The first regiospecific, enantiospecific total synthesis of 6-oxoalstophylline and an improved total synthesis of alstonerine and alstophylline as well as the bisindole alkaloid macralstonine

Article abstract of DOI:10.1021/ol051208y

(Chemical Equation Presented) A Wacker sequence has been modified to rapidly generate ring E of (-)-alstonerine, (+)-6-oxoalstophylline, and (-)-alstophylline via a domino process. This one-pot sequence provides facile entry into the dihydropyranyl enone unit of many Alstonia alkaloids.

Full text of DOI:10.1021/ol051208y

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3501-3504
The First Regiospecific, Enantiospecific
Total Synthesis of 6-Oxoalstophylline
and an Improved Total Synthesis of
Alstonerine and Alstophylline as Well as
the Bisindole Alkaloid Macralstonine
Xuebin Liao, Hao Zhou, Xiangyu Z. Wearing, Jun Ma, and James M. Cook*
Department of Chemistry, UniVersity of WisconsinsMilwaukee,
3210 North Cramer Street, Milwaukee, Wisconsin 53211
capncook@uwm.edu
Received May 23, 2005
ABSTRACT
A Wacker sequence has been modified to rapidly generate ring E of (−)-alstonerine, (+)-6-oxoalstophylline, and (−)-alstophylline via a domino
process. This one-pot sequence provides facile entry into the dihydropyranyl enone unit of many Alstonia alkaloids.
Indole alkaloids of the macroline/sarpagine type comprise
one of the largest groups of structurally related indole natural
products.1-3 It has been reported that a number of bisindole
alkaloids isolated from Alstonia2,4 species have been shown
to exhibit antimalarial activity5,6 against the drug-resistant
K1 strains of Plasmodia falciparum including macralstonine
acetate 4 and its O-methyl ether 5.6 Macralstonine 37 was
synthesized via the biomimetic coupling of (+)-macroline
and alstophylline 2 under acidic conditions by Le Quesne et
al.8,9 (+)-Macroline has been synthesized in enantiospecific
fashion by Bi10 and could be obtained via an improved
process of Liu et al.11 in gram quantities. However, alsto-
phylline 2, originally synthesized by Liu,12 was not available
in large quantities due to the difficulty in forming the
dihydropyranyl enone system in ring E. This cis-fused
dihydropyranyl enone unit is present in many other indole
alkaloids including alstonerine,13 alstonisine,13 Na-demethyl-
alstonisine,14,15 alstofoline,15 isoalstonisine,15 16-hydroxyal-
stonisine,16 and Nb-demethylalstophylline oxindole.17 It is
(8) Burke, D. E.; Cook, J. M.; LeQuesne, P. W. J. Am. Chem. Soc. 1973,
95, 546.
(9) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J. M. J.
Chem. Soc., Chem. Commun. 1972, 1346.
(10) Bi, Y.; Cook, J. M. Tetrahedron Lett. 1993, 34, 4501.
(11) Liu, X.; Zhang, C.; Liao, X.; Cook, J. M. Tetrahedron Lett. 2002,
43, 7373.
(12) Liu, X.; Deschamps, J.; Cook, J. M. Org. Lett. 2002, 4, 3339.
(13) Gilman, R. E. Ph. D. Thesis, University of Michigan, 1959.
(14) Kam, T.-S.; Choo, Y. M. Tetrahedron 2000, 56, 6143.
(15) Kam, T. S.; Choo, Y. M. Phytochemistry 2004, 65, 603.
(16) Kam, T. S.; Choo, Y. M. J. Nat. Prod. 2004, 67, 547.
(17) Rahman, A.; Silva, W. S. J.; Alvi, K. A.; DeSilva, K. T. D.
Phytochemistry 1987, 26, 865.
(1) Lounasmaa, M.; Hanhinen, P.; Westersund, M. The Sarpagine Group
of Indole Alkaloids; 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;
Elsevier Science: New York, 1995; Vol. 9.
(3) Chatterjee, A.; Banerji, J.; Banerji, A. J. Indian Chem. Soc. 1949,
51, 156.
(4) Elderfield, R. C.; Gilman, R. E. Phytochemistry 1972, 11, 339.
(5) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, J. M.; Kirby,
G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(6) Keawpradub, N.; Kirby, G. C.; Steele, J. C. P.; Houghton, P. J. Planta
Med. 1999, 65, 690.
(7) Cook, J. M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
10.1021/ol051208y CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/07/2005

