The enantiospecific, stereospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-majvinine, (+)-10-methoxyaffinisine, and (+)-Na-methylsarpagine, as well as the total synthesis of the Alstonia bisindole alkaloid macralstonidine

Article abstract of DOI:10.1021/jo030055u

The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-N_a-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been accomplished. This approach employed the Schoellkopf chiral auxiliary for the stereospecific construction of the desired D-(+)-tryptophan unit required for the asymmetric Pictet-Spengler reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd⁰ coupling process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline (2) and N_a-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other alkaloids for it is stereospecific and either enantiomer can be prepared with ease.

Full text of DOI:10.1021/jo030055u

Th e En a n tiosp ecific, Ster eosp ecific Tota l Syn th esis of th e Rin g-A
Oxygen a ted Sa r p a gin e In d ole Alk a loid s (+)-Ma jvin in e,
(+)-10-Meth oxya ffin isin e, a n d (+)-Na -Meth ylsa r p a gin e, a s Well a s
th e Tota l Syn th esis of th e Alston ia Bisin d ole Alk a loid
Ma cr a lston id in e
Shuo Zhao,† Xuebin Liao,† Tao Wang,† J udith Flippen-Anderson,‡,§ and J ames M. Cook*,†
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, and
Laboratory for the Structure of Matter, Code 6030, Naval Research Laboratory,
4555 Overlook Avenue, SW, Washington, D.C. 20375
capncook@uwm.edu
Received February 14, 2003
The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole
alkaloids (+)-Na-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well
as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been
accomplished. This approach employed the Scho¨llkopf chiral auxiliary for the stereospecific
construction of the desired D-(+)-tryptophan unit required for the asymmetric Pictet-Spengler
reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd0 coupling
process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline
(2) and Na-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach
to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other
alkaloids for it is stereospecific and either enantiomer can be prepared with ease.
In tr od u ction
The sarpagine1 alkaloids (Figure 1) are the largest
class of natural products related to the macroline bases
and both series originate from common biogenetic inter-
mediates. Macroline2 has not been isolated as a natural
product but is believed to be a biomimetic precursor to
many Alstonia alkaloids. During the last several decades
more than 100 macroline/sarpagine related indole alka-
loids have been isolated from Alstonia macrophylla Wall,
Alstonia muelleriana Domin, Alstonia angustifolia, and
other Alstonia species.3,4 Among these alkaloids, at least
21 are bisindoles, including macrocarpamine 3a , villal-
stonine 4a , and macralstonine 5a (Figure 2). Interest in
the macroline/sarpagine alkaloids isolated from Alstonia
species originated as a result of folk tales which described
the medicinal properties of these plants.5,6 For example,
F IGURE 1. The numbering system of the sarpagine skeleton.
the base macralstonine 5a , isolated from Alstonia mac-
rophylla Wall,7,8 was reported to exhibit potent hypoten-
sive activity by Elderfield9 and Manalo7 many years ago.
With respect to the macroline/sarpagine alkaloids,
more recently, Wright et al.10 reported on the antiproto-
zoal activity of nine alkaloids from Alstonia angustifolia
against Entamoeba histolytica and Plasmodium falci-
parum in vitro. Of the nine alkaloids tested, macrocar-
pamine 3a , villalstonine 4a , and macralstonine O-acetate
5b (Figure 2) were found to possess significant activity
against both protozoa. Macrocarpamine 3a was found to
be the most active antiamoebic compound against Enta-
moeba histolytica ofthe series [ED50(95%C.I.))8.12(7.76-
* To whom correspondence should be addressed. Phone: 414-229-
5856. Fax: 414-229-5530.
† University of Wisconsin-Milwaukee.
‡ Naval Research Laboratory.
§ Present address: RCSB, Rutgers University, Piscataway, New
J ersey 08854-8087.
(1) Ingham, J . L.; Koskinen, A.; Lounasmaa, M. Progress in the
Chemistry of Organic Natural Products; Springer-Verlag: New York,
1983; p 268.
(2) Garnick, R. L.; LeQuesne, P. W. J . Am. Chem. Soc. 1978, 100,
4213.
(3) Bi, Y.; Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline
Related Alkaloids. In Studies in Natural Products Chemistry: Bioactive
Natural Products; Basha, F. Z., Rahman, A., Eds.; Elsevier Science:
Amsterdam, The Netherlands, 1993; p 383.
(4) Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline Related
Sarpagine Alkaloids. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; p 23.
(5) Cook, J . M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
(6) Chatterjee, A.; Banerji, J .; Banerji, A. J . Indian Chem. Soc. 1949,
51, 156.
(7) Isidro, N.; Manalo, G. D. J . Philipp. Pharm. Assoc. 1967, 53, 8.
(8) Talapatra, S. K.; Adityachaudhury, N. Sci. Cult. 1958, 24, 243.
(9) Elderfield, R. C.; Gilman, R. E. Phytochemistry 1972, 11, 339.
(10) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J . D.; Said, J . M.;
Kirby, G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
10.1021/jo030055u CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/17/2003
J . Org. Chem. 2003, 68, 6279-6295
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Zhao et al.
SCHEME 1
Importantly, a number of active bisindole alkaloids from
Alstonia species belong to the macroline/sarpagine family.
The biomimetic interconversions of Alstonia alkaloids and
the coupling reactions of monomeric indoles into bisin-
doles were pioneered by LeQuesne et al.2,15-17
The biomimetic synthesis of Alstonia alkaloids usually
involves the addition of a monomeric alkaloid to C-21 of
the R,â-unsaturated enone moiety of (+)-macroline.18 The
total synthesis of (+)-macroline 2 has been completed and
coupled with natural pleiocarpamine, consequently a
partial synthesis of villalstonine 4a has been achieved.19
In addition, the synthesis of geissoschizine20 coupled with
its previous conversion into epipleiocarpamine21/pleio-
carpamine22 by Sakai constituted a formal total synthesis
of pleiocarpamine 6 and villastonine 4a .22
A number of ring-A parent(H) macroline/sarpagine
indole alkaloids have been previously synthesized includ-
ing macroline,23-26 in which a ring-A unsubstituted
tetracyclic azabicyclo[3.3.1]nonane 7 (Scheme 2) was
employed as a common template. Since the total synthe-
sis of (+)-macroline 2 has been completed, the synthesis
of the ring-A oxygenated alkaloid Na-methylsarpagine 8
would result in the total synthesis of the bisindole
alkaloid macralstonidine 9. The total synthesis of these
bisindoles in optically active form, therefore, requires the
enantiospecific preparation of the monomeric indole
alkaloid Na-methylsarpagine 8. As illustrated in Scheme
F IGURE 2. Biological activity of macrocarpamine 3a , villal-
stonine 4a , and macralstonine 5a .
8.48) µM] although it was only one-fourth as potent as
the standard drug emetine.10 Villalstonine 4a was found
to be the most potent alkaloid against Plasmodium
falciparum [ED50(95% C.I.) ) 2.92(1.11-3.14) µM] of the
alkaloids tested. The results of these in vitro studies
provide some basis for the traditional use of the plant
extract from Alstonia angustifolia for the treatment of
amoebic dysentery and malaria by the people of the
Malay peninsula.10 In addition, the studies by Wright et
al. coupled with the ethanopharmacological reports in-
dicated these bisindoles are orally active.10 It has also
been reported that the monomeric alkaloids exhibited
very little antiprotozoal activity.10 This suggests that at
least part of both of the ring systems present in the
dimeric alkaloids are essential for potent activity. The
structural studies via molecular modeling of the standard
antiamoebic drug emetine and the base usambarensine
also support this suggestion.11 The cytotoxic activity of
villalstonine 4a against KB cells was also evaluated and
found to be similar to its antiamoebic activity.10 However,
the standard antiamoebic drug emetine is highly toxic
to KB cells but is three times less toxic to amoebae than
to KB cells. Therefore, villalstonine 4a appears to have
a more favorable antiamoebic/cytotoxic ratio as compared
to emetine.10,11
(13) Newman, A. H.; Ostrowski, N.; Channing, M. A.; Rice, K. C.
Abs. Soc. Neurosci. 1989, 15, 703.
(14) Kawai, R.; Sawada, Y.; Channing, M.; Newman, A. H.; Dunn,
B.; Rice, K. C.; Blasberg, R. G. J . Pharm. Exp. Ther. 1990, 255, 826.
(15) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J . M.
J . Chem. Soc., Chem. Commun. 1972, 1346.
(16) Garnick, R. L. Ph.D. Thesis, Northeastern University, 1977.
(17) Esmond, R. W.; LeQuesne, P. W. J . Am. Chem. Soc. 1980, 102,
7116.
(18) Burke, D. E.; Cook, G. A.; Cook, J . M.; Haller, K. G.; Lazar, H.
A.; LeQuesne, P. W. Phytochemistry 1973, 12, 1467.
(19) Bi, Y.; Cook, J . M. Tetrahedron Lett. 1993, 34, 4501.
(20) Yu, S.; Berner, O. M.; Cook, J . M. J . Am Chem. Soc. 2000, 122,
7827.
(21) Sakai, S.; Shinma, N. Heterocycle 1976, 4, 985.
(22) Yu, S.; Cook, J . M. Department of Chemistry, University of
Wisconsin-Milwaukee, unpublished.
(23) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J . M. J . Am. Chem.
Soc. 1994, 116, 9027.
(24) Fu, X.; Cook, J . M. J . Am. Chem. Soc. 1992, 114, 6910.
(25) Fu, X.; Cook, J . M. J . Org. Chem. 1993, 58, 661.
(26) Zhang, L. H. Ph.D. Thesis, University of Wisconsin-Milwaukee,
1990.
Recent interest in synthetic chemistry in this series
has grown considerably in an enantiospecific sense to
permit comparison of the biological properties of the
unnatural alkaloids to those of the natural products.12-14
(11) Quetin-Leclercq, J .; Dupont, L.; Wright, C. W.; Phillipson, J .
D.; Warhurst, D. C.; Angenot, L. J . Pharm. Belg. 1991, 46, 82.
(12) Pert, C. B.; Danks, J . A.; Channing, M. A.; Eckelman, W. C.;
Larson, S. M.; Bennett, J . M., J r.; Burke, T. R.; Rice, K. C. FEBS Lett.
1984, 177, 281.
6280 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
SCHEME 2
SCHEME 3
1, macralstonidine 9 could be constructed from condensa-
tion of macroline 2 (northern unit) and Na-methyl-
sarpagine 8 (southern unit) via the biomimetic coupling
process of LeQuesne.2,16
substituted azabicyclo[3.3.1]nonanes required for the
total synthesis of ring-A substituted sarpagine alkaloids
(Scheme 2).34
The initial goal was to develop a general route to ring-A
oxygenated indole alkaloids. Consequently, an ideal
approach to these bases might rest on the multigram
synthesis of a common, optically active intermediate that
could be employed for the synthesis of many related
natural products. This common intermediate would, at
the very least, contain the requisite stereochemistry and
tetracyclic ring system which could be readily function-
alized for further elaboration. In 1988, an enantiospecific
synthesis of the (-)-Nb-benzyltetracyclic ketone 7a
(Scheme 2) was reported and extended to multihundred
gram scale.26,35-39 This intermediate has been employed
for the total synthesis of (-)-alstonerine,40 (-)-suaveo-
line,25 (+)-macroline,19,27,28 and anhydromacrosalhine-
methine41 as well as the ajmaline-related alkaloids (-)-
raumacline, (-)-Nb-methylraumacline,24,25 ajmaline, and
alkaloid G.42,43,44
With the recent completion of the enantiospecific
synthesis of (+)-macroline 2 as well as the improved route
to (+)-macroline 2 (from D-tryptophan)27 and the anti-
pode, (-)-macroline (from L-tryptophan),28 a broader
search for antiprotozoal activity can be initiated that may
lead to more selective antimalarial agents in the future.
The syntheses of ring-A oxygenated indole alkaloids are
rare in comparison to the synthesis of the unsubstituted
(parent) bases. This stems from the difficulty in incor-
poration of the oxygen functionality into ring-A during
the latter stages of the synthetic sequence.29 Therefore,
an enantiospecific, regiospecific synthetic route to such
alkaloids might require the installation of the oxygen
functionality early in the sequence. A synthetic route to
ring-A oxygenated tryptophans would provide material
that could be employed in the total synthesis of these
ring-A oxygenated alkaloids. The synthetic route should
also be capable of scale-up to provide large quantities of
intermediates which could be employed for other syn-
thetic routes as well as for biological screening.
The total synthesis of sarpagine indole alkaloids [from
D-(+)-tryptophan] via the trans 1,3-transfer of asymmetry
during the Pictet-Spengler reaction23,26,30,31 has prompted
the development of an enantiospecific route to ring-A
oxygenated D-(+)- or L-(-)-tryptophans and their deriva-
tives. For the approach to these indole-substituted amino
acids, the Scho¨llkopf auxiliary32 has been chosen since
this provided a route to either D-(+)- (from L-valine) or
L-(-)- (from D-valine) tryptophans on large scale.33 The
substituted indoles could then be converted into ring-A
To apply the same approach to the synthesis of ring-A
oxygenated indole alkaloids, a route to the ring-A oxy-
genated tetracyclic ketone 12 would be required that was
capable of scale-up to multigram levels. Retrosyntheti-
cally, the ring-A oxygenated tetracyclic ketone 10 (Scheme
3) could be envisaged to arise via a regiospecific Dieck-
mann condensation. This intermediate could originate
from trans diester 11, which would be available from the
asymmetric Pictet-Spengler reaction of an optically
active ring-A alkoxylated D-tryptophan analogue (Scheme
(34) Zhao, S.; Liao, X.; Cook, J . M. Org. Lett. 2002, 4, 687.
(35) Yoneda, N. Chem. Pharm. Bull. 1965, 13, 1231.
(36) Soerens, D.; Sandrin, J .; Ungemach, F.; Mokry, P.; Wu, G. S.;
Yamanaka, E.; Hutchins, L.; Dipierro, M.; Cook, J . M. J . Org. Chem.
1979, 44, 535.
(27) Liu, X.; Cook, J . M. 37th National Organic Symposium, 2001,
Bozeman, MT.
(28) Liu, X. Ph.D. Thesis, University of Wisconsin-Milwaukee, 2002.
(29) Hamaker, L. K. Ph.D. Thesis, University of Wisconsin-
Milwaukee, 1995.
(30) Czerwinski, K. M.; Deng, L.; Cook, J . M. Tetrahedron Lett. 1992,
33, 4721.
(31) Wang, T.; Cook, J . M. Org. Lett. 2000, 2, 2057.
(32) Scho¨llkopf, U.; Lonsky, R.; Lehr, P. Liebigs Ann. Chem. 1985,
413.
(33) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J .; Yu, S.; Cook, J .
M. J . Org. Chem. 2001, 66, 4525.
(37) Trudell, M. L. Ph.D. Thesis, University of Wisconsin-Milwau-
kee, 1989.
(38) Zhang, L. H.; Cook, J . M. Heterocycles 1988, 27, 1357.
