Synthesis of the octahydroindole unit of aeruginosins via asymmetric hydrogenation of the Diels-Alder adducts of 2-amido-2,4-pentadienoate

Article abstract of DOI:10.1016/j.tet.2007.09.078

An optically active octahydroindole, the core unit of aeruginosins (Choi) was synthesized. The Diels-Alder reaction of Danishefsky's diene with methyl (Z)-2-acetamido-2,4-pentadienoates provided the adducts regioselectively in good yield. The adducts were

Full text of DOI:10.1016/j.tet.2007.09.078

Tetrahedron 63 (2007) 12740–12746
Synthesis of the octahydroindole unit of aeruginosins via
asymmetric hydrogenation of the Diels–Alder adducts
of 2-amido-2,4-pentadienoate
*
Yoichiro Hoshina, Takayuki Doi and Takashi Takahashi
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
Received 31 August 2007; accepted 28 September 2007
Available online 2 October 2007
Abstract—An optically active octahydroindole, the core unit of aeruginosins (Choi) was synthesized. The Diels–Alder reaction of
Danishefsky’s diene with methyl (Z)-2-acetamido-2,4-pentadienoates provided the adducts regioselectively in good yield. The adducts
were converted to the L-Choi precursor by asymmetric hydrogenation, followed by acid cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
need to overcome the following two important points: (i)
how the Diels–Alder reaction proceeds regioselectively at
the g,d positions in 7 and (ii) which derivative related to 5
is suitable for catalyst-controlled asymmetric hydrogenation
to induce stereochemistry at the 2-position independent of
the cyclohexenyl group. The cyclization of 4, after isomeri-
zation under thermodynamic conditions could provide 3
Aeruginosin 298-A (1a), isolated from Microcystis aerugi-
nosa (NIES-298), exhibited inhibitory activity toward serine
proteases (Fig. 1).1 Other aeruginosins2 and related com-
pounds, oscillarin (1b)3 and aeruginosin EI461 (1c)4,5 have
also been studied for biological interests. Most of the aerugi-
nosins have an unusual amino acid core structure 2-carboxy-
6-hydroxyoctahydroindole (L-Choi), and aeruginosin EI461
(1c) has 3a,7a-di-epi-L-Choi.5 From the interest of their
binding mode to the target proteins3,6 and chemical struc-
tures of L-Choi, the total synthesis of aeruginosins3,5,7–9
and the synthesis of Choi10,11 have been demonstrated by
several groups. Recently, we have reported a combinatorial
library synthesis of aeruginosin derivatives by peptide elon-
gation at both C-terminus and N-terminus of a polymer-sup-
ported L-Choi, providing a 300 times more potent trypsin
inhibitor.12 Herein, we report an efficient synthesis of the
Choi derivative via catalyst-controlled asymmetric hydroge-
nation as a key step.
HO
H
O
H
NH
NH2
N
H
N
N
H
N
H
O
O
OH
HO
OH
Aeruginosin 298-A (1a)
HO
H
O
H
N
H
N
Diels–Alder reaction is a powerful tool for the construction
of a six-membered ring system. As for dienes, 1-methoxy-
3-trimethylsiloxy-1,3-butadiene13 (Danishefsky’s diene) is
widely used for the syntheses of 2-cyclohexenones due to
its availability, high reactivity, and regioselectivity. It was
reported that the protected L-Choi 2 utilized in the synthesis
of aeruginosin 298-A was prepared from ketone (ꢀ)-endo-3
by stereoselective reduction with LS-Selectride.8b There-
fore, we planned the synthesis of (ꢀ)-endo-3 as illustrated
in Scheme 1, which includes Diels–Alder reaction of 6 and
7, asymmetric hydrogenation of 2-amidoacrylate derivative
5, and acid cyclization of 4. To achieve the synthesis, we
NH
NH2
N
H
N
O
O
OH
Oscillarin (1b)
HO
H
7a
3a
O
H
N
NH2
N
H
O
O
OH
HO
Aeruginosin EI461 (1c)
Figure 1. Structures of aeruginosin 298-A, oscillarin, and aeruginosin
EI461.
* Corresponding author. E-mail: ttak@apc.titech.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.078

Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
Table 1. Preparation of the precursor for asymmetric hydrogenation
12741
because it is easy to epimerize at the 3a position in 4 under
strongly acidic conditions.
Entry
7
6
Conditionsa Yield
of 9 (%)
Yield from One-pot yield
9 to 11
(%)
from 7 to 11
(%)
HO
O
1
2
3
4
5
6
7
7a 6A
I
57 (59:41)b
28 (57:43)b
42 (54:46)b
39 (56:44)b
H
H
7a 6A II
7a 6A III
7a 6A IV
7a 6B
7a 6B
7b 6B
7a
3a
H
Boc
2
H
(ref 8b)
2
N
N
I
I
I
62 (56:44)b 87 (57:43)
Bn
CO2R
CO2Bn
59 (58:42)
52 (90:10)
(L-Choi)
69 (59:41) 91 (Cis)c
52 (Trans)c
(–)-endo-3
8
7b 6B
I
O
O
Asymmetric
Hydrogenation
H
H
The numbers in parentheses refers to the ratio of cis:trans isomers (deter-
mined by 1H NMR analysis).
3a
2
a
I: Neat, 180 ꢁC, 30 min; II: xylene, 180 ꢁC, 30 min; III: xylene, micro-
wave, 180 ꢁC, 10 min; IV: neat, microwave, 180 ꢁC, 3 min.
The cis and trans isomers were inseparable.
The stereoisomers were partially separated before use.
PHN
CO2Me
PHN
( )-5
CO2Me
b
4 (P = Boc or Ac)
c
δ
γ
SiO
Diels-Alder
Reaction
proceeded at the g,d positions in 7a with complete regiose-
lectivity. When the reaction was carried out at 180 ꢁC in
p-xylene, the yield decreased to 28% due to decomposition
of 7a (Entry 2). The reaction was complete in 10 min under
microwave irradiation, whereas the yield was 42% in xylene
and 39% in the absence of solvent (Entries 3 and 4). We next
reacted diene 6B with 7a. The adduct 9aB was provided in
62% yield (Entry 5). The reaction of 6B with acetyl pro-
tected dienamide ester 7b also afforded the corresponding
adduct 9bB in 69% (Entry 7). The endo/exo stereoselectiv-
ity, however, was not induced in all reactions.
+
MeO
PHN
CO2Me
6
7
Scheme 1. Synthetic strategy of the key intermediate 3.
