Bioinspired and concise synthesis of (±)-stemoamide

Article abstract of DOI:10.1002/anie.201005833

Natural inspiration: A concise total synthesis of (±)-stemoamide was completed in eight steps with a 37 % overall yield. A bioinspired N-acyliminium ion cyclization and an unprecedented dynamic ruthenium-catalyzed cyclocarbonylation ensured the high efficiency of the synthesis. A novel silver-mediated cyclization of an allenic alcohol shows potential for the future asymmetric synthesis of the target. TMS=trimethylsilyl. Copyright

Full text of DOI:10.1002/anie.201005833

DOI: 10.1002/anie.201005833
Bioinspired Synthesis
Bioinspired and Concise Synthesis of (Æ )-Stemoamide**
Yan Wang, Lili Zhu, Yuying Zhang, and Ran Hong*
Dedicated to Professor Guo-Qiang Lin
Stemona alkaloids have interesting biological properties and
over 100 structurally diverse compounds have been identified
so far.[1] The common pyrrolo[1,2-a]azepine core associated
with the polycyclic architecture inspired many intriguing
synthetic strategies. The innovation of powerful synthetic
methods greatly improved the efficiency of the synthesis of
these alkaloids.[2] In 1992, Xu and co-workers isolated the
tricyclic stemoamide (1) from Stemona tuberosa Lour, the
Chinese traditional medicine that has been used for the
treatment of respiratory diseases such as asthma, bronchitis,
petusis, and tuberculosis.[3] Since the first asymmetric total
synthesis of (Æ )-stemoamide was completed by Williams
et al., numerous efforts have been devoted to the efficient
construction of this tricyclic system.[4,5] The ingenious seven-
step racemic synthesis reported by Jacobi and Lee marks a
milestone among these.[4d] Nevertheless, a general synthetic
strategy remains elusive.
Scheme 1. Biomimetic approach toward stemoamide (1).
To begin the synthesis, a modified procedure for the
alkynylation of the aldehyde 6 with propargyl trimethylsilane
(5) was undertaken.[8] The desired propargylic alcohol was
obtained in 93% yield on a gram scale by careful control of
the reaction temperature, reaction time, and exclusion of air
and moisture (Scheme 2). After protection of the alcohol with
TBS, the corresponding bromide 7 reacted with succinimide
and subsequent reduction using NaBH4 gave the hemiaminal
8 in excellent yield. Encouraged by the intramolecular
cyclization of an allylsilane with an iminium ion as reported
by the Speckamp group and others,[9] the requisite allylsilane
9 was prepared through hydrogenation using the Lindlar
catalyst and subsequent reduction using the same protocol.[10]
However, under these reaction conditions only the diene A
was isolated as a single product [Eq. (1); TBS = tert-butyldi-
methylsilyl, TFA = trifluoroacetic acid, TMS = trimethyl-
silyl]. We reasoned that the allylic alcohol (or the masked
allylic alcohol 9) readily underwent elimination via an allylic
cation intermediate. Gratifyingly, when the propargylsilane 8
was subjected to a SnCl4-promoted cyclization,[11] the chlori-
nated product B was isolated in 56% yield[12] [Eq. (2)].
Lowering the reaction temperature and using 1.0 equivalent
of SnCl4 altered the product distribution to afford the allenic
product 10 in 33% yield. After extensive experimentation,
Seger et al. proposed an iminium-ion-based biosynthetic
pathway from a putative precursor, spermidine (2).[6] This
proposal suggests that the construction of the azepine ring 3
through an iminium ion is a stereochemical defining step
(Scheme 1, top) in which preorganization of the reacting
partners facilitated by an enzyme is most likely involved. The
innovative radical-zipping strategy in which a reversal of the
polar disconnection is executed by the groups of Cossy and
Khim resulted in a trans configuration of C9 and C9a.[5]
Inspired by the biogenetic proposal,[6] we envisioned a
bioinspired approach in which the formation of the azepine
4 is accomplished through a cationic cyclization and then
construction of the lactone ring by cyclocarbonylation[7] and
reduction of the corresponding butenolide (Scheme 1,
bottom) would furnish the target and diminish obstacles
encountered in previous syntheses. Herein we describe the
successful synthesis of (Æ )-stemoamide based on this
approach.
