Total synthesis of (±)-stemonamide, (±)-isostemonamide, (±)-stemonamine, and (±)-isostemonamine using a radical cascade

Article abstract of DOI:10.1016/j.tet.2008.06.091

A total synthesis of (±)-stemonamide and (±)-isostemonamide has been achieved by using a radical cascade that involves two endo-selective cyclizations. (±)-Stemonamine and (±)-isostemonamine are synthesized by chemoselective reduction of (±)-stemonamide and (±)-isostemonamide, respectively.

Full text of DOI:10.1016/j.tet.2008.06.091

Tetrahedron 64 (2008) 8773–8779
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-stemonamide, (ꢀ)-isostemonamide, (ꢀ)-stemonamine,
and (ꢀ)-isostemonamine using a radical cascade
*
Tsuyoshi Taniguchi, Hiroyuki Ishibashi
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2008
Received in revised form 25 June 2008
Accepted 25 June 2008
Available online 28 June 2008
A total synthesis of (ꢀ)-stemonamide and (ꢀ)-isostemonamide has been achieved by using a radical
cascade that involves two endo-selective cyclizations. (ꢀ)-Stemonamine and (ꢀ)-isostemonamine are
synthesized by chemoselective reduction of (ꢀ)-stemonamide and (ꢀ)-isostemonamide, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Isostemonamide
Isostemonamine
Radical cascade
Stemonamide
Stemonamine
1. Introduction
O
O
Me
Me
O
O
O
O
MeO
MeO
Stemona alkaloids such as (ꢁ)-stemonamide (1) and (ꢁ)-iso-
stemonamide (2) and their reduced compounds, (ꢀ)-stemonamine
(3) and (ꢀ)-isostemonamine (4), were isolated from the roots of
Stemona japonica, which have been used in Chinese and Japanese folk
medicine as cough medicines and insecticides.1,2 Their tetracyclic
structure including contiguous spirocyclic quaternary centers pro-
vides attractive target molecules for total synthesis.3,4 We wish to
report herein a total synthesis of (ꢀ)-stemonamide (1) and (ꢀ)-iso-
stemonamide (2) using a radical cascade as the key step and the
synthesis of (ꢀ)-stemonamine (3) and (ꢀ)-isostemonamine (4) by
chemoselective reduction of (ꢀ)-1 and (ꢀ)-2, respectively (Fig. 1).5
N
N
X
X
X = O: stemonamide (1)
X = H2: stemonamine (3)
X = O: isostemonamide (2)
X = H2: isostemonamine (4)
Figure 1. Stemonamide and related alkaloids.
O
O
O
Br
1
N
N
O
2. Results and discussion
6
5
Scheme 1. Retrosynthetic analysis.
2.1. Synthesis of ( )-stemonamide (1) and ( )-isostemonamide
(2) using radical cascade involving two endo-selective
cyclizations
Synthesis of
6 was begun by condensation of 1,2-cyclo-
pentanedione and 4-(tert-butyldimethylsilyloxy)butylamine fol-
lowed by acylation of the resulting imine with acryloyl chloride in
the presence of N,N-diethylaniline to give enamide 7 (Scheme 2).
After removal of the TBS group of 7, mesylation of alcohol 8 fol-
lowed by bromination of the resultant mesylate with lithium bro-
mide afforded the radical precursor 6.
Our strategy for the synthesis of (ꢀ)-stemonamide (1) is shown
in Scheme 1. Compound (ꢀ)-1 was envisaged to arise from tricyclic
compound 5, which, in turn, was obtained by a Bu3SnH-mediated
radical cascade of 6 involving two endo-selective cyclizations.
When a boiling solution of enamide 6 in toluene was treated
with Bu3SnH in the presence of 1,10-azobiscyclohexanecarbonitrile
(ACN), a mixture of almost equal amounts of tricyclic compound 10
* Corresponding author. Tel.: þ81 76 234 4474; fax: þ81 76 234 4476.
E-mail address: isibasi@p.kanazawa-u.ac.jp (H. Ishibashi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.091

8774
T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
OTBS
O
H2N
Ph
benzene, reflux;
CH2=CHCOCl
Et2NPh, 0 °C
O
Mg(OMe)2
MeO
O
HO
O
NIS, TfOH
NaOMe (cat)
13
OR
N
CH2Cl2, rt
92%
MeOH, reflux
85%
N
I
O
35-55%
H
O
7: R = TBS
8: R = H
O
15
TsOH, wet acetone, rt, 96%
O
Me
O
I
O
Me
Bu3SnH
ACN
MsCl, iPr2NEt
DME, 0 °C;
(MeBO)3
PdCl2(dppf)2
Cs2CO3
O
O
MeO
MeO
O
N
Br
N
toluene
reflux
55%
LiBr, rt, 83%
O
dioxane
reflux
89%
N
N
O
O
H
H
6
9
O
O
16
17
H
H
Scheme 4. Synthesis of 17.
O
O
N
N
hexafluorophosphate in the presence of TfOH12 gave 19. Iodination
of NIS/TfOH gave an unsatisfactory result. Suzuki–Miyaura coupling
of 19 with trimethylboroxine/PdCl2(dppf)2 afforded compound 20
(Scheme 5) in 89% yield.
11
10
(ca. 1 : 1)
Scheme 2. Synthesis and radical cyclization of 6.
and its stereoisomer 11 was obtained in 55% total yield (Scheme 2).
Formation of 10 and 11 may be best explained by a radical cascade
that involves a 7-endo-selective cyclization of an alkyl radical onto
the alkenic bond of enamide6 followed by a 5-endo cyclization of
O
+
I
–
PF6
N
Ph
O
MeO
the resulting a
-amidoyl radical 9.7
Mg(OMe)2
2
NaOMe (cat)
TfOH
The mixture of compounds 10 and 11 was then subjected to
aldol reaction with benzaldehyde to give an inseparable mixture of
a,b-unsaturated ketones 12a,b in 76% yield (Scheme 3). A sub-
sequent addition reaction of 12a,b with lithium ethyl propiolate
afforded the adducts 13 and 14 in 50% and 48% isolated yields, re-
spectively. X-ray crystallographic analysis of 13 and 14 confirmed
their structures, indicating that the phenyl groups of the mixture
12a,b have stereochemistries as depicted in Scheme 3.8 Formation
of 13 and 14 might be a result of an attack of lithium ethyl pro-
piolate on the convex faces of 12a,b, respectively.
14
O
N
I
H
MeOH, reflux
75%
CH2Cl2, rt
84%
18
Me
O
I
O
Me
MeO
(MeBO)3
PdCl2(dppf)2
Cs2CO3
O
O
MeO
O
N
dioxane
reflux
89%
N
O
H
H
19
20
Scheme 5. Synthesis of 20.