(39) Zhang, L. H.; Cook, J . M. Heterocycles 1988, 27, 2795.
(40) Zhang, L. H.; Cook, J . M. J . Am. Chem. Soc. 1990, 112, 4088.
(41) Gan, T.; Cook, J . M. Tetrahedron Lett. 1996, 37, 5033.
(42) Li, J .; Cook, J . M. J . Org. Chem. 1998, 63, 4166.
(43) Li, J . Ph.D. Thesis, University of Wisconsin-Milwaukee, 1999.
(44) Soerens, D. Ph.D. Thesis, University of Wisconsin-Milwaukee,
1978.
J . Org. Chem, Vol. 68, No. 16, 2003 6281

Zhao et al.
SCHEME 4
ration required for koumidine in a 5:1 ratio. This is
opposite to the characteristic E-configuration required for
the C(19)-C(20) double bond in the sarpagine alkaloids.
Magnus50 reported the total synthesis of the antipode of
(-)-koumidine (from L-tryptophan); however, establish-
ment of the double bond (Z:E 1:1) was still not stereospe-
cific. Several other groups have encountered a similar
problem during the synthesis of the C(19)-C(20) double
bond in the related alkaloid geissoschizine; the ratio of
E to Z was very good but not reported as stereospecific.51-53
Recently, Martin’s total synthesis of geissoschizine with
stereoselective establishment of the double bond was
carried out by an elimination process.54 Rawal and Bosch
reported the total synthesis of Strychnos alkaloids with
stereocontrolled establishment of the double bond by a
Heck coupling reaction,55-57 and this novel method has
been applied toward the enantiospecific total synthesis
of the Corynanthe indole alkaloids.20 However, no total
synthesis of members of the ring-A substituted sarpagine
series has appeared to date.
En an tiospecific Syn th esis of 5-Meth oxylated D(+)-
Tr yp top h a n s for In d ole Alk a loid Tota l Syn th esis.
A number of synthetic routes to substituted tryptophans
have been considered earlier (Scheme 5).58,59 However,
attempts to execute these in a practical sense met with
only limited success. The principal reason for the failure
of the second and fourth approaches, as represented in
Scheme 5, originated from the inability of the chiral
auxiliary to tolerate the harsh conditions of the Fischer-
indole cyclization.60 The third approach in Scheme 5
provided a poor yield of indole with low stereoselectivity.60
Consequently, the Scho¨llkopf chiral auxiliary61 was cho-
sen here for the preparation of the desired D-(+)-tryp-
tophan would be available from L-valine, while the
L-(-)-isomer would originate from D-valine. This chiral
auxiliary had been employed earlier for the preparation
of 1-benzenesulfonyl-6-methoxy-D-(-)-tryptophan ethyl
ester.61 The success of this sequence rested on the ability
to scale-up the first few steps to multihundred gram
levels.
3). This approach would also require the base-catalyzed
epimerization at C(5) in trans diester 11 followed by ring
closure of the cis-fused system to provide the tetracyclic
ketone 10. Precedent for this originates from the previous
work of Soerens, Zhang, and Trudell.36,44-48
This ketone 10 could be employed to prepare the stable
ring-A oxygenated sarpagine indole alkaloid, (+)-majvi-
nine 14 (Scheme 4). It was felt the development of a
synthetic route to (+)-majvinine 14 would also lead to
the synthesis of a series of ring-A oxygenated sarpagine
indole alkaloids. Furthermore, (+)-majvinine 14, presum-
ably, could be converted into the ring-A oxygenated indole
alkaloid Na-methylsarpagine 8 (Scheme 4), a key mono-
meric unit of the bisindole alkaloid macralstonidine 9 (see
Scheme 1). This 10-hydroxysarpagine base was suscep-
tible to oxidation, consequently its isolation from plants
was problematic.
Th e J app-Klin gm an n /Fisch er -In dole P r ocess. The
well-known Fischer-indole cyclization,62 via a thermally
mediated [3,3]sigmatropic rearrangement, was chosen as
the means to generate (from p-anisidine 15) large quanti-
ties of 5-methoxy-3-methylindole 17 (Scheme 6). The
synthesis of 5-methoxy-D-tryptophan via this route could
Common structural features of the sarpagine indole
alkaloids include the E-ethylidene double bond at C(19)-
C(20) and the asymmetric centers at C-3(S), C-5(R), C-15-
(R), and C-16(R) (see Figure 1 for the numbering system
of the sarpagine skeleton). These stereocenters provided
much of the interest in the design of a general approach
to these alkaloids. Sakai49 earlier reported the partial
synthesis of (-)-koumidine, which contained a similar
skeleton to that of the sarpagine series; however, the
double bond in (-)-koumidine was present in the Z-
configuration and the chirality at C(16) was S rather than
R. Establishment of the stereochemistry of the C(19)-
C(20) double bond in (-)-koumidine by Sakai via an
elimination process yielded the more stable Z-configu-
(50) Magnus, P.; Mugrage, B.; Deluca, M. R.; Cain, G. A. J . Am.
Chem. Soc. 1990, 112, 5220.
(51) Hachmeister, B.; Thielke, D.; Winterfeldt, E. Chem. Ber. 1976,
109, 3825.
(52) Bohlmann, C.; Bohlmann, R.; Rivera, E. G.; Vogel, C.;
Manandhar, M. D.; Winterfeldt, E. Liebigs Ann. Chem. 1985, 1752.
(53) Overman, L. E.; Robichaud, A. J . J . Am. Chem. Soc. 1989, 111,
300.
(54) Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79.
(55) Rawal, V. H.; Michoud, C.; Monested, R. J . Am. Chem. Soc.
1993, 115, 3030.
(56) Bonjoch, J .; Sole, D.; Bosch, J . J . Am. Chem. Soc. 1995, 117,
11017.
(57) Bonjoch, J .; Sole, D.; Garcia-Rubio, S.; Bosch, J . J . Am. Chem.
Soc. 1997, 119, 7230.
(58) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon Press: Oxford, UK, 1989; Vol. 7.
(45) Trudell, M. L.; Soerens, D.; Weber, R. W.; Hutchins, L.;
Grubisha, D.; Bennett, D.; Cook, J . M. Tetrahedron 1992, 48, 1805.
(46) 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.
(47) Zhang, L. H.; Trudell, M. L.; Hollinshead, S. P.; Cook, J . M. J .
Am. Chem. Soc. 1989, 111, 8263.
(48) Zhang, L. H.; Gupta, A. G.; Cook, J . M. J . Org. Chem. 1989,
54, 4708.
(49) Kitajima, M.; Takayama, H.; Sakai, S. J . Chem. Soc., Perkin
Trans. 1 1991, 1773.
(59) Barrett, G. C. Chemistry and Biochemsitry of the Amino Acids;
Chapman and Hall: London, UK, 1985.
(60) Liu, R. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1996.
(61) Scho¨llkopf, U. Pure Appl. Chem. 1983, 55, 1799.
(62) Robinson, B. The Fischer Indole Synthesis; J ohn Wiley &
Sons: New York, 1982.
6282 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
SCHEME 5
SCHEME 6
SCHEME 7
the regiospecific bromination in high yield, protection/
deactivation of the indole N(H) group was required. This
was accomplished by stirring 16 with either BOC anhy-
dride or benzenesulfonyl chloride. A detailed study of the
electrophilic vs free radical bromination of various 3-me-
thylindoles follows here.
also be employed for the L(-)-isomer from the antipode
of the Scho¨llkopf auxiliary.60
Ethyl 5-methoxy-3-methylindole-2-carboxylate 16 was
prepared on a large scale from p-anisidine 15 and ethyl
R-ethylacetoacetate by the Fischer-indole cyclization via
a J app-Klingemann azo-ester intermediate (Scheme 6).63
This process was developed by Abramovitch and Shapiro
as well as reviewed.32,64 Alkaline hydrolysis of ester 16
and subsequent copper/quinoline-mediated decarboxyla-
tion of the carboxylic acid that resulted furnished the
5-methoxy-3-methylindole 17 in excellent yield. Care
must be exercised on decarboxylation of the correspond-
ing acid on a large scale. The best yields were obtained
when the carboxylic acid was fully dried and the decar-
boxylation was executed at reflux in a well-stirred
minimum amount of distilled quinoline (1.5-2 equiv of
quinoline with respect to the carboxylic acid). Only a
catalytic amount of copper powder was required to ensure
yields of 16 in excess of 90% (Scheme 6). To carry out
R egiosp ecific Br om in a t ion of 3-Met h ylin d oles.
With the Na-protected 3-methylindoles 18a and 18b in
hand, the bromination of 3-methylindoles with NBS was
carried out under two sets of conditions (Scheme 7). In
the electrophilic bromination process, 3-methylindoles
were simply heated with NBS in refluxing carbon tetra-
chloride in the absence of the radical initiator (AIBN) to
provide 20a and 20b, respectively, in high yield. In the
radical bromination process, 3-methylindoles were heated
in refluxing CCl4 and then treated with NBS and AIBN
to provide 19a and 19b; in this process, NBS was
admixed with AIBN. This mixture was then added to the
refluxing solution of 3-methylindole in CCl4. After 5 min,
AIBN was added again, if necessary. The competition
between electrophilic and free radical bromination has
been studied65,66 in methyl-substituted anisoles on treat-
ment with NBS. The regiospecific bromination of 3-me-
(63) Health-Brown, B.; Philpott, P. G. J . Chem. Soc. 1965, 7185.
(64) Abramovitch, R. A.; Shapiro, D. S. J . Chem. Soc., Perkin Trans.1
1956, 4589.
J . Org. Chem, Vol. 68, No. 16, 2003 6283

Zhao et al.
SCHEME 8
SCHEME 9
E n a n t iosp ecific Syn t h esis of 5-Met h oxyt r yp t o-
p h a n s via th e Sch o1llk op f Ch ir a l Au xilia r y. The
approach to the preparation of the desired 5-methoxy-
lated D(+)-tryptophans for indole alkaloid synthesis was
based on the regiospecific bromination at C(3) of the N(1)
BOC-protected derivative of 3-methylindole 18a . Since
the BOC group can be removed under different condi-
tions, in comparison to the benzenesulfonyl group, this
extended the use of the Scho¨llkopf/Fischer-indole protocol
employed previously.68 In practice, 5-methoxy-3-meth-
ylindole 17 was protected with the BOC group at the N(1)
position to afford 1-tert-butyloxycarbonyl-3-methylindole
18a . With indole 18a in hand, the AIBN-initiated re-
giospecific bromination67 of 3-methyl-indole 18a at the
3-methyl group was accomplished by using NBS as the
brominating agent in cyclohexane or carbon tetrachloride
(Scheme 8). The 3-bromomethylindole 19a was very labile
and not stable to chromatographic purification and could
not be readily crystallized. In most cases it was dried and
used in the next step as crude material without further
purification (see the Experimental Section for details).
However, it was also converted into the 3-hydroxymeth-
ylindole (see the Experimental Section) for characteriza-
tion. The crude 3-bromoalkylindole 19a was treated with
the anion derived from the Scho¨llkopf chiral auxiliary 21
at -78 °C to afford a single diastereomer 22 (Scheme 8)
in 93% yield.
As illustrated in Scheme 8, the pyrazine chiral auxil-
iary was stable to strongly alkaline conditions, conse-
quently it served as an excellent protecting group for the
amino acid ester function. The pyrazine group (see
Scheme 9) could be removed under acidic conditions to
provide the BOC-protected 5-methoxy-D-tryptophan ethyl
ester 23 in high yield. In contrast, the BOC could be
removed initially (xylenes, reflux) to provide intermediate
24, which could be hydrolyzed to afford 5-methoxy-D-
tryptophan ethyl ester 25. Introduction of the methyl
group at N(1) was carried out by removal of the BOC
protecting group under thermal conditions and Na-
methylation in a one-pot process (Scheme 10) to provide
Na-methyl D-(+)-tryptophan ethyl ester 27. In this fashion
Na-H-5-methoxy- and Na-methyl- 5-methoxytryptophans
were available in optically active form for the total
synthesis of indole alkaloids.
thylindoles at either the C(3) alkyl group (radical bro-
mination) or the indole 2-position via electrophilic attack
also has been investigated and the details have been
reported.60,67
Although the presence of an electron-withdrawing
group at the N(1) position of 18a or 18b should deactivate
the C(2) position, the electrophilic bromination of indoles
18a and 18b occurred readily at C(2) when they were
stirred with NBS in the absence of a radical initiator
(Scheme 8). In the case of 18a and 18b, two contrasting
factors were involved in the electrophilic vs free radical
process. Even though indoles are reactive aromatic
systems, the presence of an electron-withdrawing group
at the N(1) position would be expected to deactivate them
to electrophilic attack at C(2). However, since the meth-
oxyl group has been employed to promote the electrophilic
bromination of methyl-substituted anisoles,65 it plays the
same role in the bromination of indoles 18a and 18b at
the C(2) position. Consequently, deactivation of the indole
2,3-double bond by the N(1) protecting group and activa-
tion by the methoxyl group at the C(5) position of indoles
18a and 18b are delicately balanced. A slight change in
reaction conditions in the bromination process promoted
the reaction in the direction of either the electrophilic or
free radical bromination process.
Examination of these results demonstrated that the
regiospecific bromination of 3-methyl-5-methoxyindoles
can be controlled by judicious choice of the reaction
conditions and the choice of the protecting group at the
N(1) position. In the presence of an activating group such
as a methoxyl moiety, the protection of indoles at the N(1)
position should be accomplished before the bromination
is carried out. The 3-methylindoles protected in this
fashion (e.g. 18a and 18b) should lead to either 3-bro-
momethylindoles or 2-bromo-3-methylindoles based on
the choice of the reaction conditions (free radical vs
electrophilic). In the absence of ring-A oxygenated acti-
vating groups, free radical bromination at the 3-methyl
group should be facilitated by the electron-withdrawing
group at the N(1) position of the 3-methylindole. On the
other hand, to brominate 3-methylindoles at the C(2)
position even when they lack the ring-A activating
substituent, the bromination should proceed before the
protection sequence is executed.
As illustrated in Scheme 11, hydrolysis of the tryp-
tophan ethyl ester 29 provided 5-methoxy-D-(+)-tryp-
(65) Gruter, G. M.; Akkerman, O. S.; Bickelhaupt, F. J . Org. Chem.
1994, 59, 4473 and references therein.
(66) Goldberg, Y.; Bensimon, C.; Alper, H. J . Org. Chem. 1992, 57,
6374.
(67) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 3103.
(68) Allen, M. S.; Hamaker, L. K.; La Loggia, A. J .; Cook, J . M.
Synth. Commun. 1992, 22, 2077.
6284 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
SCHEME 10
[3-(trifluoro-methylhydroxymethylene)-(+)-camphorate]-
europium(III)} employed in the work of Zhang on the
parent tetracyclic ketone 7a .26 Racemic material of 31
was obtained from the intended racemization of the
benzylation process by warming the imine formation/
reduction step to room temperature. This process pro-
vided a racemic sample of 31 as a control for the chiral
shift experiment. The enantiomeric purity of 31 proved
to be greater than 98% with use of this NMR technique.