[*] Y. Wang, L. Zhu, Y. Zhang, Prof. Dr. R. Hong
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: rhong@mail.sioc.ac.cn
Homepage: http://honglab.labways.com
[**] We are grateful to the National Basic Research Program of China
(2010CB833200), the Shanghai Rising Star Program (08A14079),
the National Natural Science Foundation of China (20702058 and
20872157), and CAS for their generous financial support. We thank
Dr. Jie Sun (SIOC) for X-ray analysis and Dr. Rob Hoen (Barcelona
Science Park, Spain) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005833.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2787

Communications
ketone and the Ru/hydride
complex II. After the H-
rebound, the corresponding
intermediate trans-II would
have a favorable conforma-
tion to promote the ruthe-
nium-catalyzed CO inser-
tion and subsequent reduc-
tion of the terminal alkene.
Thus, the reductive elimina-
tion completes the catalytic
cycle to generate the
desired trans-12. When CO
gas was excluded, the epi-
merization at C8 was not
observed when using the
Scheme 2. Synthesis of (Æ)-stemoamide (1): a) nBuLi (1.0 equiv), THF, À788C, 93%; b) TBSCl (1.4 equiv),
DBU (1.4 equiv), CH2Cl2, RT, 1 h, 87%; c) succinimide (2.0 equiv), K2CO3 (2.0 equiv), DMF, RT; d) NaBH4
(5.0 equiv), EtOH, 08C, 93% (two steps); e) FeCl3 (1.0 equiv), toluene, 08C, 2 h, 86%; f) TBAF (3.0 equiv),
THF, RT, 96%; g) [Ru3(CO)12] (3 mol%), CO (10 atm), TEA, 1008C, 6 h, 81%; h) NaBH4 (4.0 equiv), NiCl2
(0.3 equiv), MeOH, RT, 2 h, 74% (recryst.). DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMF=N,N’-dimethyl-
formamide, TBAF=tetra-n-butylammonium fluoride, TEA=triethylamine, THF=tetrahydrofuran.
pre-catalyst
[Ru3(CO)12]
and only a small amount of
diene product from the
elimination of OH group
anhydrous FeCl3 successfully promoted the cyclization to give
10 in a 3:1 d.r. with 86% yield in toluene.
The subsequent removal of the TBS group, careful
separation of the two diastereomers on silica gel, and product
isolation allowed identification of the major isomer as cis-11
as determined by X-ray diffraction analysis.[13] Based on the
structure elucidation, we initially pro-
posed that trans-11 would preferentially
undergo cyclocarbonylation through a
metallacycle intermediate. Therefore, a
proximity enabled carbonylation would
preferentially convert the trans isomer
into the desired butenolide. The mixture
of the two distereoisomers of 11 (cis/
trans = 3:1) was thereby subjected to the
ruthenium-catalyzed CO-insertion reac-
tion.[7a] Surprisingly, only trans-12 was
isolated, as was confirmed by X-ray
analysis.[14] It is evident that the cis-11
was also converted into trans-12 during
the carbonylation. To confirm this
unprecedented epimerization of the
allenic alcohol,[15] the pure cis-11 was
subjected to the reaction conditions and
the trans-butenolide 12 was the only
product isolated in 83% yield. The
proposed mechanism indicates that an
equilibrium between cis-II and trans-II
allows both isomers of 11 to be con-
verted into one diastereomer of 12
(Scheme 3). In the presence of CO gas,
the active species “Ru(CO)x”[16] would
react with 11 to form the intermediate
ruthenium alkoxy complex cis-II, and
the subsequent CO-insertion is hindered
because of the weak interaction between
the allene moiety and the metal center;
was found.[10] This observation suggests that the CO insertion
of trans-II may be the driving force for the complete
conversion of cis-II into trans-II. Notwithstanding, the
epimerization of the allenic alcohol remains obscure and
requires additional mechanistic studies. When trans-12 was
subjected to a known nickel-catalyzed reduction[4b] and
instead
a
b-hydride elimination is
Scheme 3. Proposed mechanism for the dynamic ruthenium-catalyzed CO insertion into 11. The
favored to afford the intermediate thermal ellipsoids of the X-ray structures are shown at 50% probability.
