Total Synthesis of Lycopalhine A

Article abstract of DOI:10.1055/s-0036-1588878

The total synthesis of lycopalhine A featuring the construction of a tricyclic system via cleavage of a cyclopropane ring and an ensuing intramolecular Michael addition, stereoselective introduction of a 2-aminoethyl moiety via a reaction of allyltrimethy

Full text of DOI:10.1055/s-0036-1588878

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–S
A
paper
Synthesis
Y. Ochi et al.
Paper
Total Synthesis of Lycopalhine A
Yuji Ochi1
O
O
O
O
O
O
Satoshi Yokoshima*
Tohru Fukuyama*
H
H
S
Dess–Martin
periodinane
O
H
N
N
Ar
H
HO
H
H
R
H
R
O
N
Graduate School of Pharmaceutical Sciences, Nagoya
University, Furo-cho, Chikusa-ku, Nagoya 464-8601,
Japan
yokosima@ps.nagoya-u.ac.jp
fukuyama@ps.nagoya-u.ac.jp
N
pyridine
CH2Cl2
r.t. to 40 °C
S O
Me
H
Ar
H
HO
O
(
+)-lycopalhine A
R = (CH2)3OPMP
Dedicated to Professor Dieter Enders on the occasion
th
of his 70 birthday
Received: 26.07.2016
Accepted after revision: 09.08.2016
Published online: 14.09.2016
O
O
N
H
HO
3
H
6
H3
O
6
DOI: 10.1055/s-0036-1588878; Art ID: ss-2016-c0526-op
16
OH
HO
H
H
H
Abstract The total synthesis of lycopalhine A featuring the construc-
tion of a tricyclic system via cleavage of a cyclopropane ring and an en-
suing intramolecular Michael addition, stereoselective introduction of a
13
13
N
N
O
N
Me
1
5
OH
15
H
1
6
Me
2-aminoethyl moiety via a reaction of allyltrimethylsilane with a sulfo-
fawcettimine (1)
lycopalhine A (2)
isopalhinine A (3)
nyliminium ion, and a stereoselective intramolecular aldol reaction is
reported.
OH
H
O
H
NOH
H
Key words alkaloid, aminal, cyclopropanation, Michael addition, poly-
cyclic system
O
H
H
H
O
HN
N
N
O
A variety of alkaloids have been isolated from the genus
Lycopodium. The lycopodium alkaloids are classified based
Me
Me
Me
2
huperzine Q (4)
sieboldine A (5)
lycoposerramine S (6)
on their core structures, with the fawcettimine-type lyco-
podium alkaloids constituting one of the major classes.
These alkaloids have a hydrindane skeleton fused to a nine-
membered ring containing a nitrogen atom (Figure 1). In
fawcettimine (1), the nitrogen atom forms a hemiaminal
moiety with a carbonyl group at C13, resulting in the for-
mation of a tetracyclic skeleton. Additional bonds or func-
tional groups generate a range of related alkaloids with
Figure 1 Structures of selected fawcettimine-type lycopodium alka-
loids
reaction and an L-proline-mediated 5-endo-trig intramolec-
ular Mannich reaction as the key reactions. Soon after the
first total synthesis had been completed, we disclosed our
own synthesis of (+)-lycopalhine A, featuring the construc-
tion of a tricyclic system via the cleavage of a cyclopropane
3
more complicated structures, rendering this structure an
4,5
8
attractive target for synthetic studies. Lycopalhine A (2) is
just one of such fawcettimine-type alkaloids.
ring and an ensuing intramolecular Michael addition.
Herein, we describe a detailed account of our synthesis.
Our retrosynthesis is shown in Scheme 1. Cleavage of
the aminal and the β-hydroxy ketone moieties would gen-
erate the tricycle 7. The 2-aminoethyl moiety and the
formyl group were removed from 7, leading to the tricar-
bonyl compound 8. These carbonyl groups could be used
both to install the carbon units and to construct the tricy-
clic system. The C13–N bond at the β-position of the car-
bonyl group could be easily formed via an intramolecular
nucleophilic addition between the amide and enone moi-
eties in 9. A connection at C4–C13 would generate cyclo-
Lycopalhine A (2) was first isolated from Palhinhaea cer-
nua (syn.: Lycopodium cernuum) by Zhao and co-workers.6
As compared with fawcettimine, C16 is connected to C6 to
form a β-hydroxy ketone moiety and a cyclopentane ring.
An additional nitrogen atom participates in the formation
of a pyrrolidine ring and an aminal moiety. The first total
synthesis of lycopalhine A was reported by Williams and
7
Trauner in 2016. The densely functionalized hexacyclic
structure was elegantly constructed via a Pauson–Khand
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

B
Synthesis
Y. Ochi et al.
Paper
propane 10, which could in turn be constructed via the in-
tramolecular cyclopropanation of 11. The side chain on the
cyclohexane ring in 11 could be introduced by means of a
Claisen–Johnson rearrangement, which required cyclohex-
enol 12 as a substrate.
zene,12 and subsequent treatment with DBU afforded enone
16. Iodination at the α-position of the carbonyl group pro-
ceeded without incident, and the side chain unit was intro-
9
13
duced by means of the Suzuki–Miyaura coupling with 18.
14
1,2-Reduction of enone 19 gave cyclohexenol 20, which
was subjected to the Claisen–Johnson rearrangement to
yield 21.
O
O
H
H
H
The next task was to construct the tricyclic system via
cyclopropanation (Scheme 3). Ester 21 was converted into
aldehyde 22 via reduction with lithium aluminum hydride,
followed by oxidation with Dess–Martin periodinane
(DMP).15 The Roskamp reaction was applied to aldehyde 22
H
N
HO
H
H
N
H
NHMe
CHO
N
Me
H
H
OHC
O
lycopalhine A (2)
7
16
to give the β-keto ester, which was subjected to a diazo
O
O
O
O
transfer reaction involving 2-azido-1,3-dimethylimidaz-
H
O
4
17
olinium hexafluorophosphate (ADMP, 24). Refluxing the
NHR'
NHR'
resulting diazoester 25 in the presence of the catalyst A in
H
R
H
R
13
H
R
NR'
18
toluene induced cyclopropanation to give 26 in 55% yield.
13
H
After basic hydrolysis of the ester moiety in 26, the result-
ing carboxylic acid 27 was condensed with tosylamide, and
the TBS group was removed by treatment with TBAF, giving
alcohol 28. Oxidation of 28 with DMP15 facilitated the cleav-
age of the cyclopropane at the β-position of the carbonyl
group, and an ensuing intramolecular Michael addition of
the imide moiety generated tricycle 32a in 80% yield. The
entire process was so fast that we could not isolate ketone
29 or enone 31.
O
O
O
8
9
10
R = (CH2)3OP
O
O
R
NHR'
N2
[O]
OH
R
[O]
12
11
R = (CH2)3OP
Having succeeded in constructing the tricyclic system,
we next focused on introducing a one-carbon unit at C15
Scheme 1 Retrosynthesis of lycopalhine A
(Scheme 4). Reduction of the three carbonyl groups in 32a
Our synthesis began with the preparation of the cyclo-
using diisobutylaluminum hydride (DIBAL-H) afforded triol
hexenol 20 for use in the Claisen–Johnson rearrangement
33a, two hydroxy groups in which were tied up as an ace-
(
1
Scheme 2). Protection of a hydroxy group in cyclohexane-
,3,5-triol (13) with a TBS group, followed by enzymatic
acetylation with vinyl acetate and lipase QLM, generated 14
tonide. While mesylation of 34a followed by an S 2 reac-
N
tion with potassium cyanide gave 35a in good yield, the
yields of DIBAL-H reduction of 32a and the acetonide for-
mation of 33a were not good (32% and 50%, respectively).
Since the lability of the hemiaminal moiety appeared to be
the main reason for the poor result, we decided to replace
the Ts group with a more strongly electron-withdrawing
10
in >99% ee. After tosylation of the remaining hydroxy
11
group in 14, the acetyl group was removed by basic meth-
anolysis. The resulting alcohol 15 was oxidized with 2-
azaadamantane-N-oxyl (AZADO) and (diacetoxyiodo)ben-
1
) TsCl, Et3N
1) AZADO
PhI(OAc)2
buffer (pH 7.4)
MeCN, r.t.
OH
1) NaH, Et N
TBSCl, THF
OH
Me N•HCl
OTs
3
3
CH2Cl2, 0 °C
9%
40 °C, 95%
9
I2, DMAP
2
) lipase QLM
vinyl acetate
EtOAc, r.t.
quant
2
) K2CO3
MeOH, r.t.
98%
2) DBU
CH2Cl2, r.t.
88%
HO
OH
TBSO
OAc
TBSO
OH
TBSO
O
CH Cl , r.t.
2
2
13
14
15
16
91% (2 steps)
CO2Et
B
OPMP
NaBH4
CeCl •7H O
MeC(OEt)3
o-nitrophenol
I
R
R
18
3
2
PdCl2(dppf)
AsPh3, K3PO4
THF–H2O, r.t.
MeOH, 0 °C
m-xylene, reflux
58% (3 steps)
TBSO
O
TBSO
O
OPMP
TBSO
OH
TBSO
17
19
20
R = (CH2)3OPMP
21
R = (CH2)3OPMP
Scheme 2 Preparation of cyclohexene 21 via a Claisen–Johnson rearrangement
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

C
Synthesis
Y. Ochi et al.
Paper
N3
PF6
NMe
O
O
O
O
OEt
CO2Et
R
CHO
R
MeN
OEt
1
2
) LiAlH4, THF
r.t., 92%
N2CHCO2Et
SnCl2
N2
R
24
R
) DMP, NaHCO3
CH2Cl2, r.t., 97% TBSO
CH2Cl2, r.t.
98%
Et3N, MeCN
THF, r.t.
TBSO
TBSO
TBSO
98%
21
22
23
25
R = (CH2)3OPMP
O
O
1) CDI, THF;
ArSO2NH2
DBU
O
DMP
pyridine
O
O
A
aq NaOH
H
H
H
CO2Et
toluene
reflux
EtOH
91%
OH 2) TBAF, THF
86% (2 steps)
NHTs
CH2Cl2
r.t. to 40 °C
R
R
R
55%
TBSO
TBSO
HO
26
27
28
O
O
O
O
O
H
O
O
NHTs
O
t-Bu
N
H
H
H
O Cu O
H
R
NTs
N
t-Bu
NHTs
NHTs
R
R
R
80%
H
O
HO
O
A
O
29
30
31
32a
R = (CH2)3OPMP
Scheme 3 Construction of the tricyclic system
sulfonyl group [i.e., 2-nitrobenzensulfonyl (Ns) group].19 To
our delight, the use of 32b as a substrate improved the
yields of the reduction with DIBAL-H and the formation of
the acetonide to give 33b and 34b in 71% and 68% yield, re-
spectively. Although the subsequent mesylation proceeded
dium borohydride to furnish alcohol 39. The Mitsunobu re-
action of 39 with N-methylnosylamide proceeded smoothly
to give 40 in 97% yield.2
1,22
O
OH
without problems, the S 2 reaction of the mesylate with
H
H
N
O
OH
PPTS
potassium cyanide did not give the desired product. Investi-
gation of the crude reaction mixture suggested that the Ns
group decomposed during the reaction. The cyanide ion
might have attacked the electron-deficient benzene ring of
the Ns group. A 4-(trifluoromethyl)benzenesulfonyl group
was next chosen to construct the tricycle 32c. Reduction
with DIBAL-H and the subsequent formation of acetonide
proceeded in 88% and 80% yields, respectively. After
mesylation of the remaining hydroxy group, the crucial SN2
reaction with potassium cyanide proceeded smoothly, giv-
ing 35c in 90% yield. Thus, we have established a robust
route for the introduction of a single carbon unit at C15.
We next turned our attention to the introduction of a 2-
aminoethyl moiety at C3 (Scheme 5). Treatment of 35c with
BF ·OEt activated the hemiaminal moiety to generate a sul-
DIBAL-H
CuSO4
H
R
H
R
NR'
NR'
THF
–78 to 0 °C
acetone, r.t.
15
H
H
B
O
HO
A
3
2a–c
R = (CH2)3OPMP
33a–c
O
O
H
H
O
O
1) MsCl, Et3N
CH2Cl2, r.t.
H
R
H
R
NR'
NR'
2) KCN, 18-c-6
DMSO, 80 °C
15
H
H
HO
C
NC
34a–c
35a–c
3
2
yield
fonyliminium ion, which was attacked by allyltrimethylsi-
lane from the convex face, giving 36 in 96% yield as a single
diastereomer. After protecting the liberated hydroxy group
with a TBS group, reductive cleavage of the sulfonyl group,
followed by protection of the resulting secondary amine
compound
R'
A (dr)
B
C
a
b
c
Ts
Ns
32% (2:1)
71% (1:1)
88% (3:1)
50%
68%
80%
83%
–
90%
p-CF3C6H4SO2
20
with a Boc group, afforded 38. The Lemieux–Johnson oxi-
dation of 38 gave an aldehyde, which was reduced with so-
Scheme 4 Introduction of one carbon unit at C16
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

D
Synthesis
Y. Ochi et al.
Paper
OH
1) TBSOTf
2,6-lutidine
CH2Cl2
OTBS
H
OTBS
H
O
SiMe3
BF3·OEt2
CH2Cl2
H
H
O
BocOSu
Et3N
0
°C, 93%
3
H
R
H
R
H
R
H
R
NR'
NH
NBoc
NR'
DMF, 40 °C
92%
2
) Mg, MeOH
–
78 to 0 °C
96%
40 °C, 96%
H
H
H
H
NC
NC
NC
NC
35c
36
37
38
R = (CH2)3OPMP
R' = SO2C6H4-p-CF3
Ns
N
Ns
N
1
2
) OsO4, NaIO4
OTBS
OH
OTBS
H
OTBS
Me
Me
2
1
8
,6-lutidine
,4-dioxane–H2O
9%
H
1) DIBAL-H
toluene
–78 °C, 93%
H
NsNHMe
Ph3P, DEAD
TAS-F
H
R
H
R
H
R
NBoc
NBoc
NBoc
) NaBH4, MeOH
4%
toluene
97%
2) NaBH4
THF, MeOH
DMF, r.t.
97%
7
H
H
H
0
9
°C to r.t.
7%
NC
NC
HO
39
40
41
Ns
N
Ns
Ns
Ns
N
OH
O
H
Me
Me
N
N
O
H
O
H
DMP
NaHCO3
Me
Me
KOH
H
H
R
H
R
HO
H
OH
MeOH
0 °C to r.t.
98%
NBoc
CH2Cl2, r.t.
NBoc
98%
H
NBoc
NBoc
H
H
OPMP
OPMP
H
H
HO
OHC
4
2
43
44
45
Scheme 5 Introduction of a 2-aminoethyl moiety and construction of the β-hydroxy ketone moiety
Having installed all the units required for the synthesis
of lycopalhine A, the remaining task was to construct the
ring system including the β-hydroxy ketone and the aminal.
It should be emphasized that the order of the ring forma-
tion was critical to the completion of the total synthesis.
Since we realized that the aminal moiety could not be con-
structed prior to the formation of the β-hydroxy ketone
moiety, the β-hydroxy ketone moiety was constructed in
the following manner. A 2-step reduction of the cyano
group afforded alcohol 41, and the TBS group was cleaved
with TAS-F. The resulting diol 42 was oxidized with DMP,15
giving ketoaldehyde 43 in 98% yield. Upon treatment with
potassium hydroxide in methanol, 43 underwent an intra-
molecular aldol reaction to afford β-hydroxy ketone 44 in
trifluoroacetic acid (TFA) afforded hemiaminal 48. Removal
of the Ns group from 48 was effected by treatment with
benzenethiol and potassium phosphate. Addition of acetic
acid followed by heating promoted the formation of the
aminal moiety to give 49 in good yield. Finally, the benzoyl
group was cleaved by basic methanolysis to afford lycopal-
hine A (2) and its C16 epimer 50.7
In conclusion, we have achieved the total synthesis of
(+)-lycopalhine A (2) in 41 steps and 2.1% overall yield. The
features of our synthesis include the construction of the tri-
cyclic system via cleavage of a cyclopropane ring and an en-
suing intramolecular Michael addition, stereoselective in-
troduction of a 2-aminoethyl moiety via a reaction of allyl-
,25
trimethylsilane with
a sulfonyliminium ion, and a
98% yield as a single isomer. It should be noted that con-
stereoselective intramolecular aldol reaction.
ducting the aldol reaction in tetrahydrofuran in the pres-
ence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base
provided a 2:5 mixture of 44 and its diastereomer 45,23 and
the diastereomer 45 could be completely converted into 44
by treatment with potassium hydroxide in methanol.
Having succeeded in forming the β-hydroxy ketone
moiety, the characteristic aminal moiety was next con-
structed (Scheme 6). Protection of the hydroxy group in 44
with a benzoyl group, followed by oxidative cleavage of the
1H NMR (400 MHz) and 13C NMR (100 MHz)) spectra were recorded
on a JEOL-ECS400 instrument, unless otherwise noted. Chemical
shifts for H NMR are reported in parts per million (ppm) downfield
1
from TMS (δ) or relative to the singlet for residual CHCl at 7.26 ppm
3
or pyridine at 7.19 ppm as the internal standard. Coupling constants
are reported in hertz (Hz). Standard abbreviations are used for spin
13
multiplicity. Chemical shifts for C NMR were reported in ppm rela-
tive to the center line of a triplet at 77.0 ppm for CDCl or a triplet at
3
24
PMP group, afforded alcohol 46, which was oxidized with
DMP to give aldehyde 47. Cleavage of the Boc group using
123.4 ppm for pyridine-d . IR spectra were recorded on a JASCO
5
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

E
Synthesis
Y. Ochi et al.
Paper
(
1R,3S,5S)-1-Acetoxy-3-(p-toluenesulfonyloxy)-5-(tert-butyldi-
Ns
N
Ns
N
1
2
) BzCl
pyridine
methylsilyloxy)cyclohexane (51)
O
H
O
Me
Me
OH
To a solution of 14 (29.7 g, 102 mmol), Et N (35.4 mL, 254 mmol), and
Me N·HCl (9.7 g, 102 mmol) in CH Cl (300 mL) was added TsCl (29.0
g, 152 mmol) at 0 °C. The mixture was stirred for 1 h. To decompose
the remaining TsCl, N,N-dimethylethylenediamine (ca. 18.0 mL) was
added to the reaction mixture. After stirring for another 10 min, H O
was added to the mixture. The resulting solution was extracted with
CH Cl (3 ×). The combined organic phases were washed with brine,
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
and the residue was purified by flash column chromatography (SiO2;
H
3
92%
3
2
2
HO
H
BzO
H
) CAN
MeCN
H2O, 0 °C
NBoc
NBoc
OPMP
H
H
2
89%
44
46
2
2
Ns
N
2
4
DMP
NaHCO3
O
Me
H
TFA
CH Cl
n-hexane–EtOAc, 10:1) to give 51 (44.9 g, 99%) as a colorless oil; [α]D24
–
1.88 (c = 1.00, CHCl3).
CH2Cl2
BzO
H
2
2
CHO
98%
–78 °C to r.t.
IR (film): 2954, 2930, 2857, 1738, 1598, 1471, 1365, 1241, 1178,
1
NBoc
–1
099, 1036, 935, 861, 813, 778 cm .
H
1
47
H NMR (400 MHz, CDCl ): δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2
3
Hz, 2 H), 4.61 (dddd, J = 11.5, 11.5, 4.6, 4.6 Hz, 1 H), 4.36 (dddd, J =
Ns
1
1.5, 11.5, 4.6, 4.6 Hz, 1 H), 3.53 (dddd, J = 11.5, 11.5, 4.6, 4.6 Hz, 1 H),
O
O
N
H
Me
H
H
2.43 (s, 3 H), 2.18 (ddd, J = 11.5, 4.6, 4.6 Hz, 1 H), 2.15–2.03 (m, 2 H),
H
N
PhSH, K3PO4
MeCN;
2
1
.00 (s, 3 H), 1.48 (ddd, J = 11.5, 11.5, 11.5 Hz, 1 H), 1.43 (ddd, J = 11.5,
1.5, 11.5 Hz, 1 H), 1.29 (ddd, J = 11.5, 11.5, 11.5 Hz, 1 H), 0.82 (s, 9 H),
BzO
H
BzO
H
AcOH
N
N
–0.01 (s, 3 H), –0.02 (s, 3 H).
OH
O
Me
r.t. to 50 °C
13
H
H
C NMR (100 MHz, CDCl ): δ = 170.0 (C), 144.8 (C), 134.1 (C), 129.9
3
89% (2 steps)
4
8
49
(CH), 127.6 (CH), 75.2 (CH), 66.6 (CH), 65.3 (CH), 41.4 (CH ), 40.2
(CH ), 37.1 (CH ), 25.6 (CH ), 21.6 (CH ), 21.0 (CH ), 17.9 (C), –4.9
2
O
2
2
3
3
3
H
H
(CH3).
H
N
H
K2CO3
HRMS (ESI+): m/z calcd for C21H34O SSiNa: 465.1743; found:
465.1744.
HO
H
+
6
OH
MeOH, r.t.
H
N
N
N
89%
Me
Me
H
H
(1R,3S,5S)-1-Hydroxy-3-(p-toluenesulfonyloxy)-5-(tert-butyldi-
lycopalhine A (2)
epi-lycopalhine A (50)
methylsilyloxy)cyclohexane (15)
Scheme 6 Completion of the synthesis
To a solution of 51 (44.9 g, 101 mmol) in MeOH (1.00 L) was added
K CO (21.4 g, 152 mmol) at r.t. and stirring was continued at r.t. for 2
2
3
h. The solution was evaporated and the residue was partitioned be-
FT/IR-4100 Fourier Transform Infrared Spectrophotometer and were
tween EtOAc and H O. The aqueous phase was further extracted with
2
–1
reported in wavenumbers (cm ). High-resolution mass spectra
HRMS) were obtained on a JEOL JMS-T100LP AccuTOF LC-plus either
EtOAc and the combined organic phases were washed with brine,
(
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
2
4
in positive electrospray ionization (ESI) method or in positive direct
analysis in real time (DART) ionization method, using PEG as the in-
ternal standard. Melting points were determined on a Yanaco Micro
Melting Point Apparatus. Analytical TLC was performed on Merck
precoated analytical plates, silica gel 60 F254, 0.25 mm thick. Prepara-
tive TLC separations were performed on Merck analytical plates (0.25
or 0.50 mm thick) precoated with silica gel 60 F254. Flash chromatog-
raphy separations were performed on Kanto Chemical Silica Gel 60
and the residue was purified by flash column chromatography (SiO2;
n-hexane–EtOAc, 5:1 → 2:1) to afford 15 (39.6 g, 98%, >99.5% ee) as a
colorless oil. The enantiomeric excess was determined by HPLC analy-
sis with a chiral HPLC column (DAICEL CHIRALCEL AD-H, 4% i-PrOH in
n-hexane, 1.0 mL/min at 25 °C, 210 nm). The retention times corre-
sponding to 15 and its enantiomer are 30.9 and 27.1 min, respective-
ly; [α]D25
–1.32 (c = 1.00, CHCl
).
3
IR (film): 2953, 2930, 2857, 1598, 1470, 1360, 1256, 1176, 1099,
(spherical, 40–100 mesh), unless otherwise noted. Reagents were
–1
1
049, 956, 931, 873, 836, 777 cm .
commercial grades and were used without any purification. Anhyd
THF, Et O, toluene, and CH Cl were purchased from Kanto Chemicals
1
H NMR (400 MHz, CDCl ): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2
3
2
2
2
Hz, 2 H), 4.42 (dddd, J = 10.5, 10.5, 4.6, 4.6 Hz, 1 H), 3.57 (dddd, J =
Co., Inc., and were purified using a Glass Contour Solvent System. An-
hyd benzene and DMF were purchased from Kanto Chemicals Co., Inc.
and stored over activated MS. Anhyd MeOH, EtOH, and MeCN were
also purchased from Kanto Chemicals Co., Inc. and stored over acti-
vated 3Å MS. (1R,3S,5S)-3-[(tert-Butyldimethylsilyl)oxy]-5-hydroxy-
10.5, 10.5, 4.6, 4.6 Hz, 1 H), 3.57 (dddd, J = 10.5, 10.5, 4.6, 4.6 Hz, 1 H),
2.44 (s, 3 H), 2.18–2.08 (m, 1 H), 2.08–1.94 (m, 2 H), 1.91 (d, J = 5.0 Hz,
1 H), 1.50 (ddd, J = 12.0, 10.5, 10.5 Hz, 1 H), 1.48 (ddd, J = 12.2, 10.5,
10.5 Hz, 1 H), 1.33 (ddd, J = 12.0, 10.5, 10.5 Hz, 1 H), 0.83 (s, 9 H), 0.00
1
0
26
(s, 3 H), –0.01 (s, 3 H).
cyclohexyl acetate (14), 1-allyloxy-4-methoxybenzene, and bis(N-
27
13
tert-butylsalicylaldiminato)copper(II) were prepared according to
the literature. All reactions sensitive to oxygen or moisture were con-
ducted under an argon atmosphere.
C NMR (100 MHz, CDCl ): δ = 144.7 (C), 134.3 (C), 129.8 (CH), 127.6
3
(CH), 75.8 (CH), 65.7 (CH), 65.1 (CH), 43.4 (CH ), 40.8 (CH ), 40.5
2
2
(CH ), 25.7 (CH ), 21.6 (CH ), 18.0 (C), –4.9(CH ).
2
3
3
3
HRMS (ESI+): m/z calcd for C19H32O SSiNa: 423.1637; found:
5
423.1622.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

