Efficient total synthesis of (-)-stemoamide

Article abstract of DOI:10.1039/c0ob00850h

An efficient diastereoselective synthesis of (-)-stemoamide has been accomplished from a pyroglutamic acid derivative in eight steps and with 24% overall yield. The synthesis features an intramolecular samarium diiodide-promoted 7-exo-trig cyclization of

Full text of DOI:10.1039/c0ob00850h

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Efficient total synthesis of (-)-stemoamide†
Toshio Honda,* Tomoha Matsukawa and Kazunori Takahashi
Received 8th October 2010, Accepted 19th November 2010
DOI: 10.1039/c0ob00850h
An efficient diastereoselective synthesis of (-)-stemoamide
has been accomplished from a pyroglutamic acid derivative
in eight steps and with 24% overall yield. The synthesis
features an intramolecular samarium diiodide-promoted 7-
exo-trig cyclization of a ketyl radical generated from the
corresponding aldehyde.
biological properties as well as their structural diversity, this class
of natural products has received considerable attention in recent
years, and the first total synthesis of 1 was accomplished by
Williams and co-workers in 1994.4 Thereafter several syntheses
and synthetic approaches to 1 have appeared sequentially, with
newly developed synthetic methods and strategies having been
applied to construct its core skeleton as the target molecule.5
The crucial step for the synthesis of 1 lies in the construction
of a tricyclic ring system by controlling the stereogenic centers
at the 1, 3a, 10a and 10b positions. We thought that the most
straightforward way to construct the desired stereochemistry at
the 10a position must be the use of (S)-pyroglutamic acid as the
starting material. Construction of a g-butyrolactone fused on the
seven-membered ring could be achieved by a carbon–carbon bond
formation between 3a and 10b (stemoamide numbering system as
depicted in Fig. 1) by exploitation of an intramolecular samarium
diiodide-promoted conjugate addition of a ketyl radical6 generated
in situ from a corresponding aldehyde, to an a,b-unsaturated ester,
followed by a stereoselective installation of a methyl group at the 1-
position at the last stage of the synthesis. Our retrosynthetic route
for 1 is depicted in Scheme 1. The synthetic strategy we planned
here would require relatively short reaction sequences compared
to those in previous works.5
Stemoamide 1, isolated from the roots and rhizomes of Ste-
monaceous plants together with its related polycyclic alkaloids,
stemonine 2, stenine 3 and stemospironine 4, is the structurally
simplest alkaloid among the Stemona class of natural products
(Fig. 1).1 The roots of Stemona tuberosa Lour and related Stemona
species (Stemonaceae) are used in Chinese traditional medicine as
antitussive agents2 and also as insecticides and anthelmintics.3
Thus, the requisite key aldehyde (11) was prepared starting
from the known lactam (5)5d–f as follows. Alkylation of the
lactam (5) with 2-(4-bromobutoxy)tetrahydro-2H-pyran7 in the
presence of NaHMDS at -15 ◦C in DMF afforded an alkylation
product (6) in 88% yield. After removal of the silyl group of
6 upon treatment with ammonium fluoride in MeOH under
reflux, the resulting primary alcohol 7 was converted to the
aldehyde (8) by Swern oxidation. Wittig reaction of 8 with methyl
(triphenylphosphoranylidene)acetate in acetonitrile at ambient
temperature gave the (E)-olefin (9), in 82% yield from 7, which on
treatment with p-TsOH in MeOH furnished the primary alcohol
(10) in 92% yield. Oxidation of the alcohol (10) by Swern oxidation
provided the desired aldehyde (11) in 85% yield.
With the pivotal precursor in hand, we attempted a samarium
diiodide-promoted carbon–carbon bond forming reaction via
a 1,4-conjugate addition of a ketyl radical generated in situ
from aldehyde 11 under various reaction conditions. First, an
intramolecular coupling of aldehyde 11 was conducted with 5.0
equivalents of samarium diiodide in THF in the presence of 5.0
equivalents of MeOH as the proton source at 0 ◦C for 3 h to give
an inseparable diastereoisomeric mixture of coupling products 12
and 13 in 60% yield (Scheme 2).
Fig. 1 Structures of typical Stemona alkaloids.
The structure of 1 was determined mainly by spectroscopic
methods to contain a g-butyrolactam that forms part of a
pyrrolo[1,2-a]azepine ring system fused on a g-butyrolactone ring
with four contiguous stereogenic centers. Due to their interesting
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41,
Shinagawa-ku, Tokyo, 142-8501, Japan. E-mail: honda@hoshi.ac.jp;
Fax: +81-3-5498-5791; Tel: +81-3-5498-5791
† Electronic supplementary information (ESI) available: Detailed exper-
imental procedures and characterization data for compounds 6–18, 1H
NMR and 13C NMR spectra for the key compounds 6, 7, 9, 10, 11, 15, and
16, and also 1. See DOI: 10.1039/c0ob00850h
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rotation, mp 156–157 C (lit.,5f mp 157–158 ◦C); [a]D -204 (c
0.4, CHCl3) {lit.,5f [a]D -224 (c 0.4, CHCl3)} were comparable
to those reported in the literature.5f Further transformation of 15
to stemoamide 1 was achieved via the known g-butyrolactone 16
by reduction of its carbon–carbon double bond with nickel(II)
chloride and sodium borohydride and subsequent stereoselective
methylation of 16 with methyl iodide according to the literature
procedure.5f Again, spectroscopic data of those compounds were
similar to those reported in the literature.5f
Thus, this synthesis constitutes an alternative total synthesis of
