General approach for the synthesis of 12-methoxy-substituted sarpagine indole alkaloids including (-)-12-methoxy-Nb-methylvoachalotine, (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline

Article abstract of DOI:10.1021/jo052081t

The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester 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 regiospecific, stere

Full text of DOI:10.1021/jo052081t

General Approach for the Synthesis of 12-Methoxy-Substituted
Sarpagine Indole Alkaloids Including
(-)-12-Methoxy-Nb-methylvoachalotine,
(+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and
(-)-Fuchsiaefoline
Hao Zhou, Xuebin Liao, Wenyuan Yin, Jun Ma, and James M. Cook*
Department of Chemistry, UniVersity of WisconsinsMilwaukee, 3210 North Cramer Street,
Milwaukee, Wisconsin 53211
capncook@uwm.edu
ReceiVed October 4, 2005
The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester was completed by combination of
the Larock heteroannulation process with a Scho¨llkopf-based chiral auxiliary in good yield. This ester
was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-Na-
methylvellosimine, (+)-12-methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-Nb-methylvoachalotine
in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed
cross-coupling processes served as key steps. The quaternary center at C(16) of 12-methoxy-Nb-
methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-Na-methylvellosimine
and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by
the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion
at [C(6)] to form a cyclic ether [C(6)-O(17)]. After oxidative formation of the R-ester at C(16), the
ether bond was reductively cleaved with TFA/Et3SiH in high yield. The DDQ-mediated oxidative
cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps in order to provide
a versatile entry into the voachalotine alkaloids.
Introduction
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 positions
10, 11, and 12. Examples of 12-methoxy-substituted indole
alkaloids include (+)-12-methoxy-Na-methyl-vellosimine, (+)-
12-methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-Nb-
methylvoachalotine, as shown in Figure 1. Important structural
features of these natural products include the asymmetric centers
at C-3(S), C-5(R), C-6(R), C-15(S), and C-16(S), the E-
configuration of the olefinic bond at C(19)-C(20), as well as
Sarpagine and ajmaline are biogenetically related alkaloids
which have been isolated from various species of Rauwolfia
broadly distributed throughout Asia and Africa.1-9 These plants
(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.
Tetrahedron 1988, 44, 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/jo052081t CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/08/2005
J. Org. Chem. 2006, 71, 251-259
251

Zhou et al.
FIGURE 1. Examples of sarpagine and ajmaline indole alkaloids.
the 12-methoxy group in ring A. 12-Methoxy-Nb-methylvoacha-
lotine is also of interest for it contains a quaternary carbon at
position 16, in which the hydroxymethyl group is found at the
axial position while the methyl ester function is equatorial. Such
a quaternary carbon center also exists in many other indole
alkaloids including (-)-polyneuridine,10 (-)-voachalotine,11
macusine A,12 11-methoxymacusine A,13 and (-)-11-hydroxy-
Na-methylmacusine A,14 as illustrated in Figure 1. Polyneuridine
aldehyde15 and voachalotinal16 also contain a similar quaternary
carbon center; however, in these examples, the aldehyde function
is located in the axial position instead of the hydroxymethyl
group. Polyneuridine aldehyde, a sarpagine alkaloid, is believed
to be the biogenetic precursor17 of the ajmaline-related alkaloid
(+)-quebrachidine;18 a subunit of the bisindole (+)-alstomac-
roline. (+)-Alstomacroline was isolated from the root bark of
A. macrophylla collected in Thailand and exhibited potent
activity against drug-resistant strains of malaria parasites (IC50
of 1.2 µM against the K1 strain of Plasmodium falciparum).19
Le Quesne et al. reported a biomimetic coupling process on
condensation of natural (+)-quebrachidine with macroline to
furnish (+)-alstomacroline.20 The bases (+)-12-methoxy-Na-
methylvellosimine and (+)-12-methoxyaffinisine have been
recently isolated from the bark of Rauwolfia bahiensis,21 the
structures of which were determined by detailed analysis of the
1H NMR, 13C NMR, and 2D NMR spectra. However, the
biological activity of these two alkaloids has not been reported.
Two quaternary indoles, (-)-fuchsiaefoline and (+)-12-meth-
oxy-Nb-methylvoachalotine were isolated from Peschiera fuch-
siaefolia in 1987.9 Their structures were determined by 1H and
13C NMR. 12-Methoxy-Nb-methylvoachalotine was reported to
inhibit avian myeloblastosis virus reverse transcriptase.22 This
inhibition was dependent on the template primer used. In
Brazilian folk medicine, victims of bites by poisonous animals
are usually treated with plant extracts derived from the diverse
national flora including Tabernaemontana catharinensis. 12-
Methoxy-Nb-methylvoachalotine, isolated from the root bark of
T. catharinensis, completely inhibited the lethal dose in the rat
when it had been injected 20 s after 2 LD50 with South
American rattlesnake venom at 1.7 mg/100 g.23 Ajmaline has
been employed in the treatment of cardiac arrhythmias for
decades; however, no detailed data on 12-methoxyajmaline has
appeared. Herein, we report the first enantiospecific total
synthesis of 12-methoxy-Nb-methylvoachalotine, (+)-12-meth-
oxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-
fuchsiaefoline. Bond constructions critical to the synthesis of
these alkaloids include the E-ethylidene stereochemistry at
C(19)-C(20) and the quaternary center at C(16), as mentioned.
(10) Antonaccio, L. D.; Pereira, N. A.; Gilbert, B.; Vorbrueggen, H.;
Budzikiewicz, H.; Wilson, J. M.; Durham, L. J.; Djerassi, C. J. Am. Chem.
Soc. 1962, 84, 2161.
(11) Defay, N.; Kalsin, M.; Pecher, J.; Martin, R. H. Bull. Soc. Chim.
Belg. 1961, 70, 475.
(12) McPhail, A. T.; Robertson, J. M.; Sim, G. A. J. Chem. Soc. 1963,
1832.
(13) Verpoorte, R.; Bohlin, L.; Dwuma-Badu, D.; Rolfesen, W.; Strom-
bom, J. J. Nat. Prod. 1983, 46, 572.