F
Synthesis
Y. Ochi et al.
Paper
(5S)-5-tert-Butyldimethylsilyloxycyclohex-2-enone (16)
PdCl (dppf)·CH Cl (4.74 g, 5.80 mmol), K PO (24.0 g 113 mmol),
2
2
2
3
4
AsPh (1.81 g, 5.91 mmol), and H O (120 mL) at 0 °C. After stirring for
To a solution of 15 (56.0 g, 140 mmol) and PhI(OAc)2 (98.0 g, 304
mmol) in MeCN (580 mL) and phosphate buffer (pH 7.4, 580 mL) was
added AZADO (1.58 g, 10.4 mmol) at 0 °C. The reaction mixture was
allowed to warm to r.t. After stirring for 2 h at r.t., the reaction was
quenched with aq Na S O . The resulting solution was extracted with
3
2
2
h at r.t., the reaction was quenched with aq NH Cl. The resulting
4
solution was extracted with EtOAc. The combined organic phases
were washed with brine, dried (Na SO ), and filtered. The filtrate was
2
4
concentrated in vacuo and the residue was purified roughly by flash
2
2
3
column chromatography (SiO ; n-hexane–EtOAc, 50:1 → 10:1) to af-
EtOAc (3 ×). The combined organic phases were washed with brine,
2
ford a 5:1 mixture of 19 and 16 (20.86 g) as a yellow oil, which was
used in the next step without further purification. The spectroscopic
dried (Na SO ) and filtered. The filtrate was concentrated in vacuo.
2
4
The residue was dissolved in CH Cl (1.00 L), and DBU (25.5 mL, 171
2
2
data for 19 were collected after purification by PTLC (SiO ; toluene–
mmol) was added at 0 °C. After stirring for 1.5 h at 0 °C, aq NH Cl was
2
4
26
acetone, 100:1); [α]D
+1.98 (c = 1.00, CHCl3).
added. The resulting mixture was extracted with CH Cl (3 ×). The
2
2
combined organic phases were washed with brine, dried (Na SO )
and filtered. The filtrate was concentrated in vacuo and the residue
IR (film): 2953, 2929, 2896, 2856, 1676, 1508, 1471, 1380, 1231,
1106, 1041, 866, 835, 777 cm .
2
4
–1
was purified by flash column chromatography (SiO ; n-hexane–
1
2
H NMR (400 MHz, CDCl ): δ = 6.85 (s, 4 H), 6.61 (dd, J = 4.6, 3.2 Hz, 1
3
25
EtOAc, 1:0 → 10:1) to give 16 (28.5 g, 91%) as a pale yellow oil; [α]D
10.4 (c = 1.00, CHCl3).
IR (film): 2955, 2930, 2894, 2857, 1682, 1472, 1389, 1253, 1103, 939,
H), 4.17 (dddd, J = 9.6, 7.3, 4.6, 4.1 Hz, 1 H), 3.88 (t, J = 6.4 Hz, 2 H),
3
Hz, 1 H), 2.47 (dd, J = 16.0, 9.6 Hz, 1 H), 2.42–2.30 (m, 3 H), 1.86 (tt, J =
7.6, 6.4 Hz, 2 H), 0.86 (s, 9 H), 0.05 (s, 6 H).
+
.75 (s, 3 H), 2.66 (dd, J = 16.0, 4.1 Hz, 1 H), 2.57 (ddd, J = 17.8, 4.6, 4.6
–1
836, 777 cm
.
1
13
H NMR (400 MHz, CDCl ): δ = 6.85 (ddd, J = 10.1, 5.0, 3.2 Hz, 1 H),
C NMR (100 MHz, CDCl ): δ = 198.0 (C), 153.7 (C), 153.0 (C), 141.9
3
3
6.03 (d, J = 10.1 Hz, 1 H), 4.22 (dddd, J = 9.6, 7.5, 4.7, 4.1 Hz, 1 H), 2.64
(CH), 139.3 (C), 115.4 (CH), 114.6 (CH), 67.8 (CH ), 67.7 (CH), 55.7
2
(dd, J = 16.0, 4.1 Hz, 1 H), 2.58 (ddd, J = 18.3, 5.0, 4.7 Hz, 1 H), 2.46 (dd,
(CH ), 48.2 (CH ), 35.9 (CH ), 28.1 (CH ), 26.0 (CH ), 25.8 (CH ), 17.9
3
2
2
2
2
3
J = 16.0, 9.6 Hz, 1 H), 2.36 (dddd, J = 18.3, 7.5, 3.2, 2.7 Hz 1 H), 0.86 (s,
(C), –4.8 (CH ), –4.9 (CH ).
3
3
9
H), 0.05 (s, 6 H).
HRMS (ESI+): m/z calcd for C22H34O SiNa: 413.2124; found: 413.2112.
4
13
C NMR (100 MHz, CDCl ): δ = 198.6 (C), 146.8 (CH), 130.0 (CH), 67.5
3
(
(
CH), 48.0 (CH ), 35.5 (CH ), 25.7 (CH ), 17.9 (C), –4.8 (CH ), –4.9
CH3).
2
2
3
3
(1S,5S)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-methoxyphen-
oxy)propyl]cyclohex-2-enol (20)
HRMS (ESI+): m/z calcd for C12H22O SiNa: 249.1287; found: 249.1284.
2
To a solution of 19 containing a small amount of 16 in MeOH (500 mL)
was added CeCl ·7H O (28.3 g, 76.0 mmol) and NaBH (2.43 g, 64.3
3
2
4
(
5S)-2-Iodo-5-tert-butyldimethylsilyloxycyclohex-2-enone (17)
mmol) at 0 °C. After stirring for 2 h at 0 °C, the reaction was quenched
with aq NH Cl. The solution was evaporated and the residue was par-
To a solution of 16 (16.4 g, 72.4 mmol) and DMAP (17.7 g, 145 mmol)
in CH Cl (40.0 mL) was added I2 (20.5 g, 80.8 mmol) in CH Cl (500
mL) slowly at 0 °C. The reaction mixture was allowed to warm to r.t.
After stirring for 2 h at r.t., the reaction was quenched with aq
Na S O . The resulting solution was extracted with CH Cl . The com-
4
titioned between EtOAc and H O. The aqueous phase was further ex-
2
2
2
2
2
tracted with EtOAc and the combined organic phases were washed
with brine, dried (Na SO ), and filtered. The filtrate was concentrated
2
4
in vacuo and the residue was purified roughly by flash column chro-
2
2
3
2
2
matography (SiO ; n-hexane–EtOAc, 20:1 → 0:1) to afford a 5:1 mix-
bined organic phases were washed with brine, dried (Na SO ), and fil-
2
2
4
ture of 20 and an alcohol derived from 16 (20.4 g) as a yellow oil,
which was used in the next step without further purification. The
spectroscopic data for 20 were collected after purification by PTLC
tered. The filtrate was concentrated in vacuo and the residue was pu-
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 50:1)
2
26
to afford 17 (22.5 g, 88%) as a pale yellow oil; [α]D +11.0 (c = 1.00,
26
(
SiO ; toluene–acetone, 100:1); [α]D
–3.04 (c = 1.00, CHCl3).
CHCl3).
2
IR (film): 3445, 2950, 2928, 2857, 1508, 1470, 1322, 1231, 1044, 962,
835, 777 cm .
IR (film): 2953, 2929, 2893, 2856, 1690, 1591, 1471, 1322, 1254,
–1
–1
1106, 962, 837, 776 cm .
1
1
H NMR (400 MHz, CDCl ): δ = 6.82 (s, 4 H), 5.38 (m, 1 H), 4.23 (d, J =
3
H NMR (400 MHz, CDCl ): δ = 7.61 (dd, J = 5.3, 3.8 Hz, 1 H), 4.27
3
3.2 Hz, 1 H), 3.98 (m, 1 H), 3.91 (t, J = 6.4, Hz, 2 H), 3.75 (s, 3 H), 3.38
(
(
(
1
dddd, J = 9.2, 6.9, 5.0, 3.7 Hz, 1 H), 2.85 (dd, J = 15.6, 5.0 Hz, 1 H), 2.67
dd, J = 15.6, 9.2 Hz, 1 H), 2.63 (ddd, J = 18.3, 5.3, 3.7 Hz, 1 H), 2.45
ddd, J = 18.3, 6.9, 3.8 Hz, 1 H), 0.85 (s, 9 H), 0.05 (s, 6 H).
3
(d, J = 10.1 Hz, 1 H), 2.35–2.26 (m, 2 H), 2.23–2.16 (m, 2 H), 2.13 (ddd,
J = 13.8, 4.1, 3.7 Hz, 1 H), 1.94 (m, 1 H), 1.82 (ddd, J = 13.8, 5.0, 1.8 Hz,
H), 0.88 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H).
1
C NMR (100 MHz, CDCl ): δ = 191.2 (C), 155.1 (CH), 103.5 (C), 67.2
3
13
C NMR (100 MHz, CDCl ): δ = 172.9 (C), 153.2 (C), 139.2 (C) 119.2
(
(
CH), 46.7 (CH ), 39.3 (CH ), 25.6 (CH ), 17.9 (C), –4.8 (CH ), –4.9
CH3).
3
2
2
3
3
(
(
(
CH), 115.5 (CH), 115.5 (CH), 114.6 (CH), 114.6 (CH), 68.3 (CH ), 66.7
2
CH), 66.7 (CH), 55.7 (CH ), 37.5 (CH ), 34.3 (CH ), 30.7 (CH ), 27.6
2
2
2
2
HRMS (ESI+): m/z calcd for C12H21IO SiNa: 375.0253; found:
2
CH ), 25.8 (CH ), 18.0 (C), –4.9 (CH ), –5.1 (CH ).
3
3
3
3
375.0249.
HRMS (ESI+): m/z calcd for C22H36O SiNa: 415.2281; found: 415.2264.
4
(
S)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-methoxyphen-
Ethyl 2-{(1S,5R)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-meth-
oxyphenoxy)propyl]cyclohex-2-en-1-yl}acetate (21)
oxy)propyl]cyclohex-2-enone (19)
To a solution of 1-allyloxy-4-methoxybenzene (14.2 g, 86.5 mmol) in
THF (120 mL) was added 9-BBN (0.5 M solution in THF, 152 mL, 76.0
mmol) at r.t. and the solution was heated at reflux for 2 h. In another
flask 17 (20.6 g, 58.5 mmol) was dissolved in THF (240 mL). To this
solution were added the above solution containing boron reagent 18,
To a solution of 20 containing a small amount of an impurity in m-
xylene (200 mL) was added triethyl orthoacetate (200 mL) and o-ni-
trophenol (400 mg, 2.88 mmol) at r.t. and the solution was heated at
reflux for 13.5 h. After cooling to r.t., the solvent was evaporated. The
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