(-)-stemoamide.
In this synthesis, however, the expected diastereoselectivity
could not be obtained in the key cyclization step. Fortunately, when
a samarium diiodide-promoted carbon–carbon bond forming
reaction was carried out with 5.0 equivalents of samarium diiodide
in THF in the presence of HMPA at 0 ◦C for 3 h, the desired
lactone 16 was isolated in 55% yield, [a]D -97.8 (c 0.3, CHCl3)
{lit.,5f [a]D -94.0 (c 0.4, CHCl3)}, together with a trace amount of
the diastereoisomer (17).‡ Again, a stereoselective methylation of
16 afforded stemoamide 1.
Similar stereocontrol in different reactions depending upon the
reaction conditions was also observed by several groups dur-
ing samarium diiodide-promoted coupling reaction of carbonyl
compounds in the presence or absence of HMPA.8 For further
investigation of the stereoselectivity, the (Z)-isomer of olefin 18,
prepared from 5 in five steps involving Ando’s variant of the Wittig
reaction9 as a key step, was subjected to the coupling reaction
(Scheme 3).
Scheme 1 Retrosynthetic route for (-)-stemonamide 1.
By careful examination of their NMR spectra, the structures
of the products were assumed to be 125d and 135j,5k with a ratio
of 1 : 0.9. To confirm their structures unambiguously, partially
separated 12 was treated with phenylselenyl bromide in the
presence of LiHMDS in THF at -78 ◦C for 2 h to give selenide 14,
which upon subsequent treatment with 30% hydrogen peroxide
gave butenolide 15 as an oxidative elimination product in 85%
yield. Spectroscopic data of 15 including its specific optical
Again, the desired compound 16 was obtained by the reaction
of 18 with samarium diiodide in the presence of HMPA in 39%
yield, as the major coupling product. On the other hand, a similar
Scheme 2 Synthesis of stemoamide by a SmI2-promoted coupling of 11 in the absence of HMPA.
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from the corresponding aldehyde. The strategy developed here is
applicable to the synthesis of other types of alkaloids including
the Stemona class of natural products.
This research was supported financially in part by a grant for
The Open Research Center Project and a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan.
Notes and references
‡ Compound (17) could not be isolated in pure form, unfortunately, due
to the small amount available.
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5 Total and formal syntheses of (-)- and ( )-stemoamide:(a) A. Kinoshita
and M. Mori, J. Org. Chem., 1996, 61, 8356; (b) P. A. Jacobi and K. Lee,
J. Am. Chem. Soc., 2000, 122, 4295; (c) M. K. Gurjar and D. S. Reddy,
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Xu, W. Liu, C. Sun and H. Zhai, Synlett, 2009, 2188; (l) Recent review
for the synthesis of Stemona alkaloids: R. Alibe´s and M. Figueredo,
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6 For reviews of SmI2-mediated reaction, see: (a) J. A. Soderquist,
Aldrichim. Acta, 1991, 24, 15; (b) G. A. Molander, Chem. Rev., 1992, 92,
29; (c) G. A. Molander, Org. React., 1994, 46, 211; (d) G. A. Molander
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C. R. Harris, Tetrahedron, 1998, 54, 3321; (f) G. A. Molander, Acc.
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Scheme 3 SmI2-promoted coupling of 11 and 18 in the presence of
HMPA.
reaction of 18 in the absence of HMPA furnished a mixture of
12 and 13 in moderate yield, with a ratio of 1 : 0.7. These results
clearly indicated that the stereochemistry at the carbon–carbon
double bond did not affect the stereoselectivity of the product(s)
for the samarium diiodide-promoted coupling and suggested that
the chelation transition model usually observed6m,n in the absence
of HMPA might not be involved in the coupling reaction in the
presence of HMPA.
Although the precise reaction mechanism remained unclear,
the observed stereoselectivity would be rationalized by assuming
that the coupling reaction in the presence of HMPA proceeded
through the most sterically favored diradical transition state (TS-
A), where two functional groups were located in an energetically
preferable diequatorial-like orientation as depicted in Fig. 2. The
strong redox potential of samarium diiodide in the presence of
HMPA10 would make it possible to generate diradicals, as the key
intermediate, as suggested by Matsuda and co-workers.8a
7 T. L. Bouder, L. Viau, J.-P. Gue´gan, O. Maury and H. L. Bozec, Eur. J.
Org. Chem., 2002, 3024.
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F. Matsuda, Synlett, 1997, 479; (b) K. Suzuki, H. Matsukawa, G.
Matsuo, H. Koshino and T. Nakata, Tetrahedron Lett., 2002, 43, 8653;
(c) N. Hori, H. Matsukawa, G. Matsuo, H. Koshino and T. Nakata,
Tetrahedron, 2002, 58, 1853.
9 (a) K. Ando, J. Org. Chem., 1997, 62, 1934; (b) K. Ando, J. Org. Chem.,
1999, 64, 8406.
Fig. 2 Plausible transition state for the stereoselectivity.
In summary, we were able to establish an efficient stereoselective
synthesis of (-)-stemoamide 1 starting from the known lactam 5,
readily accessible from pyroglutamic acid, in eight steps and with
24% overall yield. Our synthesis features a samarium diiodide-
promoted 7-exo-trig cyclization of a ketyl radical generated in situ
10 (a) J. Inanaga, M. Ishikawa and M. Yamaguchi, Chem. Lett., 1987,
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Lett., 1997, 38, 1137; (e) M. Shabangi, J. M. Sealy, J. R. Fuchs and R.
A. Flowers Jr., Tetrahedron Lett., 1998, 39, 4429.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 673–675 | 675
©