well-known that the design of natural product based libraries
has become an important tool in the development of drugs.18
In the present case, this required development of an efficient
route to synthesize these alkaloids and their hybrids. Fur-
thermore, (+)-6-oxoalstophylline 1 (Figure 1), isolated from
Scheme 1
equiv of Na2CO3 in refluxing MeOH overnight, after which
time the desired secondary alcohol 11, which contained the
Figure 1.
Scheme 2
Alstonia species in 2004,16 represents the first example of a
natural product with oxygenation at carbon-6 of the macro-
line skeleton. Because of its unique structure, it was decided
to design a synthesis of this alkaloid in enantiospecific
fashion via a method amenable to construct ring E of other
alkaloids. Herein, we report the first total synthesis of
6-oxoalstophylline 1 as well as a much-improved total
synthesis of (-)-alstonerine and (-)-alstophylline 2. Estab-
lishment of the double bond in ring-E was accomplished by
a key palladium(II) (Wacker oxidation) mediated carbon-
oxygen bond formation in domino fashion.
As illustrated in Scheme 1 (retrosynthetic analysis), the
strategy here rested on the use of the palladium π-olefin19
(or Wacker oxidation) process, an IBX-mediated conversion,
a base-induced retro-Michael reaction, and a chemospecific
hydroboration. The stereocenters at C(3), C(5), C(15), and
C(16) were controlled in stereospecific fashion.
The synthesis began with the 6-epi-Na-methylgardneral 7,
which had been prepared in eight reaction vessels from
iodoaniline 6 (300 g scale) in a regiospecific, stereospecific
fashion.12 The aldehydic group of 7 was reduced with sodium
borohydride to afford 11-methoxyaffinisine 8 in 95% yield.
As illustrated in Scheme 2, the hydroxyl group of 8 was
then protected as a triisopropylsilyl ether 9, and this was
followed by a hydroboration-oxidation11,12 sequence at 25
°C. The desired C(19) secondary alcohol 10 could be
obtained in 90% yield, accompanied by 6% of the tertiary
alcohol. This mixture was then stirred in the presence of 5
(18) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int.
Ed. 2003, 42, 3996.
(19) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
3502
Org. Lett., Vol. 7, No. 16, 2005