2. Results and discussion
The Boc and acetyl protected dienamide esters 7a and 7b
were prepared from the phosphonates 8a and 8b with acro-
lein by Burk method,14 respectively (Scheme 2). The reac-
tion of Danishefsky’s diene 6A with 7a was carried out
effectively at 180 ꢁC in the absence of solvent for 30 min
to provide 9aA in 57% yield as an inseparable mixture of
two diastereomers (Table 1, Entry 1). The reaction
Treatment of 9aA with 5 mM aqueous HCl in THF13 pro-
vided a 30:70 mixture of 5a and 10 in which an alkenyl moi-
ety isomerized to a conjugated ketone as thermodynamically
stable form. Therefore, we needed not to form a conjugated
ketone in a cyclohexane ring. We next converted 9aB and
9bB to 11a and 11b by treatment with KF in methanol, re-
spectively (Entries 5 and 7). It is noted that removal of the
TBS group in cis-9bB gave cis-11b in 91% yield, whereas
the trans-9bB gave trans-11b in only 52% yield due to the
fact that unknown polar products were formed (Entry 7).
The cycloaddition and deprotection were sequentially per-
formed in one pot. From 7a and 6B, 11a was obtained in
59% overall yield as a 58:42 diastereomer mixture (Entry
6). From 7b and 6B, 11b was obtained in 52% with
a 90:10 ratio (Entry 8).
δ
tetramethyl-
guanidine
OMe
O
OMe
γ
+
P
THF
O
–78 °C to rt
PHN
CO2Me
PHN
CO2Me
8a : P = Boc
8b : P = Ac
7a : P = Boc (quant.)
7b : P = Ac (80%)
5a : P = Boc
SiO
7a, or 7b
180 °C
Table 1
HCl
THF-H2O
(94%)
SiO
H
+
H
Asymmetric hydrogenation of enamides (ꢂ)-11a (cis:
trans¼58:42) and (ꢂ)-11b (cis:trans¼90:10) was performed
utilizing an Rh–(S,S)-Me-DuPHOS system (Scheme 3).15,16
Both of the enamides underwent asymmetric hydrogenation
in the presence of 5 mol % of [(COD)Rh–(S,S)-Me-DuPHO-
S]OTf in 2-propanol17 under H2 (0.1 MPa) leading to the
corresponding amino acid derivatives 12a and 12b in quan-
titative yields, respectively, as a mixture of diastereomers
(Table 2). Therefore, the enantiomeric excesses of the prod-
ucts were analyzed after conversion to cis-fused (ꢀ)-exo-3
and (ꢀ)-endo-3, reported previously.8b As shown in Scheme
3, treatment of 12 with 6 M aqueous HCl/dioxane at 100 ꢁC
induced elimination of methanol, removal of the protecting
groups, and sequential cyclization to form the bicyclic ami-
no acid 13. Dibenzylation of 13 in situ afforded (ꢀ)-exo-3
and (ꢀ)-endo-3, which were isolated by silica gel column
MeO
PHN
MeO
(3.0 eq.)
O
CO2Me
NHBoc
CO2Me
9aA : P = Boc,
9aB : P = Boc,
9bB : P = Ac,
Si = TMS
Si = TBS
Si = TBS
6A : Si = TMS
6B : Si = TBS
H
H
NOE 14%
10
(5a : 10 = 3 : 7)
O
KF
MeOH
H
9aB
H
9bB
Table 1
MeO
PHN
CO2Me
11a : P = Boc
11b : P = Ac
Scheme 2. Preparation of Diels–Alder adducts 11.

12742
Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
Table 2. Yields of 12 and 3, and enantiomeric excesses of 3
chromatography. The yields and enantiomeric excesses
(ee’s) determined by chiral HPLC analysis are summarized
in Table 2. From the Boc protected derivative 12a, 3 was ob-
tained with low ee’s (up to 41% ee) (Entry 1). On the other
hand, from the acetyl protected derivative 12b, highly enan-
tiorich compounds were obtained, (ꢀ)-exo-3 in 32% (95%
ee) and (ꢀ)-endo-3 in 21% (95% ee) (Entry 2). Both (ꢂ)-
cis-11b and (ꢂ)-trans-11b were independently converted
to 3 in the same yields and ee’s (Entries 3 and 4). Thus,
this asymmetric hydrogenation proceeded efficiently by the
catalyst-control without influence of the stereochemistry on
the cyclohexyl group.16 The higher H2 pressure gave lower
ee’s (Entry 5). The difference in the ee values derived
from the protecting groups would be caused by the enantio-
selectivity of the asymmetric hydrogenation step. The bi-
dentate chelation of a substrate–Rh–(S,S)-Me-DuPHOS
complex would be weaker in the N-Boc derivative than in
the N-acetyl derivative due to the steric effect and/or less
electron donation of the O-t-Bu group.16,18 The optical
purity of (ꢀ)-endo-3 was further enriched (>99% ee) by
recrystallization from ethanol/hexane. The absolute stereo-
chemistry was determined by the optical rotation of exo-3
and endo-3.8b,10 Acid-mediated isomerization of (ꢀ)-exo-3
to (ꢀ)-endo-3 was performed in 32% yield with recovery
of (ꢀ)-exo-3 (43%) as we reported previously.12a,19 Chiral
HPLC analysis proved that this isomerization proceeded
without loss of optical purity. It has been reported that
(ꢀ)-endo-3 and (ꢀ)-exo-3 are easily converted to the pro-
tected L-Choi (2) and 3a,7a-di-epi-L-Choi, respectively.5,8b
Entry
11
Yields and ee’sa (%)
12
(ꢀ)-exo-3
(ꢀ)-endo-3
1b
2b
3b
4b
5c
(ꢂ)-11a (58:42)
(ꢂ)-11b (90:10)
(ꢂ)-cis-11b
>99
>99
96
95
94
35 (37)
32 (95)
32 (93)
35 (95)
37 (85)
23 (41)
21 (95)
25 (94)
27 (94)
29 (82)
(ꢂ)-trans-11b
(ꢂ)-cis-11b
a
The numbers in parentheses refer to the enantiomeric excesses determined
by chiral HPLC analysis.
Rh catalyst (5 mol %), 0.1 MPa, 3 h.
b
c
Rh catalyst (5 mol %), 0.4 MPa, 14 h.
asymmetric hydrogenation catalyzed by an Rh–DuPHOS
system inducing high enantiomeric excess at the 2-position
in 12b. Finally, acid cyclization provided the cis-fused
(ꢀ)-endo-3 with 95% ee and (ꢀ)-exo-3 with 95% ee. This
synthetic methodology will be useful for the synthesis of
Choi derivatives by utilization of other substituted Danishef-
sky’s dienes and/or substituted 2-(acetoamido)pentadi-
enoates.
