Regiospecific, enantiospecific total synthesis of the alkoxy-substituted indole bases, 16-epi-Na-methylgardneral, 11-methoxyaffinisine, and 11-methoxymacroline as well as the indole alkaloids alstophylline and macralstonine

Article abstract of DOI:10.1021/ol020101x

(matrix presented) A regiospecific, enantiospecific approach to the synthesis of ring-A-substituted indole alkaloids was developed via a doubly convergent strategy. The asymmetric Pictet-Spengler reaction and enolate-driven palladium cross-coupling proces

Full text of DOI:10.1021/ol020101x

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3339-3342
Regiospecific, Enantiospecific Total
Synthesis of the Alkoxy-Substituted
Indole Bases, 16-epi-N -Methylgardneral,
a
11-Methoxyaffinisine, and
11-Methoxymacroline as Well as the
Indole Alkaloids Alstophylline and
Macralstonine
,†
Xiaoxiang Liu,† Jeffrey R. Deschamp,‡ and James 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 AVe., SW, Washington, DC 20375
capncook@uwm.edu
Received May 16, 2002
ABSTRACT
A regiospecific, enantiospecific approach to the synthesis of ring-A-substituted indole alkaloids was developed via a doubly convergent
strategy. The asymmetric Pictet−Spengler reaction and enolate-driven palladium cross-coupling processes were both executed in stereospecific
fashion and served as the stereochemical basis of this approach. The synthesis of 16-epi-N -methylgardneral (15), 11-methoxyaffinisine (16),
a
and 11-methoxymacroline (22) has been accomplished in high yield and in enantiospecific fashion. Moreover, the key C-19 ketosarpagine
system (borane adducts) 19a,b employed for the construction of 11-methoxymacroline (22) was also transformed into alstophylline 25, which
resulted in completion of the total synthesis of the bisindole macralstonine (1).
Indole alkaloids of the sarpagine/macroline-type comprise
one of the largest groups of structurally related indole natural
products.1-3 Interest in the macroline/sarpagine alkaloids
originated as a result of folk tales that described the medicinal
properties of the plants from which these alkaloids were
isolated.1-3 Malaria is the world’s most common tropical
parasitic disease, and there are an estimated 300-500 million
cases of malaria each year. The emergence of multidrug
resistant strains of the parasite is exacerbating the situation.
In regard to the present work, various indole alkaloids
isolated from Alstonia species have shown important anti-
protozoal activity.4,5 To date, it is clear the dimeric alkaloids
are much more potent than the monomeric units that
comprise them against Plasmodia falciparum malaria. More
† University of Wisconsin-Milwaukee.
‡ Naval Research Laboratory.
(1) Lounasmaa, M.; Hanhinen., P.; Westersund, M. The Sarpagine Group
of Indole Alkaloids. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 1999; Vol. 52.
(2) Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline Related
Sarpagine Alkaloids. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9, p 23.
(3) Chatterjee, A.; Banerji, J.; Banerji, A. J. Indian Chem. Soc. 1949,
51, 156.
(4) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, J. M.; Kirby,
G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(5) Keawpradub, N.; Kirby, G. C.; Steele, J. C. P.; Houghton, P. J. Planta
Med. 1999, 65, 690.
10.1021/ol020101x CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