The benzylation of the Nb-nitrogen function could be
carried out without racemization if care was taken to
keep the imine intermediate cold during the reduction
and to limit the reaction time (3 h). At the very beginning,
tryptophan 27 was treated with benzaldehyde at room
temperature and the tetrahydro-â-carbolines 35a ,b were
also obtained. Activation of the indole ring was affected
by the 5-methoxyl group and the Pictet-Spengler cy-
clization of the intermediate Nb-benzylidene imine 34
took place at 25 °C (Scheme 13).73 This problem was
overcome by lowering the reaction temperature to 0 °C.
Under these conditions, only Nb-benzyl derivative 31 was
observed after sodium borohydride reduction and in
excellent yield.
SCHEME 11
If the Pictet-Spengler cyclization was carried out in
CH2Cl2/TFA, decomposition of the 5-methoxyindole 31
took place, which resulted in a low yield of trans diester
33 (<40%). However, since it was known that the trans
diester 33 was the thermodynamically more stable
isomer, advantage could be taken of the carbocation-
mediated isomerization of the cis isomer into the desired
trans isomer 33.38,39,74 The Pictet-Spengler reaction was
carried out under modified conditions. Nb-Benzyltryp-
tophan 31 was stirred with aldehyde 32 in acetic acid
and CH2Cl2, which provided a mixture of both diastere-
omers. TFA was then added to epimerize at C(1) all of
the cis isomer into the desired trans diester 33. The
stereochemistry of the trans diester 33 was later con-
firmed by single-crystal X-ray analysis (Figure 3).75
Syn th esis of Rin g-A Oxygen a ted Tetr a cyclic Ke-
ton es a n d Th eir Ap p lica tion to th e Tota l Syn th esis
of Rin g-A Oxygen a ted In d ole Alk a loid s. When trans
diester 33 was treated with at least 2 equiv of sodium
hydride in the presence of excess methanol (Scheme 13),
a regiospecific Dieckmann cyclization occurred as devel-
oped by Zhang.39 The first equivalent of sodium hydride
epimerized the stereocenter at position C(3) of 33 and
the second equivalent was employed in the Dieckmann
condensation. The base-mediated epimerization occurred
only at C(3) in agreement with previous results.23 The
best results for this process were realized when 3 equiv
of NaH and 3.5 equiv of CH3OH were employed in
refluxing toluene. Hydrolysis of the â-ketoester 36 and
decarboxylation under basic conditions were then achieved
in one step to provide the ring-A oxygenated tetracyclic
ketone 37 (Scheme 13). Furthermore, Na-H tetracyclic
ketone 44 was also prepared via this approach as the
template for the synthesis of ring-A oxygenated Na-H
indole alkaloids including sarpagine 1.
tophan 30. The optical rotation of 30 in acetic acid was
in good agreement with the reported value.69 The race-
mization of the chiral center of the amino acid 30 was
not observed under the conditions of hydrolysis (8 h).
Treatment of 29 under the same conditions of hydrolysis
for an additional 72 h returned the same amino acid 30
with the same optical rotation observed on hydrolysis of
29 for only 8 h. This provided an enantiospecific entry
into either 5-methoxy-D-(+)- or L-(-)-tryptophan and
their derivatives.70,71
Stu d ies of th e Asym m etr ic P ictet-Sp en gler Re-
a ction a n d Its Ap p lica tion to Rin g-A Oxygen a ted
D-(+)-Tr yptoph an System s. With 5-methoxylated D-(+)-
tryptophans 23, 25, and 27 in hand (Schemes 9 and 10),
the conversion of D-tryptophan 27 into the natural
alkaloids turned to the enantiospecific trans transfer of
chirality observed in the asymmetric Pictet-Spengler
reaction.40,72
As illustrated in Scheme 12, tryptophan 27 was treated
with benzaldehyde at 0 °C, followed by sodium boro-
hydride reduction (at -5 °C) to afford Nb-benzyl-Na-
methyltryptophan ethyl ester 31 (greater than 98% ee)
1
in 92% yield. The optical purity of 31 was verified by H
NMR spectroscopy with the chiral shift reagent {tris-
(73) Zhao, S. Ph.D. Thesis, University of Wisconsin-Milwaukee,
2001.
(69) Porter, J .; Dykert, J .; Rivier, J . Int. J . Peptide Protein Res. 1987,
30, 13.
(70) Blaikie, K. G.; Perkin, W. H. J . Chem. Soc. 1924, 296.
(71) Somie, M.; Fukiu, Y. Heterocycles 1993, 36, 1859.
(72) Zhang, L. H.; Cook, J . M. Heterocycles 1988, 27, 1607.
(74) Cox, E. D.; Hamaker, 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.
(75) Flippen-Anderson, J .; Deschamps, J . Laboratory for the Struc-
ture of Matter, Naval Research Laboratory, Washington, DC.
J . Org. Chem, Vol. 68, No. 16, 2003 6285

Zhao et al.
SCHEME 12
SCHEME 13
As illustrated in Scheme 14, Na-BOC-protected tryp-
tophan 23 was treated with benzaldehyde at room
temperature, followed by sodium borohydride reduction
(at -5 °C) to afford Na-BOC-protected Nb-benzyltryp-
tophan ethyl ester 38 in 94% yield. The Na-BOC-protected
tryptophan ethyl ester 38 was then stirred with methyl
3-formylpropionate 32 in the presence of p-TSA in
refluxing toluene. This process provided both the trans
and cis diastereomers in a ratio of 7:3 (trans:cis). The
structures of these isomers were assigned by 2D NMR
spectroscopy as well as by analogy to other systems of
known stereochemistry.38,39,74 Because of the presence of
the Na-BOC group, the cis isomer 39b cannot be con-
verted into the desired trans isomer 39a . Presumably,
electron withdrawal by the BOC group decreased the
stability of the carbocationic intermediate 40 (Scheme
15), consequently the C(1)-N(2) bond cleavage/isomer-
ization does not occur.
F IGURE 3. X-ray crystal structure (some of the atoms have
been removed for clarity) of trans diester 33 showing labeling
of the non-hydrogen atoms. Thermal ellipsoids are at the 20%
probability level, and hydrogen atoms are shown as small balls
of an arbitrary radius. It is clear the C3-C3A and N4-C14
bonds are axial while the C5-C5A bond is equatorial.
high yield. The Dieckmann condensation (10 equiv of
NaH, 10 equiv of CH3OH) with lactam 42 was then
carried out, followed by hydrolysis to provide the Na-H
tetracyclic ketone 44. This provided the required building
block for the synthesis of Na-H ring-A oxygenated (C-10)
indole alkaloids.
In summary, the tetracyclic ketones 37 and 44 in the
important ring-A oxygenated series were diastereospe-
cifically prepared via the asymmetric Pictet-Spengler/
Dieckmann protocol. In addition, this new process can
be carried out on multihundred gram scale because the
intermediate trans diester 33 and target tetracyclic
ketones 37 and 44 can be purified by crystallization.
Therefore, the tetracyclic ketones 37 and 44 can now be
used as key templates for the synthesis of optically pure
ring-A oxygenated sarpagine and macroline indole alka-
An alternate route to 44 was then explored (Scheme
16). The Na-BOC-substituted tryptophan ethyl ester 38
was stirred with acetal 41 in TFA and CHCl3 at reflux
to execute the Pictet-Spengler reaction. After the excess
TFA and the solvent were removed, the crude reaction
product was heated in toluene. This sequence provided
a route to the trans lactam 42, stereospecifically and in
6286 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
SCHEME 14
mp) for this base were identical with those reported for
the natural product.79 The overall yield of the two steps
was finally improved to 90% by a modified workup
procedure. The troublesome Ph3PdO was removed by
extracting the aqueous layer [14 was present as the
hydrochloride salt and still soluble in H2O (before neu-
tralization)] with Et2O after which basification/extraction
provided 14. A second sarpagine alkaloid, (+)-10-meth-
oxyaffinisine 49, was synthesized in enantiospecific
fashion by this route. The aldehyde 14 was reduced with
sodium borohydride to provide (+)-10-methoxyaffinisine
49 in over 90% yield (Scheme 18). The spectral data (1H
NMR, 13C NMR, IR, and MS) for (+)-10-methoxyaffinisine
49 were identical with those reported for the natural
product and the optical rotations ((2°) were within
experimental error {[R]26 +78 (c 0.2, CHCl3); lit.80 [R]D
D
loids. This route can also be employed for the synthesis
of ring-A oxygenated (C-10) L-tryptophan alkyl esters
permitting entry into both antipodes of the natural
products for biological screening.
+75 (c 0.62, CHCl3)}. The stereochemistry of (+)-majvi-
nine 14 was later confirmed by single-crystal X-ray
analysis (Figure 4).75
This represented the first total synthesis of ring-A
alkoxylated indole alkaloids in the sarpagine/macroline
series. It is noteworthy for it is both enantiospecific and
stereospecific. The stereocontrolled intramolecular pal-
ladium-mediated cross-coupling reaction provided the
first stereospecific solution to the problem of the stere-
ochemistry of the C(19)-C(20) E-ethylidene function in
the ring-A oxygenated sarpagine indole alkaloids. The
synthesis of 14 (from tryptophan ethyl ester 27) was
accomplished in 10 steps (8 reaction vessels) and in 28%
overall yield.
The alkaloid (+)-majvinine 14 was then employed for
the synthesis of (+)-Na-methylsarpagine 8. As illustrated
in Scheme 18, (+)-majvinine 14 was treated with 6 equiv
of dry BBr3 in CH2Cl2 at -78 °C for 1 h, after which the
solution was allowed to warm to room temperature and
stirring continued for 2 h. The reaction mixture was
degassed carefully before adding the BBr3 because the
phenol 50 would readily undergo air (O2) oxidation. After
the reaction was completed on analysis by TLC (silica
gel), cold, concentrated aq NH4OH was added to adjust
the pH to 8. The mixture was then admixed with silica
gel (see the Experimental Section) and directly passed
through a wash column to provide 50. This compound
was then treated (without further purification) with
sodium borohydride in ethanol. Reduction of aldehyde 50
by sodium borohydride in EtOH provided Na-methyl-
sarpagine 8 in 90% yield. The spectral data and optical
rotation for 8 were in excellent agreement with the
natural product.
Th e En a n tiosp ecific, Ster eosp ecific Tota l Syn -
th esis of (+)-Ma jvin in e (14) a n d (+)-10-Meth oxya ffi-
n isin e (49). As illustrated in Scheme 17, the Na-Me-Nb-
benzyltetracyclic ketone 37 was stirred with palladium
on carbon under 1 atm of hydrogen under acidic condi-
tions, during which the benzyl group was successfully
removed. The control of the acidity of the reaction
solution was critical. Tetracyclic ketone 37 was first
mixed with EtOH, after which a saturated solution of
HCl/EtOH was added dropwise until ketone 37 com-
pletely dissolved. The solvent was then removed under
reduced pressure. Dry EtOH was added into the flask to
dissolve the HCl salt of 37. This process eliminated the
excess HCl. If too much HCl(g) were present, 37 would
form a ketal on reaction with EtOH. Alkylation of the
Na-Me-Nb-H tetracyclic ketone 45 with Z-1-bromo-2-iodo-
2-butene 46 under basic conditions smoothly took place
to provide the Na-Me-Nb-Z-2′-iodo-2′-butenyl tetracyclic
ketone 47 in 80% yield. The Z-1-bromo-2-iodo-2-butene
46 had been synthesized in three steps by following the
procedure of Corey76 and Ensley.77 This bromide 46 had
been employed by several groups in the total syntheses
of geissoschizine and strychnine.20,55,56,78 The last step in
Scheme 17 was the key intramolecular cyclization cata-
lyzed by Pd0. This was the first time, in a stereospecific
manner, the E-ethylidene function has been incorporated
into any of the ring-A alkoxylated indoles in the sarpagine/
macroline series (81% yield).
With the key E-ethylidene intermediate 48 in hand,
the next step rested on the simple transformation of
ketone 48 to aldehyde 14 via addition of a Wittig reagent.
This could be followed by hydrolysis to afford the natural
product (+)-majvinine 14. When 48 was stirred with CH3-
OCH2PPh3Cl in the presence of t-BuO-K+, the enol ether
was formed. Since the C-17 aldehydo function in 14 was
known to be in the more stable position, this material
was directly hydrolyzed to provide the aldehyde 14 in
90% yield. Both transformations were carried out in the
same reaction vessel. The spectral data (1H NMR, IR, MS,
In agreement with the doubly convergent approach
to these bisindole alkaloids, the total synthesis of
(+)-macroline 2 (from D-tryptophan) or the antipode
[(-)-macroline (from L-tryptophan)] can be accomplished
now in 12.3% overall yield via the improved route of
Liu.27,28 The key features of this route will be presented
here.23,27,28,81 The ketone 51, available in 27% overall yield
from the asymmetric Pictet-Spengler reaction and eno-
late driven Pd0-mediated coupling process, was converted
into the desired aldehyde 52 via the Wittig/hydrolysis
process (illustrated in Scheme 19). This aldehyde 52 was
(76) Corey, E. J .; Kirst, H. A.; Katzenellenbogen, J . A. J . Am Chem.
Soc. 1970, 92, 6314.
(77) Ensley, H. E.; Buescher, R. R.; Lee, K. J . Org. Chem. 1982, 47,
404.
(78) Kuehne, M. E.; Wang, T.; Seraphin, D. J . Org. Chem. 1996,
61, 7873.
(79) Banerji, A.; Chakrabarty, M. Phytochemistry 1977, 16, 1124.
(80) Kam, T. S.; Iek, I. H.; Choo, Y. M. Phytochemistry 1999, 51,
839.
(81) Liu, X.; Deschamps, J . R.; Cook, J . M. Org. Lett. 2002, 4, 3339.
J . Org. Chem, Vol. 68, No. 16, 2003 6287

Zhao et al.
SCHEME 15
SCHEME 16
SCHEME 18
SCHEME 17
Since the enantiospecfic total synthesis of macroline 2
had been accomplished by Bi et al. and the enantiomer
completed by Liu,19,23,82 this work culminated in the total
synthesis of macralstonidine 9, the first Alstonia bisin-
dole to fall to total synthesis (see Scheme 1).
Con clu sion
The macroline/sarpagine related ring-A oxygenated
indole alkaloids, as well as the corresponding bisindoles,
exhibit important biological activity.10,83-86 Furthermore,
bisindoles are of special significance because they exhibit
more potent antimalarial activity than the monomeric
units which comprise them.10,87 The first enantiospecific
total synthesis of the Alstonia bisindole alkaloid macra-
reduced with sodium borohydride and the alcohol that
resulted was converted into a triisopropylsilyl ether 53
with imidazole serving as the base. The triisopropylsilyl
ether 53 was then subjected to the conditions of hydrobo-
ration (9 equiv of BH3‚THF, rt, 3 h; H2O2/OH- oxidation)
to provide 54 obtained as a mixture of the two Nb-borane
complexes. The alcohol that resulted was converted into
the methyl ketone by a Swern oxidation followed by
treatment with 1 equiv of HCl (1 N aq) to completely
cleave the Nb-borane moieties to provide ketone 55 as
the sole product (76% overall yield from 54). Methylation
of 55 with methyl iodide followed by removal of the silyl
group with TBAF furnished macroline 2 in excellent
yield.