Ph
Ph
O
O
Oxidative cleavage of alkenes 17 with OsO4/NaIO4 afforded ke-
tone 21 in 88% yield (Scheme 6). -Methylenation of ketone 21 with
Eschenmoser’s salt13 in the presence of various bases such as KH or
LDA afforded the unsaturated ketone 23 in poor yield. Similar
PhCHO
KOH
a
H
H
O
O
N
N
10 + 11
+
MeOH
rt, 76%
a
-
12b
12a
methylenation using paraformaldehyde/N-methylanilinium tri-
fluoroacetate14 also gave an unsatisfactory result. We therefore
examined another route to 23. Treatment of ketone 21 with tert-
butoxybis(dimethylamino)methane (Bredereck’s reagent)15 gave
enaminone 22, whose reduction with DIBAL16 followed by meth-
Ph
Ph
EtO2C
EtO2C
OH
OH
CO2Et
+
BuLi
H
H
O
O
N
N
THF, -78 °C
ylation with MeI afforded a-methylenated ketone 23 in 67% yield
(Scheme 6). Similarly, compound 20 was converted to 26 in good
yield.
13
50%
14
48%
Finally, RhCl3-mediated isomerization of the double bond17 of
exo-methylene ketone 23 gave (ꢀ)-stemonamide (1) (mp 232–
233 ꢂC, lit.3 mp 240–241 ꢂC) along with 27 in 31% and 63% yields,
respectively. Spectral data of (ꢀ)-1 were in accord with those of
natural (ꢁ)-1, kindly provided by Professor Ye. 1H NMR spectra of
the unexpected compound 27 showed it to be a single stereoiso-
Scheme 3. Synthesis of 13 and 14.
Treatment of the adduct 13 with magnesium methoxide in
boiling MeOH9 afforded methyl tetronate (
-methoxy- -un-
saturated lactone) 15 in 85% yield (Scheme 4). -Methylation of the
-unsaturated bond of this tetronate with LDA/methyl iodide10
giving a compound such as 17 failed, and hence an alternative
method of -methylation was examined. Iodination of 15 with N-
b
a,b
a
a,b
mer. It is presumed that an attack of RhCl3 on the same side (
of 9-H of 23 brings about isomerization of the double bond to give
(ꢀ)-1, whereas, when RhCl3 attacks the opposite side ( -face) of
9-H, and reduction of the double bond with RhCl3 takes place to give
27. Therefore, the methylgroup of27 seemed tohavea -orientation.
-face) of 9-H
b-face)
a
iodosuccinimide (NIS) in the presence of trifluoromethanesulfonic
acid (TfOH) gave iodide 16. Treatment of compound 16 with tri-
methylboroxine in the presence of PdCl2(dppf)2 (Suzuki–Miyaura
coupling)11 afforded methylated compound 17 in high yield
(Scheme 4).
a
b
On the other hand, RhCl3 attacked the same side (
b
of 26 to afford (ꢀ)-isostemonamide (2) (mp 223–224 ꢂC, lit.3 mp
225–227 ꢂC) quantitatively. Spectral data of (ꢀ)-2 were in accord
with those of natural (ꢁ)-2 (Scheme 7).
Similarly, iodination of compound 18, prepared from 14 with
magnesium methoxide, by bis(trimethylpyridine)iodonium

T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
8775
O
spectral data of which were in accord with those of a natural one
(Scheme 8).
Me
O
O
MeO
OsO4 (cat), NaIO4
CH(NMe2)2OtBu
17
acetone-H2O (1:1)
88%
DMF, 100 °C
O
N
O
H
Me
O
O
MeO
Lawesson's
reagent
Raney Ni
(W-2)
21
O
O
( )-4
40%
( )-2
+
( )-3
56%
Me
Me
MeO
N
S
toluene
reflux
EtOH
reflux
DIBAL
CH2Cl2
-78 °C;
O
O
O
O
MeO
100%
28
N
MeI, rt
N
O
NMe2
O
Raney Ni
(W-2)
H
H
67% (from 21)
EtOH
22
23
0 °C-rt
( )-4
77%
O
Me
O
Scheme 8. Synthesis of (ꢀ)-4 and (ꢀ)-3.
O
MeO
OsO4 (cat), NaIO4
CH(NMe2)2OtBu
20
Surprisingly, the same reduction of 28 also afforded, in 56%
yield, the unexpected (ꢀ)-stemonamine (3), the spectral data of
which were in accord with those of a natural one. This result might
indicate that (ꢀ)-stemonamine (3) and (ꢀ)-isostemonamine (4)
can easily interconvert to each other. This phenomenon is identical
with the fact that natural stemonamine (3) and isostemonamine (4)
are isolated as racemate forms.2a We assumed that a cleavage of the
spirocyclic ring as depicted in Scheme 9 might result in an isom-
tBuOH-H2O (1:1)
DMF, 100 °C
N
O
H
62%
24
O
O
Me
Me
DIBAL
CH2Cl2
-78 ºC;
O
O
O
O
MeO
MeO
N
N
MeI, rt
74% (from 24)
O
NMe2
O
H
H
erization between (ꢀ)-3 and (ꢀ)-4, since they have
b
-amino car-
bonyl and vinylogous
b
-amino carbonyl moieties.
25
26
Scheme 6. Synthesis of 23 and 26.
O
O
O
Me
Me
Me
O
O
O
O
O
O
MeO
MeO
MeO
2.2. Synthesis of ( )-stemonamine (3) and ( )-
isostemonamine (4) from ( )-stemonamide (1)
and ( )-isostemonamide (2)
N
N
N
isostemonamine (4)
stemonamine (3)
We next examined a conversion of (ꢀ)-(1) or (ꢀ)-(2) to
(ꢀ)-stemonamine (3) or (ꢀ)-isostemonamine (4) by reduction of
the corresponding lactam carbonyl group. p-Methoxyphenylth-
ionophosphine sulfide dimer (Lawesson’s reagent)18 is known to
convert the lactam carbonyl groups into the corresponding thio-
carbonyl derivatives selectively even in the presence of ketone
and lactone groups.19 Therefore, we examined reduction of the
thiocarbonyl group of lactam, prepared from (ꢀ)-(1) or (ꢀ)-2,
with Raney nickel. We were delighted to find that treatment of
(ꢀ)-(2), obtained in large quantities, with Lawesson’s reagent
afforded the desired thiocarbonyl lactam 28 quantitatively.