2788
www.angewandte.org ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 2787 –2790

Received: September 17, 2010
Revised: December 20, 2010
Published online: February 17, 2011
subsequent recrystallization, (Æ )-stemoamide (1) was iso-
lated in 74% yield and was identical to the natural pro-
duct.[3,4i]
To secure a future asymmetric synthesis of stemoamide,[17]
the resolution of 11 was pursued. The compound trans-11 was
envisioned to undergo a favorable cyclization with the
Keywords: carbonylation · cyclization · epimerization ·
.
natural products · total synthesis
À
participation of the pseudoequitorial C8 OH group. To our
delight, preliminary screening showed that upon treatment of
11 (cis/trans = 77:23) with AgNO3 (0.8 equiv) and CaCO3
(0.8 equiv; Marshallꢀs conditions),[18] trans-11 was preferen-
tially transformed into the tricylic trans-13, and cis-11 was
recovered in good yield (64%, > 98% d.r.) after 32 hours.[10]
The carbophilic silver catalyst activates the distal double bond
as shown in the intermediates V and VI (Scheme 4). The
former silver complex is thought to undergo an SN2-type
[1] Reviews: a) R. A. Pilli, M. C. F. de Oliveira, G. B. Rosso in The
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[3] W.-H. Lin, Y. Ye, R.-S. Xu, J. Nat. Prod. 1992, 55, 571.
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Tetrahedron Lett. 1994, 35, 6417; b) Y. Kohno, K. Narasaka,
Bull. Chem. Soc. Jpn. 1996, 69, 2063; c) A. Kinoshita, M. Mori, J.
Org. Chem. 1996, 61, 8356; d) P. A. Jacobi, K. Lee, J. Am. Chem.
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2002, 43, 295; g) M. P. Sibi, T. Subramanian, Synlett 2004, 1211;
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2006, 71, 3287; i) N. Bogliotti, P. I. Dalko, J. Cossy, Synlett 2006,
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9528; k) S. Torssell, E. Wanngren, P. Somfai, J. Org. Chem. 2007,
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[5] epi-Stemoamide: a) N. Bogliotti, P. I. Dalko, J. Cossy, Synlett
2005, 349; b) S.-K. Khim, A. G. Schultz, J. Org. Chem. 2004, 69,
7734; c) P. Gao, Z. Tong, H. Hu, P.-F. Xu, W. Liu, C. Sun, H. Zhai,
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[6] a) C. Seger, K. Mereiter, E. Kaltenegger, T. Pacher, H. Greger,
O. Hofer, Chem. Biodiversity 2004, 1, 265; b) The C3 lactone unit
of stemonine was recently proposed from leucine, see: H.
Greger, J. Schinnerl, S. Vajrodaya, L. Brecker, O. Hofer, J. Nat.
Prod. 2009, 72, 1708.
[7] a) Ruthenium-catalyzed cyclocarbonylation: E. Yoneda, T.
Kaneko, S.-W. Zhang, K. Onitsuka, S. Takahashi, Org. Lett.
2000, 2, 441, and references therein; b) Pd-catayzed cyclocarbo-
nylation: H. Alper, D. Leonard, J. Chem. Soc. Chem. Commun.
1985, 511; c) Radical lactonization: M. D. Bachi, E. Bosch, J.
Org. Chem. 1992, 57, 4696.
Scheme 4. Proposed mechanism for the silver-mediated cyclization of
an allenic alcohol.
[8] A. Blum, W. Hess, A. Studer, Synthesis 2004, 2226.
[9] a) H. Hiemstra, W. N. Speckamp, Tetrahedron Lett. 1983, 24,
1407; b) H. Hiemstra, M. H. A. M. Sno, R. J. Vijn, W. N. Speck-
amp, J. Org. Chem. 1985, 50, 4014. For selected reviews on
iminium ion cyclization, see: c) B. E. Maryanoff, H.-C. Zhang,
J. H. Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104,
1431; d) J. Royer, M. Bonin, L. Micouin, Chem. Rev. 2004, 104,
2311; e) W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56,
3817; f) H. Hiemstra, W. N. Speckamp in Comprehensive
Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming),
Pergamon, Oxford, UK, 1991, p. 1047.
cyclization with the proximal OH group to give trans-13.[19]
However, in the case of VI, the pseudoaxial C8-OH group
would have to adopt the unfavorable conformer VII that
would then lead to cis-13.[20] Clearly, the later cyclization is
slow because of the high energy barrier, and as a consequence
cis-11 would not undergo reaction and trans-11 would be
transformed into the cyclized product. Through this mode of
reaction, stemoamide can be enantioselectively synthesized
from a chiral propargylic alcohol.[21]
[10] See the Supporting Information for details.
