Total synthesis of ent-dihydrocorynantheol by using a proline-catalyzed asymmetric addition reaction

Article abstract of DOI:10.1021/ol0530575

9-Tosyl-3,4-dihydro-β-carboline reacted with 3-ethyl-3-buten-2-one in the presence of (S)-proline to give (3R,12bR)-3-ethyl-12-tosyl-3,4,6,7,8,9,-10, 11,12,12b-decahydro-1H-indolo[2,3-a]quinolizin-2-one in complete enantio- and diastereoselectivity. The c

Full text of DOI:10.1021/ol0530575

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1533-1535
Total Synthesis of
ent-Dihydrocorynantheol by Using a
Proline-Catalyzed Asymmetric Addition
Reaction
Takashi Itoh,* Masashi Yokoya, Keiko Miyauchi, Kazuhiro Nagata, and
Akio Ohsawa
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
itoh-t@pharm.showa-u.ac.jp
Received December 17, 2005
ABSTRACT
9-Tosyl-3,4-dihydro-â-carboline reacted with 3-ethyl-3-buten-2-one in the presence of (S)-proline to give (3R,12bR)-3-ethyl-12-tosyl-3,4,6,7,8,9,-
10,11,12,12b-decahydro-1H-indolo[2,3-a]quinolizin-2-one in complete enantio- and diastereoselectivity. The compound thus obtained was readily
transformed to ent-dihydrocorynantheol in three steps.
In recent years, asymmetric syntheses with organic com-
pounds as catalysts have attracted much attention1 due to
their environmentally benign nature compared with conven-
tional transition metal catalysts, and there have been many
reactions in which chiral amines such as proline,2 amino
acids, and their derivatives3 are used as catalysts. Despite
intense studies of this area, however, there are few reports4
which adopted the methodology as a tool for asymmetric
total synthesis of natural products.
In the course of our research for the synthesis of chiral
1-substituted 1,2,3,4-tetrahydro-â-carboline derivatives,5 we
found that 9-tosyl-3,4-dihydro-â-carboline (1)6 is a good
substrate for the asymmetric addition of methyl ketones in
the presence of (S)-proline.7 We further investigated the
reaction using various methyl ketone derivatives, and found
that the use of 3-ethyl-3-buten-2-one resulted in concise
asymmetric synthesis of ent-dihydrocorynantheol. This paper
describes these results.
Although there are many reports concerning diastereose-
lective synthesis of indole alkaloids,8 to carry out the
synthesis in an enantioselective manner remains a formidable
challenge.9 1,2,3,4-Tetrahydro-â-carboline derivatives having
(1) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3276. (c)
List, B. Acc. Chem. Res. 2004, 37, 548. (d) Alleman, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37,
558.
(2) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395.
(3) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
(4) (a) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D.
W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482. (b) Mangion, I. K.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696.
(5) (a) Itoh, T.; Matsuya, Y.; Enomoto, Y.; Ohsawa, A. Tetrahedron
2001, 57, 7277. (b) Itoh, T.; Miyazaki, M.; Ikeda, S.; Nagata, K.; Yokoya,
M.; Matsuya, Y.; Enomoto, Y.; Ohsawa, A. Tetrahedron 2003, 59, 3527.
(6) Rey, A. W.; Szarek, W. A. Can. J. Chem. 1992, 70, 2922.
(7) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org.
Lett. 2003, 5, 4301.
10.1021/ol0530575 CCC: $33.50
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Published on Web 03/17/2006

