unexpected isomerization product or via an intermediate
accompanied by the undesired isomer. Moreover, its asym-
metric total synthesis has not yet been achieved. Herein,
we present the first total synthesis of (ꢀ)-hippodamine (3)
by a target-oriented approach based on our one-pot asym-
metric azaelectrocyclization protocol, in which all stereo-
genic centers of the objective azaphenalene ring have been
created in a highly stereocontrolled manner.
Scheme 1. (A) Chiral Piperidine Synthesis via One-Pot
Asymmetric 6π-Azaelectrocyclization; (B) Retrosynthesis
of Hippodamine
Figure 1. Structure of azaphenalene alkaloids.
Over the past five years, we have developed synthetic
methods for multisubstituted chiral piperidine compounds
based on a one-pot asymmetric azaelectrocyclization pro-
tocol from (ꢀ)-7-isopropyl-cis-1-amino-2-indanol (4),
ethyl (Z)-2-iodo-4-oxobutenoate 5, and vinylstannane 6
(Scheme 1A).6 This reaction integration of three components7
is a practical variant of a stepwise one under the kinetic
conditions8 and has played an important role in our recent
accomplishments of natural alkaroid syntheses.6b,dꢀf We
expected that this strategy could be applied to the facile
asymmetric synthesis of hippodamine (3). As shown in our
retrosynthesis (Scheme 1B), we envisioned the azaphena-
lene ring of 3 could be stereoselectively constructed by the
intramolecular Mannich reaction of 2β,4R,6R-trisubsti-
tuted chiral piperidine compound 7, whose substitution
pattern would be favorable for the desired cyclization.
The 2β and 4R substituents of 7 would be derived from
the tetracyclic compound 8 by stereoselective alkylation
of the aminal moiety and diastereoselective hydrogenation
of the olefin moiety based on its characteristic structure.
The enantiomerically pure compound 8 including the
C-6 stereogenic center was planned to be synthesized in
one step via one-pot asymmetric 6π-azaelectrocyclization
from three components: (þ)-4, 5, and 6,6-ethylenedioxy-
1-hexenylstannane 9.
knowledge, not only the C-4 ester but also the C-6 arylic or
alkenyl group in the azatriene was essential for the smooth
electrocyclization as described in Scheme 1A.6,9 Therefore
optimization of the reaction conditions would be required
in the case of vinylstannane 9 which has a saturated alkyl
moiety. To obtain a criterion, we first attempted the reaction
utilizing our previously established conditions.6a Thus, the
mixture of conventionally prepared (þ)-410 and ethyl (Z)-2-
iodo-4-oxobutenoate 59 in DMF was added to stannane 911
and stirred in the presence of a Pd catalyst at 80 °C. Surpris-
ingly, the reaction proceeded smoothly in only 20 min to
afford the desired tetracyclic aminal 8 in 81% yield as a single
stereoisomer. This unexpected but favorable result clearly
showed that the accelerative effect of the C-6 olefinic sub-
stituent was not significant under these one-pot thermal
conditions in contrast with that of C-4 ester, which led to
the extension of the applicable scope of C-6 substituents.12
With the optically pure compound 8 in hand, we next
examined its conversion to 2β,4R,6R-trisubstituted piper-
idine intermediate7 (Scheme 3). According toour previous
reports,6b,f the conjugated double bond of compound 8
was reduced by Raney nickel to afford the desired 4R ester
10 in 84% yield with excellent chemo- and stereoselectivity
confirmed by an NOE experiment. To avoid the steric
repulsion with the C-6R substituent which was completely
restricted in pseudoaxial conformation, the reduction was
considered to occur predominantly from the less hindered
β-face. Then, the chemoselective reduction of ethyl ester to
Our synthesis commenced with the examination of a one-
pot azacyclization (Scheme 2). Based on our accumulated
(6) (a) Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.;
Katsumura, S. Org. Lett. 2006, 8, 3809. (b) Kobayashi, T.; Hasegawa,
F.; Tanaka, K.; Katsumura, S. Org. Lett. 2006, 8, 3813. (c) Kobayashi, T.;
Takeuchi, K.; Miwa, J.; Tsuchikawa, H.; Katsumura, S. Chem. Commun.
2009, 3363. (d) Li, Y.; Kobayashi, T.; Katsumura, S. Tetrahedron Lett.
2009, 50, 4482. (e) Sakaguchi, T.; Kobayashi, S.; Katsumura, S. Org.
Biomol. Chem. 2011, 9, 257. (f) Kobayashi, T.; Hasegawa, F.; Hirose, Y.;
Tanaka, K.; Mori, H.; Katsumura, S. J. Org. Chem. 2012, 77, 1812.
(7) Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 39, 404.
(8) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660.
(9) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org.
Chem. 2001, 66, 3099.
(10) Kobayashi, T.; Tanaka, K.; Miwa, J.; Katsumura, S. Tetra-
hedron: Asymmetry 2004, 15, 185.
(11) The stannane 9 was readily synthesized from 5-hexyn-1-ol in
three steps; see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX