An efficient total synthesis of (±)-stemonamine

Article abstract of DOI:10.1021/ol800433r

An efficient first approach to the Stemona alkaloid (±)-Stemonamine has been developed on the basis of a key TiCI₄ promoted tandem Semipinacol rearrangement/Schmidt reaction and a Dieckmann condensation reaction.

Full text of DOI:10.1021/ol800433r

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1763-1766
An Efficient Total Synthesis of
(()-Stemonamine
Yu-Ming Zhao, Peiming Gu, Yong-Qiang Tu,* Chun-An Fan, and Qingwei Zhang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received February 26, 2008
ABSTRACT
An efficient first approach to the Stemona alkaloid (()-Stemonamine has been developed on the basis of a key TiCl4 promoted tandem
Semipinacol rearrangement/Schmidt reaction and a Dieckmann condensation reaction.
Stemonamine (1a, Figure 1), as a member of the Stemona
family, was isolated from the roots of Stemona japonica, which
was used in China and Japan for centuries as a drug for the
treatment of respiratory diseases and insecticides.1,2 The chal-
having the spirocyclic stemonamide nucleus have been
revealed.
The first total syntheses of (()-stemonamide (1c) and (()-
isostemonamide (1d) have been disclosed on the basis of
N-acyliminium chemistry and aldol spirocyclization by Kende
et al. in 2001.4 Recently, Ishibashi and co-workers developed
another approach to (()-1c and (()-1d using a radical cascade
strategy.5 To the best of our knowledge, however, total synthesis
of stemonamine (1a) has not yet been reported.
During the course of our studies on tandem reactions of
R-hydroxy epoxides for constructing the 2-quaternary 1,3-
diheteroatom units, we recently discovered a novel and highly
efficient tandem semipinacol rearrangement/Schmidt reaction
of R-siloxy epoxy azides (Scheme 1).6 This synthetic method
is powerful for the construction of functionalized azaqua-
ternary carbon centers. Herein, we report the first total
synthesis of (()-1a as an application of this method.
As shown in Scheme 2, our retrosynthetic consideration
of 1a was focused on the efficient establishment of tetracyclic
skeleton. We envisioned that the γ-lactone ring could be
Figure 1. Stemonamine and related alkaloids.
lenging molecular architecture containing two contiguous
quaternary centers and a tetracyclic skeleton has attracted
considerable interest to synthetic organic chemists.2 Over
the past years, several total syntheses of Stemona alkaloids
have been reported,3 but few total syntheses of alkaloids
(3) See also ref 2 and references cited therein.
(4) (a) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org. Lett.
2001, 3, 2505. (b) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J.
Tetrahedron 2002, 58, 61.
(1) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Ueno, S. J. Chem. Soc.,
Chem. Commun. 1973, 125
.
(2) For recent reviews, see: (a) Pilli, R. A.; Ferreira de Oliveira, M. C.
Nat. Prod. Rep. 2000, 17, 177. (b) Pilli, R. A.; Rosso, G. B.; de Oliveira,
M. C. F. In The Alkaloids; Cordell, G. A., Ed.; Elsevier: New York, 2005;
(5) Taniguchi, T.; Tanabe, G.; Muraoka, O.; Ishibashi, H. Org. Lett.
2008, 10, 197.
(6) Gu, P. M.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y. F; Zhang, F. M. Org.
Lett. 2006, 8, 5271.
Vol. 62, pp 77–173. (c) Greger, H. Planta Med. 2006, 72, 99
.
10.1021/ol800433r CCC: $40.75
Published on Web 03/26/2008
2008 American Chemical Society