A subsequent reduction of 28 with Raney nickel (W-2) in reflux-
ing EtOH provided, in 40% yield, (ꢀ)-isostemonamine (3), the
Scheme 9. Equilibrium between 3 and 4.
We soon found, however, that such isomerization did not occur
at a low temperature. When compound 28 was treated with Raney
nickel in EtOH at 0 ꢂC, (ꢀ)-4 was obtained in 77% yield. Similarly,
treatment of (ꢀ)-stemonamide (1) with Lawesson’s reagent affor-
ded, in 98% yield, (ꢀ)-29, whose reduction with Raney nickel at 0 ꢂC
gave (ꢀ)-stemonamine (3) in 79% yield (Scheme 10).
O
Me
O
O
MeO
Lawesson's
reagent
Raney Ni
(W-2)
( )-1
( )-3
N
toluene
reflux
99%
EtOH
0 °C-rt
79%
S
O
O
Me
Me
29
O
O
O
O
MeO
MeO
Scheme 10. Synthesis of (ꢀ)-3.
RhCl •x
H2O
3
( )-(1) +
31%
Me
EtOH-H2O (10:1)
reflux
N
N
N
O
O
H
9
H
3. Conclusions
27
63%
23
We achieved a total synthesis of (ꢀ)-stemonamide (1) and
(ꢀ)-isostemonamine (2) by using a radical cascade involving two
endo-selective cyclizations as the key step. The present synthesis
clearly demonstrates the usefulness of the radical cascade process
for the synthesis of nitrogen-containing polycyclic compounds.
We also performed the synthesis of (ꢀ)-stemonamine (3) and
(ꢀ)-isostemonamine (4) by reduction of the thiocarbonyl lactams
29 and 28, prepared from (ꢀ)-(1) and (ꢀ)-(2), respectively, with
Raney nickel.
O
Me
O
O
9
MeO
RhCl3•xH2O
( )-(2)
100%
EtOH-H2O (10:1)
reflux
O
H
26
Scheme 7. Synthesis of (ꢀ)-1 and (ꢀ)-2.

8776
T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
4. Experimental
evaporation of the solvent, the residue was chromatographed on
silica gel containing KF (10% w/w)22 (hexane/AcOEt, 1:2) to give
4.1. General
a mixture of 10 and 11 (399 mg, 55%) as colorless solids: IR (CHCl3)
n
1750, 1680 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 1.31–1.43 (1H, m),
Infrared (IR) spectra were recorded on a Shimadzu FTIR-8100
spectrophotometer for solutions in CHCl3. 1H NMR and 13C NMR
spectra were measured on a JEOL EX 500 (500 MHz) or a JEOL JNM-
1.50–2.07 (9H, m), 2.15–2.06 (6H, m), 4.04 (1/2H, d, J¼14.6 Hz), 4.12
(1/2H, d, J¼14.6 Hz); 13C NMR (125 MHz, CDCl3)
d 22.6, 23.1, 23.9,
24.2, 25.5, 27.58, 27.63, 28.0, 28.6, 29.4, 30.1, 30.7, 34.3, 34.7, 39.6,
40.3, 44.6, 46.9, 73.3, 74.2, 175.4, 176.0, 212.4. Anal. Calcd for
EX 270 (270 MHz) spectrometer. Chemical shifts (d) quoted are
relative to tetramethylsilane. High-resolution mass spectra (HRMS)
were obtained with a JEOL JMS-SX-102A mass spectrometer. Col-
umn chromatography was carried out on silica gel 60 N (Kanto
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.34; H, 8.50; N,
6.88.
Kagaku Co., Ltd., spherical, neutral, 63–210
mm) or on alumina 90
4.5. A mixture of 12a and 12b
(Merck, neutral, 63–200 m) under pressure.
m
To a solution of the mixture of 10 and 11 (399 mg, 1.93 mmol) in
MeOH (7 mL) containing 10% KOH was added benzaldehyde
(225 mg, 2.12 mmol). After stirring for 24 h, the reaction mixture
was poured into a saturated NH4Cl solution and extracted with
EtOAc. The organic layer was washed with brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica gel
(hexane/AcOEt, 1:1) to give a mixture of 12a and 12b (433 mg, 76%,
ca. 1:1 mixture of diastereoisomers) as a pale yellow amorphous
4.2. N-[4-(tert-Butyldimethylsilyloxy)butyl]-N-
(5-oxocyclopentenyl)acrylamide (7)
A mixture of 1,2-cyclopentanedione20 (10 g, 102 mmol) and 4-
(tert-butyldimethylsilyloxy)butylamine21 (20.8 g, 102 mmol) in
benzene (350 mL) was heated under reflux with azeotropic re-
moval of water for 2 h. After cooling at 0 ꢂC, acryloyl chloride
(11.1 g, 122 mmol) and N,N-diethylaniline (22.8 g, 153 mmol) were
added dropwise and the mixture was stirred at room temperature
for 1 h. The reaction mixture was diluted with water and extracted
with AcOEt. The organic layer was washed successively with
a saturated aqueous solution of NaHCO3 and brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica gel
(hexane/AcOEt, 3:1) to give 7 (12.0–19.2 g, 35–56%) as a pale yel-
solid: IR (CHCl3)
CDCl3) 1.39–1.97 (8H, m), 2.03–2.13 (1H, m), 2.25–2.34 (1H, m),
n ;
1720, 1680, 1630 cmꢁ1 1H NMR (500 MHz,
d
2.45–2.68 [(2þ1/2)H, m], 2.73 (1/2H, td, J¼14.6, 3.7 Hz), 3.00 (1/2H,
dd, J¼15.9, 6.7 Hz), 3.12 (1/2H, ddd, J¼17.7, 8.5, 3.1 Hz), 4.04–4.07
(1/2H, m), 4.20 (1/2H, td, J¼10.4, 4.3 Hz), 7.27–7.58 (6H, m); 13C
NMR (125 MHz, CDCl3) d 22.9, 25.1, 25.3, 26.6, 27.7, 28.9, 29.4, 29.5,
30.0, 30.4, 30.8, 32.0, 39.47, 39.51, 42.8, 44.8, 73.9, 74.3, 128.78,
128.84, 129.8, 130.0, 130.4, 130.9, 132.1, 132.9, 134.6, 134.8, 134.9,
136.0, 175.4, 176.3, 202.3, 206.3; HRMS calcd for C19H21NO2
295.1572, found 295.1572.
low oil: IR (CHCl3)
CDCl3) 0.02 (6H, s), 0.87 (9H, s), 1.49–1.61 (4H, m), 2.51–2.55 (2H,
n ;
1720, 1655, 1620 cmꢁ1 1H NMR (270 MHz,
d
m), 2.70–2.75 (2H, m), 3.59 (2H, t, J¼6.1 Hz), 3.65 (2H, t, J¼7.1 Hz),
5.60 (1H, dd, J¼10.2, 2.0 Hz), 6.16 (1H, dd, J¼10.2, 6.1 Hz), 6.35 (1H,
dd, J¼16.8, 2.0 Hz), 7.46 (1H, t, J¼2.8 Hz); 13C NMR (67.8 MHz)
d
ꢁ5.3, 18.3, 24.6, 25.9, 29.8, 33.7, 46.9, 62.6, 128.0, 128.2, 144.6,
4.6. Esters 13 and 14
157.3, 165.4, 203.8; HRMS calcd for C18H31NO3Si 337.2073, found
337.2073.
