Total Synthesis of (-)-Stemoamide by Sequential Overman/Claisen Rearrangement

Article abstract of DOI:10.1055/s-0035-1561948

The enantioselective total synthesis of (-)-stemoamide using Overman/Claisen rearrangement of an allylic 1,2-diol is reported. The enantiopure allylic 1,2-diol was efficiently prepared from naturally occurring dimethyl tartrate. The chirality transfer reactions through two consecutive [3,3]-sigmatropic rearrangements proceeded with complete diastereoselectivity in a one-pot process.

Full text of DOI:10.1055/s-0035-1561948

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
A
special topic
Y. Nakayama et al.
Special Topic
Synthesis
Total Synthesis of (–)-Stemoamide by Sequential Overman/Claisen
Rearrangement
Yasuaki Nakayama
Yuichiro Maeda
Naoto Hama
NH2
CCl3
cat. BHT, t-BuPh
160 °C;
O
Overman/Claisen
OBn
EtO2C
MeC(OEt)3, BHT
140 °C
O
Takaaki Sato*
Noritaka Chida*
CCl3
HN
O
O
Department of Applied Chemistry, Faculty of Science and Technology,
H
OBn
Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522,
Japan
takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
N
EtO2C
O
H
O
EtO2C
H
Received: 21.01.2016
Accepted after revision: 23.02.2016
Published online: 22.03.2016
charides (Scheme 1).7–10 In our synthetic plan for (–)-
stemoamide (1), cyclic orthoamide 3 would be efficiently
synthesized from dimethyl tartrate (2). Then, the sequential
Overman/Claisen rearrangement of 3 would give access to
acyclic intermediate 4. This sequential reaction could install
two consecutive stereocenters including the C–N bond. The
subsequent cyclizations by iodolactonization and lactam-
ization would differentiate two ethyl esters of 4, and pro-
vide the bicyclic compound 5, which would be converted
into (–)-stemoamide (1).
DOI: 10.1055/s-0035-1561948; Art ID: ss-2016-c0050-st
Abstract The enantioselective total synthesis of (–)-stemoamide us-
ing Overman/Claisen rearrangement of an allylic 1,2-diol is reported.
The enantiopure allylic 1,2-diol was efficiently prepared from naturally
occurring dimethyl tartrate. The chirality transfer reactions through
two consecutive [3,3]-sigmatropic rearrangements proceeded with
complete diastereoselectivity in a one-pot process.
Key words alkaloid, allylic compound, diol, sigmatropic rearrange-
ment, total synthesis
NH2
CCl3
OH
O
CO2Me
OBn
MeO2C
EtO2C
Stemona alkaloids consist of polycyclic frameworks with
the pyrrolo[1,2-a]azepine core as a common structure, and
has been shown to possess a variety of biological activities
such as insecticidal, anthelmintic, and antitussive effects.1
For example, the roots of Stemona tuberosa have been used
in Chinese and Japanese folk medicine as antitussive agents
and insecticides. (–)-Stemoamide (1) was isolated from
these extracts by the Xu group in 1992, and is now known
as a representative alkaloid in this class (Scheme 1).2 It con-
tains a tricyclic structure including a γ-lactam and a γ-lac-
tone moiety. This relatively simple structure renders it a
synthetic target to demonstrate the utility of new methods.
Williams and co-workers disclosed the first total synthesis
of (–)-1 in 1994.3a After their report, a number of racemic
and enantioselective total syntheses have been reported by
using their own strategies.3,4 In this communication, we re-
port the total synthesis of (–)-stemoamide (1), whose key
step is the sequential Overman/Claisen rearrangement of
an allylic 1,2-diol.
OH
O
2
3
Overman/Claisen
CCl3
lactamization
EtO2C
O
H
HN
O
N
OBn
O
H
H
OBn
O
H
EtO2C
iodolactonization
4
I
5
O
H
N
O
H
O
(–)-stemoamide (1)
H
Scheme 1 Synthetic plan for (–)-stemoamide (1)
Our total synthesis of (–)-stemoamide (1) began with
one-carbon homologation using a Swern oxidation and a
Wittig reaction of the known alcohol 6,11 which was pre-
pared from dimethyl L-tartrate in three steps (Scheme 2).
Cleavage of the TBS group in 8 with TBAF and hydrogena-
tion of the enol ether provided the primary alcohol 9. After
Swern oxidation of 9, exposure of the crude aldehyde to vi-
nyl Grignard reagent provided allylic alcohol 10 in 83% yield
Our research group has reported synthetic strategy cap-
italizing on the sequential Overman/Claisen rearrange-
ment5,6 of acyclic allylic 1,2-diols, which derives from natu-
rally occurring polyols such as tartaric acid and monosac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
Y. Nakayama et al.
Special Topic
Synthesis
(2 steps). The resulting alcohol was subjected to the John-
son-type Claisen rearrangement at 140 °C in the presence
of 2-nitrophenol,12 providing the γ,δ-unsaturated ester in
87% yield. Allylic 1,2-diol 11 was then obtained by removal
of the acetonide group in 80% aqueous AcOH.
CCl3CN, cat. DBU
cat. ZnCl2
OH
OBn
11
EtO2C
CH2Cl2, 0 °C
OH
NH2
CCl3
O
cat. BHT, t-BuPh
OBn
EtO2C
160 °C
(COCl)2, DMSO
Et3N, CH2Cl2
O
O
O
3: 92%
TBSO
TBSO
CCl3
OH
O
–78 °C to r.t.
O
O
O
HN
O
6
7
OBn
12
1. TBAF, THF, r.t.
92%
EtO2C
ClPh3P
OBn
OH
TBSO
OBn
t-BuOK, THF
–30 °C to r.t.
2. H2, Pd/C (5 wt%)
THF, r.t., 97%
CCl3
O
8
MeC(OEt)3, BHT
140 °C
HN
O
93% (2 steps)
OBn
EtO2C
1. (COCl)2, DMSO
Et3N, CH2Cl2
–78 °C to r.t.
O
O
OH
13
CCl3
HO
OBn
OBn
10
2. CH2=CHMgCl
CH2Cl2, 0 °C
83% (2 steps)
HN
O
HO
O
O
9
OBn
EtO2C
1. 2-nitrophenol
MeC(OEt)3, toluene
140 °C, 87%
EtO2C
4: 47% (single diastereomer)
OH
Scheme 3 Sequential Overman/Claisen rearrangement in a one-pot
sequence
OBn
EtO2C
2. 80% AcOH aq
60 °C, 93%
OH
11
Scheme 2 Synthesis of allylic 1,2-diol (11)
lactone without generation of the seven-membered lac-
tone. Furthermore, the cyclization of the trichloroacet-
amide was also not observed probably due to the suppres-
sion of the nucleophilicity by trichloromethyl group. The
remaining carboxylic acid of 15 then underwent the γ-lact-
amization with EDCI [1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride] and DMAP, accompanied
by cleavage of the trichloroacetyl group to give 5 in 60%
yield over two steps. Reduction of the alkyl iodide required
the two-step procedure including elimination and hydroge-
nation with Rh/Al2O3. After conversion of benzyl ether 16
into bromide 17, the seven-membered ring was then
formed with NaH and TBAI in 73% yield.3b Finally, the total
synthesis of (–)-stemoamide (1) was achieved by regio- and
stereoselective methylation according to reported proce-
dure.3b,g The spectral data of our synthetic sample was iden-
tical to those for natural products and previously reported
synthetic samples on the basis of 1H NMR, 13C NMR, IR,
HRMS, and optical rotation.
In summary, we have accomplished the total synthesis
of (–)-stemoamide (1), featuring a sequential Overman/
Claisen rearrangement of an enantiopure allylic 1,2-diol.
The reaction differentiated two hydroxy groups without
protection of the homoallylic alcohol, and proceeded in
complete stereoselective fashion. The present synthesis
demonstrated the utility of our method for enantioselective
total syntheses of natural products.
The stage was now set for the pivotal Overman/Claisen
rearrangement of allylic 1,2-diol 11 (Scheme 3). Treatment
of 11 with CCl3CN (1.3 equiv) in the presence of catalytic
amount of DBU and ZnCl2 gave cyclic orthoamide 3 in 92%
yield. Addition of ZnCl2 was critical to prevent the genera-
tion of the undesired bis(imidate), which was formed by in-
stallation of two equivalents of CCl3CN. A solution of cyclic
orthoamide 3 and a catalytic amount of BHT (butylated
hydroxytoluene, 4-methyl-2,6-di-tert-butylphenol)8c,d,13 in
t-BuPh was heated to 160 °C in a sealed tube, initiating the
ring opening of the cyclic orthoamide. The Overman rear-
rangement of the generated imidate 12 provided allylic al-
cohol 13, which was then subjected to the Johnson-type
Claisen rearrangement in a one-pot sequence. The two free
hydroxy groups of 11 was successfully differentiated
through the sequential rearrangement without use of pro-
tecting groups. Furthermore, both chirality transfer reac-
tions14 took place in the highest level of the stereoselectivi-
ty, with 4 isolated in 47% yield as a single diastereomer.
With acyclic compound 4 bearing two contiguous ste-
reocenters in hand, we turned our attention to construct
the tricyclic framework of (–)-stemoamide (1) (Scheme 4).
The synthetic challenge in this stage was the differentiation
of two ethyl esters embedded in 4. Both ester groups were
hydrolyzed with Ba(OH)2 without affecting the trichloro-
acetamide. Gratifyingly, we found that iodolactonization of
the resulting bis(acid) 14 successfully differentiate two car-
boxylic acids through the stereoselective synthesis of the γ-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
Y. Nakayama et al.
Special Topic
Synthesis
36.1 mmol) in CH2Cl2 (18 mL) was then added dropwise via cannula
at –78 °C. After stirring for 40 min at –78 °C, Et3N (20 mL, 150 mmol)
was added dropwise to the solution. The resulting mixture was
stirred for 15 min at –78 °C, allowed to warm to r.t., quenched with
sat. aq NaHCO3 (90 mL) and H2O (90 mL), and extracted with hexane
(2 × 90 mL). The combined organic extracts were washed with H2O
(2 × 30 mL) and brine (30 mL), dried (Na2SO4), and concentrated to
give the corresponding aldehyde 7,11 which was immediately used in
the next reaction without further purification.
CCl3
O
CCl3
O
HO2C
HN
H
I2 , NaHCO3
N
OBn
H
O
H
PO2C
THF/H2O, 0 °C
OBn
O
CO2P
H
I
15
4: P = Et
14: P = H
Ba(OH)2, MeOH/H2O
0 °C to r.t., 83%
O
H
EDCI, DMAP
1. DBU, THF, r.t., 73%
N
H
t-BuOK (16.2 g, 144 mmol) was added to a mixture of (benzyl-
oxymethyl)triphenylphosphonium chloride (60.6 g, 144 mmol) and
THF (340 mL) at –78 °C. The resulting mixture was allowed to warm
to –30 °C. After stirring for 1.5 h at –30 °C, a solution of the crude al-
dehyde 7 in THF (18 mL) was added dropwise to the ylide via cannula
at –30 °C. This mixture was stirred for 30 min at –30 °C, allowed to
warm to r.t., quenched with sat. aq NaHCO3 (90 mL) and H2O (90 mL),
and extracted with hexane (2 × 90 mL). The combined organic ex-
tracts were washed with brine (30 mL), dried (Na2SO4), and concen-
trated. The residue was purified by silica gel column chromatography
(hexane/EtOAc 75:1 to 10:1) to give 12.8 g of a mixture of two enol
ethers 8 (93% over 2 steps, E/Z = 1:1.2). For analytical samples, the
two isomers were separated by HPLC (PEGASIL Silica 120-5, 250 × 20
mm, UV 254 nm, hexane/EtOAc, 9:1, 10 mL/min, E-isomer: tR = 8.7
min, Z-isomer: tR = 10.2 min).
O
H
OBn
THF, r.t.
2. Rh/Al2O3 (50 wt%)
H2, THF, r.t., 99%
O
H
60% (2 steps)
5
I
O
O
H
1. Pd/C (100 wt%)
H2, EtOH, r.t., 99%
H
N
N
H
H
H
H
O
O
2. CBr4, PPh3
CH2Cl2, r.t., 92%
O
H
O
OBn
Br
H
16
17
R
O
H
NaH, TBAI
N
O
H
LiN(TMS)2
MeI, THF
–78 °C, 52%
18: R = H
1: R = Me
DMF, 0 °C
73%
O
H
Scheme 4 Total synthesis of (–)-stemoamide (1)
(E)-8
28
Colorless oil; Rf = 0.67 (hexane/EtOAc, 3:1); [α]D –14.4 (c 1.05,
CHCl3).
IR (film): 2930, 2858, 1655, 1252, 1171, 1021, 838 cm–1
.
Reactions were performed in oven-dried glassware fitted with rubber
septa under an argon atmosphere. Toluene, DMSO and t-BuPh were
distilled from CaH2. DMF was distilled from CaSO4. MeOH was dis-
tilled from CaSO4. All distilled solvents, CH2Cl2, and EtOH were dried
over activated 3Å molecular sieves. THF (dehydrated, stabilizer free)
was purchased from Kanto Chemical Co., Inc. Commercial reagents
were used without further purification. TLC was performed on Merck
60 F254 precoated silica gel plates, which were visualized by expo-
sure to UV (254 nm) or stained by submersion in ethanolic ninhydrin
or ethanolic phosphomolybdic acid solution followed by heating on a
hot plate. Flash column chromatography was performed on silica gel
(Silica Gel 60 N; 63–210 or 40–50 mesh, Kanto Chemical Co., Inc.).
Preparative TLC was performed on Merck 60 F254 0.5 mm precoated
silica gel plates. 1H NMR spectra were recorded at 500 MHz with JEOL
ECA-500 spectrometers. 13C NMR spectra were recorded at 125 MHz
with Jeol ECA-500 spectrometers. Chemical shifts are reported in
ppm with reference to solvent signals [1H NMR: CDCl3 (7.26), C6D6
(7.16), CD3OD (3.31); 13C NMR: CDCl3 (77.16), C6D6 (128.06), CD3OD
(49.00)]. Standard abbreviations were used to denote signal patterns.
IR spectra were recorded using a Bruker Alpha FT-IR spectrometer.
Mass spectra (ESI-TOF) were measured with a Waters, LCT Premier
XE. Melting points were measured with a Mitamura-Riken microhot
stage. Optical rotations were measured with a Jasco P-2100 polarime-
ter.
1H NMR (CDCl3, 500 MHz): δ = 7.39–7.30 (m, 5 H), 6.65 (d, J = 12.6 Hz,
1 H), 4.89 (dd, J = 12.6, 8.9 Hz, 1 H), 4.80 (d, J = 11.5 Hz, 1 H), 4.75 (d,
J = 11.5 Hz, 1 H), 4.30 (dd, J = 8.9, 8.9 Hz, 1 H), 3.80–3.67 (m, 3 H), 1.43
(s, 3 H), 1.41 (s, 3 H), 0.90 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 151.1 (CH), 136.5 (C), 128.7 (CH),
128.3 (CH), 127.8 (CH), 108.5 (C), 101.6 (CH), 81.9 (CH), 76.7 (CH),
71.5 (CH2), 62.2 (CH2), 27.4 (CH3), 27.0 (CH3), 26.0 (CH3), 18.5 (C), –5.2
(CH3), –5.3 (CH3).
HRMS (ESI): m/z calcd for C21H34O4SiNa: 401.2124; found: 401.2114.
(Z)-8
Colorless oil; Rf = 0.64 (hexane/EtOAc, 3:1); [α]D26 +1.5 (c 1.25, CHCl3).
IR (film): 2930, 2858, 1668, 1370, 1253, 1217, 1075, 837 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.37–7.29 (m, 5 H), 6.24 (dd, J = 6.3, 0.9
Hz, 1 H), 4.91 (ddd, J = 8.9, 8.3, 0.9 Hz, 1 H), 4.85 (d, J = 12.6 Hz, 1 H),
4.79 (d, J = 12.6 Hz, 1 H), 4.49 (dd, J = 8.9, 6.3 Hz, 1 H), 3.80–3.66 (m, 3
H), 1.42 (s, 6 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 149.0 (CH), 137.1 (C), 128.7 (CH),
128.2 (CH), 127.6 (CH), 108.8 (C), 104.4 (CH), 82.5 (CH), 74.4 (CH2),
71.4 (CH), 62.8 (CH2), 27.4 (CH3), 27.1 (CH3), 26.1 (CH3), 18.6 (C), –5.2
(CH3), –5.3 (CH3).
The structures of the intermediates 19–22 prepared during the syn-
thetic sequence on the way to (–)-stemoamide (1) are provided along
with their 1H and 13C NMR spectra in the Supporting Information.
HRMS (ESI): m/z calcd for C21H34O4SiNa: 401.2124; found: 401.2114.
{(4S,5S)-5-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}methanol (9)
({(4S,5S)-5-[2-(Benzyloxy)vinyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}methoxy)(tert-butyl)dimethylsilane (8)
Bu4NF (1.0 M in THF, 44 mL, 44 mmol) was added to a solution of enol
ether 8 (E/Z = 1:1.2, 12.8 g, 33.7 mmol) in THF (340 mL) at 0 °C. This
solution was allowed to warm to r.t., maintained for 1 h at r.t., and
quenched with sat. aq NH4Cl (85 mL) and H2O (85 mL). The mixture
was extracted with EtOAc (2 × 85 mL). The combined organic extracts
Oxalyl chloride (6.3 mL, 72 mmol) was added dropwise to a solution
of DMSO (7.7 mL, 110 mmol) and CH2Cl2 (340 mL) at –78 °C. The solu-
tion was stirred for 30 min at –78 °C. A solution of alcohol 611 (9.99 g,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
Y. Nakayama et al.
Special Topic
Synthesis
were washed with brine (25 mL), dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography (hex-
ane/EtOAc, 1:1) to give 8.19 g of a mixture of two alcohols 19 (92%,
E/Z = 1:1.2). For analytical samples, the two isomers were separated
by HPLC (PEGASIL Silica 120-5, 250 × 20 mm, UV 254 nm, hex-
ane/EtOAc 2:3, 10 mL/min, Z-isomer: tR = 9.0 min, E-isomer: tR = 10.5
min).
cannula at –78 °C. After stirring for 1 h at –78 °C, Et3N (13 mL, 95
mmol) was added dropwise to the solution. The resulting mixture
was stirred for 10 min at –78 °C, allowed to warm to r.t., quenched
with sat. aq NaHCO3 (40 mL) and H2O (40 mL), and extracted with
hexane (2 × 50 mL). The combined organic extracts were washed
with H2O (2 × 12 mL) and brine (12 mL), dried (Na2SO4), and concen-
trated to give the corresponding aldehyde, which was immediately
used in the next reaction without further purification.
(E)-19
Vinylmagnesium bromide (1.0 M in THF, 32 mL, 32 mmol) was added
to a solution of the crude aldehyde in CH2Cl2 (160 mL) at 0 °C. This
solution was stirred for 1.5 h at 0 °C, quenched with sat. aq NH4Cl (40
mL) and H2O (40 mL), and extracted with hexane (2 × 40 mL). The
combined organic extracts were washed with brine (12 mL), dried
(Na2SO4), and concentrated. The residue was purified by silica gel col-
umn chromatography (hexane/EtOAc, 10:1 to 6:1) to give 3.82 g of a
mixture of allylic alcohols 10 (83% over 2 steps, dr = 1:1). For analyti-
cal samples, the two isomers were separated by HPLC (PEGASIL Silica
120-5, 250 × 20 mm, UV 254 nm, hexane/EtOAc, 3:2, 10 mL/min, less
polar diastereomer: tR = 9.1 min, polar diastereomer: tR = 9.7 min).
24
Colorless oil; Rf = 0.56 (hexane/EtOAc, 1:1); [α]D –63.2 (c 0.99,
EtOAc).
IR (film): 3455, 2986, 2873, 1655, 1380, 1169, 1051 cm–1
1H NMR (C6D6, 500 MHz): δ = 7.14–7.03 (m, 5 H), 6.42 (d, J = 12.6 Hz,
1 H), 4.82 (dd, J = 12.6, 8.9 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 4.34 (d,
J = 12.0 Hz, 1 H), 4.30 (dd, J = 8.9, 8.9 Hz, 1 H), 3.64–3.58 (m, 2 H),
3.43–3.36 (m, 1 H), 1.68 (s, 1 H), 1.43 (s, 3 H), 1.39 (s, 3 H).
13C NMR (C6D6, 125 MHz): δ = 151.1 (CH), 137.1 (C), 128.7 (CH), 128.4
(CH), 127.7 (CH), 108.5 (C), 102.3 (CH), 82.2 (CH), 76.3 (CH), 71.4
(CH2), 60.8 (CH2), 27.6 (CH3), 27.2 (CH3).
.
10 (Less Polar Diastereomer)
HRMS (ESI): m/z calcd for C15H20O4Na: 287.1259; found: 287.1265.
21
Colorless oil; Rf = 0.76 (hexane/EtOAc, 1:1); [α]D –38.5 (c 1.10,
CHCl3).
(Z)-19
23
Colorless oil; Rf = 0.62 (hexane/EtOAc, 1:1); [α]D –39.5 (c 1.11,
IR (film): 3455, 2986, 2867, 1371, 1215, 1091 cm–1
.
EtOAc).
1H NMR (CDCl3, 500 MHz): δ = 7.36–7.26 (m, 5 H), 5.90 (ddd, J = 17.2,
10.6, 5.7 Hz, 1 H), 5.36 (ddd, J = 17.2, 1.4, 1.4 Hz, 1 H), 5.24 (ddd,
J = 10.6, 1.4, 1.4 Hz, 1 H), 4.51 (s, 2 H), 4.30–4.26 (m, 1 H), 4.10 (ddd,
J = 8.0, 8.0, 3.4 Hz, 1 H), 3.76 (dd, J = 8.0, 4.9 Hz, 1 H), 3.66 (ddd, J = 9.5,
6.9, 5.7 Hz, 1 H), 3.61 (ddd, J = 9.5, 7.5, 6.3 Hz, 1 H), 2.40 (br s, 1 H),
2.00 (dddd, J = 14.0, 7.5, 6.9, 3.4 Hz, 1 H), 1.87 (dddd, J = 14.0, 8.0, 6.3,
5.7 Hz, 1 H), 1.40 (s, 6 H).
13C NMR (CDCl3, 125 MHz): δ = 138.3 (C), 136.2 (CH), 128.5 (CH),
127.83 (CH), 127.77 (CH), 116.9 (CH2), 108.8 (C), 83.0 (CH), 74.9 (CH),
73.2 (CH2), 72.4 (CH), 67.4 (CH2), 34.3 (CH2), 27.4 (CH3), 27.1 (CH3).
IR (film): 3460, 2986, 2934, 2876, 1667, 1372, 1217, 1062 cm–1
.
1H NMR (C6D6, 500 MHz): δ = 7.11–7.01 (m, 5 H), 5.79–5.76 (m, 1 H),
5.18 (dd, J = 8.3, 8.0 Hz, 1 H), 4.53 (dd, J = 8.3, 6.3 Hz, 1 H), 4.31–4.21
(m, 2 H), 3.81–3.74 (m, 2 H), 3.70–3.63 (m, 1 H), 2.30–1.90 (m, 1 H),
1.43 (s, 3 H), 1.37 (s, 3 H).
13C NMR (C6D6, 125 MHz): δ = 148.1 (CH), 137.3 (C), 128.8 (CH), 128.4
(CH), 127.6 (CH), 108.9 (C), 105.4 (CH), 82.6 (CH), 74.1 (CH2), 72.2
(CH), 62.0 (CH2), 27.5 (CH3), 27.2 (CH3).
HRMS (ESI): m/z calcd for C15H20O4Na: 287.1259; found: 287.1265.
HRMS (ESI): m/z calcd for C17H25O4: 293.1753; found: 293.1755.
Pd/C (10%, 410 mg, 5.0 wt%) was added to a solution of alcohols 19
(E/Z = 1:1.2, 8.19 g, 31.0 mmol) in THF (160 mL) at r.t. The mixture
was stirred under H2 (1 atm) at r.t. for 14 h, filtered through a pad of
Celite, washed with EtOAc (160 mL), and concentrated. The residue
was purified by silica gel column chromatography (hexane/EtOAc, 7:1
to 1:1) to give 8.01 g of alcohol 9 (97%); colorless oil; Rf = 0.52
(hexane/EtOAc, 1:1); [α]D21 –23.6 (c 1.08, CHCl3).