(82) Bi, Y. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1994.
(83) Svoboda, G. H.; Blake, D. A. Catharanthus Alkaloids 1974, 45.
(84) Kingston, D. G.; Li, B. T.; Ionescu, F.; Mangino, M. M.; Sami,
S. M. J . Pharm. Sci. 1978, 67, 249.
(85) Harada, M.; Ozaki, Y. Chem. Pharm. Bull. 1976, 24, 211.
(86) Keawpradub, N.; Kirby, G. C.; Steele, J . C. P.; Houghton, P. J .
Planta Med. 1999, 65, 690.
(87) Farnsworth, N. R.; Blomster, R. N.; Buckley, J . P. J . Pharm.
Sci. 1967, 56, 23.
6288 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
F IGURE 4. X-ray crystal structure of (+)-majvinine 14 showing labeling of the non-hydrogen atoms. Thermal ellipsoids are at
the 20% probability level, and hydrogen atoms are shown as small balls of an arbitrary radius.
SCHEME 19
synthesis of (+)-majvinine 14 was completed (from
5-methoxytryptophan 27) in eight reaction vessels and
an overall yield of 27.5%. Many macroline/sarpagine
related ring-A oxygenated indole alkaloids have not fallen
to total synthesis to date due to the difficulty of incor-
porating an oxygen moiety regiospecifically into ring-A
in the latter stages of the synthetic route. Hence, the
synthetic route developed here can be employed for the
total synthesis of a number of macroline/sarpagine
related ring-A oxygenated indole alkaloids in both the
Na-Me and Na-H series, as well as bisindoles. The total
synthesis of the bisindole described here is doubly
convergent for both Na-methylsarpagine 8 and (+)-
macroline 2 were prepared via the same stereospecific
chemical processes including the asymmetric Pictet-
Spengler reaction and the enolate-driven Pd°-coupling
process.
Exp er im en ta l Section
Gen er a l Meth od . Reagent and solvent purification, workup
procedures, and analyses were in general performed as
described previously.33
Eth yl 5-Meth oxy-3-m eth ylin d ole-2-ca r boxyla te (16). To
a mixture of p-anisidine 15 (91 g, 0.74 mol), concentrated aq
HCl (185 mL), and water (350 mL) was added a solution of
NaNO2 [(53.6 g, 0.77 mol) in 100 mL of water] in a dropwise
manner at -5 °C. After addition, the mixture was stirred at 0
°C for 15 min and brought to pH 3-4 by addition of sodium
acetate (60 g, 0.74 mol). In a separate flask, a solution of ethyl
R-ethylacetoacetate (100 g, 0.64 mol) in ethanol (500 mL) at 0
°C was treated with an aq solution of KOH (0.64 mol in 50
mL of H2O), followed by addition of ice (1000 g). The diazonium
salt prepared above was immediately added to this alkaline
solution. The mixture was then adjusted to pH 5-6 and stirred
at 0 °C for 3 h. After the solution was kept for a further 12 h
at 4 °C, the mixture was extracted with ethyl acetate (4 ×
200 mL). The combined extracts were washed with brine and
dried (MgSO4). Most of the solvent was removed under reduced
pressure and the liquid residue was added dropwise to a
solution of 14.5% ethanolic HCl previously heated to 70 °C.
This reaction is exothermic! After addition, the mixture was
held at 78 °C for 2 h. The solvent was removed under reduced
pressure and the residue was treated with water (100 mL) and
CH2Cl2 (300 mL). The aq layer was extracted with CH2Cl2 (3
lstonidine 9 has been accomplished. Since only small
amounts of 9 have been isolated from plants, this alkaloid
has not been evaluated in regard to biological activity to
the authors’ knowledge. The route described above could
be employed to prepare 9 for screening as well as its
enantiomers. This work also culminated in the first
regiospecifc, enantiospecific, stereospecific total synthesis
of the ring-A oxygenated indole alkaloids (+)-majvinine
14, (+)-10-methoxyaffinisine 49, and (+)-Na-methyl-
sarpagine 8 in the sarpagine/macroline series. In this
approach the key template, Nb-benzyltetracyclic ketone
37, as well as 44, was synthesized in stereospecific
fashion by the asymmetric Pictet-Spengler reaction and
a stereocontrolled Dieckmann cyclization. An intramo-
lecular palladium (enolate-mediated) coupling reaction
was employed to introduce the C(19)-C(20) E-ethylidene
function in the ring-A oxygenated sarpagine alkaloids in
stereospecific fashion, as well as macroline 2. The total
J . Org. Chem, Vol. 68, No. 16, 2003 6289

Zhao et al.
× 100 mL) and the combined organic layers were washed with
brine and dried (Na2SO4). Purification on a short wash column
(silica gel, ethyl acetate/hexane, 1:3) gave 16 as a white solid
(110 g, 74%): mp 151.0-152.5 °C (lit.70 mp 151-152 °C); IR
(4 × 100 mL). The combined organic layers were washed with
brine and dried (MgSO4). The solvent was removed under
reduced pressure to afford 17 as a brown solid (43.7 g,
93.6%): mp 68-69 °C (lit.70 mp 66 °C); IR (KBr) 2930, 1609,
1
(KBr) 3331, 2929, 1668 cm-1
;
1H NMR (250 MHz, CDCl3) δ
1380, 1218, 820 cm-1; H NMR (250 MHz, CDCl3) δ 2.30 (s,
1.40 (t, 3H, J ) 7.2 Hz), 2.61 (s, 3H), 3.90 (5, 3H), 4.42 (q, 2H,
J ) 7.3 Hz), 7.01 (m, 2H), 7.30 (d, 1H, J ) 7.6 Hz). EIMS m/e
(rel intensity) 233 (M+, 37 0.8), 187 (100), 172 (20.7), 140 (10).
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found:
C, 66.84; H, 6.48; N, 6.02.
3H), 3.91 (s, 3H), 6.85 (dd, 1H, J ) 8.8,2.5 Hz), 6.95 (s, 1H),
7.01 (d, 1H, J ) 2.3 Hz), 7.25 (d, 1H, J ) 8.8 Hz), 7.80 (br, 1H,
D2O exchangeable). Anal. Calcd: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.70; H, 6.78; N, 8.72.
5-Meth oxy-3-m eth ylin d ole (17), La r ge Sca le. A mixture
of 16 (481 g, 2.06 mol), EtOH (1000 mL), KOH pellets (85%,
401 g, 7.16 mol), and water (670 mL) was heated to reflux for
1 h. The volume was reduced to 670 mL under reduced
pressure and brought to acidic pH with an aq solution of 3 N
HCl. The precipitate that resulted was collected on a filter,
washed with distilled water, and dried in a vacuum oven at
80 °C to afford 5-methoxy-3-methyl-indole-2-carboxylic acid as
a white solid (398 g, 1.93 mol). This acid was then heated to
Eth yl 5-Meth oxy-3-m eth ylin d ole-2-ca r boxyla te (16),
La r ge Sca le. A solution (1300 mL) of concentrated aq HCl
was diluted to 3000 mL. This solution was then used to
dissolve p-anisidine 15 (616 g, 5 mol). After the anisidine was
dissolved, the acidic solution was transferred into a 12-L,
three-neck flask, cooled in an ice-water bath, while sodium
nitrite (414 g, 6 mol) was dissolved in 1000 mL of H2O, then
cooled in an ice bath to ∼0 °C. This solution (sodium nitrite)
was then placed in an addition funnel, and added into the
acidic anisidine solution slowly at 0 °C with stirring (overhead
stir). After the addition, the solution was stirred for 3 h at 0
°C. The solution was brought to pH 3-4 by addition of sodium
acetate (328 g, 4 mol) in portions.
KOH (85% pellet, 365 g, 5.5 mol) was dissolved in 500 mL
of H2O, then cooled to 0 °C. In a 22-L, three-necked flask, ice
(5000 g) was added into EtOH (5000 mL), after which ethyl
R-ethylacetoacetate (869 g, 5.5 mol) was added to this ice cold
alcohol solution. The mixture was stirred with an overhead
stirrer, after which the above cold KOH solution was added
quickly. The mixture was stirred for 15 min, after which the
diazonium salt solution was poured in. The whole mixture was
kept at 0 °C with stirring overnight. The mixture was kept at
0 °C for another 10 h before CHCl3 was used to extract the
solution. The black organic layer was washed with H2O, and
then dried (Na2SO4). The solvent was removed under reduced
pressure.
A 3.3-L sample of 3 N HCl in EtOH was preheated to 65 °C
in a 5-L flask equipped with an overhead stirrer, reflux
condenser, and an addition funnel. The above black residue
was added at a rate rapid enough to keep the solution at reflux
due to the exotherm. [Ca u tion : At first, the reaction is slow,
consequently do not add too much hydrazone, otherwise this
will effect a very fast reaction and blow out the solution.] After
finishing the addition, turn on the heating mantle again to
keep the mixture at reflux for 30 min more. Cease heating at
this point and put the flask in the cold room (2-4 °C)
overnight. The solid that formed was filtered and washed with
H2O until pH 6-7. The filtrate was collected and the solvent
was removed under reduced pressure. The residue was treated
with H2O (500 mL) and CH2Cl2 (2000 mL). The aq layer was
extracted with CH2Cl2 (3 × 500 mL) and the combined organic
layers were washed with brine and dried (Na2SO4). After the
solvent was removed under reduced pressure, the solid residue
was combined with the above solid that had been filtered from
the reaction mixture. Purification by recrystallization provided
a white solid (864 g, 74%). The physical and spectral properties
of 16 were identical with those reported immediately above.
185 °C in
a well-stirred (mechanical stirrer) mixture of
quinoline (710 mL) and copper powder (17 g) under nitrogen
for 2.5 h (monitored by TLC). The copper powder was removed
by filtration, after which the filtrate was brought to pH 2-3
with an aq solution of 6 N HCl and the resulting solution was
extracted with diethyl ether (4 × 650 mL). The combined
organic layers were washed with brine and dried (MgSO4). The
solvent was removed under reduced pressure to afford 17 as
a brown solid (246 g, 74%). The physical and spectral proper-
ties of 17 were identical with those reported immediately
above.
1-ter t-Bu t yloxyca r b on yl-5-m et h oxy-3-m et h ylin d ole
(18a ). A solution of 5-methoxy-3-methylindole 17 (384 g, 2.39
mol) in acetonitrile (3000 mL) under nitrogen was stirred at
room temperature with di-tert-butyl dicarbonate (558 g, 2.49
mol) and DMAP (15 g, 0.12 mol). The resulting mixture was
stirred at room temperature for 12 h and the solvent was
removed under reduced pressure. The residue was dissolved
in ethyl acetate (3000 mL), washed with an aq solution of 1 N
HCl (2 × 900 mL) and brine (1500 mL), and dried (Na2SO4).
After removal of the solvent under reduced pressure, the
residue solidified to afford 18a as a white solid (595 g, 95%):
mp 58-60 °C; IR (KBr) 2974, 1721, 1452 cm-1; 1H NMR (250
MHz, CDCl3) δ 1.67 (s, 9H), 2.23 (s, 3H), 3.87 (s, 3H), 6.92
(dd, 1H, J ) 8.5, 2.6 Hz), 7.25 (s, IH), 7.33 (br, 1H), 7.98 (d,
1H, J ) 8.4 Hz); EIMS m/e (rel intensity) 261 (M+, 21.2), 205
(100.0), 161 (63.6), 146 (63.3). Anal. Calcd for Cl5H19NO3‚1/
4H2O: C, 67.92; H, 7.35; N, 5.28. Found: C, 68.12; H, 7.17; N,
5.26.
1-Ben zen esu lfon yl-5-m eth oxy-3-m eth ylin d ole (18b). A
solution of 17 (39 g, 0.24 mol) in dry THF (800 mL) was treated
at -78 °C with n-butyllithium (2.5 M in hexane, 107 mL, 0.266
mol) under nitrogen. The mixture was stirred at -78 °C for
20 min and then allowed to slowly warm to room temperature.
After 2 h, a clear solution was obtained, which was cooled to
-78 °C and treated with benzenesulfonyl chloride (36 mL, 0.28
mol). The reaction mixture was stirred at -78 °C for 30 min
and then at room temperature for 4 h. The solvent was
removed under reduced pressure to give a yellow solid that
was recrystallized from a mixture of ethyl acetate and hexane
to afford 18b as a yellow solid (68 g, 94%): mp 137-138 °C;
IR (KBr) 3100, 2924, 1609 cm-1; 1H NMR (250 MHz, CDCl3) δ
2.20 (s, 3H), 3.80 (s, 3H), 6.88 (d, 1H, J ) 2.3 Hz), 6.92 (dd,
1H, J ) 9.0, 2.4 Hz), 7.27 (s, 1H), 7.4 (t, 2H, J ) 7.2 Hz), 7.50
(d, 1H, J ) 7.2 Hz), 7.85 (m, 3H). Anal. Calcd for C16H15NSO3:
C, 63.77; H, 5.02; N, 4.65. Found: C, 63.54; H, 4.98; N, 4.32.
5-Meth oxy-3-m eth ylin d ole (17). A mixture of 16 (72 g,
0.3 mol), EtOH (150 mL), KOH pellets (85%, 60 g, 0.9 mol),
and water (100 mL) was heated to reflux for 1 h. The volume
was reduced to 100 mL under reduced pressure and brought
to acidic pH with an aq solution of 3 N HCl. The precipitate
that resulted was collected on a filter, washed with distilled
water, and dried in
a vacuum oven at 80 °C to afford
5-methoxy-3-methylindole-2-carboxylic acid as a white solid
(61.5 g, 100%): mp 202-203 °C (lit.70 mp 200-201 °C). This
acid (59.5 g, 0.29 mol) was then heated to reflux in a well-
stirred (mechanical stirrer) mixture of distilled quinoline (125
mL) and copper powder (2.5 g) under nitrogen for 2.5 h. The
copper powder was removed by filtration, after which the
filtrate was brought to pH 2-3 with an aq solution of 6 N HCl
and the solution that resulted was extracted with diethyl ether
1-ter t-Bu tyloxyca r bon yl-3-br om om eth yl-5-m eth oxyin -
d ole (19a ). To a boiling solution of 1-tert-butyloxycarbonyl-
5-methoxy-3-methylindole 18a (50 g, 0.192 mol) in CCl4 (4000
mL) was added a mixture of N-bromosuccinimide (38 g, 0.211
mol) and AIBN (500 mg) in one portion. After 2 min, another
portion of AIBN (350 mg) was added. The mixture was heated
to reflux for 40 min. The succinimide was removed by filtration
and washed with CCl4 (2 × 150 mL). The solvent was removed
6290 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
under reduced pressure to afford 3-bromo-methylindole 19a
as a brown oil (64 g, 87%): 1H NMR (250 MHz, CDCl3) δ 1.66
(s, 9H), 3.89 (s, 3H), 4.66 (s, 2H), 6.97 (dd, 1H, J ) 9.1, 2.6
Hz), 7.12 (d, 1H, J ) 2.5 Hz), 7.13 (s, 1H), 8.04 (d, 1H, J ) 8.9
Hz). EIMS m/e 341 (M+, 14), 339 (M+, 15), 283 (10), 238 (10),
204 (70), 160 (100), 144 (20). 3-Bromomethylindole 19a is very
labile and could not be purified by chromatography or distil-
lation. It was characterized by converting 3-bromomethylindole
19a into 3-hydroxymethylindole as follows. A solution of
3-bromomethylindole 19a (100 mg) in a mixture of THF (5 mL)
and water (5 mL) was treated with a saturated aq solution of
NaHCO3 (2 mL). The mixture was stirred for 30 min and
extracted with ethyl acetate (3 × 20 mL). The combined
organic layers were washed with brine and dried (Na2SO4).