To solution of ethyl propiolate (232 mg, 2.34 mmol) in THF
(5 mL) was added dropwise 1.6 M solution of n-butyllithium in
hexane (1.46 mL, 2.34 mmol) at ꢁ78 ꢂC and the mixture was
stirred at the same temperature for 30 min. To this solution was
added dropwise a solution of the mixture of 12a and 12b
(230 mg, 0.778 mmol) in THF (5 mL) and the mixture was stirred
at ꢁ78 ꢂC for 20 min. The reaction mixture was quenched with
a saturated NH4Cl solution at ꢁ78 ꢂC and then extracted with
EtOAc. The organic layer was washed with brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica
gel (hexane/EtOAc, 1:1). The first eluent gave 13 (151 mg, 50%) as
4.3. N-(4-Bromobutyl)-N-(5-oxocyclopentenyl)acrylamide (6)
To a solution of 8 (4.90 g, 22.0 mmol) and diisopropylethylamine
(4.82 g, 37.3 mmol) in DME (140 mL) was added dropwise meth-
anesulfonyl chloride (3.77 g, 32.9 mmol) at 0 ꢂC, and the mixture
was further stirred at room temperature for 1.5 h. LiBr (9.54 g,
110 mmol) was added, and the mixture was further stirred at room
temperature for 8 h. The reaction mixture was diluted with water
and extracted with AcOEt. The organic layer was washed with
brine, dried (MgSO4), and concentrated. The residue was chroma-
tographed on silica gel (hexane/AcOEt, 1:1) to give 6 (5.21 g, 83%) as
a colorless oil; 1H NMR and 13C NMR spectra of 6 showed it to be
colorless crystals, mp 209–211 ꢂC (EtOAc/MeOH): IR (CHCl3)
n
1705, 1675 cmꢁ1 1H NMR (270 MHz, CDCl3)
;
d
1.29 (3H, t,
J¼7.1 Hz), 1.40–1.50 (3H, m), 1.72–1.84 (4H, m), 2.06–2.40 (3H,
m), 2.67–2.92 (3H, m), 3.24 (1H, dd, J¼14.3, 10.2 Hz), 4.17–4.26
(1H, m), 4.22 (2H, q, J¼7.1 Hz), 5.87 (1H, br), 6.87 (1H, t-like),
a mixture of two rotamers: IR (CHCl3)
NMR (270 MHz, CDCl3)
n
1720, 1660, 1620 cmꢁ1; 1H
1.66 (2H, tt, J¼7.4, 7.1 Hz), 1.87 (2H, tt,
d
J¼7.4, 6.4 Hz), 2.55–2.58 (2H, m), 2.74–2.79 (2H, m), 3.43 (2Hꢃ17/
20, t, J¼6.4 Hz), 3.55 (2Hꢃ3/20, t, J¼6.4 Hz), 3.68 (2H, t, J¼7.1 Hz),
5.62 (1H, dd, J¼10.1, 1.6 Hz), 6.15 (1H, dd, J¼16.8, 10.1 Hz), 6.36 (1H,
dd, J¼16.8, 1.6 Hz), 7.50 (1H, t, J¼2.6 Hz); 13C NMR (67.8 MHz,
7.21–7.40 (5H, m); 13C NMR (67.5 MHz, CDCl3)
d 14.0, 24.0, 25.7,
28.4, 30.3, 30.5, 31.7, 41.2, 42.2, 62.0, 76.2, 77.6, 79.3, 87.5, 127.2,
127.3, 128.4, 128.7, 136.8, 140.5, 153.2, 178.3. Anal. Calcd for
C
24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C, 73.29; H, 7.00;
N, 3.55. The second eluent gave 14 (149 mg, 48%) as colorless
crystals, mp 190.5–192 ꢂC (EtOAc/MeOH): IR (CHCl3)
1705,
1675 cmꢁ1 1H NMR (270 MHz, CDCl3)
1.21–1.35 (1H, m), 1.30
CDCl3)
d 24.6, 26.6, 29.5, 33.5, 33.6, 44.6, 45.9, 128.0, 128.2, 144.3,
157.6,165.5, 203.8. Anal. Calcd for C12H16BrNO2: C, 50.37; H, 5.64; N,
4.89. Found: C, 50.77; H, 5.84; N, 4.96.
n
;
d
(3H, t, J¼7.1 Hz), 1.55–1.70 (4H, m), 1.83–2.06 (2H, m), 2.23–2.32
(2H, m), 2.62–2.92 (5H, m), 3.90 (1H, d, J¼14.3 Hz), 4.01 (1H, br),
4.23 (2H, q, J¼7.1 Hz), 6.79 (1H, t-like), 7.26–7.31 (1H, m), 7.37–
4.4. A mixture of 10 and 11
To a boiling solution of 6 (1.00 g, 3.50 mmol) in toluene (350 mL)
was added dropwise a solution of Bu3SnH (1.53 g, 5.24 mmol) and
ACN (1,1-azobiscyclohexanecarbonitrile) (171 mg, 0.699 mmol) in
toluene (100 mL) over 5 h by employing a syringe-pump technique,
and the mixture was further heated at reflux for 1 h. After
7.39 (4H, m); 13C NMR (67.5 MHz, CDCl3)
d 14.0, 22.1, 25.1, 28.2,
28.4, 29.4, 30.3, 41.4, 62.2, 76.4, 79.0, 81.0, 86.7, 123.6, 123.7,
127.4, 128.5, 129.0, 136.2, 142.1, 153.3, 176.3. Anal. Calcd for
C24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C, 73.30; H, 6.99;
N, 3.57.