3. Experimental
3.1. General information
1H spectra were recorded on JEOL Model ECP-400
(400 MHz) or ECA-400 (400 MHz) spectrometer. Chemical
shifts are reported in parts per million from tetramethyl-
silane with the solvent resonance as the internal standard
(chloroform-d: d 7.26, dimethylsulfoxide-d6: d 2.50). Data
are reported as follows: chemical shift, integration, multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
br¼broad, and m¼multiplet), coupling constants (Hz), and
assignment. 13C NMR spectra were recorded on JEOL
Model ECP-400 (100 MHz) or ECA-400 (100 MHz) spec-
trometer with complete proton decoupling. Chemical shifts
are reported in parts per million from tetramethylsilane
with the solvent resonance as the internal standard (chloro-
form-d: d 77.0, dimethylsulfoxide-d6: d 39.6). Infrared spec-
tra were recorded on Perkin-Elmer Spectrum One or
Shimadzu IRPrestige-21 FT-IR spectrometer. Mass spectra
were obtained on JMN1100 (FAB) or (ESI-TOF) mass
spectrometers. Analytical thin-layer chromatography was
performed on silica gel TLC plates. Visualization was
accomplished with UV light and ethanol solution of phos-
phomolybdic acid or ninhydrin/H2O/1-butanol solution fol-
lowed by heating. Column chromatography was performed
on Merck silica gel 60 (0.063–0.200 mm) or Nacalai silica
gel 60 (spherical, neutrality). Optical rotations were mea-
sured with JASCO P-1020 or Horiba SEPA-300 polarimeter.
Chiral HPLC was performed on Shimadzu LC-10 series
system. The column was Daicel Chiralcel OJ or OD-H
4.6ꢃ250 mm. Peak areas were integrated with 214 nm.
O
H2, Rh(cod)2OTf
H
(S,S)-Me-DuPHOS
i-PrOH
( )-11a : P = Boc
( )-11b : P = Ac
H
MeO
PHN
CO2Me
12a : P = Boc
12b : P = Ac
O
H
BnBr, NaHCO3
DMF, 60 °C
HCl
H2O-dioxane
100 °C
H
HN
CO2H
HCl
13
O
O
H
H
+
H
Bn
H
N
N
Bn
CO2Bn
CO2Bn
(–)-exo-3
(–)-endo-3
HCl, dioxane, 65 °C, 32%
Scheme 3. The synthesis of (ꢀ)-exo-3 and (ꢀ)-endo-3.
3.1.1. Methyl 2-tert-butoxycarbonylamino-2-(dimethoxy-
phosphinyl)acetate (8a). A solution of methyl 2-benzyl-
oxycarbonylamino-2-(dimethoxyphosphinyl)acetate (2.3 g,
7.0 mmol) and (Boc)2O (1.8 mL, 7.7 mmol) in MeOH
(25 mL) was treated with 5% palladium–carbon (0.23 g) un-
der a hydrogen atmosphere (0.1 MPa) for 24 h. The reaction
In summary, we have demonstrated the synthesis of the
optically pure octahydroindole that is a core unit of aerugi-
nosins (L-Choi). The Diels–Alder reaction of Danishefsky-
type diene 6 with the dienamides 7 in the absence of solvent
provided the adducts as a mixture of stereoisomers with
complete regioselectivity. The adduct 11b underwent

Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
12743
mixture was filtered through CeliteÒ, and the filtrate was
concentrated under vacuum. The residue was purified by sil-
ica gel column chromatography (hexane/EtOAc¼1/2–
dienamide 7a (150 mg, 0.66 mmol) and trans-1-methoxy-
3-trimethylsilyloxy-1,3-butadiene (6A, 0.39 mL, 2.0 mmol)
was heated at 180 ꢁC for 30 min. The reaction mixture was
purified by silica gel column chromatography (spherical,
neutrality, hexane/EtOAc¼2/1–EtOAc only) to afford 9aA
(150 mg, 57%, cis:trans¼59:41 (determined by 1H NMR)).
1H NMR (400 MHz, CDCl3) d 0.12 and 0.33 (9H, s), 1.46
and 1.47 (9H, s), 1.56–1.70 (1H, m), 1.85–2.25 (3H, m),
2.57–2.69 and 2.73–2.84 (1H, m), 3.31 and 3.32 (3H, s),
3.66–3.73 and 3.82–3.90 (1H, m), 3.77 and 3.78 (3H, s),
5.00 and 5.09 (1H, br s and d, J¼4.3 Hz), 6.06 and 6.12
(1H, br s), 6.72 and 6.79 (1H, d and s, J¼9.7 Hz); 13C
NMR (100 MHz, CDCl3) d 0.2 and 0.3, 22.9, 28.1, 28.7
and 29.0, 37.5 and 37.9, 52.2, 55.9 and 56.1, 75.9, 80.4,
102.8, 103.5, 137.2, 153.5 and 153.7, 154.4, 165.5; IR
(neat) 3335, 2955, 1728, 1660, 1489, 1368, 1253, 1167,
1
EtOAc) to afford 8a (2.1 g, 99%). H NMR (400 MHz,
CDCl3) d 1.46 (9H, s), 3.78–3.89 (9H, m), 4.88 (1H, dd,
J¼9.2, 22.7 Hz), 5.35 (1H, br d, J¼8.2 Hz).
3.1.2. Methyl 2-acetylamino-2-(dimethoxyphosphinyl)-
acetate (8b). A solution of methyl 2-benzyloxycarbonyl-
amino-2-(dimethoxyphosphinyl)acetate (5.7 g, 17 mmol)
and acetic anhydride (4.4 mL, 47 mmol) in MeOH
(48 mL) was treated with 10% palladium–carbon (0.59 g)
under a hydrogen atmosphere (0.3 MPa) for 24 h. The reac-
tion mixture was filtered through CeliteÒ, and the filtrate was
concentrated under vacuum. The residue was crystallized
from EtOAc and hexane to afford 8b (3.7 g, 90%). 1H
NMR (400 MHz, CDCl3) d 2.09 (3H, s), 3.80–3.86 (9H,
m), 5.24 (1H, dd, J¼8.9, 22.2 Hz), 6.40 (1H, br d,
J¼7.8 Hz).
1084, 884, 846, 759 cmꢀ1
.