G
Synthesis
Y. Ochi et al.
Paper
residual oil was purified by flash column chromatography (SiO ; n-
Hz, 1 H), 2.23 (ddd, J = 18.3, 5.6, 5.6 Hz, 1 H), 2.12 (t, J = 7.6 Hz, 2 H),
2.06–1.94 (m, 2 H), 1.93–1.85 (m, 1 H), 1.84–1.73 (m, 1 H), 1.47 (ddd,
J = 12.4, 10.1, 9.6 Hz, 1 H), 0.88 (s, 9 H), 0.06 (s, 6 H).
2
hexane–EtOAc, 1:0 → 20:1) to afford 21 (16.4 g, 58% for 3 steps) as a
26
pale yellow oil; [α]D –34.8 (c = 1.00, CHCl3).
1
3
IR (film): 2951, 2929, 2856, 1733, 1508, 1471, 1232, 1105, 1039, 835,
C NMR (100 MHz, CDCl ): δ = 202.4 (CH), 153.7 (C), 153.0 (C), 137.2
3
–1
775 cm
.
(C), 121.3 (CH), 115.4 (CH), 114.6 (CH), 67.9 (CH ), 67.4 (CH), 55.6
2
1
(CH
3
), 47.24 (CH
2
), 38.6 (CH
2
), 35.2 (CH
2
), 32.4 (CH), 30.6 (CH ), 27.5
2
H NMR (400 MHz, CDCl ): δ = 6.82 (s, 4 H), 5.38–5.37 (m, 1 H), 4.14
3
(
CH ), 25.8 (CH ), 18.1 (C), –4.7 (CH ), –4.7 (CH ).
(q, J = 7.4 Hz, 2 H), 3.96–3.80 (m, 2 H), 3.76 (s, 3 H), 2.80–2.65 (m, 1
2
3
3
3
H), 2.61 (dd, J = 15.1, 4.1 Hz, 1 H), 2.28 (dd, J = 15.1, 9.6 Hz, 1 H), 2.25–
.15 (m, 1 H), 2.13 (t, J = 7.6 Hz, 1 H), 2.05–19.2 (m, 2 H), 1.90–1.85
m, 1 H), 1.85–1.75 (m, 1 H), 1.46 (ddd, J = 12.4, 10.1, 10.1 Hz, 1 H),
HRMS (ESI+): m/z calcd for C24H38O SiNa: 441.2437; found: 441.2431.
4
2
(
Ethyl 4-{(1S,5R)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-meth-
oxyphenoxy)propyl]cyclohex-2-en-1-yl}-3-oxobutanoate (23)
1.25 (t, J = 7.4 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 172.9 (C), 153.7 (C), 153.1 (C), 137.8
To a solution of 22 (22.2 g, 53.0 mmol) in CH Cl (750 mL) were added
3
2
2
(
(
(
(
C), 120.9 (CH), 115.4 (CH), 114.6 (CH), 68.0 (CH ), 67.9 (CH), 60.2
SnCl (1.12 g, 5.91 mmol) and ethyl diazoacetate (15% solution in tol-
uene, 61.0 mL, 80.2 mmol) at 0 °C. After stirring for 1 h at r.t., aq
2
2
CH ), 55.6 (CH ), 38.4 (CH ), 38.2 (CH ), 35.3 (CH ), 34.6 (CH), 30.5
2
3
2
2
2
CH ), 27.5 (CH ), 25.9 (CH ), 18.1 (C), 14.2 (CH ), –4.7 (CH ), –4.7
NH Cl was added at 0 °C. The resulting solution was extracted with
2
2
3
3
3
4
CH3).
CH Cl (3 ×). The combined organic phases were washed with brine,
2
2
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
and the residue was purified by flash column chromatography (SiO2;
HRMS (ESI+): m/z calcd for C26H42O SiNa: 485.2699; found: 485.2714.
2
4
5
n-hexane–EtOAc, 10:1 → 5:1) to give 23 (26.1 g, 98%) as a pale yellow
oil; [α]D –39.8 (c = 1.00, CHCl3).
2
-{(1R,5R)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-methoxyphen-
26
oxy)propyl]cyclohex-2-en-1-yl}ethanol (52)
IR (film): 2951, 2928, 2856, 1724, 1508, 1231, 1106, 1040, 835, 775
To a solution of 21 (28.0 g, 60.5 mmol) in THF (900 mL) was added
–1
cm
.
LiAlH4 (2.53 g, 66.6 mmol) at 0 °C. After stirring for 2 h at 0 °C, H O
2
1
(
2.60 mL), 3 M aq NaOH (2.60 mL), and H O (7.80 mL) were succes-
H NMR (400 MHz, CDCl ): δ = 12.13 (s, 0.13 H), 6.81 (s, 4 H), 5.42–
2
3
sively added at the same temperature, and then the resulting mixture
was filtered through a pad of Celite. The filtrate was concentrated in
vacuo. The residual oil was purified by flash column chromatography
5.30 (m, 1 H), 5.00 (s, 0.14 H), 4.19 (q, J = 7.1 Hz, 0.28 H), 4.18 (q, J =
7.1 Hz, 2.72 H), 3.95–3.80 (m, 3 H), 3.76 (s, 3 H), 3.42 (s, 1.66 H), 2.85–
2.55 (m, 1.67 H), 2.54–2.51 (m, 1.12 H), 2.30–1.70 (m, 7 H), 1.45–1.30
(m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
13
(
SiO ; n-hexane–EtOAc, 5:1 → 2:1) to afford 52 (23.1 g, 92%) as a pale
2
27
yellow oil; [α]D
–38.1 (c = 1.00, CHCl3).
C NMR (100 MHz, CDCl ): δ = 202.1 (C), 177.2 (C), 172.5 (C), 167.0
3
IR (film): 3409, 2950, 2929, 2856, 1508, 1231, 1105, 1041, 835, 775
(C), 153.7 (CH), 153.1 (CH), 138.2 (C), 137.6 (C), 120.9 (CH), 115.4
–1
cm
.
(CH), 114.6 (CH), 90.7 (CH), 68.0 (CH), 68.0 (CH ), 67.4 (CH), 61.3
2
1
(CH
2
), 59.9 (CH
2 3 2 2 2
), 55.7 (CH ), 50.0 (CH ), 46.9 (CH ), 39.1 (CH ), 38.2
H NMR (400 MHz, CDCl ): δ = 6.82 (s, 4 H), 5.36 (d, J = 5.5 Hz, 1 H),
.89 (dd, J = 9.2, 6.4 Hz, 2 H), 3.85–3.78 (m, 1 H), 3.76 (s, 3 H), 3.74–
.60 (m, 2 H), 2.50–2.35 (m, 1 H), 2.25–2.05 (m, 3 H), 2.05–1.85 (m, 4
3
(
(
(
CH ), 37.9 (CH ), 35.4 (CH ), 35.2 (CH ), 34.9 (CH), 33.0 (CH), 30.6
3
3
2
2
2
2
CH ), 27.5 (CH ), 25.9 (CH ), 18.2 (C), 14.2 (CH ), 14.1 (CH ), –4.7
2
2
3
2
3
CH3).
H), 1.85–1.70 (m, 1 H), 1.56–1.44 (m, 2 H), 1.37 (ddd, J = 12.3, 11.0,
10.6 Hz, 1 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H).
HRMS (ESI+): m/z calcd for C28H44O SiNa: 527.2804; found: 527.2789.
6
13
C NMR (100 MHz, CDCl ): δ = 153.7 (C), 153.1 (C), 137.8 (C), 120.3
3
(
(
(
CH), 115.4 (CH), 114.6 (CH), 68.4 (CH), 68.1 (CH ), 60.5 (CH ), 55.7
Ethyl 4-{(1S,5R)-5-[(tert-Butyldimethylsilyl)oxy]-2-[3-(4-meth-
oxyphenoxy)propyl]cyclohex-2-en-1-yl}-2-diazo-3-oxobutanoate
(25)
2
2
CH ), 38.4 (CH ), 35.7 (CH ), 35.5 (CH ), 34.4 (CH), 30.6 (CH ), 27.6
3
2
2
2
2
CH ), 26.0 (CH ), 18.1 (C), –4.6 (CH ), –4.7 (CH ).
2
3
3
3
To a solution of 23 (26.0 g, 51.5 mmol) and Et N (14.9 mL, 107 mmol)
in MeCN (93.0 mL) and THF (370 mL) was added 2-azido-1,3-di-
HRMS (ESI+): m/z calcd for C24H40O SiNa: 443.2594; found: 443.2584.
3
4
methylimidazolium hexafluorophosphate (24; 17.6 g, 61.8 mmol) at
2
-{(1S,5R)-5-[(tert-Butyldimethylsilyl)oxy)-2-[3-(4-methoxyphen-
0
°C. After stirring for 1 h at the same temperature, EtOAc and aq
oxy)propyl]cyclohex-2-en-1-yl}acetaldehyde (22)
NH Cl were added. The resulting solution was extracted with EtOAc.
4
To a solution of 52 (23.0 g, 54.7 mmol) in CH Cl (600 mL) were added
2
2
The organic phase was washed with brine, dried (Na SO ), and fil-
2
4
NaHCO3 (28.0 g, 333 mmol) and Dess–Martin periodinane (25.5 g,
0.2 mmol) at 0 °C. After stirring for 1 h at r.t., H O was added at the
tered. The filtrate was concentrated in vacuo and the residue was pu-
6
2
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 10:1)
2
same temperature. The resulting solution was extracted with CH Cl
26
2
2
to give 25 (26.68 g, 98%) as a pale yellow oil; [α]D –27.3 (c = 1.00,
(
(
3 ×). The combined organic phases were washed with brine, dried
Na SO ), and filtered. The filtrate was concentrated in vacuo and the
CHCl3).
2
4
IR (film): 2952, 2929, 2856, 2132, 1718, 1654, 1508, 1470, 1306,
residue was purified by flash column chromatography (SiO ; n-hex-
2
–1
26
1231, 1106, 1070, 835, 775 cm .
ane–EtOAc, 10:1) to give 22 (22.2 g, 97%) as a colorless oil; [α]D –44.3
c = 1.00, CHCl3).
IR (film): 2951, 2928, 2856, 1724, 1508, 1231, 1106, 1040, 835, 775
1
(
H NMR (400 MHz, CDCl ): δ = 6.81 (s, 4 H), 5.46–5.32 (m, 1 H), 4.28
3
(q, J = 7.3 Hz, 2 H), 3.94–3.78 (m, 3 H), 3.75 (s, 3 H), 3.10 (dd, J = 16.0,
–1
3.2 Hz, 1 H), 2.93 (dd, J = 16.0, 9.6 Hz, 1 H), 2.92–2.80 (m, 1 H), 2.20
ddd, J = 17.0, 5.0, 5.0 Hz, 1 H), 2.12 (t, J = 7.6 Hz, 2 H), 2.22–1.94 (m, 2
H), 1.93–1.84 (m, 1 H), 1.84–1.72 (m, 1 H), 1.42 (ddd, J = 12.4, 10.1,
0.1 Hz, 1 H), 1.32 (t, J = 7.3 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H).
cm
.
(
1
H NMR (400 MHz, CDCl ): δ = 9.78 (dd, J = 2.3, 1.4 Hz, 1 H), 6.82 (s, 4
3
H), 5.48–5.36 (m, 1 H), 3.96–3.82 (m, 3 H), 3.76 (s, 3 H), 2.90–2.75 (m,
1
1
H), 2.63 (ddd, J = 17.0, 4.1, 1.4 Hz, 1 H), 2.52 (ddd, J = 17.0, 8.7, 2.3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