After removal of solvent under reduced pressure, purification
of the residue by flash chromatography (silica gel, EtOAc)
afforded 1-tert-butyloxycarbonyl-3-hydroxymethyl-5-methoxy-
indole as white crystals: mp 145-146 °C; IR (KBr) 3138, 2931,
absence of AIBN, a mixture of 18b, N-bromosuccinimide, and
CCl4 was heated to reflux for 3 h and afforded exclusively
20b : mp 148-150 °C; IR (KBr) 3064, 2839, 1609 cm-1 1H
;
NMR (250, MHz, CDCl3) δ 2.15 (s, 3H), 3.85 (s, 3H), 6.80 (d,
1H, J ) 2.1 Hz), 6.95 (dd, 1H, J ) 8.6, 2.2 Hz), 7.40 (t, 2H, J
) 8.2 Hz), 7.50 (t, 1H, J ) 8.6 Hz), 7.81 (d, 2H, J ) 8.5 Hz),
8.17 (d, 1H, J ) 8.5 Hz); EIMS m/e 381 (M+, 30.6), 379 (M+,
26.4), 240 (74.0), 238 (71.9), 159 (100). Anal. Calcd for C16H14
-
BrNSO3‚1/2H2O: C, 49.37; H, 3.88; N, 3.60. Found: C, 49.20;
H, 3.52; N, 3.34.
(3R,6S)-3-(1-ter t-Bu tyloxycar bon yl-5-m eth oxy-3-in doyl)-
m eth yl-3,6-di-h ydr o-6-isopr opyl-2,5-dieth oxypyr azin e (22).
To a solution of (3S)-3,6-di-hydro-6-isopropyl-2,5-diethoxy-
pyrazine 21 (38.5 g, 0.182 mol) in dry THF (770 mL) under
nitrogen was added n-BuLi (2.5 M in THF, 50.8 mL, 0.127 mol)
dropwise at -78 °C. The resulting solution was stirred at -78
°C for 30 min and a solution of crude 3-bromomethylindole
19a (64 g, about 0.17 mol) in THF (490 mL) was slowly added.
The resulting mixture was stirred at -78 °C for 20 h, allowed
to slowly warm to room temperature, and then treated with a
saturated aq solution of NaHCO3 (80 mL). The THF was
removed under reduced pressure and the residue was parti-
tioned between brine (240 mL) and CH2Cl2 (900 mL). The aq
layer was washed with CH2Cl2 (3 × 170 mL). The combined
organic layers were washed with brine (240 mL) and dried
(Na2SO4). After removal of solvent under reduced pressure,
the residue was purified by chromatography (hexane/ethyl
acetate, 6/1) to afford 22 as a colorless oil (75 g, 93%) that was
crystallized from hexane to yield 22 as white needles: mp 74-
1
1720, 1478 cm-1; H NMR (250 MHz, CDCl3) δ 1.52 (t, 1H, J
) 5.7 Hz, D2O exchangeable), 1.66 (s, 9H), 3.87 (s, 3H), 4.81
(d, 2H, J ) 5.7 Hz), 6.96 (dd, 1H, J ) 9.0, 2.6 Hz), 7.12 (d, 1H,
J ) 2.4 Hz), 7.55 (5, 1H), 8.02 (d, 1H, J ) 9.0 Hz); EIMS m/e
277 (M+, 18.7), 221 (100.0), 177 (29.4), 160 (84.8), 133 (42.4).
Anal. Calcd for C15H19NO4: C, 64.98; H, 6.86; N 5.05. Found:
C, 64.81; H, 7.00; N, 5.00. The crude product of 3-bromo-
methylindole 19a was flash evaporated under reduced pres-
sure with dry THF three times and used in the next step
without further purification.
CCl4 has been replaced by cyclohexane to carry out this
bromination at reflux. This provided 19a in the same yield.
1
76 °C; H NMR (250 MHz, CDCl3) δ 0.68 (d, 3H, J ) 6.7 Hz),
0.96 (d, 3H, J ) 6.9 Hz), 1.22 (t, 3H, J ) 7.1 Hz), 1.32 (t, 3H,
J ) 7.1 Hz), 1.89 (s, 9H), 2.18 (m, 1H), 3.13 (m, 2H), 3.58 (t,
1H, J ) 3.4 Hz), 3.85 (s, 3H), 4.02-4.20 (m, 4H), 4.28 (q, 1H,
J ) 8.8 and 4.6 Hz), 6.88 (dd, 1H, J ) 9.0 and 2.6 Hz), 7.04 (d,
1H, J ) 2.5 Hz), 7.34 (s, 1H), 7.97 (d, 1H, J ) 8.9 Hz); 13C
NMR (CDCl3) 14.27, 16.65, 28.26, 29.42, 31.74, 55.78, 56.16,
60.45, 60.53, 60.80, 82.82, 102.90, 112.42, 115.55, 116.68,
124.91, 130.05, 132.37, 149.61, 155.71, 162.31, 163.50; EIMS
m/e (rel intensity) 471 (M+, 5.4), 212 (33.9), 204 (49.7), 160
(100.0), 159 (25.3). Anal. Calcd for C26H37N3O5: C, 66.24; H,
7.86; N 8.92. Found: C, 66.18; H, 8.07; N, 8.84.
1-Ben zen esu 1fon yl-3-b r om om et h yl-5-m et h oxyin d ole
(19b). A solution of 18b (35.5 g, 0.118 mol) in CCl4 (500 mL)
was heated to reflux after which a mixture of N-bromosuccin-
imide (22.2 g, 0.123 mol) and AIBN (500 mg) was carefully
added portionwise over 5 min. After completion of the addition,
three additional portions of AIBN (3 × 200 mg) were added
every 30 min. After 3 h the mixture was cooled to room
temperature and the succinimide that resulted was filtered
off and washed with CCl4 (3 × 50 mL). The solvent was
removed under reduced pressure to yield a brown solid. A
further purification by recrystallization from diethyl ether
afforded 19b as off-white crystals (37 g, 82.5%): mp 116-118
1-ter t-Bu tyloxyca r bon yl-5-m eth oxytr yp top h a n Eth yl
Ester (23). To a solution of pyrazine 22 (75 g, 0.16 mol) in
THF (450 mL) at 0 °C was added an aq solution of 2 N HCl
(380 mL). After the solution was allowed to warm to room
temperature, the mixture was stirred for 40 min and then
poured into a cold aq solution of NH4OH to a final pH of ca. 9.
The resulting solution was concentrated under reduced pres-
sure and CH2Cl2 (1500 mL) was added. The aq layer was
extracted with CH2Cl2 (2 × 570 mL). The combined organic
layers were washed with brine and dried (Na2SO4). After
removal of solvent under reduced pressure, valine ethyl ester,
which resulted from hydrolysis of the chiral auxiliary, was
removed by high-vacuum distillation. This valine ethyl ester
could be reused. The residue that remained was purified by
flash chromatography (ethyl acetate/hexane, 1/4, followed by
°C; IR (KBr) 3103, 2856, 1607 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 3.85 (s, 3H), 4.60 (s, 2H), 6.95 (dd, 1H, J ) 8.7, 2.4
Hz), 7.05 (d, 1H, J ) 2.3 Hz), 7.45 (t, 2H, J ) 7.6 Hz), 7.55 (d,
1H, J ) 8.0 Hz), 7.65 (s, 1H), 7.85 (m, 3H); EIMS m/e (rel
intensity) 381 (M+, 21.4), 379 (M+, 18.3), 240 (51.1), 238 (53.4),
160 (39.1), 159 (100), 116 (77). Anal. Calcd for C16H14BrNO3S:
C, 50.54; H,3.71; N, 3.68. Found: C, 50.36; H, 3.47; N, 4.01.
1-ter t-Bu t yloxyca r b on yl-2-b r om o-5-m et h oxy-3-m et h -
ylin d ole (20a ). A mixture of 3-methylindole 18a (1.31 g, 5
mmol) and NBS (0.98 g, 5.5 mmol) in anhydrous CCl4 (10 mL)
was heated to reflux under nitrogen. When all of the NBS had
been converted into succinimide, which floated on the surface
of the CCl4, the reaction solution was cooled to room temper-
ature. The succinimide was removed by filtration and washed
with CCl4 (2 × 2 mL). The combined filtrates were concen-
trated under reduced pressure to afford 20a as a brown solid
(1.61 g, 95%). The residue was crystallized from a mixture of
CCl4 and hexane to afford 1-tert-butyloxycarbonyl-2-bromo-5-
methoxy-3-methylindole (20a ) as a white solid: mp 82-84 °C.
1H NMR (250 MHz, DMSO-d6) δ 1.62 (s, 9H), 2.18 (s, 3H), 3.79
(s, 3H), 6.91 (dd, 1H, J ) 9.0, 2.5 Hz), 7.07 (d, 1H, J ) 2.4
Hz), 7.38 (d, 1H, J ) 9.1 Hz). EIMS m/e (rel intensity) 341
(M+, 18.9), 339 (M+, 21.0), 285 (27.4), 283 (28.6), 241 (92.1),
1
ethyl acetate) to afford 23 (56 g, 96%) as a clear oil. H NMR
(250 MHz, CDCl3) δ 1.22 (t, 3H, J ) 7.1 Hz), 1.60 (br, 2H),
1.64 (s, 9H), 2.93 (dd, 1H, J ) 14.4, 7.7 Hz), 3.18 (dd, 1H, J )
14.5, 5.1 Hz), 3.80 (m, 1H), 3.83 (5, 3H), 4.18 (q, 2H, J ) 71.
Hz), 6.91 (dd, 1H, J ) 8.9, 2.5 Hz), 7.01 (d, 1H, J ) 2.5 Hz),
7.43 (5, 1H), 7.98 (d, 1H, J ) 8.7 Hz); EIMS m/e (rel intensity)
362 (M+, 3.7), 204 (21.6), 161 (11.4), 160 (100.0), 103 (15.6).
This material was employed in a later experiment.
D-(-)-5-Meth oxytr yp top h a n Eth yl Ester (25) a n d Its
HCl Sa lt. A solution of pyrazine 22 (50 g, 0.106 mo1) in
xylenes (2000 mL) was degassed and kept at reflux for 48 h.
Examination of the reaction mixture by TLC (silica gel;
hexane:EtOAc 5:1) indicated the disappearance of starting 22
and the appearance of a new component (lower Rf). After
removal of solvent in vacuo, a small portion of the residue was
purified by flash chromatography (silica gel; hexane:EtOAc 5:1)
239 (100.0), 226 (38.3), 224 (43.4). Anal. Calcd for C15H18
-
BrNO3: C, 52.94; H, 5.29; N, 4.12. Found: C, 52.72; H, 5.41;
N, 3.87.
1-Be n ze n e su lfon yl-2-b r om o-5-m e t h oxy-3-m e t h ylin -
d ole (20b) was isolated as a byproduct with 19b when a
mixture of 18b, N-bromosuccinimide, AIBN, and CCl4 was
heated to reflux without continuous addition of AIBN. In the
J . Org. Chem, Vol. 68, No. 16, 2003 6291

Zhao et al.
to afford (3R,6S)-3-(5-methoxy-3-indoyl)-methyl-3,6-di-hydro-
6-isopropyl-2,5-diethoxypyrazine 24. 1H NMR (250 MHz,
CDCl3) δ 0.63 (d, 3H, J ) 6.8 Hz), 0.92 (d, 3H, J ) 6.9 Hz),
1.24 (t, 3H, J ) 7.0 Hz), 1.34 (t, 3H, J ) 7.1 Hz), 2.18 (m, 1H),
3.23 (d, 2H, J ) 4.7 Hz), 3.36 (t, 1H, J ) 3.4 Hz), 3.85 (s, 3H),
4.1 (m, 4H), 4.32 (q, 1H, J ) 4.5 Hz), 6.79 (d, 1H, J ) 8.7 Hz),
6.91 (d, 1H, J ) 2.3 Hz), 7.11 (d, 1H, J ) 2.4 Hz), 7.18 (d, 1H,
J ) 8.7 Hz), 7.86 (br, 1H, D2O exchangeable). 13C NMR (CDCl3)
δ 14.28, 14.41, 16.54, 19.02, 29.60, 31.36, 55.95, 56.81, 60.34,
60.42, 101.63, 111.32, 111.91, 123.56, 123.68, 129.97, 131.10,
153.90, 162.64, 163.34. This material was not further charac-
terized but was hydrolyzed in the next step. The above crude
residue was dissolved in THF (350 mL) and treated at 0 °C
with an aq solution of 2 N HCl (300 mL). The mixture was
allowed to warm to room temperature, after which it was
stirred for 2 h and treated with a cold aq solution of NH4OH
(to pH ca. 9). The resulting solution was concentrated and
extracted with EtOAc (3 × 600 mL). The combined organic
layers were washed with brine and dried (Na2SO4). The solvent
was removed under reduced pressure and the valine ethyl
ester that resulted from hydrolysis of the chiral auxiliary was
removed by Kugelrohr distillation in vacuo. Purification of the
residue by flash chromatography (silica gel; CHCl3/MeOH/
Et3N, 25/10/1) afforded 25 as an oil (24 g, 85% for the two
steps), which was converted into the HCl salt in methanolic
distillation. The resulting residue was then purified by flash
chromatography (ethyl acetate:hexane 1:4, followed by ethyl
acetate) to afford 27 (24 g, 95%) as a clear oil: mp of (HCl
salt), 207-209 °C; 1H NMR (CDCl3) δ 1.25 (t, 3H, J ) 7.1 Hz),
1.65 (br, 2H), 2.98 (dd, 1H, J ) 14.3, 7.6 Hz), 3.21 (dd, 1H, J
) 14.4, 4.8 Hz), 3.71 (s, 3H), 3.76 (dd, 1H, J ) 7.6, 5.0 Hz),
3.85 (s, 3H), 4.18 (q, 2H, J ) 7.2 Hz), 6.86 (dd, 1H, J ) 8.8,
2.4 Hz), 6.89 (s, 1H), 7.05 (d, 1H, J ) 2.4 Hz), 7.17 (d, 1H, J
) 8.9 Hz); EIMS m/e 276 (M+, 5.2), 203 (6.0), 174 (100.0). Anal.
