Novel and efficient synthetic path to proaporphine alkaloids: Total synthesis of (±)-stepharine and (±)-pronuciferine

Article abstract of DOI:10.1021/ol052841m

A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where an unprecedented carbon-carbon bond forming reaction between the para-position of a phenol group and an enamide-carbo

Full text of DOI:10.1021/ol052841m

ORGANIC
LETTERS
2006
Vol. 8, No. 4
657-659
Novel and Efficient Synthetic Path to
Proaporphine Alkaloids: Total Synthesis
of (±)-Stepharine and (±)-Pronuciferine
Toshio Honda* and Hiroki Shigehisa
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received November 23, 2005
ABSTRACT
A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where
an unprecedented carbon carbon bond forming reaction between the para-position of a phenol group and an enamide-carbon took place
−
smoothly to give the desired spiro-cyclohexadienone.
Proaporphine alkaloids, a major isoquinoline alkaloid, have
been recognized as the biosynthetic precursors of aporphine
alkaloids bearing a wide range of oxygenated substitution
patterns with mainly a spiro-cyclohexadienone ring system.1
It has also been known that some of these alkaloids exhibit
interesting biological activities. For example, stepharine 1
has antihypertensive activity without side effects such as R-
or â-adrenergic blockade, sedative or depressant effects, or
ganglion blockade,2 and also inhibits cholinesterase and
pseudocholinesterase in vitro.3
The crucial step for the synthesis of these alkaloids
obviously lies in the construction of a spiro-cyclohexadienone
ring system. Although different routes to the proaporphine
skeleton involving phenol oxidation,4 photolysis,5 and Pschorr
cyclization6 of 1-benzylisoquinoline derivatives have been
developed, formation of the C8′-C1 bond serves as the key
step in many of the previous syntheses7 (Figure 1).
Figure 1. Sturctures of typical proaporphines.
Our own interest in proaporphine chemistry grew out of
a desire to develop an entirely new, perhaps practical and
general, route for the total synthesis of this class of natural
alkaloids.
(1) Kametani, T. In The Chemistry of the Isoquinoline Alkaloids; Kinkodo
Publishing Company: Sendai, Japan, 1974; Vol. 2, pp 141-150.
(2) Bhat, S. V.; Bhattacharya, B. K.; De Souza, N. J.; Dohadwalla, A.
N.; Kohl, H. Ger. Offen. 1977, CODEN GWXXBX DE 2557282 19770707.
(3) Berezhinskaya, V. V.; Trutneva, E. A. Tr. Vses. Nauchno-Issled. Inst.
Lek. Rast. 1971, 14, 66-69.
(4) (a) Kametani, T.; Yagi, H. Chem. Commun. 1967, 366-367. (b)
Kametani, T.; Yagi, H. J. Chem. Soc., Perkin Trans. 1 1967, 2182-
2184.
(5) (a) Horii, Z.; Nakashita, Y.; Iwata, C. Tetrahedron Lett. 1971, 1167-
1168. (b) Kametani, T.; Sugahara, T.; Sugi, H.; Shibuya, S.; Fukumoto, K.
Chem. Commun. 1971, 724. (c) Kametani, T.; Sugahara, T.; Sugi, H.;
Shibuya, S.; Fukumoto, K. Tetrahedron 1971, 27, 5993-5998. (d) Kametani,
T.; Fukumoto, K.; Shibuya, S.; Nemoto, H.; Nakano, T.; Sugahara, T.;
Takahashi, T.; Aizawa, Y.; Toriyama, M. J. Chem. Soc., Perkin Trans. 1
1972, 1435-1441. (e) Horii, Z.; Iwata, C.; Nakashita, Y. Chem. Pharm.
Bull. 1978, 26, 481-483.
10.1021/ol052841m CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/24/2006