H
Synthesis
Y. Ochi et al.
Paper
13
13
C NMR (100 MHz, CDCl ): δ = 192.0 (C), 161.2 (C), 153.6 (C), 153.1
C NMR (100 MHz, CDCl ): δ = 216.1 (C), 169.2 (C), 153.8 (C), 152.9
3
3
(C), 138.1 (C), 120.8 (CH), 115.4 (CH), 114.5 (CH), 76.3 (C), 68.1 (CH2),
(C), 115.3 (CH), 114.6 (CH), 68.2 (CH ), 64.4 (CH), 55.6 (CH ), 52.4 (C),
2
3
6
7.9 (CH), 61.3 (CH ), 55.7 (CH ), 43.6 (CH ), 38.6 (CH ), 35.4 (CH ),
48.4 (C), 46.1 (CH ), 41.5 (CH), 33.6 (CH ), 29.9 (CH), 29.2 (CH ), 27.5
2 2 2
2
3
2
2
2
3
3.8 (CH), 30.5 (CH ), 27.6 (CH ), 25.9 (CH ), 18.1 (C), 14.3 (CH ), –4.6
(CH ), 27.3 (CH ), 25.7 (CH ), 17.9 (C), –4.9 (CH ), –5.0 (CH ).
2
2
3
3
2 2 3 3 3
(
CH ), –4.7 (CH ).
3
3
HRMS (ESI+): m/z calcd for C26H37O SiNa : 519.2154; found:
6 2
HRMS (ESI+): m/z calcd for C28H42N O SiNa: 553.2710; found:
519.2164.
2
6
553.2693.
1
(
4S,5aS)-4-[(tert-Butyldimethylsilyl)oxy]-2a -[3-(4-methoxyphen-
1
Ethyl (4S,5aS)-4-[(tert-Butyldimethylsilyl)oxy)-2a -[3-(4-meth-
oxyphenoxy)propyl]-2-oxooctahydro-1H-cyclopropa[cd]indene-
oxy)propyl]-2-oxo-N-tosyloctahydro-1H-cyclopropa[cd]indene-
2a-carboxamide (53a)
2
a-carboxylate (26)
To a solution of 27 (930 mg, 1.96 mmol) in THF (14.0 mL) was added
1,1′-carbonyldiimidazole (980 mg, 6.08 mmol) at r.t. and the solution
was stirred at r.t. for 2 h. In another flask p-toluenesulfonamide (503
mg, 2.94 mmol) and DBU (410 μL, 2.74 mmol) were dissolved in THF
(28 mL). To this solution was added the above solution containing the
acyl imidazole reagent. After stirring for 3 h at the same temperature,
To a solution of 25 (7.00 g, 9.42 mmol) in toluene (940 mL) was added
bis(N-tert-butylsalicylaldiminato)copper(II) (A; 1.80 g, 61.8 mmol) at
r.t., and the resulting solution was heated at 110 °C for 1 h. After cool-
ing to r.t., the solvent was evaporated. The residual oil was purified by
flash column chromatography (SiO ; n-hexane–EtOAc, 20:1 → 7:1) to
2
2
7
afford 26 (3.65 g, 55%) as a white solid; mp 72.1–73.0 °C; [α]D +10.3
c = 1.00, CHCl3).
IR (film): 2951, 2931, 2856, 1732, 1508, 1231, 1106, 1033, 835, 775
EtOAc and aq NH Cl were added. The resulting solution was extracted
4
(
with EtOAc. The organic phase was washed with brine, dried
(
Na SO ), and filtered. The filtrate was concentrated in vacuo and the
2 4
–1
residue was purified by flash column chromatography (SiO ; n-hex-
2
cm
.
ane–EtOAc, 4:1) to give 53a (1.10 g, 90%) as a white amorphous solid;
1
H NMR (400 MHz, CDCl ): δ = 6.80 (s, 4 H), 4.15 (q, J = 7.3 Hz, 2 H),
27
3
[
α]D –32.1 (c = 1.00, CHCl3).
4.05–3.95 (m, 2 H), 3.87 (t, J = 6.0 Hz, 2 H), 3.74 (s, 3 H), 2.78 (dd, J =
IR (film): 3185, 2951, 2930, 2856, 1709, 1508, 1437, 1350, 1231,
17.8, 11.9 Hz, 1 H), 2.70–2.60 (m, 1 H), 2.40–2.22 (m, 3 H), 1.96–1.70
–1
1
173, 1088, 835, 775 cm .
(
(
1
m, 5 H), 1.56–1.45 (m, 2 H), 1.23 (t, J = 7.3 Hz, 3 H), 0.85 (s, 9 H), 0.02
s, 3 H), 0.01 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 10.83 (s, 1 H), 7.93 (d, J = 8.3 Hz, 2H),
3
3
7.28 (d, J = 8.3 Hz, 2 H), 6.82 (dd, J = 6.9, 2.7 Hz, 2 H), 6.75 (dd, J = 6.9,
C NMR (100 MHz, CDCl ): δ = 207.7 (C), 168.0 (C), 153.8 (C), 152.9
3
2
(
2
.7 Hz, 2 H), 4.01 (dddd, J = 6.6, 6.6, 6.6, 3.2 Hz, 1 H), 3.77 (s, 3 H), 3.73
t, J = 6.2 Hz, 2 H), 2.71 (dd, J = 18.0, 11.5 Hz, 1 H), 2.66–2.60 (m, 1 H),
.51 (dd, J = 8.0, 4.1 Hz, 1 H), 2.46 (dd, J = 18.0, 1.4 Hz, 1 H), 2.36 (s, 3
H), 2.31 (ddd, J = 15.6, 8.0, 6.6 Hz, 1 H), 2.06 (ddd, J = 13.8, 10.5, 5.0 Hz,
H), 1.96–1.82 (m, 2 H), 1.81–1.70 (m, 1 H), 1.60–1.43 (m, 3 H), 0.85
(C), 115.3 (CH), 114.6 (CH), 68.0 (CH ), 64.5 (CH), 61.3 (CH ), 55.6
2
2
(CH ), 49.5 (C), 49.1 (CH ), 46.7 (C), 34.2 (CH ), 32.3 (CH), 30.0 (CH),
3
2
2
28.3 (CH ), 28.2 (CH ), 26.7 (CH ), 25.7 (CH ), 17.9 (C), 14.1 (CH ), –4.9
2 2 2 3 3
(CH ), –5.0 (CH ).
3
3
1
HRMS (ESI+): m/z calcd for C28H42O SiNa: 525.2648; found: 525.2623.
6
(
s, 9 H), 0.010 (s, 3 H), 0.001 (s, 3 H).
1
3
C NMR (100 MHz, CDCl ): δ = 212.8 (C), 165.6 (C), 153.8 (C), 152.8
1
3
(
4S,5aS)-4-[(tert-Butyldimethylsilyl)oxy]-2a -[3-(4-methoxyphen-
(C), 144.6 (C), 136.0 (C), 129.3 (CH), 128.4 (CH), 115.2 (CH), 114.6
oxy)propyl]-2-oxooctahydro-1H-cyclopropa[cd]indene-2a-car-
(
CH), 67.9 (CH ), 64.4 (CH), 55.7 (CH ), 53.1 (C), 49.2 (C), 46.6 (CH ),
2
3
2
boxylic Acid (27)
4
2
0.0 (CH), 33.6 (CH ), 29.7 (CH), 29.1 (CH ), 26.9 (CH ), 26.7 (CH ),
5.7 (CH ), 17.9 (C), –4.9 (CH ), –5.0 (CH ).
2
2
2
2
To a solution of 26 (13.1 g, 26.1 mmol) in EtOH (250 mL) was added 1
M aq NaOH (125 mL) at 0 °C. After stirring for 1 h at r.t., EtOAc and aq
NH Cl were added. The mixture was partitioned between EtOAc and
H O. The aqueous phase was extracted with EtOAc and the combined
3
3
3
HRMS (ESI+): m/z calcd for C33H44NO SSiNa : 672.2403; found:
6
7
2
4
72.2419.
2
organic phases were washed with brine, dried (Na SO ), and filtered.
The filtrate was concentrated in vacuo and the residue was purified
2
4
1
(
4S,5aS)-4-Hydroxy-2a -[3-(4-methoxyphenoxy)propyl]-2-oxo-N-
tosyloctahydro-1H-cyclopropa[cd]indene-2a-carboxamide (28a)
by flash column chromatography (SiO ; n-hexane–EtOAc, 7:1) to af-
2
ford 27 (11.2 g, 91%, >99.5% ee) as a pale yellow oil. The enantiomeric
To a solution of 53a (1050 mg, 1.67 mmol) in THF (30.0 mL) was add-
excess was determined by HPLC analysis with a chiral HPLC column
ed TBAF (30.0 mL, 30.0 mmol, 1.0 M in THF) at 0 °C. After stirring for 3
(DAICEL CHIRALCEL AD-H, 10% i-PrOH in n-hexane, 1.0 mL/min at
h at r.t., EtOAc and aq NH Cl were added. The resulting solution was
4
2
5 °C, λ = 210 nm). The retention times corresponding to 27 and its
extracted with EtOAc. The organic phase was washed with brine,
27
enantiomer are 17.1 and 14.0 min, respectively; [α]D –0.868 (c =
.00, CHCl3).
IR (film): 2951, 2930, 2856, 1751, 1685, 1508, 1231, 1089, 1040, 835,
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
2
4
1
and the residue was purified by flash column chromatography (SiO2;
n-hexane–EtOAc, 0:1) to give 28a (820 mg, 96%) as a pale yellow
27
–1
amorphous solid; [α]
D
–31.2 (c = 1.00, CHCl ).
3
7
76 cm .
1
IR (film): 3531, 3109, 2937, 1707, 1508, 1438, 1347, 1230, 1172,
H NMR (400 MHz, CDCl ): δ = 6.85–6.75 (m, 4 H), 4.07 (dddd, J = 6.1,
3
–1
1087, 866, 825 cm .
6
1
2
.1, 6.1, 3.6 Hz, 1 H), 3.96–3.82 (m, 2 H), 3.75 (s, 3 H), 2.78 (dd, J =
7.4, 11.5 Hz, 1 H), 2.76–2.68 (m, 1 H), 2.63 (dd, J = 7.6, 3.6 Hz, 1 H),
.57 (d, J = 17.4 Hz, 1 H), 2.37 (ddd, J = 16.0, 7.6, 7.6 Hz, 1 H), 2.18
1
H NMR (400 MHz, CDCl ): δ = 10.81 (s, 1 H), 7.92 (d, J = 8.2 Hz, 2 H),
3
7.28 (d, J = 7.8 Hz, 2 H), 6.82 (dd, J = 6.9, 2.7 Hz, 2 H), 6.75 (dd, J = 6.9,
2.7 Hz, 2 H), 4.07 (dddd, J = 7.7, 7.7, 7.7, 4.1 Hz, 1 H), 3.76 (s, 3 H), 3.72
(t, J = 6.4 Hz, 1 H), 2.78 (dd, J = 19.2, 11.9 Hz, 1 H), 2.72–2.64 (m, 1 H),
2.54 (dd, J = 8.7, 4.6 Hz, 1 H), 2.42–2.37 (m, 1 H), 2.36 (s, 3 H), 2.35
(
1
(
ddd, J = 14.2, 10.5, 5.0 Hz, 1 H), 2.06 (ddd, J = 14.2, 10.5, 5.5 Hz, 1 H),
.95–1.75 (m, 3 H), 1.67–1.55 (m, 2 H), 0.86 (s, 9 H), 0.04 (s, 3 H), 0.02
s, 3 H).
(dd, J = 19.2, 2.3 Hz, 1 H), 2.20–1.95 (m, 3 H), 1.89 (ddd, J = 14.4, 10.3,
5.5 Hz, 1 H), 1.80–1.70 (m, 1 H), 1.57–1.45 (m, 2 H), 1.40 (ddd, J =
15.6, 7.7, 4.6 Hz, 1 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