10 (Polar Diastereomer)
22
Colorless oil; Rf = 0.71 (hexane/EtOAc, 1:1); [α]D –16.3 (c 1.01,
CHCl3).
IR (film): 3448, 2986, 2870, 1371, 1215, 1089 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.36–7.26 (m, 5 H), 5.86 (ddd, J = 17.2,
10.6, 5.7 Hz, 1 H), 5.35 (ddd, J = 17.2, 1.4, 1.4 Hz, 1 H), 5.23 (ddd,
J = 10.6, 1.4, 1.4 Hz, 1 H), 4.51 (s, 2 H), 4.14–4.10 (m, 1 H), 4.09 (ddd,
J = 8.0, 8.0, 4.0 Hz, 1 H), 3.73 (dd, J = 8.0, 4.3 Hz, 1 H), 3.65 (ddd, J = 9.5,
6.6, 5.4 Hz, 1 H), 3.59 (ddd, J = 9.5, 7.7, 6.0 Hz, 1 H), 2.34 (d, J = 6.6 Hz,
1 H), 1.96 (dddd, J = 14.0, 7.7, 6.6, 4.0 Hz, 1 H), 1.87 (dddd, J = 14.0,
8.0, 6.0, 5.4 Hz, 1 H), 1.410 (s, 3 H), 1.405 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 138.4 (C), 137.2 (CH), 128.5 (CH),
127.79 (CH), 127.76 (CH), 117.0 (CH2), 109.1 (C), 83.5 (CH), 75.1 (CH),
73.2 (CH2), 72.3 (CH), 67.2 (CH2), 33.8 (CH2), 27.6 (CH3), 27.2 (CH3).
IR (film): 3451, 2987, 2933, 2869, 1371, 1215, 1093 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.37–7.27 (m, 5 H), 4.53 (d, J = 12.0 Hz,
1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.02 (dt, J = 8.3, 6.0 Hz, 1 H), 3.82 (ddd,
J = 8.3, 4.3, 3.7 Hz, 1 H), 3.78 (ddd, J = 11.7, 5.2, 3.7 Hz, 1 H), 3.65 (dt,
J = 9.5, 6.0 Hz, 1 H), 3.66–3.60 (m, 1 H), 3.60 (dt, J = 9.5, 6.6 Hz, 1 H),
2.05 (dd, J = 7.5, 5.2 Hz, 1 H), 1.92 (ddd, J = 6.6, 6.0, 6.0 Hz, 2 H), 1.41
(s, 3 H), 1.40 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 138.3 (C), 128.6 (CH), 127.85 (CH),
127.82 (CH), 108.7 (C), 81.5 (CH), 74.9 (CH), 73.3 (CH2), 67.2 (CH2),
62.1 (CH2), 33.4 (CH2), 27.4 (CH3), 27.1 (CH3).
HRMS (ESI): m/z calcd for C17H25O4: 293.1753; found: 293.1742.
HRMS (ESI): m/z calcd for C15H23O4: 267.1596; found: 267.1602.
Ethyl (6S,7S,E)-9-(Benzyloxy)-6,7-dihydroxynon-4-enoate (11)
1-{(4S,5S)-5-[2-(Benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}prop-2-en-1-ol (10)
A sealed tube was charged with allylic alcohols 10 (dr = 1:1, 3.82 g,
13.1 mmol), MeC(OEt)3 (48 mL, 260 mmol), 2-nitrophenol (5.45 g,
39.2 mmol), and toluene (130 mL). The solution was heated to 140 °C
and stirred for 6 h at 140 °C. The resulting solution was cooled to r.t.,
and concentrated. The residue was purified by silica gel column chro-
Oxalyl chloride (4.1 mL, 47 mmol) was added dropwise to a solution
of DMSO (5.0 mL, 71 mmol) and CH2Cl2 (150 mL) at –78 °C. The re-
sulting solution was stirred for 40 min at –78 °C. A solution of alcohol
9 (4.21 g, 15.8 mmol) in CH2Cl2 (8.0 mL) was then added dropwise via
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
Y. Nakayama et al.
Special Topic
Synthesis
matography (hexane/EtOAc, 20:1 to 9:1) to give 4.09 g of ethyl ester
20 (87%); yellow oil; Rf = 0.57 (hexane/EtOAc, 3:1); [α]D +20.5 (c
0.98, CHCl3).
13C NMR (CDCl3, 125 MHz): δ = 172.8 (C), 138.3 (C), 136.1 (CH), 128.5
(CH), 127.80 (CH), 127.76 (CH), 126.8 (CH), 114.5 (C), 103.8 (C), 86.3
(CH), 80.0 (CH), 73.2 (CH2), 66.5 (CH2), 60.6 (CH2), 33.5 (CH2), 30.9
(CH2), 27.6 (CH2), 14.4 (CH3).
22
IR (film): 2985, 2935, 2864, 1735, 1370, 1241, 1168, 1095, 1041 cm–1
.
HRMS (ESI): m/z calcd for
488.0779.
C
20H26Cl3NO5Na: 488.0774; found:
1H NMR (CDCl3, 500 MHz): δ = 7.36–7.26 (m, 5 H), 5.84–5.75 (m, 1 H),
5.46 (dd, J = 15.5, 8.0 Hz, 1 H), 4.50 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H),
4.00 (dd, J = 8.0, 8.0 Hz, 1 H), 3.78 (ddd, J = 8.0, 8.0, 4.0 Hz, 1 H), 3.62
(ddd, J = 9.2, 6.9, 5.7 Hz, 1 H), 3.57 (ddd, J = 9.2, 6.9, 6.9 Hz, 1 H), 2.41–
2.34 (m, 4 H), 1.87 (dddd, J = 14.3, 6.9, 6.9, 4.0 Hz, 1 H), 1.85–1.77 (m,
1 H), 1.394 (s, 3 H), 1.390 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
3 (Polar Diastereomer)
25
Colorless oil; Rf = 0.65 (hexane/EtOAc, 1:1); [α]D –14.6 (c 0.85,
CHCl3).
13C NMR (CDCl3, 125 MHz): δ = 172.9 (C), 138.5 (C), 134.3 (CH), 128.5
(CH), 128.0 (CH), 127.74 (CH), 127.68 (CH), 108.5 (C), 82.4 (CH), 77.8
(CH), 73.1 (CH2), 67.1 (CH2), 60.5 (CH2), 33.7 (CH2), 32.1 (CH2), 27.7
(CH2), 27.4 (CH3), 27.1 (CH3), 14.3 (CH3).
IR (film): 3415, 3336, 2922, 2869, 1733, 1206, 1095, 824 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.37–7.26 (m, 5 H), 5.94–5.86 (m, 1 H),
5.56 (dd, J = 15.5, 8.3 Hz, 1 H), 4.54 (dd, J = 8.9, 8.3 Hz, 1 H), 4.53 (d,
J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.26 (ddd, J = 8.9, 6.9, 5.2
Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.64 (dt, J = 9.2, 6.0 Hz, 1 H), 3.60 (dt,
J = 9.2, 6.6 Hz, 1 H), 2.51 (br s, 2 H), 2.42–2.35 (m, 4 H), 1.98–1.88 (m,
2 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 172.8 (C), 138.4 (C), 136.3 (CH), 128.6
(CH), 127.76 (CH), 127.72 (CH), 125.4 (CH), 114.6 (C), 103.9 (C), 84.2
(CH), 82.2 (CH), 73.2 (CH2), 66.4 (CH2), 60.6 (CH2), 33.5 (CH2), 32.4
(CH2), 27.7 (CH2), 14.4 (CH3).
HRMS (ESI): m/z calcd for C21H30O5Na: 385.1991; found: 385.1992.
A solution of ethyl ester 20 (4.09 g, 11.3 mmol) and AcOH/H2O (4:1,
28 mL) was heated to 60 °C, and maintained at 60 °C for 5.5 h. The
resulting solution was cooled to r.t., and concentrated. The residue
was purified by silica gel column chromatography (hexane/EtOAc, 2:1
to 1:2) to give 3.40 g of allylic 1,2-diol 11 (93%); yellow oil; Rf = 0.30
(hexane/EtOAc, 1:1); [α]D24 +1.7 (c 1.44, CHCl3).