afforded R-siloxy epoxy azide 5 in 66% overall yield from
3. With 5 in hand, the key tandem semipinacol rearrange-
ment/Schmidt reaction was investigated. As expected, 5 was
treated with 2.2 equiv of TiCl4 in CH2Cl2 at -78 to 0 °C for
2 h, giving the desired amide 6 in 68% yield as a white solid.
Oxidation of alcohol 6 with PCC gave rise to the
corresponding ketone 7. Ozonolysis and subsequent aldol
condensation afforded 9 in 65% overall yield from 6 (Scheme
4). After achieving the crucial tricyclic intermediate 9, we
Scheme 1
.
Tandem Semipinacol Rearrangement/Schmidt
Reaction of R-Siloxy Epoxy Azides
Scheme 4
Scheme 2. Retrosynthetic Analysis of (()-Stemonamine
viable through a Dieckmann condensation reaction, and ring
C could be achieved from 6 through several transformations
including oxidation and aldol cyclization. As a key strategy-
level step, the Lewis acid-promoted tandem semipinacol
rearrangement/Schmidt reaction of R-siloxy epoxy azide 5
would provide the desired azaquaternary bicyclic precursor 6.
then turned our attention to construction of γ-lactone ring.
Treatment of ketone 9 with LHMDS and Mander reagent9
at –78 °C for 0.5 h gave the acylation product 10 in 95%
yield as a single diastereoisomer. In order to introduce the
second quaternary carbon center, an epoxidation was at-
tempted. However, the initial epoxidation of the enolate of
ꢀ-ketoester 10 with m-CPBA failed. To our delight, the
desired hydroxylation was accomplished under an atmo-
sphere of oxygen with catalytic amounts of CeCl3·7H2O,
giving 11a and its diastereoisomer 11b in a total yield of
92% (Scheme 4).10 These two epimers were readily separated
by column chromatography on silica gel. The relative
configuration of 11a was subsequently assigned by the later
X-ray analysis of the hydrochloride dihydrate of 1a (see
Figure 2).
As depicted in Scheme 3, our synthesis commenced with
a Grignard addition of substituted allylmagnesium chloride7
Scheme 3
As demonstrated in Scheme 5, treatment of 11a with
propionic anhydride, Et3N, and DMAP (cat.) in dry CH2Cl2
at room temperature afforded 12a in 95% isolated yield. The
next crucial step of the current total synthesis involved a
Dieckmann condensation to access the key tetronic acid ring
system. Reaction of 12a with 18-crown-6 and KOtBu in dry
benzene at room temperature for 2 h, followed by O-
methylation, proceeded in moderate yield to afford 13a. To
complete the synthesis, treatment of lactam 13a with
Lawesson’s reagent and reduction of thiolactam using W-2
Raney Ni in THF gave the racemic stemonamine (1a) in
93% yield over two steps. The structure of our synthetic
stemonamine (1a) was confirmed by the X-ray crystal-
lographic analysis of its hydrochloride dihydrate (Figure 2).
Given the fact that the γ-lactone ring in 1a could be
established by the Dieckmann condensation of 12a, the same
cyclization condition (KOtBu and 18-crown-6 in benzene at
to known compound 2.8 The epoxidation of the resulting
allylic alcohol 3, followed by protection with TMSCl,
(7) For large-scale preparation of 2-(chloromethyl)but-1-ene, see: (a)
Green, M. B.; Hickinbottom, W. J. J. Chem. Soc. 1957, 3262. (b) Magid,
R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. J. Org. Chem. 1979,
44, 359.
(8) Milligan, G. L.; Mossman, C. J.; Aubé, J. J. Am. Chem. Soc. 1995,
117, 10449–10459.
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Org. Lett., Vol. 10, No. 9, 2008

Scheme 5
benzene, toluene, or HMPA) were carefully examined in the
present cyclization, and no improved results were obtained.
Currently, we are seeking insight into this unusual reactivity
of two epimers (12a and 12b) in Dieckmann condensation
by the computation chemistry in our laboratory.
In summary, a concise and efficient total synthesis of
stemonamine (1a) was achieved for the first time in 13 steps
from the known compound 2 in an overall yield of 3.7%,
featuring a tandem semipinacol rearrangement/Schmidt reac-
tion and a Dieckmann condensation.
Figure 2. X-ray structure of stemonamine hydrochloride dihy-
drate.
rt) was subsequently applied to the corresponding propionate
product 12b,11 which resulted from the acylation of 11b.
Surprisingly, however, only degradation of starting material
was observed. A series of bases (LDA, LHMDS,
NaN{Si(CH3)3}2, KN{Si(CH3)3}2, NaH, KH, or NaOMe)
with the combination of various solvents (Et2O, THF,
(9) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1990, 70,
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (No. 30271488, 20911001) and the
Chang Jiang Scholars Program.
256.
(10) (a) Christoffers, J.; Werner, T. Synlett 2002, 119–121. (b) Christ-
offers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J. Org. Chem. 2003, 425–
431.
(11) For the preparation of 12b, see below:
Supporting Information Available: General experimental
procedures, characterization data for all compounds, and
X-ray crystallographic data for the hydrochloride dihydrade
of 1a. This material is available free of charge via the Internet
at http://pubs.acs.org.
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