I
Synthesis
Y. Ochi et al.
Paper
13
13
C NMR (100 MHz, CDCl ): δ = 212.9 (C), 165.4 (C), 153.7 (C), 152.8
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.8 (C), 153.1 (C), 153.0
3
3
(
C), 144.7 (C), 135.8 (C), 129.3 (CH), 128.3 (CH), 115.2 (CH), 114.6
(C), 144.1 (C), 143.4 (C), 137.0 (C), 135.4 (C), 132.6 (CH), 130.0 (CH),
129.8 (CH), 128.2 (CH), 127.2 (CH), 127.0 (CH), 115.5 (CH), 115.4 (CH),
115.3 (CH), 114.7 (CH), 86.6 (CH), 85.2 (CH), 73.3 (CH), 72.3 (CH), 72.0
(CH), 67.8 (CH ), 64.1 (CH), 55.6 (CH ), 52.8 (C), 49.1 (C), 46.9 (CH ),
2
3
2
3
9.7 (CH), 33.0 (CH ), 29.8 (CH), 28.3 (CH ), 26.8 (CH ), 26.5 (CH ).
2 2 2 2
(
CH), 68.8 (CH ), 68.7 (CH ), 68.4 (CH ), 66.3 (CH), 64.3 (CH), 63.8
HRMS (ESI+): m/z calcd for C27H30NO SNa : 558.1538; found:
2 2 2
7
2
(CH), 60.0 (CH), 58.8 (CH), 58.3 (CH), 55.8 (CH ), 53.5 (CH), 51.9 (C),
558.1558.
3
5
1.2 (C), 45.6 (CH), 44.6 (CH), 41.3 (CH ), 40.0 (CH ), 39.1 (CH), 38.6
2
2
(
CH ), 36.8 (CH), 36.4 (CH ), 35.0 (CH ), 31.0 (CH ), 30.2 (CH ), 25.6
1
1
2 2 2 2 2
(
2aS,2a S,4aS,7aS)-2a -[3-(4-Methoxyphenoxy)propyl]-1-tosyltet-
(CH ), 25.2 (CH ), 25.1 (CH ), 21.6 (CH).
1
2
2
2
rahydro-1H-cyclopenta[cd]indole-2,3,6(2aH,2a H,4H)-trione (32a)
HRMS (ESI+): m/z calcd for C27H35NO SNa: 540.2032; found:
5
7
To a solution of 28a (660 mg, 1.29 mmol) and pyridine (1.00 mL) in
CH Cl (30.0 mL) was added Dess–Martin periodinane (572 mg, 1.35
40.2006.
2
2
mmol) at 0 °C and the solution was stirred for 1 h at r.t. After checking
the reaction by TLC, the reaction mixture was stirred at 40 °C for 30
1
1
1
(
3aR,3a S,4aS,4a S,6S,7aS,8aR)-4a -[3-(4-Methoxyphenoxy)pro-
pyl]-2,2-dimethyl-4-tosyldecahydro-3aH-1,3-dioxa-4-azacyclo-
penta[def]fluoren-6-ol (34a)
min. After cooling to 0 °C, EtOAc and aq NH Cl were added. The result-
4
ing solution was extracted with EtOAc. The organic phase was washed
with brine, dried (Na SO ), and filtered. The filtrate was concentrated
To a solution of 33a (100 mg, 0.193 mmol) in acetone (14.0 mL) was
added anhyd CuSO4 (230 mg, 1.44 mmol) and PPTS (64 mg, 0.255
mnol) at 0 °C, and the solution was stirred for 2.5 h at r.t. After cooling
2
4
in vacuo and the residue was purified by flash column chromatogra-
phy (SiO ; n-hexane–EtOAc, 1:1 → 1:3) to give 32a (520 mg, 80%) as a
2
27
pale yellow amorphous solid; [α]D +29.6 (c = 1.00, CHCl3).
to 0 °C, EtOAc and aq NaHCO were added. The resulting solution was
3
IR (film): 2931, 1765, 1719, 1508, 1361, 1231, 1170, 1086, 826 cm–1
extracted with EtOAc. The organic phase was washed with brine,
.
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
2
4
1
H NMR (400 MHz, CDCl ): δ = 7.86 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.2
3
and the residue was purified by flash column chromatography (SiO2;
Hz, 2 H), 6.90–6.72 (m, 4 H), 4.60 (dd, J = 6.4, 3.7 Hz, 1 H), 3.93 (t, J =
n-hexane–EtOAc, 3:1 → 1:2) to give 34a (54 mg, 50%) as a white
5.5 Hz, 2 H), 3.76 (s, 3 H), 3.30 (s, 1 H), 3.13 (dd, J = 18.3, 6.4 Hz, 1 H),
2.86 (dd, J = 18.3, 3.7 Hz, 1 H), 2.78 (dd, J = 19.0, 9.2 Hz, 1 H), 2.71–
2.60 (m, 1 H), 2.45–2.34 (m, 4 H), 2.12 (dd, J = 19.0, 3.2 Hz, 1 H), 2.05–
1.89 (m, 3 H), 1.88–1.75 (m, 2 H).
27
amorphous solid; [α]D –34.7 (c = 1.00, CHCl3).
IR (film): 3502, 2938, 1508, 1470, 1382, 1339, 1232, 1162, 1040, 947,
–1
8
27 cm
1H NMR (400 MHz, CDCl
Hz, 2 H), 6.86–6.76 (m, 4 H), 5.86 (d, J = 6.9 Hz, 2 H), 4.40 (dd, J = 6.0,
.
13
): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2
3
C NMR (100 MHz, CDCl ): δ = 205.9 (C), 205.5 (C), 165.8 (C), 154.0
3
(C), 152.5 (C), 145.8 (C), 134.8 (C), 129.7 (CH), 128.3 (CH), 115.3 (CH),
4.6 Hz, 1 H), 3.93 (dd, J = 10.5, 8.2 Hz, 1 H), 3.82 (t, J = 6.0 Hz, 2 H),
3.39–3.30 (m, 1 H), 2.27 (dd, J = 6.9, 6.0 Hz, 1 H), 2.18 (ddd, J = 13.3,
7.8, 4.6 Hz, 1 H), 2.10–2.02 (m, 1 H), 2.00–1.60 (m, 8 H), 1.50–1.42 (m,
5 H), 1.33 (s, 3 H).
1
14.7 (CH), 67.6 (CH ), 59.9 (CH), 59.6 (CH), 55.7 (CH ), 46.4 (C), 44.2
2
3
(
CH ), 41.6 (CH ), 41.1 (CH ), 36.4 (CH), 34.4 (CH ), 24.6 (CH ), 21.6
2
2
2
2
2
(CH3).
HRMS (ESI+): m/z calcd for C27H29NO SNa: 534.1562; found:
7
13
C NMR (100 MHz, CDCl ): δ = 153.8 (C), 153.0 (C), 143.2 (C), 138.7
534.1560.
3
(C), 129.2 (CH), 127.7 (CH), 115.4 (CH), 114.6 (CH), 97.5 (C), 82.2 (CH),
7
2.4 (CH), 68.5 (CH ), 67.1 (CH), 62.3 (CH), 55.8 (C), 55.7 (CH ), 51.9
1
1
2
3
(
2R,2aS,2a S,3R,4aS,6S,7aS)-2a -[3-(4-Methoxyphenoxy)propyl]-1-
(
(
CH), 42.1 (CH ), 41.5 (CH), 40.6 (CH ), 39.0 (CH ), 38.7 (CH ), 29.3
CH ), 25.6 (CH ), 21.5 (CH ), 20.7 (CH ).
2
2
2
2
tosyldecahydro-1H-cyclopenta[cd]indole-2,3,6-triol (33a)
3
2
3
3
To a solution of 32a (460 mg, 0.900 mmol) in THF (100 mL) was added
DIBAL-H (8.1 mL, 8.1mmol, 1 M in n-hexane) at –78 °C. After stirring
for 10 min at the same temperature, the mixture was stirred for 1 h at
HRMS (ESI+): m/z calcd for C30H39NO SNa: 580.2345; found:
7
580.2364.
–
10 °C. Then aq 1 M NaOH (2.00 mL) was added at –40 °C. The result-
1
(
4S,5aS)-4-[(tert-Butyldimethylsilyl)oxy]-2a -[3-(4-methoxyphen-
ing solution was extracted with EtOAc. The organic phase was washed
with brine, dried (Na SO ), and filtered through a pad of Celite. The
filtrate was concentrated in vacuo and the residue was purified by
oxy)propyl]-N-[(2-nitrophenyl)sulfonyl]-2-oxooctahydro-1H-cy-
clopropa[cd]indene-2a-carboxamide (53b)
2
4
flash column chromatography (SiO ; n-hexane–EtOAc, 1:3 → 0:1) to
To a solution of 27 (930 mg, 1.96 mmol) in THF (14.0 mL) was added
1,1′-carbonyldiimidazole (980 mg, 6.08 mmol) at r.t. and the solution
was stirred at r.t. for 2 h. In another flask o-nitrobenzenesulfonamide
(594 mg, 2.94 mmol) and DBU (410 μL, 2.74 mmol) were dissolved in
THF (28 mL). To this solution was added the above solution containing
the acyl imidazole reagent. After stirring for 3 h at the same tempera-
2
afford an 2:1 diastereomeric mixture of 33a (150 mg, 32%) as a white
27
amorphous solid; [α]D –7.42 (c = 1.00, CHCl3).
IR (film): 3473, 2935, 1508, 1468, 1325, 1231, 1156, 1038, 823 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.87 (d, J = 8.2 Hz, 1 H), 7.74 (dd, J = 8.2,
3
2
.3 Hz, 1 H), 7.32–7.26 (m, 2 H), 6.82–6.71 (m, 4 H), 5.96 (d, J = 4.6 Hz,
/3 1 H), 5.80 (d, J = 10.6 Hz, 1/3 1 H), 5.59 (dd, J = 7.3, 4.1 Hz, 1/3 1 H),
.45–5.30 (m, 2/3 1 H), 5.28 (dd, J = 6.9, 6.9 Hz, 1/3 1 H), 4.35–4.20 (m,
/3 3 H), 4.10–4.00 (m, 1/3 1 H), 3.86–3.76 (m, 2/3 2 H), 3.76–3.72 (m,
H), 3.63 (dd, J = 6.0, 6.0 Hz, 2/3 1 H), 3.52 (dd, J = 6.0, 6.0 Hz, 1/3 1 H),
.46–3.34 (m, 2/3 1 H + 2/3 1 H), 2.53 (d, J = 8.0 Hz 2/3 1 H), 2.41–2.37
ture, EtOAc and aq NH Cl were added. The resulting solution was ex-
4
2
5
2
3
3
tracted with EtOAc. The organic phase was washed with brine, dried
(
Na SO ), and filtered. The filtrate was concentrated in vacuo and the
2 4
residue was purified by flash column chromatography (SiO ; n-hex-
2
ane–EtOAc, 4:1) to give inseparable products containing 53b and o-
nitrobenzenesulfonamide as a yellow oil, which was used in the next
step without further purification. The spectroscopic data for 53b
(
m, 2/3 3 H + 1/3 3 H), 2.36–2.33 (br s, 1/3 2 H), 2.33–2.10 (m, 2/3 4
H), 2.10–1.40 (m, 2/3 6 H + 1/3 4 H), 1.25–1.07 (m, 1/4 2 H), 0.98–0.95
m, 1/3 1 H).
were collected after purification by PTLC (SiO ; n-hexane–EtOAc,
2
(
27
3
:1); [α]D +10.6 (c = 1.00, CHCl3).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

