First asymmetric total syntheses of (-)-subincanadines A and B, skeletally rearranged pentacyclic monoterpenoid indole alkaloids in Aspidosperma subincanum

Article abstract of DOI:10.1021/ol061908i

We achieved the first asymmetric total syntheses of novel Aspidosperma indole alkaloids, (-)-subincanadines A and B, which involve an intramolecular diastereoselective Pictet-Spengler cyclization and an intramolecular Nozaki-Hiyama-Kishi reaction as key steps in the total syntheses.

Full text of DOI:10.1021/ol061908i

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4605-4608
First Asymmetric Total Syntheses of
)-Subincanadines A and B, Skeletally
(−
Rearranged Pentacyclic Monoterpenoid
Indole Alkaloids in Aspidosperma
subincanum
Kenta Suzuki and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
takayama@p.chiba-u.ac.jp
Received August 2, 2006
ABSTRACT
We achieved the first asymmetric total syntheses of novel Aspidosperma indole alkaloids, (−)-subincanadines A and B, which involve an
intramolecular diastereoselective Pictet
syntheses.
−Spengler cyclization and an intramolecular Nozaki−Hiyama−Kishi reaction as key steps in the total
Several structurally unique indole alkaloids, named subin-
canadines A-G (1-7) (Figure 1), have been isolated from
a Brazilian medicinal plant, Aspidosperma subincanum, by
Kobayashi et al.1 Among them, subincanadines A-C and G
(1-4) have a novel pentacyclic skeleton with a 1-azoniatri-
cyclo[5.2.2.01,6]undecane moiety. Further, the presence of a
chiral quaternary carbon at the C-16 position is a charac-
teristic that distinguishes these alkaloids from hitherto known
monoterpenoid indole alkaloids having a â-carboline skel-
eton.2 Quite recently, an approach for the construction of
the framework of subincanadine B in the racemic form was
reported in this journal.3 Herein, we disclose the first
asymmetric total syntheses of (-)-subincanadine A (1) and
(-)-subincanadine B (ent-2), which involve an intramolecular
diastereoselective Pictet-Spengler cyclization and an in-
tramolecular Nozaki-Hiyama-Kishi reaction4 as key steps
in the concise total syntheses.
(1) (a) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.;
Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449. (b) Ishiyama, H.;
Matsumoto, M.; Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Kobayashi, J.
Heterocycles 2005, 66, 651.
(2) (a) The Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; Supple-
ment to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds;
Wiley: Chichester, 1994. (b) Takayama, H.; Kitajima, M.; Kogure, N. Curr.
Org. Chem. 2005, 9, 1445.
Figure 1. Structures of subincanadines.
10.1021/ol061908i CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006

Scheme 1. Retrosynthetic Analysis
Scheme 2
Our initial synthetic plan is shown in Scheme 1. The
Pictet-Spengler reaction using ketone derivatives has not
been studied much5 compared with that using alde-
hyde derivatives; however, we anticipated that the Pictet-
Spengler cyclization of tryptamine with ketone 12a bear-
ing an optically active secondary alcohol at the R position
should provide 1,1-disubstituted tetrahydro-â-carboline de-
rivative 11 in a diastereoselective and enantioselective
manner. The Nozaki-Hiyama-Kishi reaction of ketone
derivative 9, which can be obtained by alkylation of the
secondary amine with allyl bromide 10 and transformation
of the secondary hydroxyl group, should provide tetracyclic
intermediate 8. Subsequent ring closure between the amine
and the primary alcohol was expected to complete the total
synthesis.
We initially attempted the conventional Pictet-Spengler
reaction of tryptamine with optically active ketone 12a,
which was prepared from (S)-malic acid via a six-step
operation (Scheme 2) including protection of the 1,2-
carboxylic acid-alcohol residue,6 reduction of the remaining
carboxylic acid, formation of a γ-lactone,7 BOM ether
protection of the secondary hydroxyl group, preparation of
methyl ketone by treatment with methyllithium, and finally
protection of the resultant primary alcohol. The reaction
conducted in DCM in the presence of TFA under reflux
conditions provided two 1,1-disubstituted tetrahydro-â-
carboline compounds such as 11 in a nondiastereoselective
manner, and both products showed low optical activity,
probably owing to the racemization of the chiral center in
12a during the reaction under acidic conditions.
Then, we devised the intramolecular Pictet-Spengler
reaction using carbamate 17 that tethered tryptamine and
optically active ketone 16. Hydroxy ketone 16 was prepared
from γ-lactone 14 via a four-step operation (Scheme 2): TBS
protection of the secondary hydroxyl group,7 preparation of
methyl ketone 12b by treatment with methyllithium, protec-
tion of the resultant primary alcohol, and finally removal of
the protecting group from the secondary alcohol. Carbamate
17, obtained in 83% yield by the condensation of tryptamine
and 16 with 1,1′-carbonyldiimidazole (CDI),8 was found to
exist in the hemi-aminoacetal form 18 in solution as
demonstrated by the chemical shift appearing at δ 88.9 (C-
16) in the 13C NMR spectrum (Scheme 2).
(3) Liu, Y.; Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.;
Zhai, H. Org. Lett. 2006, 8, 115.
(4) (a) For a review, see: Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (b)
Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron
Lett. 1983, 24, 5281. (c) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (d) For an
example of intramolecular reaction between ketone and vinylbromide, see:
Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2, 1601.
(5) For examples of Pictet-Spengler cyclization using ketone derivatives,
see: (a) Rodr´ıguez, J. G.; Gil-Lopetegui, P. J. Heterocycl. Chem. 1993,
30, 373. (b) Horiguchi, Y.; Nakamura, M.; Kida, A.; Komada, H.; Saitoh,
T.; Sano, T. Heterocycles 2003, 59, 691. (c) Kuo, F.-M.; Tseng, M.-C.;
Yen, Y.-H.; Chu, Y.-H. Tetrahedron 2004, 60, 12075.
Several acids and solvents were examined in our attempt
to obtain high diastereoselectivity in the Pictet-Spengler
(6) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58,
7768.
(7) Schinzer, D.; Bauer, A.; Schieber, J. Chem.-Eur. J. 1999, 5,
2492.
(8) D’Addona, D.; Bochet, C. G. Tetrahedron Lett. 2001, 42, 5227.
Org. Lett., Vol. 8, No. 20, 2006
4606