Calcd for C15H21N2O3Cl‚1/2H2O: C, 56.07; H, 6.85; N, 8.72.
Found: C, 56.05; H, 6.84; N, 9.05.
(3R,6S)-3-(1-Ben zen esu lfon yl-5-m eth oxy-3-in d oyl)m e-
th yl-3,6-d ih yd r o-6-isop r op yl-2,5-d ieth oxyp yr a zin e (28).
To a solution of (3S)-isopropyl-2,5-di-ethoxypyrazine 21 (11.8
g, 0.056 mol) in THF (200 mL) was added n-butyllithium (2.5
M in hexane, 24 mL, 0.06 mol) at -78 °C under nitrogen. The
resulting solution was stirred at -78 °C for 30 min after which
a solution of 19b (20.2 g, 0.053 mol) in THF (100 mL) under
nitrogen was added dropwise. After the mixture was allowed
to stir at -78 °C for 20 h, the reaction solution was slowly
warmed to room temperature and treated with a saturated
aq solution of (NH4)2CO3 (50 mL). Most of the THF was
removed under reduced pressure and the residue that resulted
was treated with diethyl ether to furnish two layers. The
organic layer was separated and the aq layer was extracted
with diethyl ether (3 × 100 mL). The combined organic layers
were washed with brine and dried (Na2SO4). The solvent was
removed under reduced pressure to afford 28 as a brown oil
(25.2 g, 93%): 1H NMR (250 MHz, CDCl3) δ 0.60 (d, 3H, J )
6.9 Hz), 0.84 (d, 3H, J ) 6.7 Hz), 1.20 (t, 3H, J ) 7.1 Hz), 1.28
(t, 3H, J ) 7.1 Hz), 2.10 (m, 1H), 3.1 (m, 2H), 3.20 (t, 1H, J )
3.4 Hz), 3.80 (s, 3H), 3.95 (m, 1H), 4.10 (m, 3H), 4.25 (q, 1H,
J ) 4.1 Hz), 6.85 (dd, 1H, J ) 9.0, 2.4 Hz), 6.96 (d, 1H, J )
2.0 Hz), 7.38 (t, 2H, J ) 8.0 Hz), 7.46 (t, 1H, J ) 7.7 Hz), 7.75
(d, 2H, J ) 8.6 Hz), 7.8 (d, 2H, J ) 8.6 Hz); 13C NMR (CDCl3)
δ 14.28, 14.33, 16.56, 18.95, 29.20, 31.55, 55.67, 60.53, 103.09,
113.16, 114.28, 119.08, 125.41, 126.51, 129.05, 129.70, 132.86,
133.34, 138.57, 156.34, 161.79, 163.59. EIMS m/e (rel intensity)
511 (M+, 5.2), 301 (18.8), 300 (70.9), 211 (9.5), 160 (26.0), 159
(100), 144 (29.6). The pyrazine 28 was employed in the next
step without further purification.
hydrogen chloride: mp 204-206 °C. [R]26 -4.4 (c 1, in
D
methanol); 1H NMR (free base, 250 MHz, CDCl3) δ 1.22 (t, 3H,
J ) 7.2 Hz), 1.61 (br, 2H, D2O exchangeable), 3.02 (dd, 1H, J
) 14.5, 7.8 Hz), 3.24 (dd, 1H, J ) 14.5, 5.0 Hz), 3.81 (dd, 1H,
J ) 7.7, 5.0 Hz), 3.82 (s, 3H), 4.18 (q, 2H, J ) 7.2 Hz), 6.84
(dd, 1H, J ) 8.8, 2.4 Hz), 7.02 (d, 1H, J ) 2.3 Hz), 7.07 (d, 1H,
J ) 2.4 Hz), 7.22 (d, 1H, J ) 8.8 Hz), 8.21 (br, 1H, D2O
exchangeable). EIMS (free base) m/e (rel intensity) 262 (M+,
4.6), 189 (4.7), 161 (12.2), 160 (100.0), 145 (12.3). Anal. Calcd
for C14H18N2O3‚HCl: C, 56.29; H, 6.37; N 9.38. Found: C,
56.12; H, 6.62; N, 9.10.
5-Met h oxy-1-m et h yl-(D)-t r yp t op h a n E t h yl E st er (27)
a n d Its HCl Sa lt. A solution of pyrazine 22 (50 g, 0.106 mol)
in toluene (2000 mL) was degassed and held at reflux for 48
h. Examination of the reaction mixture by TLC (silica gel;
hexane:EtOAc 5:1) indicated the disappearance of starting 22
and the appearance of a new component (lower Rf). After
removal of the solvent in vacuo, dry THF (1000 mL) was added
to dissolve the residue. The NaH (5.1 g, 60% in mineral oil,
0.127 mol) was added slowly at 0 °C. The mixture was allowed
to stir for 30 min, after which it was treated with methyl iodide
(18.0 g, 0.127 mol) and stirred for 18 h. The THF was then
removed under reduced pressure and the residue was parti-
tioned between brine (150 mL) and CH2Cl2 (600 mL). The aq
layer was washed with CH2Cl2 (3 × 120 mL). The combined
organic layers were washed with brine (150 mL) and dried
(Na2SO4). After removal of the solvent under reduced pressure,
the residue was purified by passing it through a short wash
column (silica gel; hexane:ethyl acetate 10:1) to afford (3R,6S)-
3-(1-methyl-5-methoxy-3-indoyl)methyl-3,6-dihydro-6-isopro-
pyl-2,5-diethoxy-pyrazine (26) as an oil (35 g, 85%): 1H NMR
(CDCl3) δ 0.63 (d, 3H, J ) 6.8 Hz), 0.93 (d, 3H, J ) 6.9 Hz),
1.25 (t, 3H, J ) 7.1 Hz), 1.31 (t, 3H, J ) 7.0 Hz), 2.15 (m, 1H),
3.21 (d, 2H, J ) 4.7 Hz), 3.33 (t, 1H, J ) 3.3 Hz), 3.68 (s, 3H),
3.86 (s, 3H), 4.01-4.42 (m, 5H), 6.80 (dd, 1H, J ) 8.8, 2.4 Hz),
6.92 (d, 1H, J ) 2.3 Hz), 7.15 (d, 1H, J ) 8.7 Hz), 7.18 (s, 1H).
This material was not further characterized but was used in
the next step. The solution of the above pyrazine in THF (200
mL) was stirred with an aq solution of 2 N HCl (180 mL). After
the mixture was allowed to stir at room temperature for 40
min, the THF was removed under reduced pressure and the
aq residue was brought to alkaline pH with cold aq NH4OH
at 0 °C. The solution was extracted with ethyl acetate (3 × 80
mL). The combined organic layers were washed with brine and
dried (Na2SO4). The solvent was removed under reduced
pressure and the valine ethyl ester that resulted from hy-
drolysis of the chiral auxiliary was removed by Kugelrohr
Eth yl 1-Ben zen esu lfon yl-5-m eth oxy-D-(-)-tr yp top h a n
Hyd r och lor id e (29). A mixture of 28 (7.5 g, 0.0147 mol), THF
(40 mL), and 2 N aq HCl (60 mL) was stirred at room
temperature for 2 h. The resulting precipitate was collected
by filtration to furnish the first crop of 29 as its hydrochloride
salt. The filtrate was concentrated in vacuo and the precipitate
that formed was collected to afford the second crop of 29
(combined yield 6.0 g, 93%): mp 243.5-245.0 °C; [R]26D -20.20
(c 1, in methanol); IR (KBr) 3465, 3423, 2832, 2400-3500,
1
1735, 1602 cm-1; H NMR (250 MHz, CDCl3) δ 1.15 (t, 3H, J
) 7.1 Hz), 1.65 (br, 3H), 2.90 (dd, 1H, J ) 14.5, 7.3 Hz), 3.10
(dd, 1H, J ) 14.5, 5.3 Hz), 3.70 (m, 1H), 3.75 (s, 3H), 4.10 (dq,
2H, J ) 7.1, 1.8 Hz), 6.90 (dd, 1H, J ) 8.1, 2.5 Hz), 6.95 (s,
1H), 7.35-7.6 (m, 4H), 7.85 (m, 3H). Anal. Calcd for C20H22N2-
SO5‚HCl: C, 54.79; H, 5.25; N, 6.39. Found: C, 55.16; H, 5.41;
N, 6.12.
5-Meth oxy-D-(+)-tr yp top h a n (30). A mixture of 29 (2.0
g, 0.0046 mol), H2O (20 mL), EtOH (30 mL), and NaOH (1.8
g) was heated at reflux for 8 h. The ethanol was removed under
reduced pressure. After the aq solution of residue that
remained was brought to pH 2-3 with aq 6 N HCl and
extracted with CH2Cl2 (3 × 50 mL) to remove byproducts, the
water layer was then brought to a final pH of 6-7 with aq 3
N NaOH. The water was then removed under reduced pres-
sure. The white solid residue that resulted was ground, placed
on a pad of silica gel, and eluted with a solution of CH3OH,
CHCl3, and concentrated aq NH4OH (18.5:28.5:3 by volume).
The solvent was concentrated to afford 30 as a white solid.
Further crystallization of 30 in a mixture of ethanol and water
afforded 5-methoxy-D-(+)-tryptophan 30 as white crystals (0.91
g, 85%): mp 238-240 °C; [R]25 +27.20 (c 1, in H2O) and
D
6292 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
+16.20 (c 1, in acetic acid); lit69 [R]22D +15.5 (c 1, in acetic acid);
was then allowed to cool to room temperature, and treated with
a saturated aq solution of NaHCO3 (10 mL). The organic layer
was separated, washed with brine, and dried (Na2SO4). After
removal of solvent under reduced pressure, the residue was
purified by flash chromatography (hexane/ethyl acetate, 3/1)
to afford 36 (3.5 g, 83%) as a yellow solid: mp 165-166 °C;
1H NMR (250 MHz, CDCl3) δ 2.31 (d, 1H, J ) 15.4 Hz), 2.88
(m, 2H), 3.17 (m, 1H), 3.05 (s, 3H), 3.15 (5, 3H), 3.18-3.30
(m, 3H), 3.34 (s, 3H), 4.10 (m, 1H), 6.88 (d, 1H, J ) 8.6 Hz),
7.01 (d, 1H, J ) 2.1 Hz), 7.18 (d, 1H, J ) 8.8 Hz), 7.31-7.50
(m, 5H), 11.97 (s, 1H); EIMS m/e 418 (M+, 46.4), 303 (100.0),
271 (23.9), 213 (53.6), 212 (43.9), 197 (51.2), 170 (23.2). The
â-ketoester 36 was used in the next step without further
characterization.
(6S,10S)-Meth yl-2-m eth oxy-5-m eth yl-9-oxo-12-ben zyl-
6,7,8,9,10,11-h exa h yd r o-6,10-im in o-5H-cyclooct[b]in d ole-
8-ca r boxyla te (37). A solution of â-ketoester 36 (4 g, 9.6
mmol) was dissolved in 1,4-dioxane (40 mL). The 40% aq KOH
was then added to the above solution. The resulting reaction
mixture was heated to reflux for 48 h. The solution was allowed
to cool to room temperature and the 1,4-dioxane was removed
under reduced pressure. The mixture that remained was
extracted with CH2Cl2 (3 × 20 mL). The organic layer was
separated, washed with brine, and dried (Na2SO4). The solvent
was removed under reduced pressure and the residue was
purified by flash chromatography (hexane/ethyl acetate, 3/1)
to afford 37 as white crystals (2.8 g, 82%): mp 167-168 °C;
1H NMR (300 MHz, CDCl3) δ 1.89 (m, 1H), 2.02 (m, 1H), 2.31-
2.43 (m, 2H), 2.58 (d, 1H, J ) 16.8 Hz), 3.15 (dd, 1H, J ) 16.8,
6.8 Hz), 3.50 (s, 3H), 3.70 (m, 3H), 3.80 (s, 3H), 3.96 (t, 1H, J
) 4 Hz), 6.82 (dd, 1H, J ) 8.8, 2.4 Hz), 6.89 (d, 1H, J ) 2.4
Hz), 7.14 (d, 1H, J ) 8.8 Hz), 7.19-7.27 (m, 5H); 13C NMR
(75.5 MHz, CDCl3) δ 20.5, 29.4, 29.8, 34.4, 49.0, 56.0, 56.2,
64.9, 100.3, 105.3, 109.6, 111.4, 126.7, 127.3, 128.4, 128.6,
132.4, 133.8, 138.3, 154.1, 210.1; EIMS m/e 360 (M+, 30.0),
304 (33.0), 303 (100.0), 212 (19.2), 197 (19.2). Anal. Calcd for
IR (KBr) 3575, 3462, 3382, 3043, 2950, 2831, 1629, 1602 cm-1
;
1H NMR (D2O) δ 3.15-3.35 (m, 2H), 3.70 (s, 3H), 4.10 (t, IH,
J ) 5.8 Hz), 6.78 (dd, 1H, J ) 8.9,2.3 Hz), 7.05 (d, 1H, J ) 2.3
Hz), 7.15 (s, 1H), 7.27 (d, 1H, J ) 8.9 Hz). EIMS m/e (rel
intensity) 234 (M+, 7.4), 161 (14.0), 160 (100), 145 (16.7), 117
(18.8). Anal. Calcd for C12H14N2O2: C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.15; H, 5.91; N, 11.89.