(14) Madinaveitia, A.; Valencia, E.; Bermejo, J.; Gonzalez, A. G.; Gupta,
M. P. J. Nat. Prod. 1995, 46, 572.
(15) Joule, J. A.; Ohashi, M.; Gilbert, B.; Djerassi, C. Tetrahedron 1965,
21, 1717.
(16) Pinchon, T. M.; Nuzillard, J. M.; Richard, B.; Massiot, G.; Le Men-
Oliver, L.; Sevenet, T. Phytochemistry 1990, 29, 3341.
(17) Lounasmaa, M.; Hanhinen, P. The Ajmaline Group of Indole
Alkaloids. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, 2001; Vol. 55, Chapter 1, p 1.
(18) Koskinen, A.; Lounasmaa, M. Planta Med. 1982, 45, 248.
(19) Keawpradub, N.; Kirby, G. C.; Steele, J. C.; Houghton, P. J. Planta
Med. 1999, 65, 690.
(20) Burke, D. E.; Cook, J. M.; Le Quesne, P. W. J. Am. Chem. Soc.
1973, 95, 546.
(21) Kato, L.; Braga, R. M.; Koch, I.; Kinoshita, L. S. Phytochemistry
2002, 60, 315.
(22) Juca, M. B.; Aoyama, H. Phytother. Res. 1996, 10, 113.
(23) de Fatima, M.; Batina, C.; Cintra, A. C. O.; Veronese, E. L. G.;
Lavrador, M. A. S.; Giglio, J. R.; Pereira, P. S.; Dias, D. A.; Franca, S. C.;
Sampaio, S. V. Planta Med. 2000, 66, 424.
252 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids
SCHEME 1. Synthesis of 7-Methoxy-D-tryptophan
In addition, regiospecific incorporation of the 12-methoxy group
into the indole was of paramount importance to success.
auxiliary and the 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 hydrolysis provided 7-methoxy-D-tryptophan ethyl
ester in good yield. Since the 2-iodo-6-methoxyaniline 1 and
the propargyl unit 2 could be readily prepared on large scale
(>100 g), this provided an efficient route to synthesize
7-methoxy-D-tryptophan with high diastereoselectivity; the
enantiomer, 7-methoxy-L-tryptophan, could be prepared in the
same fashion from the Scho¨llkopf chiral auxiliary from D-valine
(Scheme 1).
Construction of the Tetracyclic Ketone 9. With Na-methyl-
7-methoxy-D-tryptophan ethyl ester 6 in hand, the 12-methoxy-
tetracyclic ketone 9 was prepared in three reaction vessels, as
shown in Scheme 2. The primary amine of tryptophan 6 was
converted 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 trans-8a and cis-8b diesters in nearly quantitative
yield in a ratio of 2:1. If 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,31-34 when the Pictet-Spengler reaction was
completed, 5 equiv of TFA was added to the reaction mixture
to epimerize the cis diastereomer 8b into the desired trans
diastereomer 8a. It is important to note, the completion of the
epimerization of the 8-methoxy Na-methyldiester 8b into 8a took
7 days, which was consistent with that for the 6-methoxy Na-
methyl substituted diester. However, for the 7-methoxy Na-
methyl substituted diester, the epimerization was much faster,
Results and Discussion
Enantiospecific Synthesis of 7-Methoxy-D-tryptophan for
Indole Alkaloid Total Synthesis. Based on previous work on
the total synthesis of indole alkaloids via the asymmetric Pictet-
Spengler reaction,24 7-methoxy-D-tryptophan was required as
the chiral transfer agent and starting material to synthesize these
12-methoxy-substituted sarpagine and ajmaline alkaloids. The
required 7-methoxy-D-tryptophan ethyl ester 6 was prepared via
the Larock heteroannulation25 process from 2-iodo-6-methoxy-
aniline 126 and the propargyl-substituted Scho¨llkopf chiral
auxiliary 2 (from L-valine)27 in the presence of Pd (OAc)2, K2-
CO3, and LiCl in DMF at 100 °C in 75% isolated yield.28 The
Larock heteroannulation was also employed successfully in the
synthesis of 6-methoxy-D-tryptophan.29 The application of this
strategy to regiospecifically synthesize 4-methoxy-D-tryptophan
and 5-methoxy-D-tryptophan is currently under investigation.
The desired indole 3 could be easily purified by flash chroma-
tography. The annulation could be readily carried out both on
small scale (100 mg) and large scale (100 g) in good yield.
Hydrolysis of the Scho¨llkopf chiral auxiliary with aqueous 2 N
HCl in THF accompanied by concomitant loss of the indole-
2-silyl group provided optically active 7-methoxy-D-tryptophan
ethyl ester 4 in a single step in 92% yield. The ester 4 was then
hydrolyzed to prepare 7-methoxy-D-tryptophan 5 with 1 N aq
NaOH in ethanol for characterization.30 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
(24) 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.
(25) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(26) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
(27) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525.
(28) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249.
(29) Liu, X.; Deschamps, J. D.; Cook, J. M. Org. Lett. 2002, 4, 3339.
(30) Li, X.; Yin, W.; Sarma, P. V. V. S.; Zhou, H.; Ma, J.; Cook, J. M.
Tetrahedron Lett. 2004, 45, 8569.
(31) 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.
(32) Zhang, L. H.; Trudell, M. L.; Hollinshead, S. P.; Cook, J. M. J.
Am. Chem. Soc. 1989, 111, 8263.
(33) Zhang, L. H.; Cook, J. M. Heterocycles 1988, 27, 2795.
(34) Zhang, L. H.; Gupta, A. G.; Cook, J. M. J. Org. Chem. 1989, 54,
4708.
J. Org. Chem, Vol. 71, No. 1, 2006 253

Zhou et al.
SCHEME 2. Construction of the 12-Methoxytetracyclic Ketone 9
which is in good agreement with the carbocationic intermediate
(via resonance) proposed for this process.35,36 Dieckmann
cyclization of the trans diester 8a was followed by base-
mediated hydrolysis/decarboxylation to provide optically pure
ketone 9 in a one-pot process.
the reported value.21 For this reason, the aldehyde 13 was
reduced with NaBH4 to provide 12-methoxyaffinisine 14 (95%
yield), the optical rotation of which was in excellent agreement
with the reported value ([R]26 ) 3.3 (lit.21 [R]26 ) 3.0)). In
D
D
addition, the signals in the 1H NMR and 13C NMR spectra were
identical to the reported values.21 The aldehyde function of
intermediate 13 was then oxidized to the ethyl ester 15 with I2
Completion of the Total Synthesis of 12-Methoxy-Na-
methylvellosimine, 12-Methoxyaffinisine, and (-)-Fuchsi-
aefoline. 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. This alkylation was simple to execute, for
overalkylation in these azabicyclo[3.3.1] systems is very dif-
ficult. This is an advantage to this approach. When this ketone
11 was subjected to the conditions of the enolate-driven
palladium-catalyzed intramolecular cyclization,37-43 the penta-
cyclic 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
and KOH in EtOH, following the work of Yamada et al.,44
a
process employed earlier in our laboratory to prepare sarpagine
alkaloids.45 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
1
AgCl in EtOH.46 The H NMR spectrum, 13C spectrum, and
optical rotation of 16 were in good agreement with those of the
reported values (see Scheme 3).
Completion of the Total Synthesis of 12-Methoxy-Nb-
methylvoachalotine. Attention now turned to the establishment
of the quaternary center at C(16) of 12-methoxy-Nb-methyl-
voachalotine. Numerous efforts (aldolizations, alkylations, and
acylations of analogues of 13 devoid of methoxyl substituents
on the indole A-ring) were originally attempted, but they were
not successful.47-51 However, treatment of aldehyde 13 with
37% aq formaldehyde and KOH in MeOH via the Tollens
reaction provided the diol 17 in 85% yield (Scheme 4). The
prochiral quaternary carbon center at C-16 that contained the
1
sarpagine alkaloids.40 The H NMR and 13C NMR spectra of
13 were identical to those reported by Kato and co-workers;21
however, the optical rotation of synthetic 13 was different from
(35) Zhou, H.; Han, D.; Liao, X.; Cook, J. M. Tetrahedron Lett. 2005,
46, 4219.
(44) Yamada, S.; Morizano, D.; Yamamoto, K. Tetrahedron Lett. 1992,
33, 4329.
(45) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565.
(46) Yamazaki, N.; Dokoshi, W.; Kibayashi, C. Org. Lett. 2001, 3, 193.
(47) Martin, S. F. Tetrahedron 1980, 36, 419.
(36) Liu, X. 2002, Ph.D. Thesis, University of WisconsinsMilwaukee.
(37) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454.
(38) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.
(39) Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 7219.
(40) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057.
(41) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
(42) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bard´ıa, M.; Bonjoch, J. J.
Am. Chem. Soc. 2003, 125, 1587.
(48) Fuji, K. Chem. ReV. 1993, 93, 2037.
(49) Wang, R.; Yang, C.-W. Huaxue 1996, 54, 169.
(50) Corey, E. J.; Guaman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388.
(43) Sole´, D.; Diab, F.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746.
(51) Wang, T. Ph.D. Thesis, University of WisconsinsMilwaukee, 2001.
254 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids
SCHEME 3. Synthesis of 12-Methoxy-Na-methylvellosimine, 12-Methoxyaffinisine, and Fuchsiaefoline
structurally hindered diol in 17 was constructed in one step.
The two prochiral hydroxymethyl groups in diol 17 must now
be differentiated. This problem was solved on the basis of
previous work in our laboratory52-54 on DDQ-mediated oxida-
tions on indoles.52-57 Oxidative cyclization of diol 17 with DDQ
in THF permitted facile bond construction between the axial-
(â) hydroxymethyl function and the benzylic position at C(6).
The equatorial hydroxymethyl moiety of cyclic ether 18 which
remained was then oxidized intramolecularly with (PhSeO)2O/
PhCl at 115 °C for 30 min to furnish the aldehyde 19,58 which
was further oxidized with KOH/I2/MeOH to afford the methyl
ester 20. Hydrogenation of 20 with hydrogen and palladium to
cleave the C(6)-O(17) bond was attempted but was unsuc-
cessful. Because C(6) is a benzylic carbon atom in 20, reductive
cleavage of the C(6)-O(17) bond could be easily accomplished
with TFA/Et3SiH in CH2Cl2 in 86% yield. Subsequent quater-
nization of the Nb nitrogen function in ester 21 with MeI
provided the Nb-methiodide salt, which was then converted into
the chloride 22 on treatment with AgCl in MeOH.
It is important to note that, in the synthesis of 12-methoxy-
Nb-methylvoachalotine 22, the DDQ-mediated oxidation via a
charge-transfer complex57,59-62 permitted the selective protection
of the axial hydroxymethyl group, which permitted further
modification of the equatorial hydroxymethyl group to the
methyl ester. TFA/Et3SiH-mediated reduction released the
hydroxymethyl function to provide alcohol 21. This provided
the first stereospecific entry into the hydroxymethyl and methyl
ester groups at C(16). TFA/Et3SiH had been earlier employed
for the reduction of the carbonyl group,63 and the olefinic bond
of an R,â-unsaturated ketone.64 Herein we demonstrated that
TFA/Et3SiH could be employed for the reductive cleavage of
the ether bond. The reductive cleavage of the benzylic C(6)-
O(17) bond with TFA/Et3SiH was further studied with other
(52) Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982, 47, 4933.
(53) Campos, O.; Dipierro, M.; Cain, M.; Mantei, R.; Gawish, A.; Cook,
J. M. Heterocycles 1980, 14, 975.
(54) Trudell, M. L.; Fukada, N.; Cook, J. M. J. Org. Chem. 1987, 52,
4293.
(59) Walker, D.; Hiebert, J. D. Chem. ReV. 1967, 67, 153.
(60) Braude, E. A.; Jackman, L. M.; Linstead, R. P. J. Chem. Soc. 1954,
3548.
(55) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(56) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O. Heterocycles
1979, 12, 1457.
(57) Bergman, J.; Carlsson, R.; Misztal, S. Acta Chem. Scand. B 1976,
30, 853.
(61) Braude, E. A.; Jackman, L. M.; Linstead, R. P. J. Chem. Soc. 1954,
3564.
