Synthesis of (+)-9a-epi-stemoamide via DBU-catalyzed michael addition of nitroalkane

Article abstract of DOI:10.1055/s-0029-1217558

We describe a practical synthesis of (+)-9a-epi-stemoamide, which has been achieved in six steps from α,β-unsaturated γ-butyrolactone. The main features of the current approach include a DBU-catalyzed Michael addition of nitroalkane and a reductive lactamization of nitro esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217558

2188
LETTER
Synthesis of (+)-9a-epi-Stemoamide via DBU-Catalyzed Michael Addition of
Nitroalkane
S
ynthesisof (+
e
)
-9a-epi-S
n
a
b
c
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, P. R. of China
State Key Laboratory of Catalytic Material and Reaction Engineering, Research Institute of Petroleum Processing, SINOPEC,
Beijing 100083, P. R. of China
Fax +86(21)64166128; E-mail: zhaih@mail.sioc.ac.cn
Received 9 April 2009
Figure 1), an analogue of (–)-stemoamide (1). The retro-
synthetic analysis (Scheme 1) reveals that 1 and/or 2 may
be derived from 3 by alkylative cyclization and chemo-
and stereoselective enolate methylation. Bicycles 3
should be accessible through reductive lactamization of
nitro esters 4, which in turn can be obtained from a,b-un-
saturated-butyrolactone 5 via DBU-catalyzed Michael ad-
dition.
Abstract: We describe a practical synthesis of (+)-9a-epi-stemo-
amide, which has been achieved in six steps from a,b-unsaturated
g-butyrolactone. The main features of the current approach include
a DBU-catalyzed Michael addition of nitroalkane and a reductive
lactamization of nitro esters.
Key words: Michael addition, nitroalkane, stemoamide, synthesis,
unsaturated butyrolactone
1
The extracts from Stemona species have been reportedly
applied against insect pests. Moreover, practitioners of
traditional Chinese and Japanese medicine have utilized
the roots of Stemona tuberosa Lour. and related Stemona
species to treat respiratory diseases such as asthma, bron-
chitis, petusis, and tuberculosis.3 Extensive phytochemi-
cal investigations have led to the isolation of more than 70
alkaloids of the Stemonacea family, many of which pos-
sess an aza-azulene framework.4 (–)-Stemoamide (1,
Figure 1), the structurally simplest member of the family,
was isolated along with another five structurally related
alkaloids from Stemona tuberosa by Xu and co-workers in
1992. The structure of 1 can be conceived as a butyrolac-
tone fused to a pyrrolo[1,2a]-azepine nucleus and four
contiguous stereocenters are imbedded in the tricyclic
skeleton.5 Due to its potential bioactivities and unique
structural features, stemoamide (in both racemic6,7 and
enatiomerically pure7b,8–12,13b,14 form) has emerged as an
attractive target for total synthesis. The first total synthe-
sis of natural 1 was described by Williams8 in 1994. Re-
markably, Jacobi7 accomplished a seven-step total
synthesis of 1 in both racemic and levo-form featuring a
Diels–Alder/retro-Diels–Alder reaction sequence. In or-
der to exploit the full utilities of stemoamide in drug de-
velopment, synthesis of stemoamide analogues recently
began to gain increasing attention, as demonstrated by the
work coming out of the Schultz15 and Cossy13a,c groups.
12
H
H
C
N
O
O
11
O
O
9a
9a
N
9
A
H
B
H
5
O
O
H
H
1 (–)-stemoamide
2 (+)-9a-epi-stemoamide
Figure 1 (–)-Stemoamide (1) and (+)-9a-epi-stemoamide (2)
reductive
lactamization
H
sequential
alkylation
H
O
O
O
O
9a
N
N
H
H
H
O
O
OTBDPS
H
1, 2
3
NO2
H
Michael addn
CO2Me
OTBDPS
OTBDPS
O
O
O
O
5
4
Scheme 1 Strategy for constructing the tricyclic skeleton of stemo-
amide
As outlined in Scheme 2, the present synthesis com-
menced from methyl 4-nitrobutanoate,16 which, after be-
ing catalytically deprotonated at the nitro-bearing carbon
in the presence of DBU17 (10 mol%), attacked a,b-unsat-
urated-butyrolactone 518 at the b-position and stereoselec-
tively from the face opposite to the silyloxypropyl group.
