A synthesis of (±)-stemoamide using the intramolecular propargylic Barbier reaction

Article abstract of DOI:10.1055/s-0029-1217540

A diastereoselective synthesis of the alkaloid stemoamide has been achieved using the intramolecular propargylic Barbier reaction to construct the seven-membered ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217540

LETTER
1979
A Synthesis of (±)-Stemoamide Using the Intramolecular Propargylic Barbier
Reaction
S
R
ynthesis of
(
±
)-S
o
temoamidederick W. Bates,* S. Sridhar
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Fax +65(6791)1961; E-mail: roderick@ntu.edu.sg
Received 30 January 2009
H
Abstract: A diastereoselective synthesis of the alkaloid stemo-
amide has been achieved using the intramolecular propargylic
Barbier reaction to construct the seven-membered ring.
refs. 4, 10
O
O
O
O
N
O
N
N
H
H
O
O
O
Key words: alkaloids, Barbier reaction, allenes, indium, cyclisa-
tions
1
2
Br
CO
•
O
N
H
Plants of the Stemona family, long employed in Chinese
HO
traditional medicine, have been a fertile source of polycy-
clic alkaloids. Although these alkaloids have been disap-
1
3
4
pointing in terms of their biological activity, their
structural complexity has been a challenge for synthetic
chemists. Stemoamide (1), isolated from Stemona tubero-
sa, can be considered a representative stemona alkaloid,
incorporating a butyrolactam, an azepine, and a butyrolac-
tone. Stemoamide has been the subject of a number of
syntheses using a wide variety of methods. Williams built
Scheme 1 Stemoamide retrosynthesis
of lactam 7 was substituted by sulfinate using benzene
sulfinic acid generated in situ from benzene sulfinic acid
sodium salt and trifluoroacetic acid. Displacement of the
sulfinate by a protected propargylic alcohol acetylide was
achieved in 72% yield using the method of Ley. A series
of functional group transformations from this point pro-
vided the Barbier substrate 4.
14
2
up an acyclic precursor using aldol chemistry. Olivo also
used the aldol reaction. Mori, Sibi, Gurjar,6 and
3
4
5
7
Somfai employed metathesis chemistry to construct the
seven-membered ring (Scheme 1). Cossy also employed
1
. NaBH4, EtOH, –5 °C
8
a,b
metathesis chemistry in one approach and free radical
2. HCl
O
O
8
c
O
EtO
N
N
chemistry in another. Narasaka employed oxidative rad-
H
60%
X
H
5
9
ical chemistry. Jacobi employed an oxazole Diels–Alder
1
0
1. BuLi, THF
reaction to establish two rings in a single step. Both
2
.
O
O
O
THPO
4
10
Br
N
Mori and Jacobi employed the reduction of butenolide
with nickel boride as the final step to give the butyrolac-
6
MgCl
2
ZnBr2
72%
DMSO
tone with the correct stereochemistry. Butenolide 2 ap-
peared to us to be accessible by the combination of allenol
carbonylation and intramolecular propargylic Barbier re-
action that we recently employed in a synthesis of mint-
9
2%
O
O
7
8
X = OEt
PhSO2H
99%
1
1
X = SO2Ph
lactone.
The intramolecular propargylic Barbier reaction requires
aldehyde 4 with a propargyl bromide substituent. This
was constructed starting with succinimide. Reduction of
succinimide with sodium borohydride in ethanol, fol-
lowed by quenching with hydrochloric acid gave lactam
9
1
1
X = OTHP
O
X
N
PS-ppts, MeOH
0 X = OH
MsCl, Et3N
LiBr, THF
1 X = OMs
O
12 X = Br
1
2
5
.