(62) Jackman, L. M. AdV. Org. Chem. 1960, 2, 329.
(63) West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org.
Chem. 1973, 38, 2675.
(58) Barton, D. H. R.; Brewster, A. G.; Hui, R.; Lester, D.; Ley, S. V.;
Back, T. J. J. Chem. Soc., Chem. Commun. 1978, 952.
(64) Kursanov, D. N.; Loim, N. M.; Baranova, V. A.; Moiseva, L. V.;
Zalukaev, L. P.; Parnes, Z. N. Synthesis 1973, 420.
J. Org. Chem, Vol. 71, No. 1, 2006 255

Zhou et al.
SCHEME 4. Stereocontrolled Synthesis of 12-Methoxy-Nb-methylvoachalotine
TABLE 1. Reductive Cleavage of Cyclic Ethers with Et3SiH/TFA
was cleaved and the carbonyl group was again reduced to the
alcohol. (-)-Epiaffinisine 28 could be prepared from (+)-
dehydroepiaffinisine with TFA/Et3SiH. This process also worked
well on Na-H-substituted substrates such as (+)-dehydro-16-
epinormacusine B 29 and gardnutine 31.
Conclusion
In summary, 7-methoxy-D-tryptophan 5 was prepared on 100
g scale via the combination of the Larock heteroannulation
process with 2-iodo-6-methoxyaniline 1 and the propargyl-
substituted Scho¨llkopf chiral auxiliary 2 in good yield. To the
best of our knowledge, this is the first synthesis of an optically
pure 7-alkoxytryptophan, although the Bartoli indole synthesis
has been employed to synthesize 7-substituted indoles in
moderate yield.66-69 The strategy reported here can be employed
for the synthesis of either 7-alkoxy-D- or 7-alkoxy-L-tryptophan
on large scale. The first regiospecific, enantiospecific total
synthesis of (+)-12-methoxy-Na-methylvellosimine in a concise
manner was achieved. In addition, the first synthesis of (+)-
12-methoxy-Na-methylvellosimine 13, (+)-12-methoxyaffinisine
14, (-)-fuchsiaefoline 16, and 12-methoxy-Nb-methylvoacha-
lotine 22 was accomplished (from D-tryptophan 6) in 7 reaction
vessels, 8 reaction vessels, 9 reaction vessels, and 12 reaction
vessels, respectively. The asymmetric Pictet-Spengler reaction
and an enolate-driven palladium-mediated cross coupling reac-
tion are two pivotal steps employed to establish the correct
stereochemistry in these natural products. The Tollens reaction,
DDQ-mediated cyclization, and TFA/Et3SiH reductive cleavage
of the C-O bond were employed to install the quaternary carbon
center at C(16) of 12-methoxy-Nb-methylvoachalotine and
voachalotine. Since sarpagine indole alkaloids are the proposed
biogenetic precursors of the ajmaline alkaloids17 as mentioned
substrates (see Table 1). Dehydrovoachalotine 2365 was con-
verted into voachalotine 24 in 88% yield after 23 was stirred
with TFA/Et3SiH in CH2Cl2 for 1 day at room temperature.
When aldehyde 25 was treated with TFA/Et3SiH, the cyclic ether
(66) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett.
1989, 30, 2129.
(67) Dobbs, A. J. Org. Chem. 2001, 66, 638.
(68) Dobson, D.; Todd, A.; Gilmore, J. Synth. Commun. 1991, 21, 611.
(69) Dobson, D.; Gilmore, J.; Long, D. A. Synlett. 1992, 79.
(65) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Org. Chem. 2005, 70, 3963.
256 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids
to Kugelrohr distillation at 80 °C (0.3 mmHg) to remove L-valine
ethyl ester, which could be reused. Purification of the oil which
remained by flash chromatography over silica gel (EtOAc) afforded
earlier, the strategy employed here should provide a route to
12-alkoxy substituted ajmaline alkaloids. The total synthesis of
12-methoxyajmaline and other indole alkaloids (from 7-meth-
oxytryptophan) will be reported in due course.
6 as a light yellow oil (1.69 g, 90%): [R]25 ) -6.5 (c 1.13,
D
CHCl3); FTIR 3370, 2934, 1731, 1574, 1256 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.1 Hz), 1.60 (s, 2H), 2.98 (dd,
1H, J ) 14.3, 7.5 Hz), 3.24 (dd, 1H, J ) 14.4, 4.8 Hz), 3.78 (dd,
1H, J ) 7.8, 4.8 Hz), 3.93 (s, 3H), 4.02 (s, 3H), 4.19 (q, 2H, J )
7.1 Hz), 6.62 (d, 1H, J ) 7.7 Hz), 6.81 (s, 1H), 7.00 (t, 1H, J )
7.8 Hz), 7.20 (d, 1H, J ) 8.0 Hz); 13C NMR (75.5 MHz, CDCl3)
δ 14.1, 30.6, 36.2, 55.0, 55.3, 60.8, 102.3, 109.6, 111.6, 119.4,
126.6, 128.6, 130.2, 147.8, 175.3. EIMS m/e 276 (M+); HRMS
C15H20N2O3 calcd 276.1474, found 276.1466. This material was
used directly in the next step.
Experimental Section
(5R,2S)-3,6-Diethoxy-2-isopropyl-5-[7-methoxy-2-(triethyl-
silyl)-3-indolyl]methyl-2,5-dihydropyrazine (3). The 2-iodo-6-
methoxyaniline 1 (102 g, 0.41 mol) and the Scho¨llkopf derivative
2 (179 g, 0.49 mol) were charged to a round-bottom flask, as well
as lithium chloride (17.4 g, 0.41 mol), potassium carbonate (141.3
g, 1.02 mol), palladium(II) acetate (1.84 g, 8.2 mmol), and dry
DMF (700 mL). The mixture was then degassed with a vacuum
pump three times at rt (with argon). The suspension which resulted
was heated for 36 h at 100 °C under an atmosphere of Ar. After
examination of the mixture by TLC (silica gel) indicated the
iodoaniline 1 had been consumed, the reaction mixture was cooled
to rt and diluted with EtOAc. The mixture was washed with H2O
(5 × 20 mL) to remove DMF. The organic layer was washed with
brine, dried (Na2SO4), and concentrated under reduced pressure.