Both adducts from the Michael addition seemed to have
an R-configuration at C-9 (corresponding to the number-
ing system for stemoamide) although only moderate ste-
reocontrol was observed at C-9a (dr = 2:1). The two
inseparable epimers 4, furnished in 89% combined yield,
were suitable for use directly in the subsequent transfor-
mations. Treatment with Raney Ni under an atmosphere
of H2 gas led to direct conversion of nitro esters 4 to lac-
As a part of our continuing endeavors in investigating me-
dicinally useful natural alkaloids and derivatives, we have
been interested in developing a practical and scalable
method for constructing (+)-9a-epi-stemoamide (2,
SYNLETT 2009, No. 13, pp 2188–2190
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217558; Art ID: W05209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (+)-9a-epi-Stemoamide
2189
tams 3 (86%) through hydrogenation of the nitro group
followed by lactamization. Desilylation of 3 and hydroxyl
sulfonation generated a pair of diastereomeric mesylates,
which were subjected19 to an excess amount of NaH to af-
ford tricycles 6a and 6b in a combined yield of 43% (over
the three steps from 3). Notably, epimers 6a and 6b were
produced in a 5:1 ratio because the cyclization of the two
mesylates (mixture, dr = 2:1) took place via intramolecu-
lar SN2 displacement at considerably different rates under
the reaction conditions, coinciding in what was observed
by Cossy and co-workers.13c Compounds 6a (a solid) and
6b (an oil14) were inseparable by silica gel column chro-
matography. Fortunately, careful recrystallization of the
mixture from EtOAc–MeOH (100:1) resulted in reaping
6a in pure form. Finally, deprotonation of 6a with LiH-
MDS followed by trapping with MeI provided the target
molecule 2 in 60% yield. For the first time, (+)-9a-epi-
stemoamide (2) was synthesized as a single pure com-
pound, even though the synthesis of a mixture of 1 and 2
(both in racemic form) has been disclosed in the
literature13c previously.
Acknowledgment
Financial support was provided by the grants from NSFC
(90713007; 20772141; 20625204; 20632030) and MOST_863
(2006AA09Z405; 2006AA09Z446).
References and Notes
(1) Current address: GlaxoSmithKline R&D China, Building
No. 3, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong,
Shanghai 201203, P. R. of China.
(2) Current address: Department of Chemistry, The University
of Texas at San Antonio, One UTSA Circle, San Antonio,
TX 78249-0698, USA.
(3) (a) Goetz, M.; Edwards, O. E. In The Alkaloids, Vol. 9;
Manske, R. H. F., Ed.; Academic Press: New York, 1976,
545; and references cited therein. (b) Nakanishi, K.; Goto,
T.; Ito, S.; Natori, S.; Nozoe, S. In Natural Products
Chemistry, Vol. 2; Academic Press: New York, 1975, 292.
(4) (a) Jiang, R.-W.; Hon, P.-M.; Zhou, Y.; Chan, Y.-M.; Xu,
Y.-T.; Xu, H.-X.; Greger, H.; Shaw, P.-C.; But, P. P.-H.
J. Nat. Prod. 2006, 69, 749. (b) Lin, L.-G.; Zhong, Q.-X.;
Cheng, T.-Y.; Tang, C.-P.; Ke, C.-Q.; Lin, G.; Ye, Y. J. Nat.
Prod. 2006, 69, 1051.
(5) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
(6) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69,
2063.
(7) (a) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119,
3409. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122,
4295.
O2N(CH2)3CO2Me
DBU, r.t.
OTBDPS
O
O
89%
5
H
NO2
(8) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron
Lett. 1994, 35, 6417.
H2, Ra–Ni
MeOH, r.t.
dr = 2:1
H
O
O
*
N
H
9a
CO2Me
OTBDPS
(9) (a) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356.
(b) Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287.
(10) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295.
(11) Sibi, M. P.; Subramanian, T. Synlett 2004, 1211.
(12) Olivo, H. F.; Tovar-Miranda, R.; Barragán, E. J. Org. Chem.
2006, 71, 3287.
(13) (a) Bogliotti, N.; Dalko, P. I.; Cossy, J. Synlett 2005, 349.
(b) Bogliotti, N.; Dalko, P. I.; Cossy, J. Synlett 2006, 2664.
(c) Bogliotti, N.; Dalko, P. I.; Cossy, J. J. Org. Chem. 2006,
71, 9528.
H
9
86%
O
O
OTBDPS
O
4
3
a) Et3N⋅2HF, THF, r.t.
b) MsCl, Et3N, CH2Cl2, r.t.
c) NaH, THF, r.t.
H
H
O
O
N
O
O
N
+
H
H
43% (6a + 6b, 3 steps)
6a/6b = 5:1
O
O
H
H
6a
6b
(14) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007,
72, 4246.
(15) Khim, S.-K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7734.
(16) Yu, P.; Wang, T.; Li, J.; Cook, J. M. J. Org. Chem. 2000, 65,
3173.
H
O
a) LiHMDS, THF, –78 °C
b) MeI, –78 °C
O
9a
N
H
O
6a
60%
H
(17) Rosso, G. B.; Pilli, R. A. Tetrahedron Lett. 2006, 47, 185.
