wish to acknowledge NIMH (in
part) and the Graduate School (UWM) for support of this
work.
OL0362212
(19) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057.
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Am. Chem. Soc. 2003, 125, 1587.
(22) Sole´, D.; Diab, F.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746.
(23) Yamada, S.; Morizano, D.; Yamamoto, K. Tetrahedron Lett. 1992,
33, 4329.
(24) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565.
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Gilmore, J.; Long, D. A. Synlett 1992, 79.
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Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032. (b) Pellegrin, C.; Weber,
M.; Borschberg, H. HelV. Chim. Acta. 1996, 79, 151. (c) Taniguchi, M.;
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