IR (film): 3435, 2921, 2865, 1732, 1097 cm–1
.
HRMS (ESI): m/z calcd for
C20H26Cl3NO5Na: 488.0774; found:
1H NMR (CDCl3, 500 MHz): δ = 7.37–7.27 (m, 5 H), 5.79–5.72 (m, 1 H),
5.51 (dd, J = 15.5, 6.9 Hz, 1 H), 4.52 (s, 2 H), 4.11 (q, J = 7.2 Hz, 2 H),
3.90 (dd, J = 6.9, 6.3, 1.2 Hz, 1 H), 3.70 (ddd, J = 9.2, 6.0, 4.9 Hz, 1 H),
3.68–3.63 (m, 2 H), 2.42–2.34 (m, 4 H), 1.80 (dddd, J = 14.6, 6.0, 4.6,
3.7 Hz, 1 H), 1.79–1.72 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 173.1 (C), 137.9 (C), 132.3 (CH), 130.4
(CH), 128.6 (CH), 127.9 (CH), 127.8 (CH), 75.7 (CH), 73.8 (CH), 73.5
(CH2), 68.5 (CH2), 60.5 (CH2), 33.8 (CH2), 32.6 (CH2), 27.7 (CH2), 14.3
(CH3).
488.0765.
Diethyl (3S,4S)-3-[(E)-4-(Benzyloxy)but-1-en-1-yl]-4-(2,2,2-tri-
chloroacetamido)heptanedioate (4)
A sealed tube was charged with orthoamide 3 (604 mg, 1.29 mmol),
BHT (14.3 mg, 64.7 μmol), and t-BuPh (43 mL). The solution was heat-
ed to 160 °C for 15 d. After cooling to r.t., MeC(OEt)3 (1.2 mL, 6.5
mmol) and BHT (428 mg, 1.94 mmol) were added to the solution of
the generated allylic amino alcohol. The solution was then heated to
140 °C for 75 min. After cooling to r.t., the solution was directly puri-
fied by silica gel column chromatography (hexane/EtOAc, 9:1) to give
HRMS (ESI): m/z calcd for C18H26O5Na: 345.1678; found: 345.1678.
328 mg of trichloroacetamide
4 (47%); colorless oil; Rf = 0.83
Ethyl (E)-5-{(4S,5S)-2-Amino-5-[2-(benzyloxy)ethyl]-2-(trichloro-
methyl)-1,3-dioxolan-4-yl}pent-4-enoate (3)
(hexane/EtOAc, 1:1); [α] D25 –15.3 (c 1.09, CHCl3).
IR (film): 3334, 2981, 2929, 2856, 1732, 1714, 1518, 1176, 821 cm–1
.
DBU (470 μL, 3.2 mmol) was added dropwise to a mixture of allylic
1,2-diol 11 (3.40 g, 10.5 mmol), CCl3CN (1.4 mL, 14 mmol), ZnCl2 (144
mg, 1.05 mmol), and CH2Cl2 (110 mL) at 0 °C. The mixture was main-
tained at 0 °C for 19 h, allowed to warm to r.t., and concentrated. The
residue was purified by silica gel column chromatography (hex-
ane/EtOAc, 7:1 to 4:1) to give 4.52 g of a diastereomeric mixture of
the two orthoamides 3 (92%, dr = 1:1). For analytical samples, two
diastereomers were separated by HPLC (PEGASIL Silica 120-5,
250 × 20 mm, UV 254 nm, hexane/EtOAc, 2:1, 10 mL/min, less polar
diastereomer: tR = 13.5 min, polar diastereomer: tR = 21.1 min).
1H NMR (CDCl3, 500 MHz): δ = 7.35–7.24 (m, 5 H), 6.98 (d, J = 9.5 Hz, 1
H), 5.63 (dd, J = 15.2, 6.9 Hz, 1 H), 5.36 (ddt, J = 15.2, 9.5, 1.2 Hz, 1 H),
4.48 (s, 2 H), 4.15–4.06 (m, 4 H), 3.94–3.86 (m, 1 H), 3.48 (t, J = 6.6 Hz,
2 H), 2.78–2.70 (m, 1 H), 2.47 (dd, J = 15.8, 5.7 Hz, 1 H), 2.39 (dd,
J = 15.8, 7.7 Hz, 1 H), 2.39–2.25 (m, 4 H), 2.01 (dddd, J = 14.6, 7.5, 7.5,
3.2 Hz, 1 H), 1.68 (dddd, J = 14.6, 10.9, 7.5, 6.6 Hz, 1 H), 1.24 (t, J = 7.2
Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 173.4 (C), 172.3 (C), 162.1 (C), 138.4
(C), 131.8 (CH), 129.8 (CH), 128.5 (CH), 127.7 (CH), 127.7 (CH), 92.9
(C), 73.0 (CH2), 69.6 (CH2), 60.9 (CH2), 60.9 (CH2), 54.2 (CH), 44.0 (CH),
37.2 (CH2), 33.1 (CH2), 30.7 (CH2), 26.5 (CH2), 14.31 (CH3), 14.29 (CH3).
3 (Less Polar Diastereomer)
Colorless oil; Rf = 0.72 (hexane/EtOAc, 1:1); [α]D25 –6.9 (c 1.33, CHCl3).
HRMS (ESI): m/z calcd for C24H33Cl3NO6: 536.1373; found: 536.1373.
IR (film): 3418, 3341, 2922, 2867, 1733, 1207, 1095, 824 cm–1
.
(3S,4S)-3-[(E)-4-(Benzyloxy)but-1-en-1-yl]-4-(2,2,2-trichloroacet-
amido)heptanedioic Acid (14)
1H NMR (CDCl3, 500 MHz): δ = 7.36–7.26 (m, 5 H), 5.87–5.80 (m, 1 H),
5.52 (dd, J = 15.5, 8.3 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.48 (d,
J = 12.0 Hz, 1 H), 4.45 (dd, J = 8.9, 8.3 Hz, 1 H), 4.28 (ddd, J = 8.9, 7.7,
4.3 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.66 (ddd, J = 9.5, 6.0, 6.0 Hz, 1 H),
3.61 (ddd, J = 9.5, 7.5, 6.0 Hz, 1 H), 2.57 (br s, 2 H), 2.42–2.35 (m, 4 H),
2.02–1.90 (m, 2 H), 1.24 (t, J = 7.2 Hz, 3 H).
Ba(OH)2·8H2O (3.28 g, 10.4 mmol) was added to a solution of trichlo-
roacetamide 4 (558 mg, 1.04 mmol) in MeOH/H2O (2:1, 52 mL) at 0
°C. The solution was allowed to warm to r.t., maintained for 1.5 h at
r.t., quenched with 4 M aq HCl (5.2 mL), and extracted with CHCl3
(6 × 10 mL). The combined organic extracts were washed with brine
(7 mL), dried (Na2SO4), and concentrated. The residue was purified by
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
Y. Nakayama et al.
Special Topic
Synthesis
silica gel column chromatography (hexane/EtOAc, 3:2 to 2:3) to give
417 mg of bis(acid) 14 (83%), colorless crystals; mp 102.0–103.5 °C;
Rf = 0.19 (EtOAc); [α]D26 –16.0 (c 1.62, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.85 (br s, 1 H), 7.37–7.27 (m, 5 H),
5.98 (dt, J = 15.5, 4.9 Hz, 1 H), 5.77 (ddtd, J = 15.5, 7.2, 1.4, 1.4 Hz, 1 H),
4.70 (dd, J = 7.2, 7.2 Hz, 1 H), 4.53 (s, 2 H), 4.06 (dd, J = 4.9, 1.4 Hz, 2
H), 3.80–3.74 (m, 1 H), 2.64 (dd, J = 17.5, 8.6 Hz, 1 H), 2.47 (dd,
J = 17.5, 8.6 Hz, 1 H), 2.42–2.35 (m, 1 H), 2.34 (dd, J = 8.6, 7.5 Hz, 2 H),
2.25 (dtd, J = 12.6, 7.5, 7.5 Hz, 1 H), 1.77–1.68 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 179.3 (C), 175.1 (C), 138.0 (C), 132.4
(CH), 128.6 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 81.9 (CH), 72.8
(CH2), 69.3 (CH2), 54.6 (CH), 47.0 (CH), 30.3 (CH2), 30.2 (CH2), 25.5
(CH2).