3.1.6. Mixture of methyl 2-tert-butoxycarbonylamino-3-
(4-oxocyclohex-2-enyl)acrylate (5a) and methyl (3E)-2-
tert-butoxycarbonylamino-3-(4-oxocyclohex-2-enylide-
ne)propionate (10). To a solution of the trimethylsilyl ether
9aA (140 mg, 0.35 mmol) in THF (1 mL) was added
0.005 mol/L HCl (1 mL) at room temperature. After stirring
for 2 h at this temperature, the reaction mixture was
quenched with saturated aqueous NaHCO3 and the aqueous
solution was extracted with EtOAc. The organic layer was
washed with brine, and dried over Na2SO4. The solution
was filtered, and the filtrate was concentrated under vacuum.
The residue was purified by silica gel column chromato-
graphy (hexane/EtOAc¼3/1–3/2) to afford mixture of 5a
and 10 (99 mg, total yield 94%, 5a:10¼3:7 (determined by
3.1.3. Methyl (Z)-2-tert-butoxycarbonylamido-2,4-penta-
dienoate (7a). To a solution of the phosphate 8a (1.3 g,
4.4 mmol) in THF (14 mL) was added 1,1,3,3-tetramethyl-
guanidine (0.55 mL, 4.4 mmol) and acrolein (0.33 mL,
4.4 mmol) in THF (5 mL) at ꢀ78 ꢁC. After stirring for
15 min at the same temperature, the resulting solution was
warmed to room temperature for 1 h. The reaction mixture
was quenched with 1 mol/L HCl and extracted with EtOAc.
The organic layer was washed with brine, and dried over
Na2SO4. The solution was filtered, and the filtrate was con-
centrated under vacuum. The residue was purified by silica
gel column chromatography (hexane/EtOAc¼4/1) to afford
7a (1.0 g, quant.). 1H NMR (400 MHz, CDCl3) d 1.47 (9H,
s), 3.81 (3H, s), 5.47 (1H, d, J¼10.6 Hz), 5.58 (1H, d,
J¼16.9 Hz), 6.19 (1H, br s), 6.58 (1H, ddd, J¼10.6, 10.6,
16.9 Hz), 6.93 (1H, d, J¼11.6 Hz); 13C NMR (100 MHz,
CDCl3) d 28.0, 52.3, 80.7, 124.0, 124.4, 130.7, 131.6,
153.2, 165.5; IR (neat) 3333, 2980, 1707, 1492, 1367,
1
1H NMR)). Compound 5a: H NMR (400 MHz, CDCl3)
d 1.47 (9H, s), 1.86–1.98 (1H, m), 2.19–2.28 (1H, m), 2.43
(1H, ddd, J¼4.9, 11.6, 16.7 Hz), 2.68–2.80 (1H, m), 3.50–
3.60 (1H, m), 3.81 (3H, s), 6.07 (1H, dd, J¼2.4, 10.1 Hz),
6.19 (1H, br s), 6.42 (1H, d, J¼10.2 Hz), 6.90 (1H, dd,
J¼2.7, 10.1 Hz); 13C NMR (100 MHz, CDCl3) d 28.0,
28.1, 30.7, 37.1, 52.5, 80.9, 126.6, 129.3, 129.7, 133.8,
1261, 1164, 1049, 997, 776 cmꢀ1
.
1
150.9, 164.9, 198.7. Compound 10: H NMR (400 MHz,
3.1.4. Methyl (Z)-2-acetamidopenta-2,4-dienoate (7b). To
a solution of the phosphate 8b (960 mg, 4.0 mmol) in THF
(16 mL) was added 1,1,3,3-tetramethylguanidine (0.67 mL,
5.3 mmol) and acrolein (0.36 mL, 4.8 mmol) in THF
(8 mL) at ꢀ78 ꢁC. After stirring for 30 min at the same tem-
perature, the resulting solution was warmed to room temper-
ature for 2 h. The reaction mixture was quenched with 1 mol/
L HCl and extracted with CH2Cl2. The organic layer was
washed with saturated aqueous NaHCO3 and brine, and dried
over Na2SO4. The solution was filtered, and the filtrate was
concentrated under vacuum. The residue was purified by sil-
ica gel column chromatography (hexane/EtOAc¼1/1–
CDCl3) d 1.45 (9H, s), 2.49–2.64 (2H, m), 2.85–3.09 (2H,
m), 3.77 (3H, s), 5.14 (1H, br t, J¼8.0 Hz), 5.25–5.39 (1H,
m), 5.59 (1H, d, J¼9.3 Hz), 5.99 (1H, d, J¼10.0 Hz), 6.97
(1H, d, J¼10.0 Hz); 13C NMR (100 MHz, CDCl3) d 24.1,
28.1, 36.1, 51.9, 52.8, 80.2, 128.1, 129.6, 137.9, 147.6,
154.7, 170.7, 198.9; IR (KBr) 3343, 2978, 1694, 1487,
1250, 1161, 1049, 864, 756 cmꢀ1; MS (FAB) m/z: 296
[M+H]+.
3.1.7. Methyl (Z)-2-tert-butoxycarbonylamino-3-[4-(tert-
butyldimethylsilyloxy)-2-methoxycyclohex-3-enyl]acryl-
ate (9aB, mixture of diastereomers). The mixture of the
dienamide 7a (110 mg, 0.5 mmol) and trans-3-(tert-butyl-
dimethylsilyloxy)-1-methoxy-1,3-butadiene (6B, 0.36 mL,
1.5 mmol) was heated at 180 ꢁC for 30 min. The reaction
mixture was purified by silica gel column chromatography
(spherical, neutrality, hexane/EtOAc¼8/1–4/1) to afford
9aB (138 mg, 62%, cis:trans¼56:44 (determined by 1H
1
EtOAc) to afford 7b (540 mg, 80%). H NMR (400 MHz,
CDCl3) d 2.16 (3H, s), 3.81 (3H, s), 5.49 (1H, d,
J¼9.6 Hz), 5.60 (1H, d, J¼16.5 Hz), 6.41–6.54 (1H, m),
7.05 (1H, d, J¼11.0 Hz), 7.09 (1H, br s); 13C NMR
(100 MHz, CDCl3) d 23.3, 52.4, 123.8, 124.9, 131.7, 132.8,
165.3, 169.0; IR (KBr) 2953, 1728, 1674, 1552, 1437,
1261, 1009, 770 cmꢀ1
.