recently, Houghton et al.5 showed that the bisindoles are of
particular interest for their unique selectivity against the
multidrug resistant K1 strain vs the chloroquine sensitive
T9-96 strain of P. falciparum. As a consequence, the
synthesis of the natural alkaloids and the antipodes as well
as the mismatched bisindoles,6 including analogues, has
become important. It is necessary to prepare a number of
structural analogues of these bisindoles to search for
enhanced activity/selectivity; moreover, analogues are re-
quired to study SAR at the receptor level.
is reported, which was later transformed into alstophylline
and culminated in the total synthesis of the bisindole
macralstonine 1.
Examination of the structure of bisindole 1 or 2 clearly
indicated that functionalization of ring-A with an alkoxy
group in the latter stages of the synthesis would be a difficult
process. For this reason, a strategy was adopted to incorporate
the 11-alkoxy group into ring-A of 1 from the beginning. If
successful, this would also provide a method for the synthe-
sis of many other 11-methoxy-substituted sarpagine- and
ajmaline-related indole alkaloids. On the basis of previous
work on the total synthesis of indole alkaloids via the
asymmetric Pictet-Spengler reaction,11 the 6-methoxy-D-
tryptophan was chosen as the chiral transfer agent and
starting material. Because of this, the Scho¨llkopf chiral
auxiliary required for the asymmetric induction was prepared
from the inexpensive L-valine. As shown in Scheme 1,
Many bisindole alkaloids isolated from Alstonia species
contain a ring-A-substituted methoxyl unit as illustrated in
the structures of macralstonine 1,7 19-O-methylmacralstonine
2,5 and 10-methoxyvillastonine 3 (Figure 1).8 It is important
Scheme 1a
a Reaction conditions: (1) 1% Pd(OAc)2, Na2CO3, LiCl, DMF,
100 °C, 77%. (2) 2 N aqueous HCl, EtOH, THF, from 78 to 0 °C,
86%. (3) NaH, DMF, Mel, 95%; aqueous 2 N HCl/THF, rt, 2 h,
93%.
Figure 1.
iodoaniline 4 and the propargyl unit 5,12 which had been
prepared on a 200 g scale with high diastereoselectivity from
the readily available Scho¨llkopf chiral auxiliary (from
L-valine),13 underwent Larock heteroannulation15 to provide
the protected 6-methoxy tryptophan 6 in 77% yield (300 g
scale). Hydrolysis of the Scho¨llkopf chiral auxiliary followed
by the removal of the triethylsilyl group was realized in 90%
yield in a single step to provide 7. Because the Scho¨llkopf
chiral auxiliary served as an excellent protecting group (no
racemization) for the amino acid portion of a tryptophan,
the intermediate 6 also served as the precursor to the required
Na-methyl analogue 8. The Na-methyl-6-methoxy-D-tryp-
to note that a minor change in structure resulted in
significantly enhanced antiplasmodial activity for 19-O-
methylmacralstonine 2 in comparison to the parent 1.5 From
the pioneering biomimetic coupling process of LeQuesne,9,10
these bisindole alkaloids can be envisaged to arise from
condensation of a unit of macroline with another monomeric
alkaloid. Since the coupling of macroline and alstophylline
was previously carried out by LeQuesne et al.10 to pro-
vide macralstonine 1, the synthesis of this bisindole would
now rest on the synthesis of these two monomeric units.
Herein, the regiospecific synthesis of 11-methoxymacroline
(6) Zhao, S.; Smith, K.; Morin-Deveau, A.; Johnson, M.; Mcdonald, T.;
Cook, J. M. J. Med. Chem. 2002, 45, 1559-1562.
(7) Cook, J. M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
(8) Ghedria, K.; Zeches-Hanrot, M.; Richard, B.; Massiot, G.; LeMen-
Oliver, L.; Sevenet, T.; Goh, S. H. Phytochemistry, 1988, 27, 3955.
(9) Burke, D. E.; Cook, J. M.; LeQuesne, P. W. J. Am. Chem. Soc. 1973,
95, 5, 546.
(11) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens, D.;
Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998.
(12) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525.
(13) Larock, R. C.; Yum, E. K. J. Am Chem. Soc. 1991, 113, 6689.
(14) Liu, X.; Cook, J. M. Unpublished results.
(10) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J. M. J.
Chem. Soc., Chem. Commun. 1972, 1346.
(15) Sakai, S.; Yamamoto, Y.; Hasegawa, S. Chem. Pharm. Bull. 1980,
28, 3454.
3340
Org. Lett., Vol. 4, No. 20, 2002