T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
8777
4.7. Methyl tetronate 15
acid (139 mg, 0.924 mmol) at 0 ꢂC, and the mixture was stirred at
room temperature for 24 h. The reaction mixture was diluted with
CH2Cl2 and washed successively with a saturated Na2S2O3 solution
and brine. The organic layer was dried (MgSO4) and concentrated,
and the residue was chromatographed on silica gel (EtOAc) to give
19 (139 mg, 84%) as colorless crystals, mp 205–208 ꢂC (dec) (EtOAc/
To a solution of 13 (159 mg, 0.400 mmol) in MeOH (2 mL) was
added 6–10% solution of magnesium methoxide in MeOH (1.5 mL),
and the mixture was heated at reflux for 10 h. Sodium methoxide
(4.3 mg, 0.0800 mmol) was added and the mixture was heated
under reflux for 2 days. The reaction mixture was cooled to room
temperature and poured into a saturated NH4Cl solution and then
extracted with EtOAc. The organic layer was washed with brine,
dried (MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane/EtOAc, 1:2) to give 15 (129 mg, 85%)
CH2Cl2): IR (CHCl3)
CDCl3) 1.26–1.35 (1H, m), 1.51–1.68 (4H, m), 1.84–1.97 (3H, m),
n ;
1770, 1680, 1620 cmꢁ1 1H NMR (270 MHz,
d
2.24–2.47 (3H, m), 2.74–3.05 (3H, m), 3.95 (1H, d, J¼14.7 Hz), 4.44
(3H, s), 6.40 (1H, t-like), 7.10 (2H, d, J¼8.4 Hz), 7.72 (2H, d,
J¼8.4 Hz); 13C NMR (67.5 MHz, CDCl3)
d 22.0, 25.1, 28.0, 28.9, 29.4,
as colorless crystals, mp 247–248 ꢂC (EtOAc/CH2Cl2): IR (CHCl3)
n
29.9, 40.9, 43.0, 43.9, 60.4, 74.7, 93.6, 96.2, 123.7, 130.7, 135.0, 137.7,
138.3, 169.7, 174.0, 180.6; HRMS calcd for C23H23NO4I2 630.9717,
found 630.9728.
1760, 1680, 1630 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
1.35–1.41 (2H,
m), 1.50–1.57 (1H, m), 1.71–1.80 (3H, m), 1.96 (1H, q, J¼11.6 Hz),
2.20–2.27 (2H, m), 2.49 (1H, t, J¼13.4 Hz), 2.69 (1H, t, J¼12.2 Hz),
2.80–2.99 (3H, m), 3.87 (3H, s), 4.07 (1H, d, J¼14.0 Hz), 5.12 (1H, s),
4.11. Ketone 21
6.37 (1H, s), 7.35–7.39 (5H, m); 13C NMR (125 MHz, CDCl3)
d 25.2,
26.1, 28.2, 30.0, 30.1, 32.2, 40.1, 41.2, 59.6, 75.0, 89.3, 94.4, 127.8,
127.9, 128.5, 128.7, 135.6, 135.8, 171.0, 177.9, 181.5; HRMS calcd for
To a solution of 17 (100 mg, 0.245 mmol) and sodium meta-
periodate (2.60 g, 12.3 mmol) in acetone (10 mL) and water (10 mL)
was added 4% OsO4 solution (five drops), and the mixture was
stirred at room temperature for 30 h. The reaction mixture was
diluted with water and extracted with CH2Cl2. The organic layer
was washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane/AcOEt, 1:2) to
give 21 (68.5 mg, 88%) as colorless crystals, mp 260–269 ꢂC (dec)
C
23H25NO4 379.1784, found 379.1772.
4.8. -Iodo methyl tetronate 16
a
To a solution of 15 (200 mg, 0.527 mmol) and N-iodosuccin-
imide (356 mg, 1.581 mmol) in CH2Cl2 (7 mL) was added dropwise
trifluoromethanesulfonic acid (277 mg, 1.85 mmol) at 0 ꢂC, and the
mixture was stirred at room temperature for 16 h. The reaction
mixture was diluted with CH2Cl2 and washed successively with
a saturated Na2S2O3 solution and brine. After the organic layer was
dried (MgSO4) and concentrated, and the residue was chromato-
graphed on silica gel (hexane/EtOAc, 1:2) to give 16 (306 mg, 92%)
as colorless crystals, mp 234–237 ꢂC (dec) (EtOAc/CH2Cl2): IR
(EtOAc/CH2Cl2): IR (CHCl3)
(270 MHz, CDCl3) 1.24–1.67 (3H, m), 1.78–1.85 (3H, m), 2.00–2.12
n ;
1780, 1685, 1620 cmꢁ1 1H NMR
d
(2H, m), 2.03 (3H, s), 2.21–2.37 (2H, m), 2.60 (1H, dd, J¼18.6, 7.7 Hz),
2.68–2.90 (2H, m), 3.20 (1H, dt, J¼17.1, 8.7 Hz), 4.11 (3H, s), 4.14 (1H,
d, J¼12.0 Hz); 13C NMR (67.5 MHz, CDCl3)
d 9.1, 24.7, 26.0, 27.9, 29.6,
30.0, 38.0, 40.0, 40.3, 59.6, 73.5, 91.4, 100.1, 167.9, 177.4, 206.0;
HRMS calcd for C17H21NO5 319.1420, found 319.1416.
(CHCl3) n d 1.33–
1755, 1685, 1615 cmꢁ1; 1H NMR (270 MHz, CDCl3)
1.58 (3H, m), 1.73–1.83 (3H, m), 1.89–2.05 (1H, m), 2.13–2.29 (2H,
m), 2.44 (1H, ddd, J¼16.2, 13.2, 3.0 Hz), 2.66–2.87 (3H, m), 2.92–
3.03 (1H, m), 4.11 (1H, d, J¼13.4 Hz), 4.42 (3H, s), 6.28 (1H, t-like),
7.09 (2H, d, J¼8.4 Hz), 7.69 (2H, d, J¼8.4 Hz); 13C NMR (67.5 MHz,
4.12.
a
,
b
-Unsaturated ketone 23
A
mixture of 21 (25 mg, 78.3 mmol) and tert-butoxy-
bis(dimethylamino)methane (45.8 mg, 0.263 mmol) in DMF (1 mL)
was heated at 100 ꢂC for 1.5 h. After the reaction mixture was
cooled to room temperature, the solvent was removed under re-
duced pressure to give 22. To a solution of the crude 22 in CH2Cl2
(2 mL) was added dropwise 0.94 M solution of diisobutylaluminum
hydride in hexane (0.14 mL, 0.132 mmol) at ꢁ78 ꢂC, and the mix-
ture was further stirred at ꢁ78 ꢂC for 10 min and at room tem-
perature for 30 min. To the solution was added methyl iodide
(125 mg, 0.878 mmol), and the mixture was stirred at room tem-
perature for 1 h. The reaction mixture was quenched with a satu-
rated NH4Cl solution and extracted with CH2Cl2. The organic layer
was washed with brine, dried (MgSO4), and concentrated. The
residue chromatographed on silica gel (EtOAc) to give 23 (17.3 mg,
67%) as colorless crystals, mp 230–231 ꢂC (EtOAc/CH2Cl2): IR
CDCl3)
d 25.1, 26.1, 28.2, 29.8, 30.0, 32.1, 40.3, 41.2, 47.2, 60.3, 75.3,
93.6, 96.6, 127.3, 130.4, 135.0, 136.9, 137.6, 169.5, 177.9, 178.1; HRMS
calcd for C23H23NO4I2 630.9717, found 630.9716.