Nb-Ben zyl-5-m eth oxy-1-m eth yl-(D)-tr yp top h a n Eth yl
Ester (31). To a solution of tryptophan ethyl ester 27 (20 g,
72 mmol) in dry ethanol (430 mL) at 0 °C under nitrogen was
added benzaldehyde (9.2 g, 87 mmol). The solution was stirred
at 0 °C for 5 h, cooled to -10 °C, and treated portionwise with
NaBH4 (3.3 g, 87 mmol) to keep the temperature below -5 °C
(about 3 h). After the mixture was allowed to stir for an
additional 1 h, ice water (15 mL) was added and the mixture
was allowed to warm to room temperature. The ethanol was
removed under reduced pressure and the aq residue was
extracted with EtOAc (3 × 360 mL). The combined organic
layers were washed with brine and dried (Na2SO4). After
removal of the solvent under reduced pressure, the residue
was purified by flash chromatography (ethyl acetate:hexane
1
3:1) to afford 31 as an oil (25 g, 94%). H NMR (CDCl3) δ 1.12
(t, 3H, J ) 7.1 Hz), 1.82 (br, 2H), 3.10 (m, 2H), 3.61 (m, 2H),
3.67 (s, 3H), 3.79 (s, 3H), 3.81 (d, 1H, J ) 15.5 Hz), 4.12 (q,
2H, J ) 7.1 Hz), 6.83 (s, 1H), 6.87 (dd, 1H, J ) 8.9, 2.4 Hz),
7.01 (d, 1H, J ) 2.3 Hz), 7.18 (d, 1H, J ) 8.9 Hz), 7.28 (m,
4H), 7.48 (m, 1H). CIMS m/e 367 (M+ + 1, 100). This material
was employed directly in the next step.
tr a n s-Nb-Ben zyl-3-(eth oxyca r bon yl)-6-m eth oxy-9-m e-
th yltetr ah ydr o-â-car bolin e-1-pr opion oic Acid Meth yl Es-
ter (33). To a round-bottom flask (500 mL) that contained a
solution of optically active Na-methyl-Nb-benzyl-D-tryptophan
ethyl ester 31 (20 g, 0.055 mol) in dry CH2Cl2 (120 mL) was
added aldehyde 32 (9.6 g, 0.083 mol) and HOAc (6.6 g, 0.011
mol) at 0 °C. The resulting reaction mixture was stirred at
room temperature overnight. TFA (9.5 g, 0.083 mol) was then
added at 0 °C. The resulting reaction mixture was stirred at
room temperature for 10 d and then cooled in an ice bath and
brought to pH 8 with an aq solution of NH4OH. The aq layer
was separated and extracted with CH2Cl2 (3 × 200 mL). After
the combined organic layers were washed with brine and dried
(K2CO3), the solvent was removed under reduced pressure. The
crude product was dissolved in EtOH on heating to reflux. The
solution was then cooled and stored in the refrigerator for 1
day. Most of the trans diester 33 (18 g, 70%) precipitated out
as white crystals. The mother liquor was concentrated under
reduced pressure and the residue that resulted was purified
by flash chromatography (silica gel, EtOAc:hexane 1:4) to
provide additional 33 (3 g, 12%). The combined yield of 33 (21
C
23H24N2O2: C, 76.64; H, 6.71; N, 7.77. Found: C, 76.66; H,
6.68; N, 7.76.
1-t er t -Bu t yloxyca r b on yl-N b -b e n zyl-5-m e t h oxyt r yp -
top h a n Eth yl Ester (38). To a solution of tryptophan ethyl
ester 23 (2.5 g, 6.9 mmol) in ethanol (20 mL) was added
benzaldehyde (0.81 g, 7.7 mmol). The resulting solution was
stirred at room temperature for 4.5 h after which it was cooled
to -10 °C, and then treated portionwise with NaBH4 (0.2 g,
5.0 mmol). After the mixture was stirred for an additional 1
h, ice water (2 mL) was added and the mixture was allowed
to warm to room temperature. The ethanol was removed under
reduced pressure and the aq residue was extracted with CH2-
Cl2 (3 × 50 mL). The combined organic layers were washed
with brine and dried (Na2SO4). The solvent was removed under
reduced pressure and the residue was purified by chromatog-
raphy (hexane/ethyl acetate, 2/1) to afford 38 as an oil (2.9 g,
g) was 82%: mp 155-156 °C; [R]23 -43.9 (c 1.13, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 1.39 (t, 3H, J ) 7.1 Hz), 1.98 (m,
2H), 2.41 (dt, 1H, J ) 17.5, 5.6 Hz), 2.57 (m, 1H), 3.08 (m,
2H), 3.40 (d, 1H, J ) 13.2 Hz) 3.49 (s, 3H), 3.76 (s, 3H), 3.79
(m, 2H), 3.90 (s, 3H), 4.08 (dd, 1H, J ) 10.8, 5.3 Hz), 4.32 (m,
2H), 6.9 (dd, 1H, J ) 8.8, 2.4 Hz), 7.05 (d, 1H, J ) 2.4 Hz),
7.21 (d, 1H, J ) 8.8 Hz), 7.26-7.38 (m, 5H); 13C NMR (75.5
MHz, CDCl3) δ 14.3, 20.3, 28.0, 29.6, 29.9, 51.3, 52.8, 53.4,
56.1, 56.2, 61.0, 100.4, 105.9, 109.6, 111.3, 126.8, 127.0, 128.2,
129.4, 132.8, 136.3, 139.2, 154.0, 172.9, 174.0. EIMS m/e 464
(M+, 5.6), 378 (25.2), 377 (100.0), 213 (34.8). Anal. Calcd for
1
94%). H NMR (300 MHz, CDCl3) δ 1.17 (t, 3H, J ) 7.1 Hz),
1.65 (s, 9H), 3.03 (m, 2H), 3.65 (m, 2H), 3.87 (s, 3H), 3.87 (d,
1H, J ) 14.8), 4.11 (q, 2H, J ) 7.1 Hz), 6.90 (dd, 1H, J ) 8.9,
2.4 Hz), 6.95 (d, J ) 2.4 Hz), 7.26 (m, 5H), 7.38 (d, 1H, J ) 2.4
Hz), 7.98 (br, 1H). HRMS C26H32N2O5: calcd 452.2311, found
452.2276.
2-E t h oxyca r b on yl-3-b e n zyl-9-m e t h oxy-1,2,3,3a ,4,5-
h exa h yd r oca n th in -6-on e (42). To a round-bottom flask (250
mL) that contained a solution of tryptophan ethyl ester 38 (5
g, 11 mmol) in dry CHCl3 (30 mL) was added methyl 4,4-
dimethoxybutyrate 41 (2.67 g, 16.5 mmol) and TFA (3.76 g,
33 mmol) at 0 °C. The resulting reaction mixture was heated
to reflux and then kept at reflux overnight. After removal of
the CHCl3 and excess TFA under reduced pressure, a mixture
of xylenes (150 mL) was added into the same flask. The
reaction mixture was degassed and then heated to reflux for
2 d. After removal of the solvent, CH2Cl2 (30 mL) was added
into the flask. The mixture was then cooled in an ice bath and
brought to pH 8 with an aq solution of NH4OH. The aq layer
was separated and extracted with CH2Cl2 (3 × 30 mL). After
C
27H32N2O5: C, 69.81; H, 6.94; N, 6.03. Found: C, 69.87; H,
6.94; N, 5.98.
(6S,10S)-Meth yl-2-m eth oxy-5-m eth yl-9-oxo-12-ben zyl-
6,7,8,9,10,11-h exa h yd r o-6,10-im in o-5H-cyclooct[b]in d ole-
8-ca r boxyla te (36). To a solution of trans diester 33 (5 g,
0.010 mol) in dry toluene (10 mL) under argon was added
sodium hydride (1.2 g of 60% NaH in mineral oil, 0.030 mol).
Dry methanol (1.0 mL) was added carefully to the above
mixture (a large amount of H2 was evolved at this point). The
resulting mixture was stirred at room temperature for 0.5 h,
and heated to reflux for an additional 4 h. The reaction mixture
J . Org. Chem, Vol. 68, No. 16, 2003 6293

Zhao et al.
the combined organic layers were washed with brine and dried
(K2CO3), the solvent was removed under reduced pressure. The
crude product was then purified by a wash column (silica gel,
EtOAc:hexane 1:4) to provide only 42 (2.8 g, 60%). The base
42 is the trans diastereomer, which was determined by
observing that the proton at C(1) underwent a long-range
coupling with the R proton at C(4) by 1H-1H COSY experi-
ments. 42: 1H NMR (300 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.1
Hz), 1.79 (m, 1H), 2.41 (m, 1H), 2.81 (m, 2H), 2.96 (ddd, 1H, J
) 16.4, 6.8, 2.8 Hz), 3.06 (dt, 1H, J ) 16.4, 1.8 Hz), 3.85 (s,
3H), 3.88 (dd, 1H, J ) 6.8, 1.3 Hz), 3.97 (d, 1H, J ) 14.3 Hz),
4.07-4.22 (m, 2H), 4.26 (d, 1H, J ) 14.3 Hz), 4.54 (dd, 1H, J
) 10.1, 2.1 Hz), 6.87-6.91 (m, 2H), 7.25-7.38 (m, 5H), 8.25
(dd, 1H, J ) 8.3, 0.83 Hz); 13C NMR (75.5 MHz, CDCl3) δ 14.21,
24.00, 28.31, 32.80, 52.00, 54.68, 55.62, 57.38, 60.44, 101.64,
110.81, 111.88, 116.74, 127.16, 128.20, 128.40, 129.50, 130.23,
135.59, 139.15, 156.73, 167.80, 172.44; EIMS m/e 418 (M+,
18.8), 345 (20.8), 328 (19.8), 327 (100), 253 (12.5), 198 (13.5).
HRMS C25H26N2O4: calcd 418.2018, found 418.2009.
(6S ,10S )-2-Me t h oxy-9-oxo-12-(Z-2′-iod o-2′-b u t e n yl)-
6,7,8,9,10,11-h e xa h yd r o-6,10-im in o-5H -cyclooct [b]in -
d ole (47). Tetracyclic ketone 37 (2.05 g, 5.5 mmol) was mixed
with dry EtOH (15 mL). A saturated solution of EtOH/HCl(g)
was then added dropwise into the above mixture until the solid
completely dissolved. The solvent was removed under reduced
pressure to furnish an HCl salt. The residue was then
dissolved in dry EtOH (15 mL), after which Pd/C (10%, 0.35
g) was added. The resulting mixture was allowed to stir at
room temperature under an atmosphere of hydrogen for 12 h.
After analysis by TLC (silica gel plate was exposed to NH3
vapors) indicated the absence of starting material 37, the
catalyst was removed by filtration and washed with EtOH (3
× 15 mL). The solvent was removed under reduced pressure
1
to provide Nb-H tetracyclic ketone 45 (1.36 g, 92%). H NMR
(300 MHz, CDCl3) δ 1.15-1.28 (m, 2H), 1.55-1.80 (m, 2H),
2.01-2.12 (m, 1H), 2.82 (dd, 1H, J ) 17.0, 6.7 Hz), 2.95 (d,
1H, J ) 17.0 Hz), 3.50 (t, 1H, J ) 5.8 Hz), 3.81 (m, 1H), 3.85
(s, 3H), 4.03 (br s, 1H), 4.10 (m, 1H), 6.80 (dd, 1H, J ) 8.7, 2.4
Hz), 6.96 (d, 1H, J ) 2.3 Hz), 7.20 (d, 1H, J ) 8.7 Hz), 8.16 (br
s, 1H); CIMS m/e 271 (M+ + 1, 100). This material was not
further characterized but was used directly in the next step.
The above crude residue 45 and Z-1-bromo-2-iodo-2-butene
4676,77 (2.0 g, 7.7 mmol) were dissolved in THF (25 mL) and
K2CO3 (0.5 g) was added. The resulting reaction mixture was
stirred at room temperature for 24 h, and then heated to 60
°C for 24 h. The reaction solution was cooled to room temper-
ature, and stirred at room temperature for 24 h. Analysis by
TLC (silica gel, CHCl3:C2H5OH 4:1) indicated the absence of
tetracyclic ketone 45. The K2CO3 was removed by filtration
and was washed with EtOAc (3 × 10 mL). After removal of
the solvent under reduced pressure, the crude product was
purified by flash chromatography (silica gel, EtOAc:hexane 1:9)
to provide Nb-Z-2′-iodo-2′-butenyl, tetracyclic ketone 47 (1.3
(6S,10S)-Meth yl-2-m eth oxy-9-oxo-12-ben zyl-6,7,8,9,10,-
11-h exa h yd r o-6,10-im in o-5H-cyclooct[b]in d ole-8-ca r box-
yla te (43). To a solution of trans lactam 42 (2 g, 4.8 mmol) in
dry toluene (55 mL), which had been predried by azeotropic
removal of H2O by a DST (reflux for 3 h), was added sodium
hydride (1.92 g of 60% NaH in mineral oil, 48 mmol) at room
temperature. Dry methanol (3.3 mL) was added to the above
mixture dropwise (a large amount of H2 was evolved at this
point) under Ar. The resulting mixture was stirred at room
temperature for 0.5 h and heated to reflux for an additional
72 h until analysis by 1H NMR spectroscopy indicated the
disappearance of the trans lactam 42. The reaction mixture
was then poured into an ice-cold mixture of H2O and CH2Cl2
(20 mL). The aq layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were washed with brine and
dried (K2CO3). The solvent was removed under reduced pres-
sure and the mineral oil was separated by decantation. The
resulting residue was purified by flash chromatography (silica
gel, EtOAc:hexane 1:4) to provide the Na-H, â-ketoester 43 (1.5
1
g, 80%). IR (NaCl) 1708 cm-1; H NMR (300 MHz, CDCl3) δ
1.81 (d, 3H, J ) 6.4 Hz), 1.90-2.09 (m, 2H), 2.48-2.53 (m,
2H), 2.67 (d, 1H, J ) 16.8 Hz), 3.10 (dd, 1H, J ) 16.8, 6.7 Hz),
3.35 (br s, 2H), 3.62 (s, 3H), 3.71 (d, 1H, J ) 6.6 Hz), 3.85 (s,
3H), 4.06 (br s, 1H), 5.83 (br q, 1H, J ) 6.3 Hz), 6.88 (dd, 1H,
J ) 8.8, 2.5 Hz), 6.93 (d, 1H, J ) 2.4 Hz), 7.18 (d, 1H, J ) 8.7
Hz); CIMS m/e 451 (M+ + 1, 100). Anal. Calcd for C20H23N2O2I‚
1/2H2O: C, 52.30; H, 5.27; N, 6.10. Found: C, 52.43; H, 5.50;
N, 6.06.
1
g, 75%). H NMR (300 MHz, CDCl3) δ 2.28 (d, 1H, J ) 15.6),
2.80 (dd, 1H, J ) 15.6, 5.5 Hz), 2.87 (dd, 1H, J ) 16.0, 0.78
Hz), 3.14 (dd, 1H, J ) 16.0, 5.9 Hz), 3.65 (s, 3H), 3.70 (d, 1H,
J ) 13.4 Hz), 3.76 (d, 1H, J ) 5.7 Hz), 3.81 (d, 1H, J ) 13.3
Hz), 3.85 (s, 3H), 3.94 (d, 1H, J ) 5.1 Hz), 6.80 (dd, 1H, J )
8.7, 2.5 Hz), 6.95 (d, 1H, J ) 2.4 Hz), 7.16 (d, 1H, J ) 8.7 Hz),
7.26-7.36 (m, 5H), 7.54 (s, 1H), 11.99 (s, 1H); EIMS m/e 404
(M+, 100), 372 (42), 289 (95), 281 (52), 253 (18), 199 (38). HRMS
P a lla d iu m -Ca ta lyzed Cycliza tion of (6S,10S)-2-Meth -
oxy-9-oxo-12-(Z-2′-iod o-2′-bu ten yl)-6,7,8,9,10,11-h exa h y-
dr o-6,10-im in o-5H-cyclooct[b]in dole (47) To P r ovide P en -
ta cyclic Keton e (48). A mixture of Nb-Z-2′-iodo-2′-butenyl,
tetracyclic ketone 47 (100 mg, 0.22 mmol), Pd(OAc)2 (4.93 mg,
0.022 mmol), Bu4NBr (77 mg, 0.24 mmol), PPh3 (21.9 mg, 0.084
mmol), and K2CO3 (117 mg, 0.84 mmol) in a solution of DMF-
H2O (9:1, 2.2 mL) was degassed under reduced pressure. The
mixture was then heated to 70 °C (oil bath temperature) under
an atmosphere of argon for 5 h. Analysis by TLC (silica gel,
EtOAc:hexane 3:2) indicated the absence of Nb-Z-2′-iodo-2′-
butenyl, tetracyclic ketone 47 and the presence of a new indole
component of lower Rf value. The mixture was cooled to room
temperature, diluted with EtOAc (220 mL), washed with H2O
(5 × 50 mL), and dried (K2CO3). The solvent was removed
under reduced pressure and the resulting oil was chromato-
graphed (silica gel, EtOAc:hexane 3:7) to provide pentacyclic
C
24H24N2O4: calcd 404.1736, found 404.1683.