tophan 8, employed here for the synthesis of the Na-methyl
bases, was prepared by a two step transformation from 6 in
>90% overall yield (see Scheme 1).
With the desired tryptophan unit 8 in hand, attention was
turned to the construction of the rigid 11-methoxytetracyclic
ketone, which could serve as the key template for the
synthesis of the 11-methoxyindole alkaloids. As illustrated
in Scheme 2, the primary amine in 10 was converted into
these sarpagine bases was first realized in the 10-methox-
ylated sarpagine series by employing the Pd-catalyzed
(enolate-driven) intramolecular cyclization.18,19 This impor-
tant stereoconstruction of the C(19)-C(20) olefinic bond
avoids the formation of the olefinic isomer (koumidine
series), which is the thermodynamically more stable olefin.19
As illustrated in Scheme 3, the Nb-benzyl function was
Scheme 3a
Scheme 2a
a Reaction conditions: (1) PhCHO, EtOH, rt; NaBH4, -5 °C;
HCOCH2CH2CO2Et (10), CH2Cl2, rt; 1% TFA/CH2Cl2 (∼1 equiv
TFA), rt, 12 h. (2) CF3CO2H, CH2CHCl2. (3) NaH (60%, 3.2 equiv),
MeOH (3.5 equiv), toluene, reflux; 33% KOH, dioxane, reflux.
a Reaction conditions: (1) Pd/C, EtOH/HCl, 87%. (2) (Z)-1-
Bromo-2-iodo-2-butene, THF, K2CO3, reflux, 85%. (3) 5% Pd(OAc)2,
20% PPh3, 1 equiv Bu4NBr, 4 equiv K2CO3, DMF/H2O (9:1), 65
˚C, 8 h, 82%. (4) MeOCH2PPh3Cl, KOtBu, benzene, rt, 24 h; 2 N
HCl/THF, 55 ˚C, 5 h, 85%. (5) NaBH4/EtOH, 90%. (6) KHMDS,
TIPSCI, THF, 90%.
the Nb-benzyl ester 9 by reductive amination in high yield.
The optical purity of this Nb-benzyltryptophan 9 was
determined to be greater than 98% ee by comparison of the
optical rotation with that of an authentic sample. The Pictet-
Spengler condensation between the aldehyde 10 and the Nb-
benzylamine 9 took place in the presence of the catalyst
(acetic acid/CH2Cl2) to afford a mixture (at C-1) of trans
(11b) and cis (11a) diesters in nearly quantitative yield in a
ratio of 72:28. If TFA/CH2Cl2 was employed in this process,
significant decomposition of the starting 6-methoxytryp-
tophan took place.14 Consequently, after the Pictet-Spengler
cyclization was complete, a small amount of TFA was added
to the reaction mixture after which epimerization of the
stereocenter at C(1) of the cis diastereomer took place to
give the desired trans diester 11b as the single isolable
diastereomer. Dieckmann cyclization of the trans diester 11b
followed by base-mediated hydrolysis/decarboxylation in a
one-pot process then provided the key tetracyclic ketone 12a
in 85% overall yield. The synthesis of this key ketone 12a
could then be carried out in a two-pot fashion (from 6) and
was accomplished (from iodoaniline 4) in five reaction
vessels and an overall yield of 46%.
With an efficient synthesis of the 11-methoxytetracyclic
ketone 12a in hand, attention was turned to the synthesis of
the alkoxylated sarpagine system, 16-epi-Na-methyl gardneral
15,15 a base previously obtained by Sakai from the degrada-
tion of gardnerine.16 It was felt that gardneral 15 as well as
16-epi-Na-methyl-gardnerine will be implicated as key bio-
genetic or synthetic intermediates on the route to bis-
indoles or to ajmaline alkaloids such as rauflexine.17 The
stereospecific construction of the (E)-ethylidene function in
removed under the conditions of catalytic hydrogenation. The
Nb-H function was readily alkylated with (Z)-1-bromo-2-
iodo-2-butene to provide the Nb-alkylated ketone 13 in an
overall yield of 83%. When this ketone 13 was subjected to
the conditions of the palladium-catalyzed intramolecular
cyclization, the pentacyclic ketone 14 was obtained in 82%
yield in stereospecific fashion.19 This ketone 14 was then
converted into 16-epi-Na-methyl gardneral 15 in 90% yield
via a Wittig reaction followed by hydrolysis. This could be
carried out in a one-pot process if the reaction mixture was
extracted with ether before the alkaline/CH2Cl2 workup. This
removed the phosphorus byproducts before isolation of 15.
The spectral data of 15 were identical to those reported by
Sakai.15 Reduction of the aldehyde function in gardneral 15
with NaBH4 then provided the 11-methoxy affinisine 16 in
95% yield. Although neither 15 nor 16 have been isolated
from natural sources, to date, it is felt that their structures
and expected biosynthesis bode well for their eventural
isolation from the Apocynaceae. Protection of the hydroxyl
function of 16 with TIPSCl then gave the O-TIPS ether 17
in 90% yield.
With the O-TIPS ether 17 in hand, the regioselective
hydroboration was then carried out. As illustrated in Scheme
(17) Ingham, J. L.; Koskinen, A.; Lounasmaa, M. Progress in the
Chemistry of Organic Natural Products; Springer-Verlag: New York, 1983.
(18) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057.
(19) For more detailed structural and mechanistic analysis, see: Liu, X.
Ph.D. Thesis, University of Wisconsin-Milwaukee, Milwaukee, WI, 2002.
(16) Banerji, A.; Chakrabarty, M. Phytochemistry 1974, 13, 2309.
Org. Lett., Vol. 4, No. 20, 2002
3341