Table 1. Synthesis of (-)-Alstonerine via Intramolecular Wacker Oxidation
entry
Pd source (mol %)
co-oxidant (equiv)
solvent
HOAc/H2O
HOAc/t-BuOH/H2O
HOAc/t-BuOH/H2O
HOAc/dioxane/H2O
HOAc/dioxane/H2O
HOAc/dioxane/H2O
T (°C)
yield (%)
1
2
3
4
5
6a
Na2PdCl4 (40%)
Na2PdCl4 (40%)
Na2PdCl4 (40%)
Pd(TFA)2 (40%)
Na2PdCl4 (40%)
Na2PdCl4 (40%)
t-BuOOH (1.5)
t-BuOOH (1.5)
t-BuOOH (1.5)
t-BuOOH (1.5)
t-BuOOH (1.5)
t-BuOOH (1.5)
55
55
80
80
80
80
20
37
45
40
50
60
a With 1 equiv of NaOAc.
free Nb-nitrogen function, was obtained in 92% yield. With
the secondary alcohol 11 in hand, attempts to convert it into
the ketone 12 accompanied by oxygenation at C(6) returned
a promising result. Recently, a process for the oxidation of
benzylic positions effected by IBX has been developed by
Nicolaou.20 Consequently, oxidation of the secondary alcohol
of 11 into the ketone 12 with the first equivalent of IBX
could be accomplished in 1 h, after which time an additional
3 equiv of IBX could be added to oxidize the C(6) position
of 12 to afford the desired oxygenated system in 13 (85%
overall yield). Simple alteration of the number of equivalents
of IBX could provide either the ketone 12 or the 6-oxo ketone
13. The 6-oxo ketone 13 was then stirred with methyl iodide
in THF at 0 °C to furnish the Nb-methiodide salt to undergo
a retro-Michael reaction analogous to the earlier biomimetic
work of Le Quesne and Garnick.21 This salt was stirred under
modified conditions with K2CO3 in refluxing THF to provide
the ring-opened enone 14 via the retro-Michael reaction in
greater than 90% yield. With this stable 6-oxo enone 14 in
hand, attention next turned to conversion into the corre-
sponding dihydropyranyl enone system present in the natural
6-oxoalstophylline 1. Liu12,22 and Le Quesne21 both previ-
ously reported different strategies to approach the synthesis
of alkaloids related to 6-oxoalstophylline 1, which were not
practical in the present case. To accomplish the synthesis,
an efficient and general transformation to form enones in
indole systems in the presence of methoxyl substitutents must
be developed. A domino process which permitted deprotec-
tion of the TIPS protecting group followed by carbon-
oxygen bond formation would be efficient, if successful. In
1980, Tsuji et al.23 reported that under acidic conditions R,â-
unsaturated carbonyl compounds could regioselectively be
converted into 1,3-dicarbonyl compounds. This modified
acidic Wacker-related process seemed promising. In the
model system, the macroline equivalent 15 was employed
as the substrate (Table 1). Successful transformation to (-)-
alstonerine 16 (four operations here) was accomplished in
20% yield under the original conditions of Tsuji et al.23 This
was significant because under normal Wacker conditions the
presence of a substituent on the vinylic carbon atom adjacent
to the carbonyl group resulted in no reaction or a very poor
yield.24,25 To the best of our knowledge, this is the first
example of a Wacker oxidation involving an R-substituted
R,â-unsaturated ketone. When t-BuOH or dioxane was
employed as cosolvent to provide a homogeneous solution
(entries 2 and 4, Table 1) or the reaction temperature was
increased (entry 3, Table 1), yields were improved. Replace-
ment of Na2PdCl4 with Pd(TFA)2 decreased the yield,
presumably, because the choloride ions stabilized the Pd(0)
and prevented formation of Pd black. This had facilitated
the oxidation of Pd(0) to Pd(II) in the catalytic cycle.
Surprisingly, on addition of 1 equiv of NaOAc (entry 6) to
the mixture, (-) alstonerine 16 could be obtained in 60%
yield (includes four transformations, each in greater than 85%
Scheme 3
(20) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. J. Am Chem. Soc. 2001,
123, 3183.
(21) Garnick, R. L.; LeQuesne, P. W. J. Am. Chem. Soc. 1978, 100,
4213.
(22) Liu, X. Ph.D. Thesis, University of WisconsinsMilwaukee, WI,
2002.
(23) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257.
Org. Lett., Vol. 7, No. 16, 2005
3503

yield). Further optimization and generalization of this process
are under investigation.
Scheme 4
Although the detailed mechanism is not clear, a proposed
one is illustrated in Scheme 3. The process is believed to
originally involve the fast and reversible coordination of the
alkene by the Pd(II) salt. Under acidic conditions, in the
presence of chloride ions the silyl group was cleaved to
afford nucleophilic oxygen which attacked the Pd(II) olefin
complex. â-Hydride elimination, followed by reductive
elimination (see Scheme 3), provided the desired 16, while
the Pd(0) was reoxidized to Pd(II) by t-BuOOH.
Once the optimized conditions were in hand, the process
was carried out with 6-oxo enone 14 to provide 6-oxoalsto-
phylline 1 in 57% yield. The spectral properties of 1 were
in excellent agreement with the natural product.16 It must
be pointed out that four transformations were also executed
in this one-pot process, each of which took place in over
85% yield. This represents the first synthesis of 1 and was
completed in regiospecific, enantiospecific fashion. In ad-
dition, extension of this Wacker process to the 11-methoxy-
macroline substrate 17 provided a much improved total
synthesis of alstophylline 2 (four transformations, 55%
overall yield). Because a more efficient and practical
synthesis of alstophylline 2 was accomplished, this can be
coupled with (+)-macroline (gram quantities have been
prepared11) to provide an improved total synthesis of the
bisindole alkaloid, macralstonine 3.
In conclusion, a Wacker-related process was utilized in
the first total synthesis of 6-oxoalstophylline 1, which also
provided much improved routes to (-)-alstonerine, (-)-
alstophylline, and macralstonine (Scheme 4). Because al-
stonerine, alstophylline, 6-oxoalstophylline, alstonisine, and
Nb-demethylalstophylline oxindole contain the dihydropy-
ranyl enone system in ring E, this Wacker process provides
a rapid entry into this enone system for the synthesis of a
number of indole alkaloids including bisindole alkaloids. The
one-pot domino Wacker process is efficient and practical.
Acknowledgment. We acknowledge NIMH (in part) and
the Graduate School (UWM) for support of this work.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
(25) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S. J. Org. Chem.
1987, 52, 1758.
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