(6S,10S)-Meth yl-2-m eth oxy-9-oxo-12-ben zyl-6,7,8,9,10,-
11-h exa h yd r o-6,10-im in o-5H-cyclooct[b]in d ole-8-ca r box-
yla te (44). A solution of â-ketoester 43 (1.0 g, 2.5 mmol) was
dissolved in 1,4-dioxane (10 mL). A mixture of 40% aq KOH
was then added into the above solution. The resulting reaction
mixture was heated to reflux for 48 h. The solution was then
allowed to cool to room temperature. The 1,4-dioxane was
removed under reduced pressure. The remaining mixture was
extracted with CH2Cl2 (3 × 10 mL). The organic layer was
separated, washed with brine, and dried (Na2SO4). The solvent
was removed under reduced pressure and the residue was
purified by flash chromatography (hexane/ethyl acetate, 3/1)
to afford 44 as a white solid (0.73 g, 85%). 1H NMR (300 MHz,
CDCl3) δ 1.90-1.97 (m, 1H), 2.03-2.14 (m, 1H), 2.34-2.47 (m,
2H), 2.63 (d, 1H, J ) 16.7 Hz), 3.19 (dd, 1H, J ) 16.7, 6.7 Hz),
3.73 (m, 3H), 3.85 (s, 3H), 3.94 (m, 1H), 6.83 (dd, 1H, J ) 8.7,
2.5 Hz), 6.94 (d, 1H, J ) 2.4 Hz), 7.19 (d, 1H, J ) 8.7 Hz),
7.20-7.36 (m, 5H), 7.80 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 20.40, 30.32, 34.50, 49.98, 55.89, 56.06, 64.93, 100.29, 106.37,
111.60, 111.76, 127.22, 127.28, 128.39, 128.57, 130.84, 132.88,
138.22, 154.15, 210.50. EIMS m/e 346 (M+, 32.7), 318 (9.6),
1
ketone 48 (57.5 mg, 81%). H NMR (300 MHz, CDCl3) δ 1.69
(d, 3H, J ) 6.8 Hz), 2.10-2.14 (m, 1H), 2.65-2.69 (m, 1H),
3.29 (s, 3H), 3.32-3.5 (m, 3H), 3.85 (s, 3H), 3.93-4.25 (m, 3H),
5.02 (m, 1H), 5.64 (br q, 1H, J ) 6.8 Hz), 6.80-6.90 (m, 2H),
7.05 (d, 1H, J ) 8.6 Hz). CIMS m/e 323 (M+ + 1, 100). HRMS
C
20H22N2O2: calcd 322.1681, found 322.1677. This material
was used directly in a later step.
P a lla d iu m -Ca ta lyzed Cycliza tion of (6S,10S)-2-Meth -
oxy-9-oxo-12-(Z-2′-iod o-2′-bu ten yl)-6,7,8,9,10,11-h exa h y-
dr o-6,10-im in o-5H-cyclooct[b]in dole (47) To P r ovide P en -
t a cyclic Ket on e (48), Gr a m Sca le. A mixture of Nb-Z-2′-
iodo-2′-butenyl, tetracyclic ketone 47 (1.1 g, 2.42 mmol),
290 (36.5), 289 (100), 199 (11.5), 183 (9.6). HRMS C22H22
N2O2: calcd 346.1681, found 346.1628. Anal. Calcd for C22H22
-
-
N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.46; H, 6.68; N,
7.86.
6294 J . Org. Chem., Vol. 68, No. 16, 2003

Majvinine, 10-Methoxyaffinisine, and Na-Methylsarpagine
Pd(OAc)2 (27.1 mg, 0.121 mmol), Bu4NBr (0.85 g, 2.64 mmol),
PPh3 (120 mg, 0.462 mmol), and K2CO3 (1.29 g, 9.24 mmol) in
a solution of DMF-H2O (9:1, 24 mL) was degassed under
reduced pressure. The mixture was then heated to 70 °C (oil
bath temperature) under an atmosphere of argon for 5 h.
Analysis by TLC (silica gel, EtOAc:hexane 4:1) indicated the
absence of Nb-Z-2′-iodo-2′-butenyl, tetracyclic ketone 47 and
the presence of a new indole component of lower Rf value. The
mixture was cooled to room temperature, diluted with EtOAc
(2 L), washed with H2O (5 × 500 mL), and dried (K2CO3). The
solvent was removed under reduced pressure and the resulting
oil was chromatographed (silica gel, EtOAc:hexane 3:7) to
provide pentacyclic ketone 48 (624 mg, 80%). The 1H NMR
spectrum of 48 was identical with that reported immediately
above. This material was used directly in a later step.
90%). [R]26D +78 (c 0.2, CHCl3) {lit.80 [R]D +75 (c 0.62, CHCl3)}.
1H NMR (300 MHz, CDCl3) δ 1.65 (d, 3H, J ) 6.8 Hz), 1.72
(m, 1H), 1.85 (m, 2H), 2.10 (t, 1H, J ) 10), 2.63 (d, 1H, J ) 15
Hz), 2.85 (m, 2H), 3.09 (dd, 1H, J ) 15, 5.3 Hz), 3.54 (m, 2H),
3.55 (m, 2H), 3.60 (s, 3H), 3.86 (s, 3H), 4.24 (d, 1H, J ) 8.4
Hz), 5.43 (br q, 1H, J ) 6.8 Hz), 6.84 (dd, 1H, J ) 8.8, 2 Hz),
6.94 (d, 1H, J ) 2 Hz), 7.18 (d, 1H, J ) 8.8 Hz); 13C NMR
(75.7 MHz, CDCl3) δ 12.8, 27.0, 27.5, 29.5, 32.8, 44.1, 49.6,
54.4, 56.0, 56.3, 65.0, 100.5, 103.2, 109.5, 110.7, 117.0, 127.5,
132.6, 135.4, 139.8, 153.8. EIMS m/e 338 (M+, 78.3), 337 (69.6),
323 (13.0), 307 (39.1), 293 (10.9), 226 (10), 213 (91.3), 212 (100),
198 (29.3), 197 (30.4). HRMS C21H26N2O2: calcd 338.1994,
found 338.1982. The spectral data for 49 were identical with
those reported in the literature.80
(+)-Na -Meth ylsa r p a gin e (8). To a solution (degassed at
-78 °C) of (+)-majvinine 14 (10 mg, 0.0297 mmol) in dry
methylene chloride (1 mL) at -78 °C was added a solution of
BBr3 (0.178 mL of a 1.0 M solution of BBr3 in dry CH2Cl2, 0.178
mmol) dropwise under Ar. The mixture was kept at -78 °C
for 1 h and slowly warmed to room temperature. After an
additional 2 h of stirring, the reaction solution was cooled with
a dry ice bath and treated with a concentrated aq solution of
NH4OH to pH 8. Silica gel was added directly into the above
mixture. After removal of solvent, the well-packed silica gel
was then put into a small column. The column of silica gel
was eluted with CHCl3/EtOH (v/v 9:1). Removal of CHCl3/
(+)-Ma jvin in e (14). A mixture of anhydrous potassium tert-
butoxide (276 mg, 2.45 mmol) and methoxymethyl triphen-
ylphosphonium chloride (775 mg, 2.26 mmol) in dry benzene
(11 mL) was allowed to stir at room temperature for 1 h. The
pentacyclic ketone 48 (100 mg, 0.31 mmol) in THF (3.5 mL)
was then added into the above orange solution dropwise at
room temperature. The resulting mixture was stirred at room
temperature for 24 h (the reaction progress was monitored by
1H NMR spectroscopy of a sample from the process). The
mixture was diluted with EtOAc (3 × 15 mL), washed with
H2O (3 × 1 mL) and brine (1 mL), and dried (Na2SO4). The
solvent was removed under reduced pressure and the residue
was dissolved (without further purification) in a solution of
aq 2 N HCl in H2O/THF (30 mL). The resulting solution was
stirred at 55 °C (oil bath temperature) under an atmosphere
of argon for 6 h (the reaction progress was monitored by
1
EtOH provided the aldehyde 50 (7.8 mg, 81%). H NMR (300
MHz, CDCl3) δ 1.64 (d, 3H, J ) 6.9 Hz), 1.83 (d, 1H, J ) 11.9
Hz), 2.21 (t, 1H, J ) 11.9 Hz), 2.47-2.57 (m, 2H), 3.16 (dd,
1H, J ) 15.5, 5.1 Hz), 3.27 (br s, 1H), 3.59 (s, 3H), 3.74 (m,
3H), 4.40 (d, 1H, J ) 9.4 Hz), 5.42 (br q, 1H, J ) 6.9 Hz), 6.76
(dd, 1H, J ) 8.6, 2.3 Hz), 6.81 (d, 1H, J ) 2.3 Hz), 7.10 (d, 1H,
J ) 8.6 Hz), 9.64 (s, 1H). CIMS m/e 323 (M+ + 1, 100). This
aldehyde 50 was used directly in the next step without further
characterization. The above aldehyde 50 (5.0 mg, 0.0155 mmol)
was dissolved in EtOH (1 mL). The NaBH4 (0.59 mg, 0.0155
mmol) was added to the above solution in one portion. The
mixture was then stirred at 0 °C for 4 h. The resulting reaction
mixture was then treated with acetic acid to bring the pH to
5-6. The solvent was removed under reduced pressure to
afford the crude product, which was chromatographed [silica
gel, CHCl3/MeOH (v/v 9:1)] to provide (+)-Na-methylsarpagine
8 (4.5 mg, 90%). [R]26 50 (c 0.1, MeOH) {lit.88 [R]25 52 ( 9 (c
1
analysis of the crude product by H NMR spectroscopy). After
the reaction was completed, THF was removed under reduced
pressure. The reaction mixture was washed with H2O (10 mL)
and extracted with diethyl ether (6 × 10 mL) to remove PPh3d
O. The aq layer was then brought to pH 8 with an aq solution
of NH4OH. The resulting aq layer was extracted with CH2Cl2
(3 × 10 mL), and the combined organic layers were washed
with H2O (3 × 1 mL) and brine (1 mL) and dried (Na2SO4).
The solvent was removed under reduced pressure to afford an
oil that was chromatographed (silica gel, EtOAc:hexane 3:2)
to provide pure (+)-majvinine 14 (94 mg, 90%). [R]26 99 (c
D
0.78, CHCl3). IR (NaCl) 2700, 1718 cm-1. H NMR (300 MHz,
1
D
D
CDCl3) δ 1.63 (dt, 3H, J ) 6.8, 2.0 Hz), 1.80 (dt, 1H, J ) 10,
2.0 Hz), 2.21 (br t, 1H, J ) 10 Hz), 2.57 (m, 2H), 3.22 (m, 2H),
3.50 (s, 3H), 3.73 (d, 3H, J ) 2.0 Hz), 3.85 (s, 3H), 4.38 (d, 1H,
J ) 9.1 Hz), 5.40 (br q, 1H, J ) 6.8 Hz), 6.86 (dd, 1H, J ) 8.8,
2.3 Hz), 6.92 (d, 1H, J ) 2.3 Hz), 7.17 (d, 1H, J ) 8.8 Hz),
9.63 (d, 1H, J ) 0.87 Hz); 13C NMR (75.5 MHz, CDCl3) δ 12.7,
26.4, 26.8, 29.4, 31.9, 49.5, 50.8, 54.5, 55.7, 55.9, 100.4, 102.4,
109.8, 111.3, 118.2, 127.1, 132.2, 132.7, 138.3, 154.0, 201.5.
EIMS m/e 336 (M+, 53.8), 226 (13.2), 307, (100), 293 (10.3),
0.05, MeOH)}. 1H NMR (300 MHz, CD3OD) δ 1.55 (d, 3H, J )
6.8 Hz), 1.61 (m, 1H), 1.76 (m, 2H), 2.08 (dt, 1H, J ) 10, 2.1
Hz), 2.53 (d, 1H, J ) 15 Hz), 2.69 (br t, 1H, J ) 7 Hz), 2.88
(dd, 1H, J ) 15, 5.2 Hz), 3.48 (m, 4H), 3.51 (s, 3H), 4.33 (d,
1H, J ) 10 Hz), 5.38 (br q, 1H, J ) 6.8 Hz), 6.59 (dd, 1H, J )
8.7, 2.3 Hz), 6.70 (d, 1H, J ) 2.3 Hz), 7.05 (d, 1H, J ) 8.7 Hz);
13C NMR (CD3OD) δ 13.3, 27.2, 28.0, 30.0, 33.0, 45.0, 51.6,
56.2, 57.5, 64.6, 103.0, 103.7, 110.8, 112.7, 120.8, 128.8, 132.0,
134.4, 138.0, 152.1. EIMS m/e 324 (M+, 38), 323 (23), 293 (24),
199 (100), 198 (85), 184 (47). HRMS C20H24N2O2: calcd
324.1838, found 324.1820. The EIMS data were identical with
those reported in the literature.88
213 (71.8), 212 (75.6), 198 (23.1), 197 (33.3). HRMS C21H24
-
N2O2: calcd 336.1838, found 336.1841. The spectral data were
in good agreement with those of the natural product.79 The
structure was later confirmed by single-crystal X-ray analysis.
(+)-10-Meth oxya ffin isin e (49). The (+)-majvinine 14 (5
mg, 0.015 mmol) was dissolved in MeOH (1 mL). The NaBH4
(0.57 mg, 0.015 mmol) was added to the above solution in one
portion. The mixture was then stirred at 0 °C for 8 h. The
reaction mixture was diluted with CH2Cl2 (10 mL) and poured
into cold water (2 mL). The aq layer was extracted with
additional CH2Cl2 (3 × 4 mL), and the combined organic layers
were washed with brine (2 mL) and dried (Na2SO4). The
solvent was removed under reduced pressure to afford the
crude product, which was chromatographed (with use of a pipet
as a column) to provide (+)-10-methoxyaffinisine 49 (4.6 mg,
Ack n ow led gm en t. We thank the office of Naval
Research, NIDA, and NIMH for support of this work.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for com-
pounds 14 and 33. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O030055U
(88) Waldner, E. E.; Hesse, M.; Taylor, W. I.; Schmid, H. Helv. Chim.
Acta 1967, 50, 1926.
J . Org. Chem, Vol. 68, No. 16, 2003 6295