Efficient N-alkylation was achieved cleanly in 92%
O
yield by deprotonation using butyllithium in THF, fol-
lowed by alkylation with the bromodioxolane 6 in
TsOH
O
N
acetone, H2O
Br
1
3
DMSO. The alternative sequence, N-alkylation fol-
lowed by reduction, was less effective. The ethoxy group
4
2% (four steps)
4
CHO
SYNLETT 2009, No. 12, pp 1979–1981
Advanced online publication: 03.07.2009
x
x
.x
x
.2
0
0
9
Scheme 2 Synthesis of the propargylic bromide
DOI: 10.1055/s-0029-1217540; Art ID: D03409ST
©
Georg Thieme Verlag Stuttgart · New York

1
980
R. W. Bates, S. Sridhar
LETTER
The THP group was selectively removed using a polymer- Table 1 The Intramolecular Propargylic Barbier
supported version of ppts prepared from poly-4-vinyl py-
1
5
Entry Conditions
Time Temp Yield dr
ridine and PTSA. Although the use of ppts resulted in a
similar yield, the use of the polymer-supported version
simplifies the workup procedure. Curiously, the alterna-
tive polymer-supported ppts, prepared from amberlyst 15
and pyridine, was found to be much less reactive. The re-
sulting propargylic alcohol 10 was converted into bro-
mide 12 via mesylate 11. The bromide was obtained in
(
h)
(°C)
(%)
14
82
50
70
73
82
53
51
34
0
1
2
3
4
5
6
7
8
9
0
Zn, NH Cl
12
18
12
12
18
24
16
16
20
18
20
0
>95:5
4:1
4
SnCl , NaI, DMF, H O
0
2
2
a,b
In, AcOH, H O
–5
r.t.
0
>95:5
10:1
14:1
16:1
10:1
10:1
>95:5
–
2
c,d
In, AcOH, DMF, H O
2
4
2% yield over the four steps from alkyne 9.
In, AcOH, THF, H
Oc,d
2
A number of different conditions were tested for the key
intramolecular Barbier reaction (Scheme 3, Table 1). The
use of zinc, indium, bismuth, and stannous chloride all
lead to the formation of the desired allenol 3 with one of
the two possible diastereomers predominating. The reac-
c,d
In, AcOH, THF, H O
–20
r.t.
r.t.
r.t.
r.t.
r.t.
2
In, DMF
In, DMF, H Oe
1
6
2
tion with zinc under Luche conditions (entry 1) gave an
excellent dr, but a low yield. Bismuth, under the condi-
In, THF
1
7
tions of Wada and Akiba, gave no product and only a
low yield when these conditions were modified by the
1
Bi, DMF or DMF, H Oc
2
c,d
addition of water and acetic acid (entries 10 and 11). 11
Bi, AcOH, DMF, H O
22
6:1
2
1
8
Mukaiyama’s method using stannous chloride, which
proved to be optimum in our synthesis of (–)-mintlac-
a
b
c
d
e
AcOH–H O = 4:1.
2
2
0% of allene 13 isolated.
1
1
tone, gave, in this case, a dr that was significantly lower
Scheme 2). The optimum conditions were determined to
be the use of indium in wet THF in the presence of acetic
DMF–H O or THF–H O = 8:1.
2
2
(
AcOH (4 equiv).
DMF–H O = 1:8.
2
1
9,20
acid (entry 6).
Reactions using indium in DMF result-
ed in a lower dr (entries 7 and 8). In THF, in the absence
of acetic acid, the dr proved to be excellent, but the yield
was unacceptably low due to the slowness of the reaction
(
entry 9). Too much acetic acid, however, lead to concur-
rent formation of the protio-debrominated allene 13 as
protonation of the organoindium intermediate became
competitive with cyclisation. This compound could also
be isolated from some runs using zinc.
The stereochemistry of the major diastereomer of the
allenol 3 was determined by X-ray crystallography and
•
O
N
O
(CH2)3CHO
Br
N
Figure 1 The X-ray structure of allenic alcohol 3
see Table 1
13
4
was found to correspond to that of the natural product
(Figure 1).
•
O
CHO
N
H
HO
H
3
The synthesis was completed by cyclocarbonylation of
allenol 3 following the method of Takahashi employing
triruthenium dodecacarbonyl as a catalyst in the presence
of triethylamine under a pressure of 100 psi of carbon
Ru3(CO)12, Et3N
CO (100 psi)
O
O
N
1
00 °C
O
21
81%
monoxide. Butenolide 2 was then reduced by the meth-
2
4
10
od reported by Mori and by Jacobi to give (±)-stemo-
amide (1) and its 10-epimer (6:1). After recrystallisation
(EtOAc), (±)-stemoamide (1) was obtained in 55% yield.