4.9.
a-Methyl methyl tetronate 17
A mixture of 16 (190 mg, 0.301 mmol), trimethylboroxine
(126 mg, 0.903 mmol), PdCl2(dppf)2 (13 mg, 15.1 mol), and Cs2CO3
m
(516 mg,1.51 mmol) in dioxane (10 mL) was heated at reflux for 5 h.
After cooling to room temperature, the reaction mixture was di-
luted with water and extracted with AcOEt. The organic layer was
washed with brine, dried (MgSO4), and concentrated. The residue
was chromatographed on silica gel (hexane/EtOAc, 1:2) to give 17
(109 mg, 89%) as colorless crystals, mp 215–216 ꢂC (hexane/EtOAc/
(CHCl3)
1.43–1.58 (3H, m), 1.82–1.96 (4H, m), 2.03–2.12 (1H, m), 2.05 (3H,
n ;
1765, 1750, 1685, 1665 cmꢁ1 1H NMR (500 MHz, CDCl3)
CH2Cl2): IR (CHCl3)
n
1750, 1680, 1665 cmꢁ1
;
1H NMR (270 MHz,
d
CDCl3) 1.39–1.77 (3H, m), 1.80–1.87 (3H, m), 1.90–2.00 (1H, m),
d
s), 2.24 (1H, dd, J¼16.8, 9.3 Hz), 2.77 (1H, ddd, J¼11.7, 8.3, 3.2 Hz),
2.88 (1H, ddd, J¼13.9, 10.2, 2.2 Hz), 3.75–3.78 (1H, m), 4.11 (3H, s),
4.18 (1H, d, J¼14.9 Hz), 5.43 (1H, d, J¼3.2 Hz), 6.27 (1H, d, J¼3.2 Hz);
2.06 (3H, s), 2.16–2.26 (2H, m), 2.35 (3H, s), 2.44 (1H, ddd, J¼16.3,
13.2, 3.1 Hz), 2.72–3.04 (4H, m), 4.08 (1H, d, J¼14.3 Hz), 4.09 (3H, s),
6.28 (1H, t-like), 7.16 (2H, d, J¼8.2 Hz), 7.24 (2H, d, J¼8.2 Hz); 13C
13C NMR (125 MHz, CDCl3)
d 9.2, 22.2, 26.2, 27.1, 29.2, 30.2, 40.1,
NMR (67.5 MHz, CDCl3)
d
9.03, 21.2, 25.2, 26.1, 28.3, 29.9, 30.2, 32.2,
44.8, 59.6, 72.4, 90.6, 100.3, 118.6, 142.6, 168.0, 172.6, 177.5, 195.6;
HRMS calcd for C18H21NO5 331.1420, found 331.1421.
40.1, 41.2, 59.3, 75.0, 93.1, 97.8, 127.1, 128.6, 129.2, 133.2, 135.3, 137.6,
172.9, 173.8, 178.1; HRMS calcd for C25H29NO4 407.2097, found
407.2102.
4.13. ( )-Stemonamide (1) and ( )-dihydrostemonamide (27)
4.10.
a
-Iodo methyl tetronate 19
A mixture of 23 (50 mg, 0.151 mmol) and rhodium(III) chloride
hydrate (30 mg, 0.453 mmol) in EtOH/H2O (10:1) (3 mL) was
heated at reflux for 4 h. The reaction mixture was cooled to room
temperature, the solvent was removed under reduced pressure,
and the residue was chromatographed on silica gel (hexane/AcOEt,
To a solution of 18 (100 mg, 0.264 mmol) and bis(2,4,6-trime-
thylpyridine)iodonium hexafluorophosphate (488 mg, 0.949 mmol)
in CH2Cl2 (10 mL) was added dropwise trifluoromethanesulfonic

8778
T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
1:2). The first eluent gave 27 (30.8 mg, 62%) as a colorless solid, mp
237–238 ꢂC (EtOAc/CH2Cl2): IR (CHCl3) 1770, 1685, 1665 cmꢁ1; 1H
NMR (500 MHz, CDCl3)
1630 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 1.13–1.22 (1H, m), 1.37–
n
1.41 (1H, m), 1.49–1.59 (1H, m), 1.67–1.82 (4H, m), 1.76 (3H, s), 2.01–
2.06 (1H, m), 2.08 (3H, s), 2.37 (1H, dd, J¼12.9, 5.9 Hz), 2.83–2.87
(2H, m), 3.10 (1H, dd, J¼16.6, 12.2 Hz), 3.17–3.22 (2H, m), 4.13 (3H,
d
1.21 (3H, d, J¼7.3 Hz), 1.26–1.70 (4H, m),
1.80–1.91 (2H, m),1.98–2.12 (2H, m), 2.03 (3H, s), 2.20–2.28 (2H, m),
2.69–2.80 (2H, m), 2.85 (1H, t, J¼12.2 Hz), 4.09 (3H, s), 4.14 (1H, d,
s); 13C NMR (125 MHz, CDCl3)
d 8.0, 9.3, 24.2, 24.3, 27.3, 27.8, 35.6,
J¼13.4 Hz); 13C NMR (125 MHz, CDCl3)
d
9.2, 12.6, 23.3, 26.8, 28.4,
49.1, 50.9, 59.3, 75.3, 89.2, 102.3, 134.5, 169.5, 173.5, 176.4, 199.0;
HRMS calcd for C18H23NO4 317.1627, found 317.1628. The second
eluent gave (ꢀ)-stemonamine (3) (5.7 mg, 56%) as colorless crys-
29.7, 30.2, 40.3, 44.7, 45.9, 59.7, 72.7, 90.8, 100.3, 168.3, 172.8, 177.5,
209.0; HRMS calcd for C18H23NO5 333.1576, found 333.1572. The
second eluent gave (ꢀ)-1 (15.2 mg, 31%) as colorless crystals, mp
tals, mp 159–160 ꢂC (Et2O): IR (CHCl3)
n
1750, 1710, 1665,
232–233 ꢂC (EtOAc/CH2Cl2): IR (CHCl3)
n
1765, 1725, 1685, 1665,
1630 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 1.18–1.27 (1H, m), 1.40–
1640 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
1.22–1.46 (2H, m),1.83 (1H,
1.43 (1H, m), 1.73–1.91 (5H, m), 1.77 (3H, s), 2.02 (3H, s), 2.11 (1H, td,
J¼12.8, 1.8 Hz), 2.16 (1H, dd, J¼11.0, 4.9 Hz), 2.81 (1H, t, J¼7.3 Hz),
2.89 (1H, dd, J¼12.8, 6.1 Hz), 3.04 (1H, dd, J¼15.3,14.6 Hz), 3.11–3.16
d, J¼14.0 Hz), 1.87 (3H, s), 1.95 (1H, td, J¼12.8, 8.9 Hz), 2.02 (3H, s),
2.04–2.18 (2H, m), 2.30 (1H, dd, J¼16.5, 8.5 Hz), 2.38 (1H, dd, J¼12.8,
7.3 Hz), 2.61 (1H, ddd, J¼16.7, 12.0, 7.9 Hz), 2.62 (1H, t, J¼12.8 Hz),
3.00 (1H, dd, J¼12.2, 4.9 Hz), 4.00 (3H, s), 4.19 (1H, d, J¼14.0 Hz);
(2H, m), 3.97 (3H, s); 13C NMR (125 MHz, CDCl3)
d 8.2, 9.1, 24.5, 24.8,
26.9, 28.2, 39.0, 48.9, 51.4, 58.6, 76.5, 91.8, 97.5, 135.1, 171.8, 174.8,
175.0, 198.7; HRMS calcd for C18H23NO4 317.1627, found 317.1626.