IR (film): 3298, 2931, 1707, 1521, 821 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.35–7.25 (m, 5 H), 6.93 (d, J = 9.5 Hz, 1
H), 5.66 (dd, J = 15.5, 6.9 Hz, 1 H), 5.35 (dd, J = 15.5, 9.5 Hz, 1 H), 4.49
(s, 2 H), 4.05–3.96 (m, 1 H), 3.51 (dt, J = 9.5, 6.3 Hz, 1 H), 3.49 (dt,
J = 9.5, 6.6 Hz, 1 H), 2.80–2.72 (m, 1 H), 2.54 (dd, J = 16.0, 6.6 Hz, 1 H),
2.44 (dd, J = 16.0, 7.2 Hz, 1 H), 2.42–2.30 (m, 4 H), 2.01 (dddd, J = 14.6,
7.5, 7.2, 2.9 Hz, 1 H), 1.61 (ddt, J = 14.6, 11.2, 6.6 Hz, 1 H).
HRMS (ESI): m/z calcd for C18H22NO4: 316.1549; found: 316.1548.
13C NMR (CDCl3, 125 MHz): δ = 178.9 (C), 177.8 (C), 162.2 (C), 138.2
(C), 132.4 (CH), 129.4 (CH), 128.6 (CH), 127.9 (CH), 127.8 (CH), 92.8
(C), 73.0 (CH2), 69.4 (CH2), 53.6 (CH), 43.6 (CH), 36.9 (CH2), 33.1 (CH2),
30.3 (CH2), 26.0 (CH2).
Rh/Al2O3 (5%, 103 mg, 50 wt%) was added to a solution of alkene 21
(206 mg, 653 μmol) and THF (22 mL) at r.t. The mixture was stirred
under H2 atmosphere (1 atm) at r.t. for 1 d, filtered through a pad of
Celite, washed with EtOAc (20 mL), and concentrated. The residue was
purified by silica gel column chromatography (EtOAc/MeOH, 1:0 to
9:1) to give 204 mg of benzyl ether 16 (99%); colorless oil; Rf = 0.56
(EtOAc/MeOH, 9:1); [α]D23 +20.1 (c 1.17, CHCl3).
HRMS (ESI): m/z calcd for
C20H24Cl3NO6Na: 502.0567; found:
502.0558.
(S)-5-{(2S,3R)-2-[(R)-3-(Benzyloxy)-1-iodopropyl]-5-oxotetrahy-
drofuran-3-yl}pyrrolidin-2-one (5)
IR (film): 3236, 2928, 2859, 1771, 1694, 1206, 1175, 1101 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.37–7.26 (m, 6 H), 4.49 (s, 2 H), 4.29
(ddd, J = 7.7, 5.4, 3.7 Hz, 1 H), 3.76–3.71 (m, 1 H), 3.54 (ddd, J = 10.3,
9.2, 4.9 Hz, 1 H), 3.49 (ddd, J = 9.2, 6.3, 4.6 Hz, 1 H), 2.66 (dd, J = 17.8,
9.2 Hz, 1 H), 2.42 (dd, J = 17.8, 6.9 Hz, 1 H), 2.33 (dd, J = 9.2, 6.9 Hz, 2
H), 2.34–2.27 (m, 1 H), 2.23 (ddt, J = 12.9, 7.7, 6.9 Hz, 1 H), 1.88–1.65
(m, 5 H).
13C NMR (CDCl3, 125 MHz): δ = 179.1 (C), 175.5 (C), 138.4 (C), 128.5
(CH), 127.84 (CH), 127.80 (CH), 81.9 (CH), 73.1 (CH2), 69.5 (CH2), 55.4
(CH), 45.7 (CH), 32.2 (CH2), 30.6 (CH2), 30.2 (CH2), 25.7 (CH2), 25.3
(CH2).
I2 (1.25 g, 4.91 mmol) was added to a mixture of bis(acid) 14 (787 mg,
1.64 mmol), NaHCO3 (619 mg, 7.37 mmol), and THF/H2O (1:1, 55 mL)
at 0 °C. The mixture was stirred for 3 h at 0 °C, quenched with 20% aq
Na2S2O3 (5.5 mL) and 1 M aq HCl (5.5 mL), and extracted with CHCl3
(6 × 15 mL). The combined organic extracts were washed with brine
(8 mL), dried (Na2SO4), and concentrated. The residue was filtered
through a pad of silica gel, washed with hexane/EtOAc (1:1, 400 mL),
and concentrated to give iodolactone 15, which was immediately
used in the next reaction without further purification.
EDCI·HCl (859 mg, 4.48 mmol) was added to a solution of iodolactone
15, DMAP (547 mg, 4.48 mmol), and THF (150 mL) at r.t. The solution
was maintained for 16.5 h at r.t. and concentrated. The residue was
purified by silica gel column chromatography (EtOAc) to give 436 mg
of γ-lactam 5 (60% over 2 steps); colorless crystals; mp 124.0–125.0
°C; Rf = 0.22 (EtOAc); [α]D25 +5.1 (c 0.91, CHCl3).
HRMS (ESI): m/z calcd for C18H24NO4: 318.1705; found: 318.1706.
(S)-5-[(2R,3R)-2-(3-Bromopropyl)-5-oxotetrahydrofuran-3-yl]pyr-
rolidin-2-one (17)
Pd/C (10%, 112 mg, 100 wt%) was added to a solution of benzyl ether
16 (112 mg, 353 μmol) and EtOH (12 mL) at r.t. The mixture was
stirred under H2 atmosphere (1 atm) at r.t. for 18.5 h, filtered through
a pad of Celite, washed with EtOH (15 mL), and concentrated. The res-
idue was purified by silica gel column chromatography (CHCl3 to
EtOH) to give 79.7 mg of alcohol 22 (99%); colorless crystals;
mp 107.0–108.0 °C; Rf = 0.14 (EtOAc/MeOH, 4:1); [α]D26 +53.6 (c 1.16,
MeOH).
IR (film): 3223, 2925, 2865, 1781, 1694, 1176, 1098, 748 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.72–7.40 (m, 1 H), 7.37–7.27 (m, 5 H),
4.50 (s, 2 H), 4.42 (ddd, J = 10.3, 6.3, 4.0 Hz, 1 H), 4.27 (dd, J = 6.0, 2.9
Hz, 1 H), 3.85–3.79 (m, 1 H), 3.69 (ddd, J = 9.5, 5.2, 4.0 Hz, 1 H), 3.60
(ddd, J = 9.5, 9.2, 4.0 Hz, 1 H), 2.82 (dd, J = 18.6, 10.0 Hz, 1 H), 2.69–
2.62 (m, 1 H), 2.38 (dd, J = 18.6, 3.4 Hz, 1 H), 2.40–2.25 (m, 2 H), 2.24–
2.13 (m, 2 H), 1.84 (dddd, J = 14.6, 10.3, 4.0, 4.0 Hz, 1 H), 1.78–1.68
(m, 1 H).
IR (film): 3307, 2932, 2877, 1767, 1683, 1205 cm–1
.
13C NMR (CDCl3, 125 MHz): δ = 179.4 (C), 175.0 (C), 137.9 (C), 128.6
(CH), 128.1 (CH), 128.0 (CH), 83.8 (CH), 73.5 (CH2), 69.1 (CH2), 56.4
(CH), 43.7 (CH), 35.6 (CH), 35.3 (CH2), 30.3 (CH2), 30.3 (CH2), 24.3
(CH2).
1H NMR (CD3OD, 500 MHz): δ = 4.39 (ddd, J = 8.3, 5.7, 3.7 Hz, 1 H),
3.86–3.81 (m, 1 H), 3.62 (dt, J = 10.9, 6.0 Hz, 1 H), 3.60 (dt, J = 10.9, 6.0
Hz, 1 H), 2.73 (dd, J = 17.2, 8.6 Hz, 1 H), 2.47 (dd, J = 17.2, 7.2 Hz, 1 H),
2.43 (dddd, J = 12.9, 8.6, 7.2, 5.7 Hz, 1 H), 2.37–2.27 (m, 3 H), 1.88–
1.59 (m, 5 H).