macroline alkaloid that was in agreement with biogenetic
proposals by LeQuesne.21
Scheme 4a
Conversion of dihydroalstophylline 24a,b into alstophyl-
line 25 was recently accomplished by employing the IBX
reagent of Nicolaou,20 although the yield has not yet
been maximized.19 The mass spectral fragmentation pattern
of 25 and the NMR spectra were in good agreement with
that of Schmid.23 This completed the total synthesis of
alstophylline, which had earlier been converted into the
bisindole macralstonine 1. Since (+)-macroline was previ-
ously synthesized by Bi and improved in the enantiomeric
series by Liu19 (12.3% overall yield) via the exact route
illustrated in Scheme 4 (to 22) in the parent (11-H system),
this served as a doubly convergent route to macralstonine 1.
In summary, a new efficient route to the parent 6-meth-
oxytryptophan ethyl ester was developed and scaled up to
300 g via a palladium-catalyzed heteroannulation process.
The synthesis of 16-epi-Na-methyl-gardneral 15 and 16-epi-
Na-methylgardnerine has been accomplished in high yield
and in stereospecific fashion via a Pd-catalyzed (enolate-
driven) intramolecular cyclization. The coupling of alsto-
phylline 25 and macroline 26 (Scheme 5) was carried out
a Reaction conditions: (1) 9 equiv BH3-DMS, THF, rt; H2O2,
NaOH, 90%. (2) DMSO, (COCl)2; Et3N; 1.5 equiv HCl, THF,
reflux, 80%. (3) 1.5 equiv HCl, THF, reflux, 90%. (4) Mel, THF;
KOtBu, THF/EtOH (6:1), reflux, 90%. (5) TBAF, THF, rt, 6 h,
86%. (6) 10 equiv HCl (1 N, aqueous), THF, reflux, 85%. (7) Mel,
THF; 1.5 equiv KOtBu, THF/EtOH (1:1) reflux, 95%. (8) NaOEt,
THF/EtOH.
Scheme 5a
4, the hydroboration went smoothly to give the C(19) mixture
of sec-ols 18 in 90% yield accompanied by only 6% of the
tert-ol.20 The regioselectivity has been increased to 100:0 in
a related system.19 Examination of the NOESY spectrum of
these two sec-ols indicated that the stereochemistry was
identical at C(19) but epimeric at C(20). The origin of this
interesting epimeric/scrambling at C(20) in this series is
under study.19 The Swern oxidation of the mixture of these
two sec-ols then gave the ketones 19a,b in 80% yield.
Examination of the two-dimensional COSY and NOESY
NMR experiments indicated that 19a,b contained the same
stereochemistry at C(19).20 When this mixture of ketones
19a,b was stirred with 1 equiv of aqueous HCl (1 N) in
refluxing THF, the Nb-boron-free ketone 20 was isolated in
90% yield; however, when the mixture of ketones 19a,b was
treated with 5 equiv of aqueous HCl (1 N) in refluxing THF,
the cyclized 11-methoxy-Na-methyl-trinervine 23 was iso-
lated in 85% yield. Modification of the original conditions
of LeQuesne21 for the ring-opening process (20 to 21,
Scheme 4) reported for the parent system gave the key 11-
methoxymacroline equivalent 21 in 90% yield. This stable
macroline equivalent was converted into 11-methoxy-
macroline 22 on stirring with TBAF in THF.
a Reaction conditions: (1) IBX, pTSA, toluene/DMSO (2:1), 70
°C. (2) 0.2 N HCl; see ref 10.
previously by LeQuesne and Cook et al.;10 consequently, this
completed the total synthesis of the antimalarial bisindole
alkaloid macralstonine 1.
Acknowledgment. We acknowledge the Office of Naval
Research, NIDA, and NIMH for support of this work.
Supporting Information Available: X-ray structural data
on the Na-H analogue of the trans diester 11b. This material
is available free of charge via the Internet at http://pubs.acs.org.
When the trinervine 23 was subjected to the ring-opening
conditions (MeI/THF; KOtBu/THF/EtOH), dihydroalsto-
phyllines 24a,b were isolated in 95% yield. This provided
the first example of interconversion of a trinervine base to a
OL020101X
(22) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. J. Am Chem. Soc. 2001,
123, 3183.
(23) Kishi, T.; Hesse, M.; Gemenden, C. W.; Taylor, W. I.; Schmid, H.
HelV. Chim. Acta, 1965, 48, 145.
(20) Liu, X.; Cook, J. M. Org. Lett. 2001, 3, 4023.
(21) Garnick, R. L.; LeQuesne, P. W. J. Am. Chem. Soc. 1978, 100,
4213.
3342
Org. Lett., Vol. 4, No. 20, 2002