Spectroscopic data and the melting point (180–182 °C; lit
H
NiCl2, NaBH4
MeOH, –30 °C
O
O
N
H
5
5% (recryst.)
O
1
2
4
10
1
90–191 °C, 187–188 °C, 184–185 °C ) of our synthet-
Scheme 3 The intramolecular propargylic Barbier reaction and
completion of the synthesis of (±)-stemoamide
ic material are in agreement with those reported previous-
ly.
Synlett 2009, No. 12, 1979–1981 © Thieme Stuttgart · New York

LETTER
Synthesis of (±)-Stemoamide
1981
The intramolecular propargylic Barbier reaction is an ef-
ficent method for the stereoselective formation of the
azepine moiety of the stemona alkaloids. The very high
selectivity once again achieved makes this reaction a valu-
able method for heterocycle construction.
at the same temperature for 1 h. A solution of
bromodioxolane (8.85 g, 45.3 mmol) in DMSO (60 mL) was
added slowly, and the reaction mixture was allowed to warm
to r.t. After stirring at r.t. for 18 h, H O (250 mL) was added.
2
The mixture was extracted with EtOAc (3 × 500 mL), and
the combined organic layers were washed with H O and
2
brine, then dried (MgSO ). The solvent was removed under
4
reduced pressure to give lactam (10.12 g, 92%) as a yellow
oil, which was used without purification. H NMR (500
Acknowledgment
1
MHz, CDCl ): d = 4.98 (d, J = 6.3 Hz, 1 H), 4.87 (t, J = 4.2
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 2 (grant
T206B1220RS) for support of this work.
3
Hz, 1 H), 3.98–3.92 (m, 2 H), 3.87–3.81 (m, 2 H), 3.58–3.51
(
m, 1 H), 3.46 (q, J = 7 Hz, 2 H), 3.18–3.08 (m, 1 H), 2.57–
2
.48 (m, 1 H), 2.34–2.26 (m, 1 H), 2.18–2.08 (m, 1 H), 2.02–
1
3
1.94 (m, 1 H), 1.76–1.61 (m, 4 H), 1.21 (t, J = 7 Hz, 3 H). C
References and Notes
NMR (125 MHz, CDCl ): d = 174.9, 103.8, 88.9, 64.9, 64.8,
3
6
1.3, 40.1, 31.1, 29.0, 24.8, 21.9, 15.2. IR (neat): nmax
=
(
(
(
(
1) Pilli, R. A.; de Oliviera, M. C. F. Nat. Prod. Rep. 2000, 17,
17.
2) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron
Lett. 1994, 35, 6417.
–1
2
972, 2932, 2882, 1693, 1454, 1420, 1283, 1140, 1074 cm .
1
(
14) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V.
Tetrahedron 1991, 47, 1311.
(
(
(
(
(
15) Li, Z. G.; Ganesan, A. Synth. Commun. 1998, 28, 3209.
16) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
17) Wada, M.; Akiba, K. Tetrahedron Lett. 1985, 26, 4211.
18) Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 621.
19) For reviews on indium in organic synthesis, see: (a) Augé,
J.; Kubin-Germain, N.; Uziel, J. Synthesis 2007, 1739.
3) Olivo, H. F.; Tovar-Miranda, R.; Barragán, E. J. Org. Chem.
2
006, 71, 3287.
4) (a) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356.
b) Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287.
(
(
(
(
5) Sibi, M. P.; Subramanian, T. Synlett 2004, 1211.
6) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295.
7) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007,
(
b) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149. For
the use of acetic acid with indium, see: (c) Kang, H.-Y.;
Kim, Y.-T.; Yu, Y.-K.; Cha, J. H.; Cho, Y. S.; Koh, H. Y.