(18) For the preparation of ent-(+)-5 {Lit.18a [a]D25 +31.5 (c
2.00)}, see: (a) Hanessian, S.; Hodges, P. J.; Murray, P. J.;
Sahoo, S. P. J. Chem. Soc., Chem. Commun. 1986, 754.
The enantiomer, 5 {[a]D25 –32.7 (c 2.4, CHCl3)}, was
synthesized in a similar manner18a from (R)-tert-butyl[3-
(oxiran-2-yl)propoxy]diphenylsilane, an epoxide
prepared18b–d from L-ascorbic acid: (b) Hubschwerlen, C.
Synthesis 1986, 962. (c) Sharma, G. V. M.; Punna, S.;
Krishna, P. R.; Chorghade, M. S.; Ley, S. V. Tetrahedron:
Asymmetry 2005, 16, 1125. (d) Brimble, M. A.; Park, J. H.;
Taylor, C. M. Tetrahedron 2003, 59, 5861.
2 9a-epi-stemoamide
Scheme 2 Synthesis of (+)-9a-epi-stemoamide (2)
In summary, we have realized a practical six-step20 assem-
bly of (+)-9a-epi-stemoamide (2) from a,b-unsaturated
butyrolactone 5. The main features of the current ap-
proach include DBU-catalyzed Michael addition of nitro-
alkane and reductive lactamization of nitro esters 4.
(19) This was performed by following Narasaka’s protocol.6
(20) Preparation of New Compounds
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Compounds 4: Compound 5 (1.00 g, 2.63 mmol) was mixed
with methyl 4-nitrobutanoate (580 mg, 3.94 mmol), and
DBU (40 mg, 0.26 mmol) was introduced into the system.
The mixture was stirred with no solvent at r.t. for 24 h and
concentrated. The residue was chromatographed (PE–EtOAc,
5:1) to afford 4 (1.23 g, 89%) as a colorless oil (2:1 epimers).
Synlett 2009, No. 13, 2188–2190 © Thieme Stuttgart · New York

2190
P. Gao et al.
LETTER
silica gel (EtOAc–MeOH, 4:1) to give the mesylation
1H NMR (300 MHz, CDCl3): d = 1.05 (s, 9 H), 1.05–1.92 (m,
4 H), 2.01–2.58 (m, 5 H), 2.62–2.84 (m, 2 H), 3.69 (s, 3 H),
3.60–3.79 (m, 2 H), 4.32–4.42 (m, 1 H), 4.58–4.72 (m, 1 H),
7.38–7.42 (m, 6 H), 7.63–7.68 (m, 4 H). 13C NMR (75 MHz,
CDCl3): d = 19.1, 26.3, 26.8, 28.1, 29.3, 29.4, 30.9, 31.0,
31.6, 31.9, 43.4, 43.5, 52.0, 62.7, 62.8, 80.6, 82.0, 87.7, 88.3,
127.6, 127.6, 129.6, 129.6, 133.5, 133.6, 135.5, 171.9,
172.0, 173.7, 173.8. ESI-MS: m/z (%) = 550 (100) [M + 1],
450 (7). Anal. Calcd for C28H37NO7Si: C, 63.73; H, 7.07; N,
2.65. Found: C, 64.02; H, 7.10; N, 2.62.
Compounds 3: Freshly prepared Raney Ni (ca. 1.20 g) was
added to a solution of compound 4 (1.91 g, 3.62 mmol) in
MeOH (72 mL). The mixture was hydrogenated under one
atmosphere of hydrogen at r.t. for 24 h. After Raney Ni was
filtered off, the filtrate was concentrated to give a residue,
which was chromatographed (CH2Cl2–MeOH, 30:1) to
afford compound 3 (1.455 g, 86%) as a colorless oil (2:1
epimers). 1H NMR (400 MHz, CDCl3): d = 1.04 (s, 9 H),
1.60–1.74 (m, 5 H), 2.26–2.40 (m, 5 H), 2.62–2.72 (m, 1 H),
3.64–3.75 (m, 3 H), 4.25–4.38 (m, 1 H), 7.34–7.43 (m, 6 H),
7.60–7.66 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 19.2,
24.5, 25.2, 26.8, 28.2, 29.8, 30.0, 30.6, 30.7, 31.6, 32.3, 45.3,
45.6, 55.5, 56.2, 63.0, 63.2, 81.9, 82.5, 127.7, 129.7, 133.6,
135.5, 175.3, 178.8, 179.0. ESI-MS: m/z (%) = 520 (13) [M
+ Na + MeOH], 504 (8) [M + K], 488 (97) [M + Na]. ESI-
HRMS: m/z calcd for C27H35NO4SiNa [M + Na]: 488.2233;
found: 488.2228. Anal. Calcd for C27H35NO4Si: C, 69.64; H,
7.58; N, 3.01. Found: C, 69.20; H, 7.43; N, 2.89.