cyclization of compound 18. The best result was obtained
when TMSCl was used as the Lewis acid in DCM at -78
°C, affording 19 in quantitative yield as a 9:1 mixture of
diastereomers.9 This mixture was separated by recrystalli-
zation to give single diastereomer 19, the enantiomeric excess
of which was determined to be 99% by chiral HPLC
analysis.10 The stereochemistry of the major product was
determined by NOE experiments: irradiation of the protons
on the methyl group at C16 caused a significant enhancement
of the protons on the methylene group (C14) of the side
chain, demonstrating the cis relationship of those groups as
well as the S configuration at the C-16 position. The high
diastereoselectivity of the cyclization could be interpreted
by the plausible acyliminium intermediate,11 in which the
indole nucleus would attack from the less-hindered side (anti
from the side chain), as depicted in Figure 2.
Scheme 3
Figure 2. Possible mechanism in intramolecular Pictet-Spengler
cyclization.
and 24b in 35% and 53% yield, respectively. The stereo-
chemistry of the newly formed stereogenic center in 24a and
24b was elucidated by NOE experiments (Scheme 4).
Irradiation of the protons on the methyl group at C16 in 24b
caused a significant enhancement of the protons on the
methylene group (C14) of the side chain, demonstrating the
cis relationship of these groups. On the other hand, no NOE
was observed between the protons on the methyl group at
C16 and the protons on the methylene group (C14) of the
side chain in 24a, implying the anti relationship of these
groups. Moreover, by irradiating H-19 in both tetracyclic
compounds, a significant enhancement of H-21 was ob-
served, respectively, revealing the retention of the geometry
of the double bond.14
Next, the protecting group on the primary alcohol was
switched to an MEM ether by a conventional procedure to
afford compound 20 (Scheme 3). The carbonyl group in
20 was removed by alkaline hydrolysis, and the result-
ing secondary amine was alkylated with allylic bromide 1012
to give iodide 22 in 72% overall yield from 20. The
secondary alcohol in 22 was then oxidized with IBX13 to
afford ketone 23, which was a key substrate for the
construction of the D ring in the Nozaki-Hiyama-Kishi
reaction. Treatment of 23 with NiCl2 and CrCl2 in DMSO
at room temperature gave two tetracyclic compounds 24a
1
(9) Diastereomeric ratio was determined by H NMR spectroscopy.
(10) Starting from achiral hydroxy ketone 16, we synthesized racemic
19 that was used for the control experiments on chiral HPLC analysis.
(11) For reviews of the chemistry of N-acyliminium ions, see: (a)
Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367. (b) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (c) For an example
of intramolecular cyclization through an acyliminium ion, see: Henegouwen,
W. G. B.; Fieseler, R. M.; Rutjes, F. P. J. T.; Hiemstra, H. Angew. Chem.,
Int. Ed. 1999, 38, 2214. (d) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem.
Soc. 2005, 127, 1473. (e) Nielsen, T. E.; Meldal, M. Org. Lett. 2005, 7,
2695.
In the final stage, the protecting group of the primary
alcohol in 24a was removed in 82% yield by treating with
TMSCl/NaI in MeCN15 and the resulting free alcohol was
(14) Isomerization of the geometry in trisubstituted alkenyl halide in an
intermolecular Nozaki-Hiyama-Kishi reaction was reported. See ref 4b.
(12) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307.
(13) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
Org. Lett., Vol. 8, No. 20, 2006
4607

product was completely identical to natural 1 in all respects
including the optical property: synthetic, [R]25D -10° (c 0.34,
Scheme 4
MeOH); natural, [R]23 -11° (c 1.0, MeOH).1a The spec-
D
troscopic data of the pentacyclic compound prepared from
25b were also identical to those of subincanadine B (2)
except for the optical rotation: synthetic, [R]25D -43° (c 0.35,
MeOH); natural, [R]23 +41° (c 1.0, MeOH).1a Therefore,
D
the synthetic compound corresponds to the enantiomer of
natural subincanadine B (2).
In conclusion, we achieved the first concise asymmetric
total syntheses of (-)-subincanadine A (16 steps, 2.7%
overall yield) and the ent form of natural subincanadine B
(16 steps, 6.8% overall yield), using (S)-malic acid as the
starting material. The syntheses involve an intramolecular
diastereoselective Pictet-Spengler cyclization and an in-
tramolecular Nozaki-Hiyama-Kishi reaction as key steps,
and the absolute configuration of the natural products was
demonstrated.
Acknowledgment. This work was partly supported by
Uehara Memorial Foundation.
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectral data for
compounds 12b, 16, 18-25, and synthetic (-)-subinca-
nadines A and B (1 and ent-2). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL061908I
(15) Nicolaou, K. C.; Yue, E. W.; LaGreca, S.; Nadin, A.; Yang, Z.;
Leresche, J. E.; Tsuri, T.; Naniwa, Y.; DeRiccardis, F. Chem.-Eur. J. 1995,
1, 467.
mesylated under conventional conditions to furnish spontane-
ously a pentacyclic quaternary ammonium compound. The
4608
Org. Lett., Vol. 8, No. 20, 2006