Purification by flash chromatography over silica gel (2% EtOAc/
Nb-Benzyl-7-methoxy-1-methyl-D-tryptophan Ethyl Ester (7).
Benzaldehyde (5.58 g, 52.54 mmol) was added to a mixture of
tryptophan ethyl ester 6 (7.25 g, 26.3 mmol) and Na2SO4 (18.7 g,
0.131 mol) in dry ethanol (150 mL) at 0 °C under nitrogen. The
solution was stirred at 0 °C for 8 h, cooled to -10 °C, and treated
portionwise with NaBH4 (2.03 g, 52.54 mmol), during which the
temperature was kept below -5 °C (about 1 h). After the mixture
was allowed to stir for an additional 2 h, ice-water (0.5 mL) was
added, and the mixture was allowed to warm to rt. The ethanol
was removed under reduced pressure, and the aqueous residue was
extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with brine and dried (Na2SO4). The mixture was
concentrated under reduced pressure and purified by flash chro-
matography to provide the desired ester 7 (8.64 g, 90%): 1H NMR
(300 MHz, CDCl3) δ 1.19 (t, 3H, J ) 7.1 Hz), 1.74 (bs, 1H), 3.12
(m, 2H), 3.60-3.86 (m, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 4.11 (q,
2H, J ) 7.2 Hz), 6.61 (d, 1H, J ) 7.7 Hz), 6.75 (s, 1H), 6.97 (t,
1H, J ) 7.8 Hz), 7.15 (d, 1H, J ) 8.0 Hz), 7.20-7.32 (m, 5H);
13C NMR (75.5 MHz, CDCl3) δ 14.1, 29.1, 36.2, 52.0, 55.3, 60.5,
61.2, 102.2, 109.6, 111.7, 119.2, 126.8, 127.6, 128.1, 128.4, 130.3,
139.7, 143.7, 147.4, 174.8; EIMS m/z 366 (M+). Anal. Calcd for
C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.95; H, 7.09;
N, 7.52. This material was used directly in the next step.
hexane) provided the desired 3 as a yellow oil (149 g, 75%): [R]25
D
) -23.4 (c 0.77, CHCl3); FTIR 2955, 1688, 1234 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.70 (t, 3H, J ) 6.8 Hz), 0.85-1.06 (m, 18H),
1.23 (t, 3H, J ) 7.1 Hz), 1.31 (t, 3H, J ) 7.1 Hz), 2.29 (m, 1H),
2.85 (dd, 1H, J ) 13.5, 10.6 Hz), 3.53 (dd, 1H, J ) 14.1, 3.1 Hz),
3.92 (t, 1H, J ) 3.1 Hz), 4.00 (s, 3H), 4.02-4.25 (m, 5H), 6.60 (d,
1H, J ) 7.6 Hz), 6.98 (t, 1H, J ) 7.8 Hz), 7.38 (d, 1H, J ) 8.0
Hz), 8.11 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 3.6, 7.4, 14.2,
14.3, 16.6, 19.0, 31.5, 32.1, 55.1, 58.6, 60.4, 60.6, 101.4, 113.4,
118.6, 124.0, 129.1, 131.0, 131.1, 145.6, 162.6, 163.8. Anal. Calcd
for C27H43N3O3Si: C, 66.76; H, 8.92; N, 8.65. Found: C, 66.66;
H, 8.94; N, 8.59.
7-Methoxy-D-tryptophan Ethyl Ester (4). Aqueous 2 N HCl
(6 mL) was added to a solution of 3 (0.34 g, 0.70 mmol) in THF
(8 mL) at 0 °C. The reaction mixture was stirred at rt overnight.
Ice was added to the solution, and the pH of the reaction mixture
was adjusted to 8 (pH paper) with aq NH4OH. The mixture was
extracted with EtOAc (3 × 50 mL). The combined organic layer
was dried (Na2SO4) and concentrated under reduced pressure.
Purification of the residue by flash chromatography over silica gel
(gradient elution: EtOAc/hexane, 3:7, to remove L-valine ethyl
3-(2-Benzyl-8-methoxy-9-methyl-3-propionyloxy-2,3,4,9-tet-
rahydro-1H-â-carbolin-1-yl)propionic Acid Methyl Ester (8a).
The 4-oxobutyric acid methyl ester (4.12 g, 35.49 mmol) and HOAc
(1.25 g, 20.88 mmol) were added to a round-bottom flask (250
mL) which contained a solution of optically active Na-methyl-Nb-
benzyl-D-tryptophan ethyl ester 7 (7.6 g, 20.88 mmol) in dry CH2-
Cl2 (50 mL) at 0 °C. The reaction mixture which resulted was stirred
at rt overnight. TFA (11.86 g, 0.104 mol) in CH2Cl2 (200 mL) was
then added at 0 °C. The reaction mixture which resulted was stirred
at rt for 7 d and then cooled in an ice bath after which it was brought
to pH 8 with an aqueous solution of 28% NH4OH. The aqeous
layer was separated and extracted with CH2Cl2 (3 × 100 mL). After
the combined organic layers were washed with brine and dried (K2-
CO3), the solvent was removed under reduced pressure. The residue
was purified by flash chromatography (silica gel, EtOAc/hexane
ester, then EtOAc) afforded 5 (0.17 g, 92%): [R]25 ) -2.2 (c
D
1
1.0, CHCl3); FTIR 3370, 2937, 1729, 1629, 1579, 1260 cm-1; H
NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.1 Hz), 2.45 (bs,
2H), 3.06 (dd, 1H, J ) 14.4, 7.5 Hz), 3.30 (dd, 1H, J ) 14.4, 4.8
Hz), 3.85 (dd, 1H, J ) 7.5, 4.8 Hz), 3.96 (s, 3H), 4.18 (q, 2H, J )
7.1 Hz), 6.66 (d, 1H, J ) 7.7 Hz), 7.05 (s, 1H), 7.05 (t, 1H, J )
7.8 Hz), 7.24 (d, 1H, J ) 8.0 Hz), 8.44 (s, 1H); 13C NMR (75.5
MHz, CDCl3) δ 14.1, 30.6, 54.9, 55.2, 60.9, 101.9, 111.5, 119.8,
122.5, 126.7, 128.8, 146.1, 174.9. EIMS m/e 262 (M+). This
material was used directly in the next step.