1H and 13C NMR spectral data were in accord with those of the
natural stemonamine and isostemonamine.
13C NMR (125 MHz, CDCl3)
d 8.4, 9.1, 27.3, 27.4, 29.8, 30.1, 31.8, 41.2,
59.1, 74.5, 90.0, 99.6, 136.9, 168.7, 170.9, 172.9, 175.7, 196.5; HRMS
calcd for C18H21NO5 331.1420, found 331.1415. 1H and 13C NMR
spectral data of (ꢀ)-1 were in accord with those of the natural and
Kende’s synthetic stemonamide.
4.17. Treatment of 28 with Raney nickel in EtOH at low
temperature
4.14. ( )-Isostemonamide (2)
Compound 28 (10 mg, 28.7 mmol) was treated with excess Raney
A mixture of 26 (3.0 mg, 9.05
m
mol) and rhodium(III) chloride
Ni (W-2) in EtOH (3 mL) at 0 ꢂC for 1.5 h and at room temperature
for 0.5 h. The reaction mixture was filtered and the filtrate was
concentrated and chromatographed on silica gel (hexane/EtOAc,
2:1) to give 4 (6.7 mg, 77%) as colorless crystals.
hydrate (0.4 mg, 1.81 mol) in EtOH/H2O (10:1) (0.5 mL) was
m
heated at reflux for 30 min. The reaction mixture was cooled to
room temperature, and the solvent was removed under reduced
pressure. The residue was chromatographed on silica gel (EtOAc) to
give (ꢀ)-2 (3.0 mg, 100%) as colorless crystals, mp 223–224 ꢂC
4.18. Stemonamide thiocarbonyl lactam 29
(EtOAc/CH2Cl2): IR (CHCl3)
NMR (500 MHz, CDCl3)
n
1765, 1720, 1690, 1665, 1645 cmꢁ1; 1H
1.25–1.45 (2H, m), 1.78 (1H, dd, J¼14.5,
d
A mixture of (ꢀ)-1 (3.0 mg, 9.05
mmol) and Lawesson’s reagent
(2.3 mg, 5.43 mol) in toluene (0.5 mL) was heated at reflux for 1 h.
3.7 Hz), 1.86 (3H, s), 1.92 (1H, td, J¼13.2, 9.3 Hz), 2.07 (3H, s), 2.10–
2.15 (2H, m), 2.27 (1H, ddd, J¼16.6, 12.2, 7.6 Hz), 2.35 (1H, dd,
J¼16.6, 9.3 Hz), 2.61 (1H, dd, J¼13.4, 7.3 Hz), 2.95 (1H, dd, J¼12.7,
6.6 Hz), 3.00 (1H, t, J¼19.7 Hz), 4.15 (3H, s), 4.17 (1H, d, J¼15.0 Hz);
m
After the reaction mixture was cooled to room temperature, solvent
was removed under reduced pressure. The residue was chromato-
graphed on silica gel (hexane/EtOAc, 1:1) to give 29 (3.1 mg, 99%) as
13C NMR (125 MHz, CDCl3)
d
8.3, 9.3, 26.9, 27.7, 28.0, 29.4, 29.8, 42.4,
a colorless solid, mp 175–176 ꢂC (EtOAc/CH2Cl2): IR (CHCl3)
n
1770,
59.9, 73.5, 86.5, 102.9, 136.6, 168.7, 171.7, 172.6, 174.6, 196.9; HRMS
calcd for C18H21NO5 331.1420, found 331.1417. 1H and 13C NMR
spectral data were in accord with those of the natural and Kende’s
synthetic isostemonamide.
1725, 1665, 1640 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 1.38–1.47 (1H,
m), 1.62–1.70 (1H, m), 1.81–1.84 (1H, m), 1.91 (3H, s), 2.03 (3H, s),
2.08–2.20 (3H, m), 2.52 (1H, dt, J¼12.8, 4.0 Hz), 2.97–3.01 (3H, m),
3.18 (1H, t, J¼12.8 Hz), 4.02 (3H, s), 4.83 (1H, dd, J¼9.8, 4.3 Hz); 13
C
NMR (125 MHz, CDCl3)
d 8.5, 9.1, 27.1, 27.6, 27.8, 32.8, 42.9, 46.6,
4.15. Isostemonamide thiocarbonyl lactam 28
59.4, 81.2, 88.2, 99.9,138.4,168.7,169.2,172.6,196.1; HRMS calcd for
18H21NO4S 347.1191, found 347.1120.