Compound 6a: To a stirred solution of compounds 3 (1.30
g, 2.79 mmol) in THF (20 mL), Et3N·2HF (2.00 mL, 13.9
mmol) was added, and the mixture was stirred at r.t. for 3 d.
NaHCO3 (1.20 g, 14.3 mmol) was added, and the mixture
was stirred for 10 min. The solvent was concentrated to give
a residue, which was chromatographed (EtOAc–MeOH,
10:1) to afford the epimeric primary alcohols (842 mg) as a
pale yellow solid. The alcohols were dissolved in CH2Cl2
(10 mL), and then DMAP (34 mg, 0.28 mmol), Et3N (1.20
mL, 8.61 mmol), and MsCl (0.32 mL, 4.18 mmol) were
added sequentially. The mixture was stirred at r.t. overnight,
neutralized with sat. aq NaHCO3 solution, extracted with
CHCl3–i-PrOH (4:1; 3 × 40 mL), dried (Na2SO4), and
filtered. The solvents were removed under reduced pressure,
and the residue was purified by flash chromatography on
products. The mesylates were dissolved in THF (50 mL) and
added to a stirred suspension of NaH (60%, 1.12 g, 28.0
mmol) in THF (150 mL) at 0 °C. After warming to r.t. and
stirring for 20 h, the reaction was quenched at 0 °C by the
addition of sat. aq NH4Cl solution. The mixture was
extracted with CHCl3–i-PrOH (4:1), and the combined
organic layers were dried (Na2SO4). The solvents were
removed under reduced pressure, and the residue was
purified by flash chromatography on silica gel (EtOAc–
MeOH, 100:1) to afford a mixture of 6a and 6b (252 mg,
43% over the three steps from 3) as a white solid. The ratio
of 6a/6b was found to be ca. 5:1 according to the line
integrals of the 1H NMR spectrum. A pure sample of 6a was
obtained by careful recrystallization of the 5:1 mixture of 6a/
6b from EtOAc–MeOH (100:1).
28
Analytical Data of Compound 6a: Mp 106–108 °C; [a]D
+23.3 (c 0.52, MeOH). 1H NMR (300 MHz, CDCl3): d =
1.58–1.90 (m, 4 H), 2.14–2.53 (m, 6 H), 2.60–2.68 (m, 1 H),
3.13–3.22 (m, 1 H), 3.54 (dd. J = 16.5, 7.5 Hz, 1 H), 3.78–
3.87 (m, 1 H), 4.31–4.41 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 22.1, 24.1, 30.1, 30.4, 32.9, 40.3, 48.5, 60.8,
83.2, 174.0, 174.5. MS (EI): m/z (%) = 209 (31) [M+], 191
(7), 124 (19), 110 (33), 98 (100). HRMS (EI): m/z calcd for
C11H15NO3 [M+]: 209.1052; found: 209.1047.
Compound 2: To a solution of 6a (22 mg, 0.11 mmol) in
anhyd THF (1 mL) at –78 °C was added LiHMDS solution
in THF (1.0 M, 0.19 mL, 0.19 mmol). After 1 h, MeI (13 mL,
0.21 mmol) was added at –78 °C, and the stirring was
continued for an additional 1 h. The reaction mixture was
quenched with sat. NH4Cl, warmed to r.t., and extracted with
EtOAc. The combined organic layers were dried (Na2SO4),
filtered, and concentrated to give a residue, which was
purified by silica gel chromatography (EtOAc–MeOH, 15:1)
to furnish 2 (14 mg, 60%) as a white solid: mp 86–88 °C;
[a]D28 +74.9 (c 0.30, MeOH). 1H NMR (300 MHz CDCl3):
d = 1.29 (d, J = 7.5 Hz, 3 H), 1.62–1.90 (m, 4 H), 2.18–2.56
(m, 5 H), 2.75–2.88 (m, 1 H), 2.98–3.09 (m, 1 H), 3.60–3.69
(m, 1 H), 3.83–3.93 (m, 1 H), 4.52 (dt, J = 10.5, 4.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 10.8, 21.6, 23.2, 30.0, 30.2,
38.4, 40.8, 52.3, 57.8, 80.5, 174.0, 178.0. MS (EI): m/z (%)
= 223 (37) [M+], 208 (21), 180 (20), 98 (100). HRMS (EI):
m/z calcd for C12H17NO3 [M+]: 223.1208; found: 223.1207.
Synlett 2009, No. 13, 2188–2190 © Thieme Stuttgart · New York

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