In summary, the concise synthesis of (Æ )-stemoamide was
achieved in eight steps and 37% overall yield from commer-
cially available propargylsilane. The bioinspired iminium ion
cyclization in combination with the ruthenium-catalyzed
cyclocarbonylation of an allenic alcohol ensured the con-
vergence of the synthesis. This easily scaled-up synthesis can
be combined with the silver-mediated cyclization to obviate
the installation of the stereocenter at C9a as done in previous
syntheses and pave the way to the synthesis of more complex
stemona alkaloids.
[11] a) C. Li, X. Li, R. Hong, Org. Lett. 2009, 11, 4036; b) X. Li, C. Li,
W. Zhang, X. Lu, S. Han, R. Hong, Org. Lett. 2010, 12, 1696.
[12] The chlorination was proposed to proceed through a close-SN2’
pathway; see: a) J. Pornet, Tetrahedron Lett. 1981, 22, 453; b) J.
Pornet, L. Miginiac, K. Jaworski, B. Randrianoelina, Organo-
metallics 1985, 4, 333; c) Y. Deng, X. Jin, S. Ma, J. Org. Chem.
2007, 72, 5901.
[13] The cis configuration of 11 referred to the protons at C8 and C9a,
each on the same side. The data for trans-11 was identical to that
reported in the literature (see Ref. [4n]). CCDC 799348 (cis-11)
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
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Communications
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Marshall, K. G. Pinney, J. Org. Chem. 1993, 58, 7180; d) J. A.
Marshall, R. H. Yu, J. F. Perkins, J. Org. Chem. 1995, 60, 5550;
e) For reviews on silver-mediated reactions, see: M. Naodovic,
H. Yamamoto, Chem. Rev. 2008, 108, 3132; f) J.-M. Weibel, A.
Blanc, P. Pale, Chem. Rev. 2008, 108, 3149; g) M. ꢄlvarez-Corral,
M. Muꢅoz-Dorado, I. Rodrꢆguez-Garcꢆa, Chem. Rev. 2008, 108,
3174; h) Y. Yamamoto, Chem. Rev. 2008, 108, 3199.
[14] CCDC 799392 (trans-12) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] Dynamic kinetic resolution involving allenic alcohol is extremely
rare. See a recent chemoenzymatic approach: J. Deska, C.
del Pozo Ochoa, J. E. Bꢃckvall, Chem. Eur. J. 2010, 16, 4447.
[16] The precise structure of “Ru(CO)X” is not clear. See a discussion
on multinuclear or mononuclear complexes: N. Chatani, T.
Fukuyama, F. Kakiuchi, S. Murai, J. Am. Chem. Soc. 1996, 118,
493.
[17] The two diastereomers of 10 are inseparable, and the separation
of cis-11 and trans-11 on a silica gel column is also very tedious.
Moreover, the configuration at C9a could not be epimerized
later in the synthetic route. For a gram scale synthesis, starting
from optically pure 7, the resulting stemoamide would be only
50% ee (% ee = 100%(3À1)/(3+1)) if both isomers of 11 were
carried through the synthesis.
[19] Gold catalysts (e.g. AuCl3) also exhibit excellent reactivity
toward this cyclization; see the Supporting Information for
details. The exploration on asymmetric kinetic resolution of
allenic alcohol will be reported in due course.
[20] The relative configuration of cis-13 was assigned based on the
cross-peak between H8 and H9a as observed in the two-
dimensional NOE experiment (see the Supporting Information
for details).
[21] For the synthesis of chiral propargylic alcohol through asym-
metric reduction: a) E. J. Corey, C. J. Helal, Angew. Chem. 1998,
110, 2092; Angew. Chem. Int. Ed. 1998, 37, 1986; b) asymmetric
alkynylation: D. E. Frantz, R. Faessler, E. M. Carreira, J. Am.
Chem. Soc. 2000, 122, 1806, and references therein.
[18] a) L. I. Olsson, A. Claesson, Synthesis 1979, 743; b) J. A.
Marshall, X. Wang, J. Org. Chem. 1990, 55, 2995; c) J. A.
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