Synlett 2004, 45. For the earliest use of indium in the
propargylic Barbier reaction, see: (d) Isaac, M. B.; Chan,
T.-H. J. Chem. Soc., Chem. Commun. 1995, 1003.
20) Preparation of Allenol 3
72, 4246.
(
(
8) (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,
7
1, 9528.
9) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69,
063.
10) (a) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122,
(
Acetic acid (117 mL, 2.06 mmol) followed by indium (118
mg, 1.03 mmol) were added to a solution of aldehyde 4 (140
2
(
mg, 0.51 mmol) in THF (2 mL) and H O (0.25 mL) under
2
4295. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119,
nitrogen at –20 °C. After stirring at the same temperature for
3409.
2
4 h, the reaction mixture was diluted with CHCl (100 mL).
3
(
(
11) Bates, R. W.; Sridhar, S. J. Org. Chem. 2008, 73, 8104.
12) Hubert, J. C.; Wijnberg, J. P. B. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437.
The mixture was stirred at r.t. for 10 min, and filtered
through Celite, washing with CHCl . The solvent was
3
removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (10 g,
(
13) Preparation of Acetal 6
A mixture of 4-bromobutanal (prepared by DIBAL-H
reduction of methyl 4-bromobutyrate; 3.5 g, 23.1 mmol),
ethylene glycol (3.9 mL, 69.5 mmol), and PTSA (440 mg,
1
.5% MeOH–CHCl ) to give allenic alcohol 4 (81 mg, 82%)
3
1
as a colourless solid; mp 98–100 °C. H NMR (500 MHz,
CDCl ): d = 5.11 (t, J = 1.7 Hz, 2 H), 4.35 (t, J = 7.7 Hz, 1
3
2.3 mmol) in toluene (40 mL) was heated at reflux for 1.5 h
H), 4.18–4.08 (m, 1 H), 3.99–3.94 (m, 1 H), 2.78–2.72 (m, 1
H), 2.48–2.34 (m, 2 H), 2.31–2.23 (m, 1 H), 2.16–2.08 (m, 1
using a Dean–Stark trap. The mixture was cooled to r.t.
Toluene was removed under reduced pressure, and the
residue was purified by flash column chromatography on
H), 1.98–1.86 (m, 1 H), 1.84–1.73 (m, 2 H), 1.68–1.53 (m, 2
13
H). C NMR (125 MHz, CDCl ): d = 203.7, 174.3, 110.6,
3
silica gel (150 g, 4% EtOAc–hexane) to give acetal (6, 3.3 g,
8
1.6, 67.8, 58.6, 41.7, 38.8, 30.7, 25.9, 24.7. IR: nmax = 3377,
933, 1954, 1651, 1416, 1364, 1320, 1264, 1202, 1155, 1064
1
73%) as a colourless liquid. H NMR (500 MHz, CDCl ):
3
2
d = 4.9 (t, J = 4.5 Hz, 1 H), 3.98–3.93 (m, 2 H), 3.88–3.81
–1
+
cm . MS (EI): m/z = 194 (100) [M + 1], 187 (9). HRMS:
(
m, 2 H), 3.45 (t, J = 6.8 Hz, 2 H), 2.0 (quint, J = 7.1 Hz, 2
+
m/z = calcd for C H NO = 194.1181 [M + H]; found:
1
3
11 16
2
H), 1.85–1.78 (m, 2 H). C NMR (125 MHz, CDCl ): d =
3
194.1181.
103.7, 64.9 (2 C), 33.6, 32.3, 27.1.
(
21) (a) Yoneda, E.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S.
Tetrahedron Lett. 2001, 42, 5459. (b) Yoneda, E.; Kaneko,
T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org. Lett.
Preparation of Lactam 7
n-BuLi (36.8 mL of a 1.6 M solution in hexane, 59.0 mmol)
was slowly added to a solution of lactam 5 (7.6 g, 59.0
mmol) in THF (80 mL) at –78 °C. The mixture was stirred
2000, 2, 441.
Synlett 2009, No. 12, 1979–1981 © Thieme Stuttgart · New York

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