7-Methoxy-Na-methyl-D-tryptophan Ethyl Ester (6). Pyrazine
3 (3.3 g, 6.8 mmol) and MeI (1.45 g, 10.2 mmol) in DMF (30 mL)
were cooled to 0 °C after which NaH (60%, 0.41 g, 10.2 mmol)
was added portionwise. The mixture which resulted was stirred at
0 °C for 1.5 h, quenched with ice-cold water, and diluted with
EtOAc (200 mL). The organic layer was washed with water (5 ×
20 mL), brine, dried (Na2SO4), and concentrated under reduced
pressure. The mixture obtained here was then dissolved in THF
(80 mL) and cooled to 0 °C. A cold aqueous solution of 2 N HCl
(70 mL) was slowly added to the above mixture. The mixture was
allowed to warm to rt and stirred overnight. Ice was added to the
solution, and the pH of the reaction mixture was adjusted to 8 (pH
paper) with aq 28% NH4OH. The mixture was extracted with EtOAc
(3 × 150 mL). The combined organic layer was dried (Na2SO4)
and concentrated under reduced pressure. The residue was subjected
) 1:4) to provide pure trans-8a (8.9 g, 92%): [R]25 ) -32.9 (c
D
0.31, CHCl3); FTIR 3440, 2947, 2840, 1733, 1574, 1456, 1255
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.39 (t, 3H, J ) 7.1 Hz),
1.81-2.07 (m, 2H), 2.38-2.65 (m, 2H), 2.98-3.17 (m, 2H), 3.38
(d, 1H, J ) 13.2 Hz), 3.51 (s, 3H), 3.76 (dd, 1H, J ) 10.9, 3.1
Hz), 3.83 (d, 1H, J ) 13.2 Hz), 3.89 (s, 3H), 3.95 (s, 3H), 4.06
(dd, 1H, J ) 10.5, 5.4 Hz), 4.24-4.38 (m, 2H), 6.66 (d, 1H, J )
7.6 Hz), 7.03 (t, 1H, J ) 7.9 Hz), 7.18 (d, 1H, J ) 7.8 Hz), 7.26-
7.38 (m, 5H); 13C NMR (75.5 MHz, CDCl3) δ 14.3, 20.2, 27.7,
29.7, 32.8, 51.3, 52.6, 53.2, 55.4, 55.9, 60.8, 102.7, 106.5, 111.0,
119.5, 126.9, 128.1, 128.6, 129.2, 136.0, 139.3, 147.6, 172.9, 173.9;
EIMS m/e 464 (M+, 5.6), 378 (25.2), 377 (100.0), 213 (34.8). Anal.
Calcd for C27H32N2O5: C, 69.81; H, 6.94; N, 6.03. Found: C, 69.60;
H, 6.99; N, 5.97.
(+)-12-Methoxyaffinisine (14). (+)-12-Methoxy-Na-methyl-
vellosimine 13 (50 mg, 0.149 mmol) was dissolved in EtOH (10
mL), after which NaBH4 (11.5 mg, 0.298 mmol) was added to the
J. Org. Chem, Vol. 71, No. 1, 2006 257

Zhou et al.
above solution in one portion at 0 °C. The mixture was then stirred
at rt for 4 h. The reaction mixture was diluted with CH2Cl2 (80
mL) and poured into cold water (20 mL). The aqueous layer was
extracted with additional CH2Cl2 (3 × 20 mL), and the combined
organic layers were washed with brine (20 mL) and dried (Na2-
SO4). The solvent was removed under reduced pressure to afford
the crude product which was purified by chromatography to provide
mL) and cyclic ether 18 (78 mg, 0.212 mmol). The mixture was
heated to 115 °C (oil bath temperature) for 30 min. The solution
which resulted was cooled to rt, and the solvent was removed under
reduced pressure. The oil which resulted was washed with hexane
(6 × 5 mL). The residue was dissolved in anhydrous MeOH (2
mL), and a solution of 85% KOH (37 mg, 0.551 mmol) and iodine
(70 mg, 0.276 mmol) in anhydrous MeOH (2 mL) were successively
added at 0 °C. After 1 h, the reaction mixture was diluted with
CH2Cl2 (80 mL), washed with a 10% aqueous solution of NaHSO3
(20 mL), water (20 mL), and brine (20 mL), and dried (Na2SO4).