C
Lawesson’s reagent (8.1 mg, 19.9
mmol) was added to a solution
of (ꢀ)-2 (12 mg, 33.2
m
mol) in toluene (1.5 mL), and the mixture
4.19. Treatment of 29 with Raney nickel in EtOH at low
temperature
was heated at reflux for 1 h. After removal of solvent, the residue
was chromatographed on silica gel (hexane/EtOAc, 1:1) to give 28
(12.7 mg, 100%) as a colorless solid, mp 204–206 ꢂC (dec) (EtOAc/
A mixture of 29 (10 mg, 28.7 mmol) and excess Raney Ni (W-2) in
CH2Cl2): IR (CHCl3)
n
1765, 1725, 1665, 1645 cmꢁ1
;
1H NMR
EtOH (3 mL) was stirred at 0 ꢂC for 1.5 h and at room temperature
for 0.5 h. The reaction mixture was filtered, the filtrate was con-
centrated, and the residue was chromatographed on silica gel
(hexane/EtOAc, 1:1) to give 3 (6.9 mg, 79%) as colorless crystals.
(500 MHz, CDCl3) 1.36–1.45 (1H, m), 1.63–1.72 (1H, m), 1.77–1.81
d
(1H, m), 1.89 (3H, s), 2.01–2.17 (3H, m), 2.07 (3H, s), 2.70 (1H, dd,
J¼13.4, 6.7 Hz), 2.76–2.83 (1H, m), 2.95 (1H, t, J¼13.4, 5.5 Hz), 3.04
(1H, dd, J¼17.1, 8.5 Hz), 3.21 (1H, t, J¼13.4 Hz), 4.16 (3H, s), 4.79 (1H,
d, J¼12.2 Hz); 13C NMR (125 MHz, CDCl3)
d
8.4, 9.3, 26.8, 27.2, 28.0,
Acknowledgements
29.5, 29.7, 42.7, 47.6, 59.9, 79.6, 85.4, 102.6, 137.6, 168.8, 170.9, 171.4,
196.3; HRMS calcd for C18H21NO4S 347.1191, found 347.1191.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Sciences
and Technology of Japan. We are grateful to Professor Yang Ye
4.16. Treatment of 28 with Raney nickel in EtOH at reflux:
stemonamine (3) and isostemonamine (4)
(Shanghai Institute of Materia Medica) for giving us the 1H and 13
C
NMR spectra of natural products, (ꢁ)-stemonamide, (ꢁ)-iso-
A mixture of 28 (12 mg, 33.2 mmol) and Raney Ni (W-2) (ca. 5 g)
stemonamide, (ꢀ)-stemonamine, and (ꢀ)-isostemonamine.
in EtOH (2 mL) was heated at reflux for 1.5 h. The reaction mixture
was filtered, the filtrate was concentrated, and the residue was
chromatographed on silica gel (hexane/EtOAc, 3:1/1:1). The first
eluent gave (ꢀ)-isostemonamine (4) (4.0 mg, 40%) as colorless
Supplementary data
Experimental procedures and compound characterization data
for compounds 8, 18, 20, 24, and 26. Supplementary data associated
crystals, mp 148–149 ꢂC (Et2O): IR (CHCl3)
n
1750, 1710, 1660,

T. Taniguchi, H. Ishibashi / Tetrahedron 64 (2008) 8773–8779
8779
8. Crystallographic data of 13 and 14 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC 678244
(13) and 678245 (14), respectively. Copies of these data may be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@
ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44(1223) 336033.
9. Witiak, D. T.; Tehim, A. K. J. Org. Chem. 1987, 52, 2324–2327.
10. (a) Clemo, N. G.; Pattenden, G. Tetrahedron Lett. 1982, 23, 581–584; (b) Ladlow,
M.; Pattenden, G. Tetrahedron Lett. 1985, 23, 4413–4416.
11. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
12. Campos, P. J.; Tan, C.-Q.; Rodriguez, M. A. Tetrahedron Lett. 1995, 36, 5257–5260.
13. For a recent review of the Mannich reaction, see: Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044–1070.
14. Gras, J.-L. Tetrahedron Lett. 1978, 19, 2111–2114.
15. Bredereck, H.; Simchen, G.; Rebsdat, S.; Kantlehner, W.; Horn, P.; Wahl, R.;
Hoffman, H.; Grieshaber, P. Ber. 1968, 101, 41–50.
16. Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J. Am. Chem. Soc. 1988, 110,
1985–1986.
17. (a) Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J. Am. Chem. Soc.
1976, 98, 7102–7104; (b) Andrieux, J.; Barton, D. H. R.; Patin, H. J. Chem. Soc.,
Perkin Trans. 1 1977, 359–363.
with this article can be found in the online version, at doi:10.1016/
j.tet.2008.06.091.
References and notes
1. Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17, 117–127.
2. (a) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Ueno, S. J. Chem. Soc., Chem. Com-
mun. 1973, 125–126; (b) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat. Prod. 1994, 57, 665–
669.
3. For a total synthesis of (ꢀ)-stemonamide (1) and (ꢀ)-isostemonamide (2), see:
(a) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org. Lett. 2001, 3, 2505–
2508; (b) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Tetrahedron 2002,
58, 61–74.
4. Quite recently, the first synthesis of (ꢀ)-stemonamine (3) was reported on the
basis of TiCl4 promoted tandem semipinacol rearrangement/Schmidt reaction
of a-siloxy epoxy azide. See: Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q.
Org. Lett. 2008, 10, 1763–1765.
5. For a portion of this work, see: Taniguchi, T.; Tanabe, G.; Muraoka, O.; Ishibashi,
H. Org. Lett. 2008, 10, 197–199.
6. For 7-endo-selective radical cyclizations onto the alkenic bond of enamides,
see: (a) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe,
G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922–1925; (b) Taniguchi, T.; Yonei, D.;
Sasaki, M.; Tamura, O.; Ishibashi, H. Tetrahedron 2008, 64, 2634–2641.
18. Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. Bull. Soc. Chim. Belg.
1978, 87, 223–228.
19. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278; See also: Ori, M.;
Nishio, T. Heterocycles 2000, 52, 111–116.
20. Tomari, K.; Machiya, K.; Ichimoto, I.; Ueda, H. Agric. Biol. Chem. 1980, 44, 2135–
2183.
21. Ferraz, H. M. C.; Sasahara, R. M.; Losco, P. Tetrahedron Lett. 1992, 33, 8131–8132.
22. Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968–1969.
7. For 5-endo cyclizations of a-amidoyl radicals, see: (a) Ishibashi, H.; Ishita, A.;
Tamura, O. Tetrahedron Lett. 2002, 43, 473–475; (b) Taniguchi, T.; Tamura, O.;
Uchiyama, M.; Muraoka, O.; Tanabe, G.; Ishibashi, H. Synlett 2005, 1179–1181;
(c) Takeuchi, K.; Ishita, A.; Matsuo, J.; Ishibashi, H. Tetrahedron 2007, 63, 11101–
11107; See also Ref. 6a.