J
Synthesis
Y. Ochi et al.
Paper
IR (film): 3100, 2951, 2931, 1712, 1542, 1508, 1423, 1362, 1231,
IR (film): 2934, 1766, 1722, 1541, 1508, 1368, 1231, 1177, 1037, 827
182, 1036, 835, 779 cm–1
.
cm
–1
.
1
1
1
H NMR (400 MHz, CDCl ): δ = 11.32 (br s, 1 H), 8.34 (dd, J = 7.6, 1.6
H NMR (400 MHz, CDCl ): δ = 8.40–8.36 (m, 1 H), 7.85–7.75 (m, 3 H),
3
3
Hz, 1 H), 7.75 (dd, J = 7.6, 1.6 Hz, 1 H), 7.68 (ddd, J = 7.5, 1.6, 1.6 Hz, 1
H), 7.65 (ddd, J = 7.5, 1.6, 1.6 Hz, 1 H), 6.81 (dd, J = 6.9, 2.7 Hz, 2H),
6.86–6.76 (m, 4 H), 4.75 (dd, J = 4.6, 3.2 Hz, 1 H), 4.05–3.95 (m, 1 H),
3.77 (s, 3 H), 3.30 (s, 1 H), 3.26 (dd, J = 18.3, 4.6 Hz, 1 H), 2.84 (dd, J =
18.3, 3.2 Hz, 1 H), 2.83 (dd, J = 19.0, 9.2 Hz, 1 H), 2.76–2.66 (m, 1 H),
2.55 (dd, J = 18.3, 4.6 Hz, 1 H), 2.26 (dd, J = 19.0, 1.4 Hz, 1 H), 2.22 (dd,
J = 18.3, 12.8 Hz, 1 H), 2.20–1.96 (m, 3 H), 1.95–1.82 (m, 1 H).
13
6.73 (dd, J = 6.9, 2.7 Hz, 2 H), 4.02 (dddd, J = 6.5, 6.5, 6.5, 3.2 Hz, 1 H),
3.74 (s, 3 H), 3.72–3.67 (m, 2 H), 2.78 (dd, J = 18.8, 11.4 Hz, 2 H), 2.70–
2.62 (m, 1 H), 2.55–2.45 (m, 2 H), 2.32 (ddd, J = 15.8, 8.0, 6.5 Hz, 1 H),
2.03 (ddd, J = 12.6, 11.0, 4.6 Hz, 1 H), 1.95–1.72 (m, 3 H), 1.62–1.45
C NMR (100 MHz, CDCl ): δ = 205.0 (C), 165.8 (C), 154.1 (C), 152.6
3
(
m, 3 H), 0.84 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H).
(C), 147.9 (C), 135.8 (CH), 135.6 (CH), 132.3 (CH), 130.7 (C), 124.6
13
C NMR (100 MHz, CDCl ): δ = 212.0 (C), 166.1 (C), 153.8 (C), 152.8
(CH), 115.4 (CH), 114.7 (CH), 67.8 (CH ), 60.4 (CH), 58.6 (CH), 55.7
3
2
(C), 148.2 (C), 134.6 (C), 133.3 (CH), 132.1 (CH), 131.8 (C), 124.7 (CH),
(CH ), 46.9 (C), 44.2 (CH ), 41.9 (CH ), 41.4 (CH ), 37.0 (CH), 33.5
3
2
2
2
1
15.2 (CH), 114.6 (CH), 67.8 (CH ), 64.4 (CH), 55.7 (CH ), 53.5 (C), 49.2
(CH ), 24.5 (CH ).
2
3
2
2
(
2
C), 46.6 (CH ), 40.7 (CH), 33.7 (CH ), 29.8 (CH), 29.1 (CH ), 26.9 (CH ),
2
2
2
2
HRMS (ESI+): m/z calcd for C26H26N O SNa: 565.1257; found:
2 9
565.1237.
6.7 (CH ), 25.7 (CH ), 17.9 (C), –4.9 (CH ), –5.0 (CH ).
2 3 3 3
HRMS (ESI+): m/z calcd for C32H41N O SSiNa : 703.2097; found:
2
9
2
7
03.2119.
1
1
(
[
2R,2aS,2a S,3R,4aS,6S,7aS)-2a -[3-(4-Methoxyphenoxy)propyl]-1-
(2-nitrophenyl)sulfonyl]decahydro-1H-cyclopenta[cd]indole-
1
(
4S,5aS)-4-Hydroxy-2a -[3-(4-methoxyphenoxy)propyl]-N-[(2-ni-
trophenyl)sulfonyl]-2-oxooctahydro-1H-cyclopropa[cd]indene-
a-carboxamide (28b)
To a solution of crude 53b in THF (30.0 mL) was added TBAF (30.0 mL,
0.0 mmol, 1.0 M in THF) at 0 °C. After stirring for 3 h at r.t., EtOAc
2,3,6-triol (33b)
To a solution of 32b (500 mg, 0.922 mmol) in THF (26 mL) was added
DIBAL-H (8.3 mL, 8.3mmol, 1 M in n-hexane) at –78 °C. After stirring
for 10 min at the same temperature, the mixture was stirred for 1 h at
–10 °C. Then aq 1 M NaOH (2.00 mL) was added at –40 °C. The result-
ing solution was extracted with EtOAc. The organic phase was
washed with brine, dried (Na SO ), and filtered through a pad of
2
3
and aq NH Cl were added. The resulting solution was extracted with
EtOAc. The organic phase was washed with brine, dried (Na SO ), and
4
2
4
2
4
filtered. The filtrate was concentrated in vacuo and the residue was
Celite. The filtrate was concentrated in vacuo and the residue was pu-
purified by flash column chromatography (SiO ; n-hexane–EtOAc,
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 1:3 →
2
2
0
:1) to give 28b (950 mg, 89% for 2 steps) as a pale yellow amorphous
0:1) to afford a 1:1 diastereomeric mixture of 33b (360 mg, 71%) as a
white amorphous solid; [α]D +46.2 (c = 1.00, CHCl3).
27
27
solid; [α]D +4.12 (c = 1.00, CHCl3).
IR (film): 3546, 3100, 2937, 1711, 1541, 1508, 1426, 1362, 1230,
IR (film): 3395, 2935, 2360, 1717, 1541, 1508, 1468, 1371, 1230,
–1
–1
1182, 1056, 827 cm
.
1169, 1036, 826, 761 cm
.
1
1
H NMR (400 MHz, CDCl ): δ = 11.27 (br s, 1 H), 8.34 (dd, J = 7.6, 1.6
H NMR (400 MHz, CDCl ): δ = 8.20–8.02 (m, 1 H), 7.82–7.55 (m, 3 H),
3
3
Hz, 1 H), 7.75 (dd, J = 7.6, 1.6 Hz, 1 H), 7.68 (ddd, J = 7.5, 1.6, 1.6 Hz, 1
H), 7.65 (ddd, J = 7.5, 1.6, 1.6 Hz, 1 H), 6.81 (d, J = 8.7 Hz, 2 H), 6.73 (d,
J = 9.2 Hz, 2 H), 4.20–4.11 (m, 1 H), 3.75 (s, 3 H), 3.74–3.65 (m, 2 H),
6.85–6.70 (m, 4 H), 5.96 (d, J = 4.1 Hz, 1/2 1 H), 5.76 (d, J = 6.6 Hz, 1/2
1 H), 5.50–5.38 (m, 1/2 1 H), 4.35–4.11 (m, 1/2 3 H), 3.98–3.83 (m, 1/2
5 H), 3.83–3.76 (m, 1/2 2 H), 3.75 (s, 1/2 3 H), 3.74 (s, 1/2 3 H), 3.72–
3.65 (m, 1/2 2 H), 2.87–2.61 (m, 1/2 2 H), 2.54 (dd, J = 7.6, 7.6 Hz, 1/2 1
H), 2.46–2.28 (m, 1/2 4 H), 2.21 (ddd, J = 12.4, 6.4, 6.4 Hz, 1/2 1 H),
2.51–1.61 (m, 1/2 20 H), 1.58–1.47 (m, 1/2 2 H), 1.46–1.11 (m, 1/2 4
H), 0.97–0.85 (m, 1/2 1 H).
2.85 (dd, J = 19.5, 11.7 Hz, 1 H), 2.56 (dd, J = 8.3, 4.6 Hz, 1 H), 2.55–
2.53 (m, 1 H), 2.50–2.46 (m, 2 H), 2.25–1.95 (m, 3 H), 1.90 (ddd, J =
14.1, 10.5, 5.2 Hz, 1 H), 1.85–1.75 (m, 1 H), 1.66–1.45 (m, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 212.4 (C), 165.8 (C), 153.7 (C), 152.7
3
13
(C), 148.1 (C), 134.7 (CH), 132.2 (CH), 132.1 (CH), 131.7 (C), 124.8
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.8 (C), 153.0 (C), 152.9
3
(
(
2
CH), 115.2 (CH), 114.6 (CH), 67.8 (CH ), 64.1 (CH), 55.7 (CH ), 53.3
C), 49.3 (C), 47.1 (CH ), 40.3 (CH), 33.0 (CH ), 29.9 (CH), 28.4 (CH ),
2 2 2
(C), 148.1 (C), 135.2 (CH), 134.2 (C), 134.0 (CH), 133.9 (CH), 133.3 (C),
132.3 (C), 132.1 (CH), 132.0 (CH), 131.1 (CH), 130.7 (CH), 129.5 (CH),
124.6 (CH), 124.5 (CH), 124.2 (CH), 115.5 (CH), 115.4 (CH), 114.7 (CH),
2
3
6.8 (CH ), 26.6 (CH ).
2
2
8
6.7 (CH), 86.1 (CH), 77.2 (CH), 73.1 (CH), 71.9 (CH), 68.7 (CH ), 68.4
HRMS (ESI+): m/z calcd for C26H27N O SiNa : 589.1233; found:
2
2
9
2
(CH ), 67.8(CH ), 66.2 (CH), 65.0 (CH), 64.5 (CH), 63.1 (CH), 62.2 (CH),
589.1219.
2 2
6
1.2 (CH), 58.5 (CH), 58.2 (CH), 55.7 (CH ), 52.2 (C), 51.8 (C), 45.4
3
(
(
(
(
CH ), 42.6 (CH ), 41.7 (CH ), 40.6 (CH ), 39.3 (CH ), 38.9 (CH ), 38.1
1
1
2 2 2 2 2 2
(
2aS,2a S,4aS,7aS)-2a -[3-(4-Methoxyphenoxy)propyl]-1-[(2-nitro-
CH ), 37.1 (CH), 37.0 (CH), 35.7 (CH ), 35.4 (CH ), 34.2 (CH ), 31.5
2
2
2
2
phenyl)sulfonyl]tetrahydro-1H-cyclopenta[cd]indole-
,3,6(2aH,2a H,4H)-trione (32b)
CH ), 30.9 (CH ), 30.6 (CH ), 29.0 (CH ), 25.5 (CH ), 25.1 (CH ), 23.9
1
2
2
2
2
2
2
2
CH ), 22.9 (CH ), 14.0 (CH), 11.1 (CH).
2
2
To a solution of 28b (810 mg, 1.49 mmol) and pyridine (1.10 mL) in
CH Cl (30.0 mL) was added Dess–Martin periodinane reagent (662
mg, 1.56 mmol) at 0 °C and the solution was stirred for 1 h at r.t. After
checking the reaction by TLC, the reaction mixture was stirred at
0 °C for 30 min. After cooling to 0 °C, EtOAc and aq NH Cl were add-
HRMS (ESI+): m/z calcd for C26H32N O SNa: 571.1726; found:
5
2
9
2
2
71.1710.
1
1
1
(
3aR,3a S,4aS,4a S,6S,7aS,8aR)-4a -[3-(4-Methoxyphenoxy)pro-
4
4
pyl]-2,2-dimethyl-4-[(2-nitrophenyl)sulfonyl]decahydro-3aH-1,3-
dioxa-4-azacyclopenta[def]fluoren-6-ol (34b)
ed. The resulting solution was extracted with EtOAc. The organic
phase was washed with brine, dried (Na SO ), and filtered. The fil-
2
4
trate was concentrated in vacuo and the residue was purified by flash
To a solution of 33b (220 mg, 0.401 mmol) in acetone (33.0 mL) was
added anhyd CuSO4 (530 mg, 3.32 mmol) and PPTS (150 mg, 0.598
mmol) at 40 °C and the solution was stirred for 12 h at the same tem-
column chromatography (SiO ; n-hexane–EtOAc, 1:1 → 1:3) to give
2
3
2b (580 mg, 72%) as a pale yellow amorphous solid; [α]D27 +263 (c =
1.00, CHCl3).
perature. After cooling to 0 °C, EtOAc and aq NaHCO was added. The
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