HRMS (ESI): m/z calcd for C18H23INO4: 444.0672; found: 444.0674.
13C NMR (CD3OD, 125 MHz): δ = 181.3 (C), 178.3 (C), 83.9 (CH), 62.3
(CH2), 56.7 (CH), 46.7 (CH), 32.6 (CH2), 31.2 (CH2), 31.0 (CH2), 29.6
(CH2), 26.0 (CH2).
(S)-5-{(2R,3R)-2-[3-(Benzyloxy)propyl]-5-oxotetrahydrofuran-3-
yl}pyrrolidin-2-one (16)
DBU (32 μL, 210 μmol) was added dropwise to a solution of γ-lactam
5 (62.7 mg, 141 μmol) and THF (4.8 mL) at 0 °C. This solution was al-
lowed to warm to r.t., and maintained for 12.5 h at r.t., and concen-
trated. The residue was purified by silica gel column chromatography
(EtOAc) to give 32.7 mg of alkene 21 (73%); colorless oil; Rf = 0.56
(EtOAc/MeOH, 9:1); [α]D25 +41.8 (c 1.43, CHCl3).
HRMS (ESI): m/z calcd for C11H17NO4Na: 250.1055; found: 250.1059.
PPh3 (112 mg, 426 μmol) was added to a solution of alcohol 22 (64.5
mg, 284 μmol), CBr4 (282 mg, 851 μmol), and CH2Cl2 (9.5 mL) at 0 °C.
The solution was allowed to warm to r.t., maintained for 10 h at r.t.,
and concentrated. The residue was purified by silica gel column chro-
matography (EtOAc/MeOH, 19:1) to give 75.6 mg of bromide 17
(92%); colorless oil; Rf = 0.41 (EtOAc/MeOH, 9:1); [α]D26 +24.5 (c 1.19,
CHCl3).
IR (film): 3225, 2921, 2857, 1778, 1694, 1204, 1173, 1113, 974 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
Y. Nakayama et al.
Special Topic
Synthesis
IR (film): 3225, 2928, 1771, 1694, 1259, 1201, 1181 cm–1
.
13C NMR (CDCl3, 125 MHz): δ = 177.5 (C), 174.2 (C), 77.8 (CH), 56.0
(CH), 52.8 (CH), 40.4 (CH2), 37.5 (CH), 34.9 (CH2), 30.8 (CH2), 25.8
(CH2), 22.7 (CH2), 14.3 (CH3).
1H NMR (CDCl3, 500 MHz): δ = 6.69 (br s, 1 H), 4.28 (ddd, J = 9.2, 6.0,
3.4 Hz, 1 H), 3.84–3.79 (m, 1 H), 3.50 (ddd, J = 10.0, 7.5, 5.2 Hz, 1 H),
3.46 (ddd, J = 10.0, 6.9, 5.4 Hz, 1 H), 2.70 (dd, J = 17.8, 9.2 Hz, 1 H),
2.44 (dd, J = 17.8, 7.5 Hz, 1 H), 2.41–2.29 (m, 4 H), 2.16–2.07 (m, 1 H),
2.04–1.91 (m, 2 H), 1.81–1.73 (m, 2 H).
HRMS (ESI): m/z calcd for C12H18NO3: 224.1287; found: 224.1291.
13C NMR (CDCl3, 125 MHz): δ = 179.3 (C), 175.3 (C), 81.1 (CH), 55.3
(CH), 45.9 (CH), 33.7 (CH2), 33.3 (CH2), 30.5 (CH2), 30.4 (CH2), 28.5
(CH2), 25.3 (CH2).
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Research
(B) from MEXT (26288018), and the Shorai Foundation for Science
and Technology. Y. Nakayama and Y. Maeda contributed equally to
this work.
HRMS (ESI): m/z calcd for
C11H16BrNO3Na: 312.0211; found:
312.0215.
(3aR,10aS,10bR)-Octahydro-2H-furo[3,2-c]pyrrolo[1,2-a]azepine-
2,8(1H)-dione (18)3b
Supporting Information
NaH (63% in oil, 14 mg, 360 μmol) was added to a solution of bromide
17 (35.1 mg, 121 μmol), TBAI (4.5 mg, 12.1 μmol) and DMF (12 mL) at
0 °C. The resulting mixture was stirred for 2 h at 0 °C, quenched with
1 M aq HCl (1.5 mL), and stirred for 14 h. The reaction mixture was
extracted with EtOAc (6 × 2 mL). The combined organic extracts were
washed with brine (2 × 2 mL), dried (Na2SO4), and concentrated. The
residue was purified by silica gel column chromatography (EtOAc/
MeOH, 1:0 to 19:1) to give 18.5 mg of azepane 18 (73%); colorless oil;
Rf = 0.42 (EtOAc/MeOH, 4:1); [α]D24 –143.2 (c 1.07, CHCl3).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561948.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References
(1) For reviews, see: (a) Pilli, R. A.; de Oliveira, M. C. F. Nat. Prod.
Rep. 2000, 17, 117. (b) Alibés, R.; Figueredo, M. Eur. J. Org. Chem.
2009, 2421. (c) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat.
Prod. Rep. 2010, 27, 1908.
IR (film): 2935, 1775, 1676, 1420, 1185, 1015 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 4.29 (ddd, J = 10.3, 10.3, 2.9 Hz, 1 H),
4.15 (ddd, J = 13.8, 2.3, 2.3 Hz, 1 H), 3.99 (ddd, J = 10.6, 6.9, 6.3 Hz, 1
H), 2.85 (dddd, J = 12.6, 10.3, 8.9, 6.9 Hz, 1 H), 2.71–2.64 (m, 1 H), 2.65
(dd, J = 17.5, 8.9 Hz, 1 H), 2.61 (dd, J = 17.5, 12.6 Hz, 1 H), 2.45–2.36
(m, 3 H), 2.07 (dddd, J = 12.3, 6.3, 5.7, 3.4 Hz, 1 H), 1.91–1.82 (m, 1 H),
1.71 (dddd, J = 12.3, 10.6, 10.6, 10.6 Hz, 1 H), 1.62–1.51 (m, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 174.8 (C), 174.2 (C), 79.9 (CH), 56.2
(CH), 45.0 (CH), 40.3 (CH2), 34.8 (CH2), 31.1 (CH2), 30.7 (CH2), 25.6
(CH2), 22.8 (CH2).
(2) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
(3) For total syntheses of stemoamide, see: (a) Williams, D. R.;
Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417.
(b) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(c) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356.
(d) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409.
(e) Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287. (f) Jacobi,
P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295. (g) Sibi, M. P.;
Subramanian, T. Synlett 2004, 1211. (h) Olivo, H. F.; Tovar-
Miranda, R.; Barragán, E. J. Org. Chem. 2006, 71, 3287.
(i) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007, 72,
4246. (j) Bates, R. W.; Sridhar, S. Synlett 2009, 1979. (k) Honda,
T.; Matsukawa, T.; Takahashi, K. Org. Biomol. Chem. 2011, 9, 673.
(l) Wang, Y.; Zhu, L.; Zhang, Y.; Hong, R. Angew. Chem. Int. Ed.
2011, 50, 2787. (m) Mi, X.; Wang, Y.; Zhu, L.; Wang, R.; Hong, R.
Synthesis 2012, 44, 3432. (n) Li, Z.; Zhang, L.; Qiu, F. G. Asian J.
Org. Chem. 2014, 3, 52.
(4) For formal total syntheses of stemoamide, see: (a) Gurjar, M. K.;
Reddy, D. S. Tetrahedron Lett. 2002, 43, 295. (b) Bogliotti, N.;
Dalko, P. I.; Cossy, J. Synlett 2005, 349. (c) Bogliotti, N.; Dalko, P.
I.; Cossy, J. J. Org. Chem. 2006, 71, 9528. (d) Bogliotti, N.; Dalko,
P. I.; Cossy, J. Synlett 2006, 2664. (e) Chavan, S. P.; Harale, K. R.;
Puranik, V. G.; Gawade, R. L. Tetrahedron Lett. 2012, 53, 2647.
(f) Muňoz-Bascón, J.; Hernández-Cervantes, C.; Padial, N. M.;
Álvarez-Corral, M.; Rosales, A.; Rodríguez-García, I.; Oltra, J. E.