NMR)). H NMR (400 MHz, CDCl3) d 0.16 and 0.17 (6H,
1
s), 0.92 (9H, s), 1.46 (9H, s), 1.56–1.68 (1H, m), 1.87–
2.22 (3H, m), 2.56–2.67 and 2.73–2.82 (1H, m), 3.31 and
3.32 (3H, s), 3.66–3.72 and 3.83–3.88 (1H, m), 3.77 and
3.78 (3H, s), 5.00 and 5.09 (1H, br s and d, J¼4.3 Hz),
3.1.5. Methyl (Z)-2-tert-butoxycarbonylamino-3-[4-(tri-
methylsilyloxy)-2-methoxycyclohex-3-enyl]-acrylate
(9aA, mixture of diastereomers). The mixture of the

12744
Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
6.06 and 6.16 (1H, br s), 6.72 and 6.80 (1H, d and s,
J¼9.7 Hz); 13C NMR (100 MHz, CDCl3) d ꢀ4.6 and
ꢀ4.5, 17.9, 22.9, 25.5, 28.0, 28.6 and 29.0, 37.4 and 37.8,
52.0 and 52.1, 55.8 and 56.0, 75.8, 80.2 and 80.5, 102.8,
103.5, 137.1, 153.4 and 153.6, 154.1 and 154.5, 165.3 and
165.4; IR (neat) 3337, 2932, 1727, 1661, 1473, 1368,
82.2, 129.7, 132.2, 153.4, 165.1, 207.7; IR (KBr) 1732,
1695, 1655, 1634, 1541, 1364, 1304, 1263, 1202,
1157 cmꢀ1; MS (FAB) m/z: 328 [M+H]+.
3.1.10. One-pot reaction from 7a to 11a. The mixture of
the diene 7a (100 mg, 0.45 mmol) and trans-3-(tert-butyl-
dimethylsilyloxy)-1-methoxy-1,3-butadiene (6B, 0.32 mL,
1.4 mmol) was heated at 180 ꢁC for 30 min. After cooling
to room temperature, MeOH (3 mL) and KF (81 mg,
1.4 mmol) were added to the reaction mixture. After stirring
for 40 min at this temperature, the reaction mixture was
quenched with aqueous water, and extracted with EtOAc.
The organic layer was washed with brine, and dried over
Na2SO4. The solution was filtered and the filtrate was con-
centrated under vacuum. The residue was purified by silica
gel column chromatography (hexane/EtOAc¼3/1–3/2) to
afford 11a (87 mg, 59%, cis:trans¼58:42 (determined by
1H NMR)).
1251, 1168, 1084, 878, 839, 780 cmꢀ1
.
3.1.8. Methyl (Z)-2-acetylamino-3-[4-(tert-butyldime-
thylsilanoxy)-2-methoxycyclohex-3-enyl]acrylate (9bB,
mixture of diastereomers). The mixture of the dienamide
7b (170 mg, 1.0 mmol) and trans-3-(tert-butyldimethylsilyl-
oxy)-1-methoxy-1,3-butadiene (6B, 0.72 mL, 3.0 mmol)
was heated at 180 ꢁC for 30 min. The reaction mixture was
purified by silica gel column chromatography (spherical,
neutrality, hexane/EtOAc¼2/1–EtOAc only) to afford 9bB
(270 mg, 69%, cis:trans¼59:41 (determined by 1H NMR)).
The two isomers were partially separated by silica gel col-
umn chromatography (spherical, neutrality, hexane/
EtOAc¼2/1–EtOAc only) into cis-9bB and trans-9bB. cis-
3.1.11. Methyl (Z)-2-acetylamino-3-(cis-2-methoxy-4-oxo-
cyclohexyl)acrylate (cis-11b). To a solution of the silyl
ether cis-9bB (400 mg, 1.0 mmol) in MeOH (5 mL) was
added KF (99 mg, 1.7 mmol) at room temperature. After
stirring for 1 h at this temperature, the resulting solution
was concentrated under vacuum. The residue was purified
by silica gel column chromatography (CHCl3/MeOH¼10/
1
9bB: H NMR (400 MHz, DMSO-d6) d 0.15 (3H, s), 0.16
(3H, s), 0.90 (9H, s), 1.45–1.54 (1H, m), 1.71–1.83 (1H,
m), 1.90–2.07 (2H, m), 1.93 (3H, s), 2.63–2.70 (1H, m),
3.18 (3H, s), 3.63 (3H, s), 3.78 (1H, br t, J¼3.9 Hz), 5.05
(1H, d, J¼4.1 Hz), 6.43 (1H, d, J¼9.6 Hz), 9.25 (1H, s);
13C NMR (100 MHz, DMSO-d6) d ꢀ4.5, 17.7, 22.3, 23.0,
25.5, 28.4, 35.9, 51.8, 55.2, 74.7, 103.6, 127.4, 136.4,
153.9, 164.8, 168.9; IR (neat) 3271, 2930, 2859, 1732,
1634, 1371, 1200, 1082, 839, 779 cmꢀ1. trans-9bB: 1H
NMR (400 MHz, DMSO-d6) d 0.15 (6H, s), 0.90 (9H, s),
1.44–1.55 (1H, m), 1.71–1.80 (1H, m), 1.90–2.05 (2H, m),
1.94 (3H, s), 2.60–2.71 (1H, m), 3.17 (3H, s), 3.63 (3H, s),
3.65–3.70 (1H, m), 4.94 (1H, d, J¼3.7 Hz), 6.24 (1H, d,
J¼9.6 Hz), 9.28 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d ꢀ4.5, 17.8, 22.3, 23.2, 25.5, 27.5, 35.7, 51.9, 54.7, 77.5,
103.5, 128.4, 136.0, 153.6, 164.8, 168.9; IR (neat) 3269,
2930, 2859, 1732, 1645, 1514, 1435, 1371, 1240, 1084,
1
1) to afford cis-11b (250 mg, 91%). H NMR (400 MHz,
CDCl3) d 1.79–1.90 (1H, m), 2.04–2.21 (1H, m), 2.17 (3H,
s), 2.30–2.50 (3H, m), 2.70–2.79 (1H, m), 2.93 (1H, br t,
J¼10.1 Hz), 3.34 (3H, s), 3.81 (3H, s), 3.88 (1H, br s),
6.77 (1H, d, J¼10.1 Hz), 7.11 (1H, br s); 13C NMR
(100 MHz, CDCl3) d 23.5, 25.4, 39.8, 40.1, 44.0, 52.5,
56.7, 79.9, 125.1, 136.5, 165.1, 168.9, 209.1; IR (neat)
3281, 2953, 1732, 1715, 1694, 1487, 1371, 1244, 1092,
772 cmꢀ1; HRMS (ESI-TOF) calcd for [C13H19NO5+H]+
270.1341, found 270.1343.
874, 779 cmꢀ1
.