The solvent was removed under reduced pressure, and the residue
which resulted was purified by flash chromatography on silica gel
(CH2Cl2/MeOH: 20/1) to provide methyl ester 20 (71 mg, 85%):
(+)-12-methoxyaffinisine 14 (48 mg, 95%): [R]25 ) 3.3 (c )
D
0.70, CHCl3) {lit.21 [R]D ) 3.0 (c ) 0.72, CHCl3)}; FTIR 3351,
2912, 1571 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.64 (d, 3H, J )
6.8 Hz), 1.71-1.90 (m, 3H), 2.08 (m, 1H), 2.61 (d, 1H, J ) 15.3
Hz), 2.81 (m, 2H), 3.05 (dd, 1H, J ) 15.3, 5.2 Hz), 3.46-3.54 (m,
2H), 3.54-3.64 (m, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.19 (dd, 1H,
J ) 10.0, 2.2 Hz), 5.41 (q, 1H, J ) 6.8 Hz), 6.62 (d, 1H, J ) 7.5
Hz), 6.97 (t, 1H, J ) 7.7 Hz), 7.05 (d, 1H, J ) 7.8 Hz); 13C NMR
(75.7 MHz, CDCl3) δ 12.7, 27.0, 27.4, 32.3, 32.7, 44.1, 49.4, 54.2,
55.3, 56.2, 64.9, 102.3, 103.8, 111.0, 116.7, 119.1, 126.5, 129.3,
135.7, 139.5, 147.5. EIMS m/e 338 (M+, 100), 337 (88), 307 (44),
213 (91.3), 212 (100), 198 (29.3), 197 (85). The spectral data for
14 were identical to those reported for 14 in the literature.21
(-)-Fuchsiaefoline (16). Ester 15 (35 mg, 0.09 mmol) was
dissolved in THF (4 mL) and cooled to 0 °C. The MeI (65 mg,
0.46 mmol) was added to the above solution dropwise. The reaction
mixture was stirred at 0 °C for 8 h. The solvent was removed under
reduced pressure, and the residue was purified by chromatography
over silica gel (CH2Cl2/MeOH 10/1) to provide the iodomethylated
salt. This salt was then dissolved in EtOH (3 mL), followed by the
addition of AgCl (41 mg). The mixture which resulted was stirred
at rt for 2 days. The excess AgCl and AgI which formed were
removed by filtration and washed with EtOH (10 mL). After
removal of the solvent under reduced pressure, the residue was
purified by flash chromatography over silica gel (CH2Cl2/MeOH
10/1) to afford fuchsiaefoline (32 mg, 81%): [R]25D ) -56.0 (c )
0.38, MeOH) {lit.9 [R]D ) -55.7 (c ) 0.90, MeOH)}; FTIR 3420,
1
FTIR 2945, 1730, 1571, 1458, 1256, 1114, 1017 cm-1; H NMR
(300 MHz, CDCl3) δ 1.61 (d, 3H, J ) 6.8 Hz), 1.98-2.12 (m,
2H), 3.29 (t, 1H, J ) 5.6 Hz), 3.69-3.75 (m, 3H), 3.72 (s, 3H),
3.92-3.95 (m, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.50 (d, 1H, J )
7.7 Hz), 5.36 (q, 1H, J ) 6.8 Hz), 5.75 (d, 1H, J ) 7.7 Hz), 6.65
(d, 1H, J ) 7.8 Hz), 7.03 (t, 1H, J ) 7.8 Hz), 7.28 (d, 1H, J ) 7.9
Hz); 13C NMR (75.7 MHz, CDCl3) δ 12.6, 28.8, 30.7, 32.2, 46.6,
52.1, 53.6, 55.2, 55.3, 61.1, 68.1, 72.4, 102.9, 103.3, 106.9, 111.7,
116.5, 120.2, 126.6, 128.2, 135.2, 143.4, 147.5; EIMS m/e 394
(M+). Anal. Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10.
Found: C, 70.33; H, 6.49; N, 7.32.
12-Methoxyvoachalotine (21). The TFA (0.4 mL) and Et3SiH
(0.6 mL) were added to a solution of 20 (20 mg, 0.051 mmol) in
CH2Cl2 (2 mL). The reaction mixture which resulted was stirred
in a sealed vessel at rt for 1 d, after which the solution was
concentrated under reduced pressure. The residue was dissolved
in CH2Cl2 (80 mL), and a solution of 10% aq NH4OH was added
to bring the pH to 8. The organic layer was separated, washed with
brine (2 × 20 mL), dried (Na2SO4), and evaporated under reduced
pressure. The residue that resulted was purified by preparative TLC
on silica gel (CH2Cl2/MeOH: 15/1) to provide 21 (17 mg, 86%):
1
1
1730 cm-1; H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.1
FTIR 3337, 2948, 1731, 1572, 1456, 1257, 1117 cm-1; H NMR
Hz), 1.64 (d, 3H, J ) 6.8 Hz), 2.04 (dd, 1H, J ) 13.0, 4.3 Hz),
2.86-2.94 (m, 3H), 3.32 (dd, 1H, J ) 17.3, 5.0 Hz), 3.41 (s, 3H),
3.50 (bs, 1H), 3.92 (d, 1H, J ) 18.0 Hz), 3.95 (s, 3H), 4.05 (s,
3H), 4.11-4.28 (m, 3H), 5.52 (q, 1H, J ) 6.9 Hz), 5.72 (d, 1H, J
) 15.5 Hz), 6.69-6.72 (m, 2H), 7.02-7.09 (m, 2H); 13C NMR
(75.7 MHz, CDCl3) δ 12.7, 14.0, 24.4, 27.3, 30.4, 33.6, 47.0, 47.6,
55.5, 58.2, 62.0, 62.5, 65.0, 98.8, 103.8, 110.6, 120.8, 121.5, 125.6,
127.4, 127.6, 133.0, 148.0, 170.0. EIMS m/z (rel int) 394 ((M -
1)+, 3), 381 (25), 380 (100), 379 (60), 366 (5), 365 (14), 351 (21),
335 (9), 307 (34), 293 (12), 280 (4), 279 (6), 212 (55), 197 (18).
The spectral data for 16 were identical to those reported for 16 in
the literature.9
(300 MHz, CDCl3) δ 1.62 (d, 3H, J ) 6.8 Hz), 1.82 (dt, 1H, J )
13.2, 3.4 Hz), 1.99 (bs, 1H), 2.00 (td, 1H, J ) 11.8, 2.2 Hz), 2.92
(d, 1H, J ) 16.5 Hz), 3.12 (dd, 1H, J ) 16.5, 6.4 Hz), 3.24 (t, 1H,
J ) 3.0 Hz), 3.60 (d, 1H, J ) 11.3 Hz), 3.68-3.72 (m, 3H), 3.75
(s, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 4.16 (dd, 1H, J ) 10.4, 3.4 Hz),
4.30 (d, 1H, J ) 6.1 Hz), 5.32 (q, 1H, J ) 6.8 Hz), 6.63 (d, 1H,
J ) 7.6 Hz), 6.98 (t, 1H, J ) 7.8 Hz), 7.08 (d, 1H, J ) 7.8 Hz);
13C NMR (75.7 MHz, CDCl3) δ 12.7, 22.3, 28.1, 30.2, 32.2, 47.8,
52.1, 53.2, 53.6, 55.3, 55.8, 63.0, 102.5, 105.1, 111.3, 116.2, 119.2,
126.5, 128.0, 135.8, 138.2, 147.4, 176.2; EIMS m/e 396 (M+). This
material was employed directly in the next step.