a substituent at the C-1 position widely exist in nature as a
constituent of indole alkaloids, but construction of the chiral
center at an early stage is a minor approach10 for the total
synthesis of indole alkaloids. We planned to reinvestigate
such an approach because these compounds are thought to
be general precursors for asymmetic synthesis of the
alkaloids, and found that N-tosyl-3,4-dihydro-â-carboline (1)
reacted with methyl vinyl ketones in a highly enantioselective
mannner catalyzed by (S)-proline.7 Thus, we extended our
attention to the synthesis of the addition products which have
more than two chiral centers. The first attempt was carried
out with commercially available 1-acetylcyclohexene as a
methyl ketone, and it was found that the addition product 2
was solely obtained in a completely stereoselective manner.11
Thus, the three chiral centers were formed in a single step
(Scheme 1).
Our reaction was commenced with the reaction of 1 with
3-ethyl-3-buten-2-one (4)18 in the presence of (S)-proline
(Scheme 2), and the use of 30 equiv of 419 and 30 mol % of
Scheme 2. Reaction of 9-Tosyl-3,4-dihydro-â-carboline (1)
with 3-Ethyl-3-buten-2-one in the Presene of (S)-Proline
Scheme 1. Reaction of 9-Tosyl-3,4-dihydro-â-carboline (1)
with 1-Acetylcyclohexene in the Presene of (S)-Proline
(S)-proline afforded the product 5 in a good yield of 85%
with 99% ee in the DMSO solvent.20
Since there were no intermediates observed in the reaction,
we could not conclude whether the reaction proceeded via
Mannich-Michael reaction or a Diels-Alder-type addition.
It was thought, however, that the present reaction is a
Mannich-Michael reaction rather than a hetero-Diels-Alder
reaction, because the reaction proceeded in the same manner
as with simple methyl ketones as reagents.7 The reaction of
1 and 4 proceeded smoothly when the excess amount (3
equiv) of proline was used in the presence of 10 equiv of
the enone to give quantitative yield of the product in 99%
ee in 3 days. The result suggested that the first addition step
is a rate-determining process. The stereochemistry of the
product 5 was determined by the elimination of the tosyl
group to give a ketone 6, which was synthesized by Meyers
et al.16 Thus, the formation of the D ring of the target
The result prompted us to apply the process to both
enantioselective and diastereoselective reactions using an
enamine derived from (S)-proline and 3-ethyl-3-buten-2-one
as a nucleophile to construct the D-ring of an alkaloid, which
has an ethyl group on the C-3 position to give corynanthe
alkaloids. Thus, the addition reaction was carried out with
3-ethyl-3-buten-2-one aiming at the synthesis of dihydro-
corynantheol (3),12 which was isolated from Aspidosperma
marcgravianum, and shows activity against gram-positive
bacteria. In a recent paper,13 Martin et al. performed a concise
diastereoselective synthesis of the compound in excellent
overall yield using ring-closing metathesis as a key reaction.
There are several total syntheses of 3,14 and three of them
are asymmetric synthesis with the chiral pool,15 a chiral
auxiliary,16 or a resolution step.17
(14) (a) Ziegler, F. E.; Sweeny, J. G. Tetrahedron Lett. 1969, 14, 1097.
(b) Kametani, T.; Kanaya, N.; Honda, T.; Ihara, M. Heterocycles 1981, 16,
1937. (c) Ihara, M.; Taniguchi, N.; Fukumoto, K.; Kametani, T. J. Chem.
Soc., Chem. Commun. 1987, 1438. (d) Lounasmaa, M.; Jokela, R.;
Tirkonnen, B.; Miettinen, J.; Halonen, M. Heterocycles 1992, 34, 321. (e)
Diez, A.; Villa, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M. Tetrahedron
Lett. 1993, 34, 733.
(8) (a) Monoterpenoid Indole Alkaloids, Supplement to Part 4; Saxton,
J. E., Ed.; John Wiley & Sons: Chichester, UK, 1994. (b) Rahman, A.-u.;
Basha, A. Indole Alkaloids; Harwood Academic Publishers: Amsterdam,
The Netherlands, 1998.
(9) Cox, E.; Cook, J. M. Chem. ReV. 1995, 95, 1797 and references
therein.
(15) Suzuki, T.; Sato, E.; Unno, K.; Kametani, T. Heterocycles 1985,
23, 835.
(10) (a) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51,
3108. (b) Meyers, A. I.; Miller, D. B.; White, F. H. J. Am. Chem. Soc.
1988, 110, 4778. (c) Meyers, A. I. Tetrahedron 1992, 48, 2589. (d) Martin,
S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236. (e) Martin,
S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79.
(11) The relative configuration of 2 was determined by using the NOE
analysis (see the Supporting Information). The absolute configuration was
speculated according to those of the other addition products.
(12) Gilbert, B.; Antonaccio, L. D.; Djerassi, C. J. Org. Chem. 1962,
27, 4702.
(16) Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091.
(17) Ohba, M.; Ohashi, T.; Fujii, T. Heterocycles 1991, 32, 319.
(18) Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1973, 95, 553.
(19) Since the present reaction was slow, the excess amount of the enone
was necessary for the progress of the reaction in tolerable time. The self-
reaction of enones in the presence of proline catalyst was not observed in
the present reaction; see: Ramachary, D. B.; Chowdari, N. S.; Barbas, C.
F., III Tetrahedron Lett. 2002, 43, 6743.
(20) Although the other solvents such as CH2Cl2, CH3CN, DMF, and
THF were used for the reaction, the results were inferior to that of the
DMSO solvent.
(13) Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243.
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Org. Lett., Vol. 8, No. 8, 2006

quantitatively in the ratio of E/Z ) 20. The reaction of 7
with Red-Al occurred at two reactive sites, that is, the
reductive elimination of the tosyl group and the reduction
of the ester group to an alcohol. Finally, hydrogenation of
alcohol 8 afforded ent-dihydrocorynantheol (3) in 74% yield.
Therefore, the asymmetric total synthesis of 3 was performed
in 38% overall yield via 4 steps.While our synthesis targeted
the enantiomer of the natural product, the natural series is
equally accessible by using (R)-proline as a catalyst.
In this paper, we described a new method for the
asymmetric synthesis of ent-dihydrocorynantheol using pro-
line-catalyzed asymmetric addition of 3-ethyl-3-buten-2-one
to compound 1. The procedure was readily carried out in
the presence of air and moisture to give a single stereoisomer.
With use of the addition product, the target compound was
obtained in short steps with complete stereoselectivity.
Application of the present reaction to the synthesis of other
alkaloids is under investigation in our laboratory, and the
results will be published in due course.
Scheme 3. Synthesis of ent-Dihydrocorynantheol
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
molecule was accomplished in a single step with the correct
configuration and in a high yield. Compound 5 was then
allowed to react with a Wittig reagent to give an alkene 7
OL0530575
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