3.1.12. Methyl (Z)-2-acetylamino-3-(trans-2-methoxy-4-
oxocyclohexyl)acrylate (trans-11b). To a solution of the si-
lyl ether trans-9bB (210 mg, 0.56 mmol) in MeOH (3 mL)
was added KF (51 mg, 0.87 mmol) at room temperature.
After stirring for 1 h at this temperature, the resulting solu-
tion was concentrated under vacuum. The residue was puri-
fied by silica gel column chromatography (CHCl3/
3.1.9. Methyl (Z)-2-tert-butoxycarbonylamino-3-(2-meth-
oxy-4-oxocyclohexyl)acrylate (11a, mixture of diaste-
reomers). To a solution of the adduct 9aB (140 mg,
0.30 mmol) in MeOH (1.5 mL) was added KF (19 mg,
0.33 mmol) at room temperature. After stirring for 1.5 h at
this temperature, the resulting solution was concentrated un-
der vacuum. The residue was purified by silica gel column
chromatography (hexane/EtOAc¼2/1–1/1) to afford 11a
1
MeOH¼10/1) to afford trans-11b (78 mg, 52%). H NMR
(400 MHz, CDCl3) d 1.47–1.61 (1H, m), 2.08–2.26 (1H,
m), 2.14 (3H, s), 2.30–2.49 (3H, m), 2.70–2.86 (1H, m),
2.92 (1H, dd, J¼3.7, 13.7 Hz), 3.28–3.39 (1H, m), 3.33
(3H, s), 3.80 (3H, s), 6.32 (1H, d, J¼9.6 Hz), 7.56 (1H, br
s); 13C NMR (100 MHz, CDCl3) d 23.3, 26.2, 39.6, 41.3,
46.1, 52.6, 56.9, 82.3, 129.1, 134.4, 164.7, 169.2, 207.7;
IR (neat) 3304, 2953, 1715, 1645, 1520, 1435, 1373, 1211,
1088 cmꢀ1; HRMS (ESI-TOF) calcd for [C13H19NO5+H]+
270.1341, found 270.1347.
1
(87 mg, 87%, cis:trans¼57:43 (determined by H NMR)).
The two isomers were partially separated by silica gel col-
umn chromatography (hexane/EtOAc¼3/1–1/1). cis-11a:
1H NMR (400 MHz, CDCl3) d 1.48 (9H, s), 1.80–1.93
(1H, m), 2.21 (1H, m), 2.30–2.54 (3H, m), 2.74 (1H, dd,
J¼4.8, 14.7 Hz), 3.04 (1H, m), 3.34 (3H, s), 3.80 (3H, s),
3.85 (1H, br s), 6.34 (1H, br s), 6.64 (1H, d, J¼9.7 Hz);
13C NMR (100 MHz, CDCl3) d 25.4, 28.1, 39.7, 39.8,
44.1, 52.4, 56.8, 80.0, 80.7, 126.3, 134.6, 153.5, 165.3,
208.9; IR (KBr) 3227, 2934, 1707, 1651, 1541, 1362,
1258, 1165 cmꢀ1; MS (FAB) m/z: 328 [M+H]+. trans-11a:
1H NMR (400 MHz, CDCl3) d 1.41–1.62 (1H, m), 1.48
(9H, s), 2.12–2.25 (1H, m), 2.30–2.49 (3H, m), 2.82–2.98
(2H, m), 3.25–3.41 (1H, m), 3.31 (3H, s), 3.80 (3H, s),
6.17 (1H, br s), 6.68 (1H, br s); 13C NMR (100 MHz,
CDCl3) d 26.2, 28.1, 39.5, 40.6, 46.2, 52.3, 56.8, 80.7,
3.1.13. One-pot reaction from 7b to 11b. The mixture of
the diene 7b (150 mg, 0.91 mmol) and trans-3-(tert-butyldi-
methylsilyloxy)-1-methoxy-1,3-butadiene (6B, 0.65 mL,
2.7 mmol) was heated at 180 ꢁC for 30 min. After cooling
to room temperature, MeOH (3 mL) and KF (160 mg,
2.7 mmol) were added to the reaction mixture. After stirring
for 1 h at this temperature, the resulting solution was con-
centrated under vacuum. The residue was purified by silica

Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
12745
gel column chromatography (CHCl3/MeOH¼10/1) to afford
11b (130 mg, 52%, cis:trans¼90:10 (determined by 1H
NMR)).
DuPHOS-Rh(cod)]OTf. To a solution of trans-11b (27 mg,
1.0 mmol) in 2-propanol (0.5 mL) was added [(S,S)-Me-
DuPHOS-Rh(cod)]OTf (5 mol %) in 2-propanol (0.5 mL),
and the reaction mixture was stirred under a hydrogen atmo-
sphere (0.1 MPa) for 3 h. The resulting solution was concen-
trated under vacuum. The residue was purified by silica gel
column chromatography (CHCl3/MeOH¼10/1) to afford
trans-12b (26 mg, 88%). 1H NMR (400 MHz, CDCl3, mix-
ture of diastereomers) d 1.28–1.48 (1H, m), 1.65–1.93 (2H,
m), 2.02–2.39 (5H, m), 2.04 and 2.06 (3H, s), 2.76–2.90 (1H,
m), 3.09–3.17 and 3.18–3.28 (1H, m), 3.32 and 3.34 (3H, s),
3.75 and 3.77 (3H, s), 4.61–4.74 (1H, m), 6.32 and 6.58 (1H,
d, J¼7.8 and 6.9 Hz); 13C NMR (100 MHz, CDCl3) d 23.1,
26.6 and 27.2, 34.5, 37.3 and 38.1, 39.6 and 39.9, 45.0 and
45.6, 50.1 and 50.7, 52.4 and 52.5, 56.3 and 56.4, 81.9,
169.8 and 170.3, 172.7 and 173.0, 208.4 and 208.5; IR
(neat) 3304, 2953, 1715, 1645, 1520, 1435, 1373, 1211,
1088 cmꢀ1; HRMS (ESI-TOF) calcd for [C13H21NO5+H]+
272.1498, found 272.1494.
3.1.14. Conversion of 11a to 3. A solution of Rh(COD)2OTf
(2.3 mg, 0.0050 mmol) and (S,S)-Me-DuPHOS (1.5 mg,
0.0050 mmol) in 2-propanol (0.5 mL) was stirred for 1 h to
prepare [(COD)Rh–(S,S)-Me-DuPHOS]OTf. To a solution
of (ꢂ)-11a (33 mg, 0.10 mmol, cis:trans¼58:42) in 2-propa-
nol (0.5 mL) was added [(COD)Rh–(S,S)-Me-DuPHOS]OTf
(5 mol %) in 2-propanol (0.5 mL), and the reaction mixture
was stirred under a hydrogen atmosphere (0.1 MPa) for 3 h.