12-Methoxy-Nb-methylvoachalotine (22). The synthesis of 22
from 21 was carried out analogous to the preparation of fuchsiae-
Ether (18). The DDQ (231 mg, 1.016 mmol) was added to a
solution of diol 17 (187 mg, 0.508 mmol) in THF (10 mL). The
black mixture which resulted was heated to reflux for 2 h. The
mixture was then diluted with CH2Cl2 (80 mL), washed with a
saturated solution of aq NaHSO3 (10 mL) and brine (2 × 10 mL),
and dried (K2CO3). The solvent was removed under reduced
pressure, and the residue which resulted was chromatographed
(silica gel, CH2Cl2/MeOH 10/1) to provide the cyclic ether 18 (167
foline 16 from 15 in 93% yield: [R]25 ) -102.7 (c ) 0.22,
D
MeOH) {lit.9 [R]D ) -106.2 (c ) 1, MeOH)}; FTIR 3330, 1733
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.62 (d, 3H, J ) 6.8 Hz),
1.77 (dt, 1H, J ) 12.9, 3.3 Hz), 2.64 (bt, 1H, J ) 12.3 Hz), 3.11-
3.19 (m, 2H), 3.31 (s, 3H), 3.63 (d, 1H, J ) 10.7 Hz), 3.70 (d, 1H,
J ) 10.1 Hz), 3.72 (s, 1H), 3.77-3.93 (m, 1H), 3.80 (s, 3H), 3.96
(s, 3H), 4.01 (s, 3H), 4.75 (d, 1H, J ) 6.2 Hz), 5.43 (q, 1H, J )
6.8 Hz), 5.53 (d, 1H, J ) 16.0 Hz), 6.53 (d, 1H, J ) 9.9 Hz),
6.69-6.72 (m, 1H), 7.05-7.06 (m, 2H); 13C NMR (75.7 MHz,
CDCl3) δ 12.4, 19.3, 27.9, 29.6, 33.2, 49.1, 53.1, 55.2, 55.5, 56.8,
62.9, 63.8, 64.4, 100.7, 103.8, 111.1, 120.0, 120.7, 126.2, 126.5,
127.5, 132.7, 148.0, 172.8; EIMS m/e 410 ((M - 1)+). The spectra
data for 22 were in agreement with the literature values.9
1
mg, 90%): FTIR 3380, 2920, 1571, 1457, 1256, 1007 cm-1; H
NMR (300 MHz, CDCl3) δ 1.68 (dt, 3H, J ) 6.8, 3.0 Hz), 1.95
(dd, 2H, J ) 8.7, 3.0 Hz), 2.24 (bs, 1H), 2.98 (t, 1H, J ) 2.9 Hz),
3.14 (d, 1H, J ) 7.5 Hz), 3.47-3.60 (m, 4H), 3.71 (d, 1H, J ) 9.5
Hz), 3.75 (dt, 1H, J ) 17.0, 1.9 Hz), 3.92 (s, 3H), 3.94 (s, 3H),
4.06 (dd, 1H, J ) 8.6, 5.1 Hz), 5.44 (q, 1H, J ) 6.8 hz), 5.64 (d,
1H, J ) 7.5 Hz), 6.65 (d, 1H, J ) 7.7 Hz), 7.03 (t, 1H, J ) 7.8
Hz), 7.28 (d, 1H, J ) 7.7 Hz); 13C NMR (75.7 MHz, CDCl3) δ
12.8, 28.7, 29.0, 32.2, 45.9, 47.3, 55.3, 55.4, 62.9, 66.7, 68.2, 72.1,
102.8, 103.5, 111.6, 116.1, 120.1, 126.6, 128.2, 136.5, 143.3, 147.5.
EIMS m/e 366 (M+). Anal. Calcd for C22H26N2O3: C, 72.11; H,
7.15; N, 7.64. Found: C, 72.43; H, 7.05; N, 7.40.
Voachalotine (24). The synthesis of voachalotine 24 from
dehydrovoachalotine 23 was carried out analogous to the preparation
of 21 from 20 in 88% yield: [R]25D ) -2.6 (c ) 0.8, CHCl3) [lit.11
1
-2.8 (c ) 6, CHCl3)]; FTIR 3370, 2921, 1732 cm-1; H NMR
(300 MHz, CDCl3) δ 1.63 (d, 3H, J ) 6.8 Hz), 1.81 (dt, 1H, J )
13.1, 3.5 Hz), 2.00 (ddd, 1H, J ) 13.0, 10.4, 2.4 Hz), 2.96 (d, 1H,
J ) 16.3 Hz), 3.14 (dd, 1H, J ) 16.4, 6.3 Hz), 3.24 (t, 1H, J ) 2.8
Hz), 3.57-3.72 (m, 4H), 3.63 (s, 3H), 3.75 (s, 3H), 4.18 (dd, 1H,
Methyl Ester (20). The benzeneseleninic anhydride (70%, 54
mg, 0.106 mmol) was added to a solution of dry chlorobenzene (5
258 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids
J ) 10.3, 3.3 Hz), 4.30 (d, 1H, J ) 6.2 Hz), 5.32 (q, 1H, J ) 6.8
Hz), 7.11 (t, 1H, J ) 7.4 Hz), 7.21 (t, 1H, J ) 7.5 Hz), 7.30 (d,
1H, J ) 7.8 Hz), 7.50 (d, 1H, J ) 7.7 Hz); 13C NMR (75.7 MHz,
CDCl3) δ 12.7, 22.3, 28.2, 29.1, 30.2, 47.8, 52.1, 53.2, 53.5, 55.8,
63.0, 104.9, 108.7, 116.0, 118.3, 118.8, 121.0, 126.0, 136.2, 137.2,
138.3, 176.3; EIMS m/e 366 (M+). The spectra data of 24 were in
excellent agreement with the literature values.9,70
Acknowledgment. We thank the NIMH (in part) and the
graduate school (UWM) for support of this work.
Supporting Information Available: Experimental details and
full characterization for compounds 9-13, 15, and 17 and 1H and
13C NMR spectra of compounds 6, 12, 15, 17, and 21. This material
is available free of charge via the Internet at http://pubs.acs.org.
(70) Jokela, R.; Lounasmaa, M. Heterocycles 1996, 43, 1015.
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