Chem. Eur. J. 2014, 20, 801. (g) Brito, G. A.; Sarotti, A. M.; Wipf,
P.; Pilli, R. A. Tetrahedron Lett. 2015, 56, 6664.
HRMS (ESI): m/z calcd for C11H16NO3: 210.1130; found: 210.1131.
(–)-Stemoamide (1)
n-BuLi (1.4 M in hexane, 190 μL, 270 μmol) was added to a solution of
(TMS)2NH (65 μL, 270 μmol) and THF (1.0 mL) at –78 °C. The solution
was maintained for 15 min at –78 °C. A solution of azepane 18 (16.0
mg, 76.5 μmol) in THF (500 μL) was then added dropwise to the solu-
tion of LiN(TMS)2 via cannula at –78 °C. The resulting solution was al-
lowed to warm to –40 °C, stirred for 1 h at –40 °C, cooled to –78 °C,
and stirred for 1 h. MeI (5.9 μL, 120 μmol) was then added dropwise
to the solution at –78 °C. After stirring for 15 min at –78 °C, the solu-
tion was allowed to warm to r.t., and maintained for 13.5 h at r.t. The
solution was quenched with sat. aq NH4Cl (1.0 mL) and 20% aq
Na2S2O3 (1.0 mL), and extracted with EtOAc (4 × 2 mL). The combined
organic extracts were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chroma-
tography (EtOAc/MeOH, 1:0 to 9:1) to give 8.9 mg of (–)-stemoamide
(1) (52%); colorless crystals; mp 184.0–185.0 °C (Lit.3k mp 184–185
(5) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. For reviews on
the Overman rearrangement, see: (b) Overman, L. E.; Carpenter,
N. E. In Organic Reactions; Vol. 66; Overman, L. E., Ed.; Wiley:
New York, 2005, 1–107.
21
°C); Rf = 0.52 (EtOAc/MeOH, 4:1); [α]D –180.7 (c 0.89, MeOH) {Lit.3a
[α]D26 –181 (c 0.89, MeOH)}.
IR (film): 2938, 1765, 1685, 1422, 1192, 1009 cm–1
.
(6) For selected recent reviews on the Claisen rearrangement, see:
(a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939. (b) Majumdar, K.
C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597.
(c) Majumdar, K. C.; Nandi, R. K. Tetrahedron 2013, 69, 6921.
(d) Fernandes, R. A.; Chowdhury, A. K.; Kattanguru, P. Eur. J. Org.
Chem. 2014, 2833.
1H NMR (CDCl3, 500 MHz): δ = 4.20 (ddd, J = 10.3, 10.3, 3.2 Hz, 1 H),
4.19–4.13 (m, 1 H), 3.99 (ddd, J = 10.9, 6.4, 6.4 Hz, 1 H), 2.69–2.62 (m,
1 H), 2.60 (dq, J = 12.3, 6.9 Hz, 1 H), 2.45–2.36 (m, 4 H), 2.08–2.02 (m,
1 H), 1.91–1.81 (m, 1 H), 1.71 (dddd, J = 11.7, 10.9, 10.9, 10.9 Hz, 1 H),
1.59–1.47 (m, 2 H), 1.31 (d, J = 6.9 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
Y. Nakayama et al.
Special Topic
Synthesis
(7) For selected recent reviews on cascade, tandem, and domino
reactions including sigmatropic rearrangement, see:
(10) For selected examples of sequential reactions including sigma-
tropic rearrangements, see: (a) Thomas, A. F. J. Am. Chem. Soc.
1969, 91, 3281. (b) Ziegler, F. E.; Piwinski, J. J. J. Am. Chem. Soc.
1979, 101, 1611. (c) Raucher, S.; Burks, J. E. Jr.; Hwang, K.-J.;
Svedberg, D. P. J. Am. Chem. Soc. 1981, 103, 1853. (d) Mikami, K.;
Taya, S.; Nakai, T.; Fujita, Y. J. Org. Chem. 1981, 46, 5447.
(e) Mulzer, V. J.; Bock, H.; Eck, W.; Buschmann, J.; Luger, P.
Angew. Chem., Int. Ed. Eng. 1991, 30, 414. (f) Posner, G. H.; Carry,
J.-C.; Crouch, R. D.; Johnson, N. J. Org. Chem. 1991, 56, 6987.
(g) Villemin, D.; Hachemi, M. Synth. Commun. 1996, 26, 1329.
(h) Banert, K.; Fendel, W.; Schlott, J. Angew. Chem. Int. Ed. 1998,
37, 3289. (i) Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001,
863. (j) Barriault, L.; Denissova, I. Org. Lett. 2002, 4, 1371.
(k) Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067. (l) Sauer, E. L. O.;
Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569. (m) Pelc, M. J.;
Zakarian, A. Org. Lett. 2005, 7, 1629. (n) Li, X.; Ovaska, T. V. Org.
Lett. 2007, 9, 3837. (o) Ilardi, E. A.; Isaacman, M. J.; Qin, Y.-C.;
Shelly, S. A.; Zakarian, A. Tetrahedron 2009, 65, 3261.
(11) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337.
(12) (a) Bohno, M.; Sugie, K.; Imase, H.; Yusof, Y. B.; Oishi, T.; Chida,
N. Tetrahedron 2007, 63, 6977. (b) Tanimoto, H.; Kato, T.; Chida,
N. Tetrahedron Lett. 2007, 48, 6267. (c) Kato, T.; Tanimoto, H.;
Yamada, H.; Chida, N. Heterocycles 2010, 82, 563. (d) Ammenn,
J.; Altmann, K.-H.; Belluš, D. Helv. Chim. Acta 1997, 80, 1589.
(13) Ammenn, J.; Altmann, K.-H.; Belluš, D. Helv. Chim. Acta 1997, 80,
1589.
a
(a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int.
Ed. 2006, 45, 7134. (b) Pellissier, H. Tetrahedron 2006, 62, 1619.
(c) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341. (d) Poulin,
J.; Grisé-Bard, C. M.; Barriault, L. Chem. Soc. Rev. 2009, 38, 3092.
(e) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009,
38, 3133.
(8) For the Overman rearrangement of allylic 1,2-diols, see:
(a) Momose, T.; Hama, N.; Higashino, C.; Sato, H.; Chida, N. Tet-
rahedron Lett. 2008, 49, 1376. (b) Hama, N.; Matsuda, T.; Sato,
T.; Chida, N. Org. Lett. 2009, 11, 2687. (c) Hama, N.; Aoki, T.;
Miwa, S.; Yamazaki, M.; Sato, T.; Chida, N. Org. Lett. 2011, 13,
616. (d) Nakayama, Y.; Sekiya, R.; Oishi, H.; Hama, N.; Yamazaki,
M.; Sato, T.; Chida, N. Chem. Eur. J. 2013, 19, 12052. (e) Tsuzaki,
S.; Usui, S.; Oishi, H.; Yasushima, D.; Fukuyasu, T.; Oishi, T.; Sato,
T.; Chida, N. Org. Lett. 2015, 17, 1704. For pioneering works on
the orthoamide-type Overman rearrangement of allylic 1,2-
diols, see: (f) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem.
1984, 49, 2037. (g) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc.
1989, 111, 4829.
(9) We reported the cascade-type Claisen rearrangement of allylic
1,2-diols in the total synthesis of (–)-morphine, see:
(a) Tanimoto, H.; Saito, R.; Chida, N. Tetrahedron Lett. 2008, 49,
358. (b) Ichiki, M.; Tanimoto, H.; Miwa, S.; Saito, R.; Sato, T.;
Chida, N. Chem. Eur. J. 2013, 19, 264. We also documented the
development of the orthoamide-type Claisen rearrangement
and the application to the total synthesis of (–)-kainic acid, see:
(c) Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N.
Org. Lett. 2010, 12, 5756. (d) Kitamoto, K.; Nakayama, Y.;
Sampei, M.; Ichiki, M.; Furuya, N.; Sato, T.; Chida, N. Eur. J. Org.
Chem. 2012, 4217.
(14) For selected reviews on chirality transfer through sigmatropic
rearrangement, see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tet-
rahedron: Asymmetry 1996, 7, 1847. (b) Nubbemeyer, U. Synthe-
sis 2003, 961.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H