The resulting solution was concentrated under vacuum. The
residue was purified by silica gel column chromatography
(hexane/EtOAc¼3/2–1/1) to afford 12a (34 mg, quant.).
To a solution of 12a (34 mg, 0.10 mmol) in dioxane (1 mL)
was added 6 mol/L HCl (1 mL), and the reaction mixture
was stirred for 7 h at 100 ꢁC. After removing the solvent un-
der vacuum, the residue was dissolved in DMF (1 mL).
NaHCO3 (50 mg, 0.60 mmol) and benzyl bromide
(0.048 mL, 0.40 mmol) were added to the solution, and the
resulting solution was stirred at 60 ꢁC for 3 h. After cooling
to room temperature, the reaction mixture was quenched
with aqueous NaHCO3, and extracted with EtOAc. The or-
ganic layer was washed with brine, and dried over
Na2SO4. The solution was filtered and the filtrate was con-
centrated under vacuum. The residue was purified by prepar-
ative thin-layer chromatography on silica gel (hexane/
EtOAc¼2/1) to afford (ꢀ)-exo-3 (13 mg, 35%, 37% ee)
and (ꢀ)-endo-3 (8.6 mg, 23%, 41% ee). The spectral data
of 3 are shown in Section 3.1.18.
3.1.17. Methyl 2-acetylamino-3-(2-methoxy-4-oxocyclo-
hexyl)propionate (12b, mixture of diastereomers). A
solution of Rh(cod)2OTf (23 mg, 0.050 mmol) and (S,S)-
Me-DuPHOS (15 mg, 0.050 mmol) in 2-propanol (5 mL)
was stirred for 1 h to prepare [(S,S)-Me-DuPHOS-Rh(co-
d)]OTf. To a solution of (ꢂ)-11b (270 mg, 1.0 mmol, cis:
trans¼90:10) in 2-propanol (5 mL) was added [(S,S)-Me-
DuPHOS-Rh(cod)]OTf (5 mol %) in 2-propanol (5 mL),
and the reaction mixture was stirred under a hydrogen atmo-
sphere (0.1 MPa) for 3 h. The resulting solution was concen-
trated under vacuum. The residue was purified by silica gel
column chromatography (CHCl3/MeOH¼10/1) to afford
12b (270 mg, cis:trans¼91:9 (determined by 1H NMR),
quant.).
3.1.15. Methyl 2-acetylamino-3-(cis-2-methoxy-4-oxocy-
clohexyl)propionate (cis-12b, mixture of diastereomers).
A solution of Rh(COD)2OTf (2.3 mg, 0.0050 mmol) and
(S,S)-Me-DuPHOS (1.5 mg, 0.0050 mmol) in 2-propanol
(0.5 mL) was stirred for 1 h to prepare [(CODRh–(S,S)-
Me-DuPHOS)]OTf. To a solution of cis-11b (27 mg,
1.0 mmol) in 2-propanol (0.5 mL) was added [(COD)Rh–
(S,S)-Me-DuPHOS]OTf (5 mol %) in 2-propanol (0.5 mL),
and the reaction mixture was stirred under a hydrogen atmo-
sphere (0.1 MPa) for 3 h. The resulting solution was concen-
trated under vacuum. The residue was purified by silica gel
column chromatography (CHCl3/MeOH¼10/1) to afford
cis-12b (26 mg, 96%). 1H NMR (400 MHz, CDCl3, mixture
of diastereomers) d 1.52–1.61 (1H, m), 1.69–1.82 (1H, m),
1.85–2.03 and 2.08–2.17 (3H, m), 2.06 (3H, s), 2.27–2.43
(3H, m), 2.70–2.80 (1H, m), 3.31 and 3.36 (3H, s), 3.66
and 3.87 (1H, br s), 3.77 (3H, s), 4.62–4.72 (1H, m), 6.01
and 6.07 (1H, br d, J¼8.2, 7.8 Hz); 13C NMR (100 MHz,
CDCl3) d 23.1, 25.9 and 27.0, 34.4 and 34.6, 36.7 and
36.8, 39.8 and 40.2, 43.8, 50.2 and 50.4, 52.5, 56.4 and
56.6, 78.6 and 80.3, 170.1, 173.2, 209.7 and 209.8; IR
(neat) 3306, 2953, 1748, 1715, 1435, 1373, 1207,
1089 cmꢀ1; HRMS (ESI-TOF) calcd for [C13H21NO5+H]+
272.1498, found 272.1495.
3.1.18. Conversion of 12b to 3. Benzyl (2S,3aR,7aR)- and
(2S,3aS,7aS)-1-benzyl-6-oxooctahydroindole-2-carb-
oxylate ((L)-exo-3 and (L)-endo-3). To a solution of 12b
(270 mg, 1.0 mmol, cis:trans¼91:9) in dioxane (10 mL)
was added 6 mol/L HCl (10 mL), and the reaction mixture
was stirred for 7 h at 100 ꢁC. After removing the solvent un-
der vacuum, the residue was dissolved in DMF (10 mL).
NaHCO3 (420 mg, 5.0 mmol) and benzyl bromide (0.36 mL,
3.0 mmol) were added to the solution, and the resulting solu-
tion was stirred at 60 ꢁC for 3 h. After cooling to room tem-
perature, the reaction mixture was quenched with aqueous
NaHCO3, and the aqueous layer was extracted with EtOAc.