Thus, we decided to investigate a synthesis of typical
proaporphine alkaloids, stepharine 1 and its N-methyl deriva-
tive, pronuciferine 2, isolated from Nelumbo nucifera8 and
Stephania glabra,9 respectively, as the target compounds.
There is only one report for the synthesis of 1,10 although
several syntheses of 2 have appeared to date.11
simple acylation, and B would be derived from amide C by
Bischler-Napieralski cyclization. The preparation of amide
C also would be possible from 5-bromo-3,4-dimethoxybenz-
aldehyde 3 by palladiun-catalyzed arylation, followed by
elongation of the side chain of aldehyde D.
In searching the structures of 1 and 2 for retrosynthetic
disconnection, we focused our attention on the direct
formation of the spiro-cyclohexadienone function by in-
tramolecular aromatic oxidation of a phenolic enamide A
with a hypervalent iodine reagent,12 as shown in Scheme 1,
Scheme 2
Scheme 1
where an unprecedented carbon-carbon bond formation
between the para-position of a phenol group and an enamide-
carbon was involved as the key reaction.
The key intermadiate, enamide A, would be prepared from
the corresponding 3,4-dihydroisoquinoline derivative B by
Thus, the arylation of 3-bromo-4,5-dimethoxybenzalde-
hyde13 3 with (p-hydroxyphenyl)boronic acid (1.1 equiv) was
carried out in the presence of palladium acetate (1 mol %),
triphenylphosphine (2.5 mol %), and sodium carbonate (1.2
equiv) in 1-propanol-H2O (2:1)14 at 100 °C to give biaryl
compound 4 in 85% yield. After protection of the phenolic
hydroxy group as its benzyl ether, aldehyde 5 was condensed
with nitromethane in the presence of ammonium acetate at
80 °C to afford nitrostyrene 6, which on reduction with
lithium aluminum hydride gave the corresponding phen-
ethylamine 7. Acetylation of 7 with acetyl chloride in the
presence of triethylamine provided amide 8 in 71% yield
from 5.
Since a phenolic function would be required for the
aromatic oxidation, the benzyl group of 8 was removed under
catalytic hydrogenation conditions to give phenolic com-
pound 9, before the Bischler-Napieralski cyclization.
Although two positions are possible for the Bischler-
Napieralski cyclization of 9, we assumed that the para-
position of the methoxy group would be the preferred
cyclization position. Indeed, the Bischler-Napieralski cy-
(6) Ishiwata, S.; Itakura, K.; Misawa, K. Chem. Pharm. Bull. 1970, 18,
1219-1223.
(7) Foe reviews, see: (a) Shamma, M. Alkaloids (London) 1975, 6, 170-
188. (b) Stephenson, E. K.; Cava, M. P. Heterocycles 1994, 39, 891-902
and references cited therein.
(8) Cava, M. P.; Nomura, K.; Schlessinger, R. H.; Buck, K. T.; Douglas,
B.; Raffauf, R. F.; Weisbach, J. A. Chem. Ind. 1964, 282-283.
(9) Bernauer, K. F. HelV. Chim. Acta 1963, 46, 1783-1785.
(10) Bernauer, K. HelV. Chim. Acta 1968, 51, 1120-1123.
(11) Synthesis of racemic pronuciferine, see: (a) Bernauer, K. Experientia
1964, 20, 380-381. (b) Kametani, T.; Yagi, H. J. Chem. Soc., Perkin Trans.
1 1967, 2182-2184. (c) Ishiwata, S.; Itakura, K.; Misawa, K. Chem. Pharm.
Bull. 1970, 18, 1219-1223. (d) Kametani, T.; Sugahara, T.; Sugi, H.;
Shibuya, S.; Fukumoto, K. Tetrahedron 1971, 27, 5993-5998. (e) Horii,
Z.; Nakashita, Y.; Iwata, C. Tetrahedron Lett. 1971, 17, 1167-1168. (f)
Horii, Z.; Iwata, C.; Nakashita, Y. Chem. Pharm. Bull. 1978, 26, 481-
483.
(12) For reviews, see: (a) Ochiai, M. ReV. Heteroatom Chem. 1989, 2,
92-111. (b) Moriarty, R. M. Synthesis 1990, 431-447. (c) Moriarty, R.
M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365-383. (d) Varvoglis, A.
The Organic Chemistry of Polycoordinated Iodine; VCH Publishers Inc.:
New York, 1992. (e) Kita, Y.; Tohma, H.; Yakura, T. Trends Org. Chem.
1992, 3, 113-128. (f) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96,
1123-1178. (g) Varvogolis, A. HyperValent Iodine in Organic Synthesis;
Academic Press: San Diego, CA, 1997. (h) Kitamura, T.; Fujiwara, Y.
Org. Prep. Proced. Int. 1997, 29, 409-458. Recent application to natural
product synthesis; see: (i) Mizutani, H.; Takayama, J.; Honda, T.
Tetrahedron Lett. 2002, 43, 2411-2414. (j) Mizutani, H.; Takayama, J.;
Honda, T. Synlett 2004, 328-330.
(13) Kao, C.-L.; Chem, J.-J. J. Org. Chem 2002, 67, 6772-6787.
(14) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Org. Synth.
1998, 75, 53-60.
658
Org. Lett., Vol. 8, No. 4, 2006

Scheme 3
Scheme 4
clization of 9 with phosphoryl chloride in acetonitrile
provided the desired 3,4-dihydroisoquinoline 10, regio-
selectively. The structure of 10 could be confirmed by
observation of NOEs between 5-H and 6-methoxy group,
respectively. Acylation of 10 with trifluoroacetic anhydride
yielded the key intermediate, enamide 11, in 58% yield from
8.
conditions in 79% yield. Again, the spectroscopic data of
the synthesized compound were identical with those re-
ported.16
Scheme 5
With the requisite enamide available, a study was made
for the best conditions for the aromatic oxidation.
On screening a variety of reaction conditions, such as the
species of iodine reagents, temperature, and solvents, for an
aromatic oxidation of 11, we found proper reaction conditions
for obtaining the desired cyclization product in reasonable
yield, as follows. The aromatic oxidation of 11 with PIDA
(iodobenzene diacetate) (1.1 equiv) in trifluoroethanol at 0
°C, followed by sodium borohydride reduction of the
resulting mixture, proceeded smoothly to give the desired
spiro-dienone 1 in 90% yield as the sole product. The labile
N-protecting trifluoroacetyl group was removed during this
conversion, simultaneously. The spectroscopic data of the
synthesized compound were identical with those reported in
the literature.15
In summary, we were able to develop a novel and efficient
synthesis of proaporphine alkaloids, and the synthetic strategy
developed was successfully applied to the total synthesis of
stepharine and pronuciferine. Further utilization of this
procedure in the synthesis of other types of isoquinoline and
indole alkaloids is in progress in our laboratory.
Thus, we succeeded in the facile synthesis of proaporphine
alkaloid, stepharine, in very short steps with remarkably high
yield, in which an unprecedented carbon-carbon bond-
forming reaction was involved as the key step.
Stepharine 1 was further converted into pronuciferine 2
by N-methylation with formalin under the reductive reaction
Acknowledgment. This work was supported by the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Bartley, J. P.; Baker, L. T.; Carvalho, C. F. Phytochemistry, 1994,
36, 1327-1331.
(16) Kametani, T.; Yagi, H. J. Chem. Soc., C 1967, 2182-2184.
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