The organic layer was washed with brine, and dried over
Na2SO4. The solution was filtered and the filtrate was con-
centrated under vacuum. The residue was purified by silica
gel column chromatography (hexane/EtOAc¼6/1–2/1) to
afford (ꢀ)-exo-3 (120 mg, 32%, 95% ee) and (ꢀ)-endo-3
(76 mg, 21%, 95% ee). (ꢀ)-exo-3: [a]2D7 ꢀ51.1 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.72 (1H, dq,
J¼5.2, 14.2 Hz), 1.85 (1H, dt, J¼8.2, 13.3 Hz), 1.98–2.10
(2H, m), 2.22 (1H, ddd, J¼4.8, 6.0, 19.7 Hz), 2.41 (1H,
ddd, J¼4.6, 10.5, 18.8 Hz), 2.55 (2H, d, J¼5.0 Hz), 2.80
(1H, m), 3.51 (1H, d, J¼13.3 Hz), 3.57 (1H, d, J¼8.2 Hz),
3.74 (1H, dt, J¼4.6, 9.6 Hz), 3.87 (1H, d, J¼13.3 Hz), 5.06
(1H, d, J¼11.9 Hz), 5.17 (1H, d, J¼12.4 Hz), 7.07–7.42
(10H, m); 13C NMR (100 MHz, CDCl3) d 25.3, 33.1, 34.1,
35.2, 42.0, 52.0, 59.1, 61.7, 65.7, 126.9, 128.1, 128.2,
128.4, 128.6, 135.6, 138.4, 173.5, 212.2; IR (neat) 3030,
3.1.16. Methyl 2-acetylamino-3-(trans-2-methoxy-4-oxo-
cyclohexyl)propionate (trans-12b, mixture of diastereo-
mers). A solution of Rh(cod)2OTf (2.3 mg, 0.0050 mmol)
and (S,S)-Me-DuPHOS (1.5 mg, 0.0050 mmol) in 2-propa-
nol (0.5 mL) was stirred for 1 h to prepare [(S,S)-Me-

12746
Y. Hoshina et al. / Tetrahedron 63 (2007) 12740–12746
2941, 1728, 1495, 1454, 1148 cmꢀ1; HRMS (ESI-TOF)
calcd for [C23H25NO3+H]+ 364.1913, found 364.1916.
1813; (d) aeruginosin 103: Kodani, S.; Ishida, K.; Murakami,
M. J. Nat. Prod. 1998, 61, 1046–1048; (e) aeruginosin 89:
Ishida, K.; Matsuda, H.; Okino, T.; Murakami, M. Tetrahedron
1999, 55, 10971–10988.
The enantiomeric excess was determined by chiral station-
ary-phase HPLC analysis [Daicel Chiralpak OJ, 10%
i-PrOH in hexane, flow rate 1.0 mL/min, tR 17.3 min
(2S,3aR,7aR)-isomer and 22.8 min (2R,3aS,7aS)-isomer, de-
tected at 214 nm]. (ꢀ)-endo-3: [a]2D7 ꢀ47.5 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) d 1.75 (1H, ddd, J¼6.0, 8.7,
12.8 Hz), 1.82–1.98 (2H, m), 2.18 (1H, ddd, J¼4.8, 8.2,
17.6 Hz), 2.34 (1H, ddd, J¼8.4, 8.4, 12.7 Hz), 2.39–2.49
(2H, m, H-3a), 2.49–2.55 (1H, m), 2.59 (1H, dd, J¼5.3,
15.8 Hz), 3.09 (1H, dt, J¼4.9, 8.4 Hz), 3.33 (1H, t,
J¼8.2 Hz), 3.63 (1H, d, J¼13.7 Hz), 3.85 (1H, d,
J¼13.7 Hz), 4.86 (2H, s), 7.17–7.39 (10H, m); 13C NMR
(100 MHz, CDCl3) d 26.5, 34.6, 34.7, 36.6, 42.1, 56.1,
61.6, 65.5, 66.2, 127.2, 128.0, 128.1, 128.4, 129.5, 135.6,
136.6, 173.2, 211.6; IR (KBr) 3030, 2941, 1717, 1454,
3. Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am. Chem.
Soc. 2004, 126, 6064–6071.
4. Ploutno, A.; Shoshan, M.; Carmeli, S. J. Nat. Prod. 2002, 65,
973–978.
5. Valls, N.; Vallribera, M.; Carmeli, S.; Bonjoch, J. Org. Lett.
2003, 5, 447–450.
6. (a) Sandler, B.; Murakami, M.; Clardy, J. J. Am. Chem. Soc.
1998, 120, 595–596; (b) Steiner, J. L. R.; Murakami, M.;
Tulinsky, A. J. Am. Chem. Soc. 1998, 120, 597–598.
7. Wipf, P.; Methot, J.-L. Org. Lett. 2000, 2, 4213–4216.
ꢀ
8. (a) Valls, N.; Lopez-Canet, M.; Vallribera, M.; Bonjoch, J.
J. Am. Chem. Soc. 2000, 122, 11248–11249; (b) Valls, N.;
ꢀ
Lopez-Canet, M.; Vallribera, M.; Bonjoch, J. Chem.—Eur. J.
2001, 7, 3446–3460; (c) Valls, N.; Vallribera, M.; Lopez-
ꢀ
1184, 752, 700 cmꢀ1
; HRMS (ESI-TOF) calcd for
Canet, M.; Bonjoch, J. J. Org. Chem. 2002, 67, 4945–4950.
9. (a) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta, Y.;
Nemoto, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
11206–11207; (b) Fukuta, Y.; Ohshima, T.; Gnanadesikan,
V.; Shibuguchi, T.; Nemoto, T.; Kisugi, T.; Okino, T.;
Shibasaki, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5433–
5438.
[C23H25NO3+H]+ 364.1913, found 364.1912. The enantio-
meric excess was determined by chiral stationary-phase
HPLC analysis [Daicel Chiralpak OD-H, 1% i-PrOH in hex-
ane, flow rate 1.0 mL/min, tR 37.2 min (2S,3aS,7aS)-isomer
and 30.1 min (2R,3aR,7aR)-isomer, detected at 214 nm].
(ꢀ)-endo-3 (64 mg, 95% ee) was recrystallized from
EtOH/hexane to give optically pure (ꢀ)-endo-3 (40 mg,
63%, >99% ee). [a]D28 ꢀ48.6 (c 1.00, CHCl3); lit. [a]2D0
ꢀ58.1 (c 1.00, CHCl3).8b,10
ꢀ
ꢀ
10. Bonjoch, J.; Cantena, J.; Isabal, E.; Lopez-Canet, M.; Valls, N.
Tetrahedron: Asymmetry 1996, 7, 1899–1902.
11. Toyooka, N.; Okumura, M.; Himiyama, T.; Nakazawa, A.;
Nemoto, H. Synlett 2003, 55–58.
12. (a) Doi, T.; Hoshina, Y.; Mogi, H.; Yamada, Y.; Takahashi, T.
J. Comb. Chem. 2006, 8, 571–582; (b) Hoshina, Y.; Yamada,
Y.; Tanaka, H.; Doi, T.; Takahashi, T. Bioorg. Med. Chem.
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Acknowledgements
This work was supported by a Grant-in-Aid from the Minis-
try of Education, Culture, Sports, Science and Technology,
Japan (No. 14103013).
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Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.09.078.
References and notes
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19. Acid isomerization of its methyl ester was demonstrated by
Bonjoch et al. (see Ref 8b). It was explained that the equili-
brium is due to acid-mediated b-elimination of the b-amino
ketone, vinylogous enolization, and intramolecular Michael
readdition.