K
Synthesis
Y. Ochi et al.
Paper
1
resulting solution was extracted with EtOAc. The organic phase was
washed with brine, dried (Na SO ), and filtered. The filtrate was con-
(4S,5aS)-4-Hydroxy-2a -[3-(4-methoxyphenoxy)propyl]-2-oxo-N-
{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-cyclopro-
pa[cd]indene-2a-carboxamide (28c)
2
4
centrated in vacuo and the residue was purified by flash column chro-
matography (SiO ; n-hexane–EtOAc, 1:1 → 1:2) to give 34b (160 mg,
2
To a solution of a mixture containing 53c and 4-(trifluoromethyl)ben-
zenesulfonamide in THF (250 mL) was added TBAF (190 mL, 190
mmol, 1.0 M in THF) at 0 °C. After stirring for 1 h at r.t., EtOAc and aq
27
6
8%) as a white amorphous solid; [α]D
–32.2 (c = 1.00, CHCl3).
IR (film): 3420, 2938, 1717, 1542, 1508, 1470, 1372, 1232, 1164,
–1
1078, 1039, 947, 827, 781 cm
.
NH
4
Cl were added. The resulting solution was extracted with EtOAc.
SO ), and fil-
1
The organic phase was washed with brine, dried (Na
2
4
H NMR (400 MHz, CDCl ): δ = 8.26–8.22 (m, 1 H), 7.80–7.75 (m, 3 H),
3
tered. The filtrate was concentrated in vacuo and the residue was pu-
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 0:1)
to give 28c (9.25 g, 86% for 2 steps) as a pale yellow amorphous solid;
α]D –32.1 (c = 1.00, CHCl3).
6.81 (d, J = 9.2 Hz, 2 H), 6.73 (d, J = 9.2 Hz, 2 H), 5.85 (d, J = 6.9 Hz, 1 H),
2
4.44 (dd, J = 5.5, 4.5 Hz, 1 H), 3.92 (dd, J = 10.3, 8.5 Hz, 1 H), 3.76 (s, 3
H), 3.69 (t, J = 6.2 Hz, 2 H), 3.50–3.30 (m, 1 H), 2.36 (dd, J = 6.9, 5.5 Hz,
27
[
1
1
H), 2.29–2.15 (m, 2 H), 2.15–2.07 (m, 1 H), 2.07–1.85 (m, 4 H), 1.75–
.50 (m, 3 H), 1.46 (s, 3 H), 1.39 (s, 6 H), 1.40–1.30 (m, 2 H).
IR (film): 3538, 2938, 1709, 1508, 1433, 1356, 1322, 1230, 1133,
–1
13
1062, 826 cm
.
C NMR (100 MHz, CDCl ): δ = 153.8 (C), 152.9 (C), 148.1 (C), 133.6
3
1H NMR (400 MHz, CDCl
): δ = 10.98 (s, 1 H), 8.18 (d, J = 8.2 Hz, 2 H),
(C), 133.5 (CH), 131.5 (CH), 131.0 (CH), 123.9 (CH), 115.4 (CH), 114.6
3
(
5
CH), 97.8 (C), 82.6 (CH), 72.3 (CH), 68.4 (CH ), 67.0 (CH), 62.7 (CH),
7.76 (d, J = 8.2 Hz, 2 H), 6.84–6.80 (m, 2 H), 6.78–6.70 (m, 2 H), 4.15–
4.05 (m, 1 H), 3.80–3.70 (m, 4 H), 2.81 (dd, J = 19.3, 11.7 Hz, 1 H),
2.74–2.62 (m, 1 H), 2.54 (dd, J = 8.3, 4.6 Hz, 1 H), 2.44–2.34 (m, 2 H),
2
6.2 (C), 55.7 (CH ), 52.0 (CH), 42.2 (CH ), 41.2 (CH), 40.3 (CH ), 39.4
3
2
2
(CH ), 38.7 (CH ), 29.4 (CH ), 25.5 (CH ), 20.5 (CH ).
2 2 3 2 3
2
2
.10 (ddd, J = 14.2, 9.6, 4.6 Hz, 1 H), 2.04–1.90 (m, 2 H), 1.88–1.69 (m,
H), 1.65–1.50 (m, 2 H), 1.44 (ddd, J = 15.6, 7.8, 4.6 Hz, 1 H).
HRMS (ESI+): m/z calcd for C29H36N O SNa: 611.2039; found:
2
9
611.2047
13
C NMR (100 MHz, CDCl ): δ = 212.9 (C), 165.7 (C), 153.8 (C), 152.7
3
1
(C), 142.3 (C), 135.0 (C, q, J = 32.4 Hz), 125.9 (CH, q, J = 3.8 Hz), 123.0
(
4S,5aS)-4-[(tert-Butyldimethylsilyl)oxy]-2a -[3-(4-methoxyphen-
(
CF , q, J = 271.7 Hz), 115.2 (CH), 114.7 (CH), 67.8 (CH ), 64.1 (CH),
oxy)propyl]-2-oxo-N-{[4-(trifluoromethyl)phenyl]sulfonyl}octa-
hydro-1H-cyclopropa[cd]indene-2a-carboxamide (53c)
3
2
5
5.7 (CH ), 53.1 (C), 49.3 (C), 47.0 (CH ), 40.3 (CH), 33.0 (CH ), 29.8
3
2
2
(
CH), 28.5 (CH ), 26.8 (CH ).
2
2
To a solution of 27 (9.00 g, 19.0 mmol) in THF (130 mL) was added
,1′-carbonyldiimidazole (6.15 g, 38.0 mmol) at r.t. and the solution
was stirred at r.t. for 2 h. In another flask 4-(trifluoromethyl)benzene-
sulfonamide (6.40 g, 28.5 mmol) and DBU (4.00 mL, 26.6 mmol) were
dissolved in THF (260 mL). To this solution was added the above solu-
tion containing the acyl imidazole reagent. After stirring for 4 h at the
HRMS (ESI+): m/z calcd for C27H27F NO SNa : 612.1258; found:
1
3
7
2
612.1231.
1
1
(2aS,2a S,4aS,7aS)-2a -[3-(4-Methoxyphenoxy)propyl)-1-{[4-(tri-
fluoromethyl)phenyl]sulfonyl}tetrahydro-1H-cyclopenta[cd]in-
1
same temperature, EtOAc and aq NH Cl were added. The resulting
dole-2,3,6(2aH,2a H,4H)-trione (32c)
4
solution was extracted with EtOAc. The organic phase was washed
To a solution of 28c (2.20 g, 3.88 mmol) and pyridine (3.80 mL) in
with brine, dried (Na SO ), and filtered. The filtrate was concentrated
2
4
CH Cl (130 mL) was added Dess–Martin periodinane (1.73 g, 4.07
2
2
in vacuo and the residue was purified roughly by flash column chro-
matography (SiO ; n-hexane–EtOAc, 4:1) to give a mixture of 53c and
mmol) at 0 °-C and the solution was stirred for 1 h at r.t. After check-
ing the reaction by TLC, the reaction mixture was stirred at 40 °C for
2
4
-(trifluoromethyl)benzenesulfonamide as a yellow oil, which was
used in the next step without further purification. The spectroscopic
data for 53c were collected after purification by PTLC (SiO ; n-hex-
3
0 min. After cooling to 0 °C, EtOAc and aq NH Cl were added. The re-
4
sulting solution was extracted with EtOAc. The organic phase was
washed with brine, dried (Na SO ), and filtered. The filtrate was con-
2
2
4
27
ane–EtOAc, 3:1); [α]D
–13.1 (c = 1.00, CHCl3).
centrated in vacuo and the residue was purified by flash column chro-
IR (film): 3105, 2952, 2931, 2857, 1710, 1508, 1322, 1231, 1175,
matography (SiO
pale orange amorphous solid, [α]
2
; n-hexane–EtOAc, 1:1) to give 32c (1.75 g, 80%) as a
–1
27
1062, 835, 777 cm
.
D
+32.9 (c = 1.00, CHCl ).
3
1
H NMR (400 MHz, CDCl ): δ = 11.02 (s, 1 H), 8.19 (d, J = 8.3 Hz, 1 H),
.76 (d, J = 8.3 Hz, 1 H), 6.82 (dd, J = 6.8, 2.8 Hz, 2 H), 6.74 (dd, J = 6.8,
IR (film): 2934, 1768, 1720, 1508, 1405, 1370, 1322, 1231, 1174,
1133, 1062, 827 cm .
3
–1
7
2
.8 Hz, 2 H), 4.02 (dddd, J = 6.5, 6.5, 6.5, 3.2 Hz, 1 H), 3.80–3.70 (m, 5
1
H NMR (400 MHz, CDCl ): δ = 8.13 (d, J = 8.2 Hz, 2 H), 7.77 (d, J = 8.2
3
H), 2.73 (dd, J = 18.1, 10.9 Hz, 1 H), 2.68–2.63 (m, 1 H), 2.55–2.45 (m, 2
H), 2.32 (ddd, J = 15.8, 8.0, 8.0 Hz, 1 H), 2.10 (ddd, J = 14.2, 10.1, 4.6 Hz,
1
Hz, 2 H), 6.87–6.75 (m, 4 H), 4.65 (dd, J = 6.0, 3.6 Hz, 1 H), 3.95 (t, J =
5
2
2
.5 Hz, 2 H), 3.77 (s, 3 H), 3.35 (s, 1 H), 3.16 (dd, J = 18.3, 6.0 Hz, 1 H),
.88 (dd, J = 18.3, 3.6 Hz, 1 H), 2.80 (dd, J = 19.0, 9.2 Hz, 1 H), 2.64–
.54 (m, 1 H), 2.42 (dd, J = 18.3, 4.8 Hz, 1 H), 2.15 (dd, J = 19.0, 3.0 Hz,
H), 2.00–1.81 (m, 2 H), 1.80–1.70 (m, 1 H), 1.62–1.45 (m, 3 H), 0.85
(
s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 212.9 (C), 165.9 (C), 153.8 (C), 152.8
1 H), 2.10–1.95 (m, 2 H), 1.89 (dd, J = 18.3, 11.0 Hz, 1 H), 1.95–1.55 (m,
3
(C), 142.7 (C), 135.5 (C, q, J = 32.4 Hz), 129.0 (CH), 125.9 (CH, q, J = 3.8
2 H).
Hz), 122.8 (CF , q, J = 271.7 Hz), 115.2 (CH), 114.7 (CH), 67.8 (CH ),
13
3
2
C NMR (100 MHz, CDCl ): δ = 205.6 (C), 205.0 (C), 166.1 (C), 154.1
3
6
4.3 (CH), 55.7 (CH ), 53.5 (C), 49.3 (C), 46.6 (CH ), 40.7 (CH), 33.6
3
2
(C), 152.5 (C), 141.1 (C), 136.0 (C, q, J = 32.4 Hz), 129.1 (CH), 126.3
(CH, q, J = 3.8 Hz), 122.9 (CF , q, J = 271.7 Hz), 115.4 (CH), 114.7 (CH),
67.6 (CH ), 60.1 (CH), 59.4 (CH), 55.7 (CH ), 46.6 (C), 44.1 (CH ), 41.6
(
CH ), 29.7 (CH), 29.2 (CH ), 26.9 (CH ), 26.8 (CH ), 25.7 (CH ), 17.9
2 2 2 2 3
3
(
C), –4.9 (CH ), –5.0 (CH ).
3
3
2
3
2
HRMS (ESI+): m/z calcd for C33H41F NO SSiNa : 726.2121; found:
(CH
2
), 41.0 (CH
2
), 36.4 (CH), 34.4 (CH
2
), 24.6 (CH ).
2
3
7
2
726.2147.
HRMS (ESI+): m/z calcd for C27H26F NO SNa: 588.1280; found:
3
7
588.1253.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

L
Synthesis
Y. Ochi et al.
Paper
1
1
13
(
2R,2aS,2a S,3R,4aS,6S,7aS)-2a -[3-(4-Methoxyphenoxy)propyl]-1-
C NMR (100 MHz, CDCl ): δ = 153.8 (C), 153.0 (C), 145.5 (C), 134.1
3
{[4-(trifluoromethyl)phenyl]sulfonyl}decahydro-1H-cyclopen-
(C, q, J = 32.4 Hz), 128.3 (CH), 125.6 (CH, q, J = 3.8 Hz), 123.3 (CF , q, J =
3
ta[cd]indole-2,3,6-triol (33c)
271.7 Hz), 115.4 (CH), 114.6 (CH), 97.6 (C), 82.3 (CH), 72.4 (CH), 68.4
(
4
2
CH ), 66.9 (CH), 62.8 (CH), 55.7 (C), 55.7 (CH ), 51.7 (CH), 42.0 (CH ),
1.7 (CH), 40.8 (CH ), 38.8 (CH ), 38.7 (CH ), 29.2 (CH ), 25.6 (CH ),
2 2 2 3 2
To a solution of 32c (2.20 g, 4.01 mmol) in THF (100 mL) was added
DIBAL-H (37 mL, 37 mmol, 1 M in n-hexane) at –78 °C. After stirring
for 10 min at the same temperature, the mixture was stirred for 1 h at
2
3
2
0.6 (CH3).
–10 °C. Then aq 1 M NaOH (2.00 mL) was added at –40 °C. The result-
HRMS (ESI+): m/z calcd for C30H36F NO SNa: 634.2062; found:
3 7
ing solution was extracted with EtOAc. The organic phase was
washed with brine, dried (Na SO ), and filtered through a pad of
634.2059.
2
4
Celite. The filtrate was concentrated in vacuo and the residue was pu-
1
1
1
(
3aR,3a S,4aS,4a S,6S,7aR,8aR)-4a -[3-(4-Methoxyphenoxy)pro-
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 1:3 →
2
pyl]-2,2-dimethyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}deca-
hydro-3aH-1,3-dioxa-4-azacyclopenta[def]fluoren-6-yl
methanesulfonate (54c)
0
:1) to afford a 3:1 diastereomeric mixture of 33c (2.20 g, 88%) as a
27
white amorphous solid; [α]D +20.5 (c = 1.00, CHCl3).
IR (film): 3389, 2945, 1508, 1469, 1403, 1355, 1323, 1231, 1164,
To a solution of 34c (1.54 g, 2.52 mmol) and Et N (528 μL, 3.78 mmol)
3
–1
1132, 1062, 826 cm .
in CH Cl (70 mL) was added methanesulfonyl chloride (216 μL, 2.77
2
2
1
H NMR (400 MHz, CDCl ): δ = 8.13 (d, J = 8.3 Hz, 3/4 2 H), 8.03 (d, J =
mmol) at 0 °C. After stirring for 30 min at the same temperature, aq
NaHCO was added. The resulting solution was extracted with CH Cl
The organic phase was washed with brine, dried (Na SO ), and fil-
tered. The filtrate was concentrated in vacuo and the residue was pu-
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 1:1)
to afford 54c (1.62 g, 93%) as a white amorphous solid; [α]
(c = 1.00, CHCl ).
3
8.3 Hz, 1/4 2 H), 7.83–7.73 (m, 2 H), 6.87–6.71 (m, 4 H), 6.10–5.96 (m,
3
2
.
2
3/4 1 H), 5.85 (d, J = 5.5 Hz, 1/4 1 H), 5.76–5.65 (m, 1/4 1 H), 4.90–4.76
2
4
(m, 3/4 1 H), 4.32–4.15 (m, 1 H), 4.15–4.03 (m, 3/4 1 H), 4.02–3.89 (m,
1
3
/4 1 H + 1/4 1 H), 3.89–3.80 (m, 3/4 2 H), 3.77 (s, 1/4 3 H), 3.74 (s, 3/4
H), 3.72–3.61 (m, 1/4 2 H + 1/4 1 H), 3.51 (br s, 3/4 1 H), 3.48–3.42
2
27
–37.2
D
(m, 3/4 1 H), 3.33–3.21 (br s, 1/4 1 H), 2.61 (d, J = 17.0 Hz, 3/4 10.69
3
H), 2.42 (d, J = 8.2 Hz, 3/4 1 H), 2.40–2.28 (m, 3/4 3 H), 2.27–2.18 (m,
IR (film): 3449, 2940, 1508, 1350, 1232, 1172, 1062, 943, 827 cm–1
.
1/4 2 H), 2.14 (s, 1 H), 2.11–1.73 (m, 3/4 6 H + 1/4 4 H), 1.73–1.54 (m,
3/4 2 H + 1/4 1 H), 1.54–1.38 (m, 1/4 2 H), 1.38–1.20 (m, 1/4 2 H),
1.15–0.99 (m, 1/4 1 H).
1
H NMR (400 MHz, CDCl ): δ = 8.12 (d, J = 8.2 Hz, 2 H), 7.74 (d, J = 8.2
3
Hz, 2 H), 6.86–6.75 (m, 4 H), 5.89 (d, J = 6.9 Hz, 1 H), 4.44 (dd, J = 6.0,
4,6 Hz, 1 H), 4.38–4.27 (m, 1 H), 4.06 (dd, J = 10.1, 8.2 Hz, 1 H), 3.86 (t,
13
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.8 (C), 152.8 (C), 152.7
3
J = 5.9 Hz, 2 H), 3.77 (s, 3 H), 2.91 (s, 3 H), 2.35 (dd, J = 6.9, 6.0 Hz, 1 H),
(C), 142.8 (C), 141.9 (C), 134.4 (C, q, J = 32.4 Hz), 134.5 (C, q, J = 32.4
2.25–2.06 (m, 5 H), 1.95 (d, J = 14.2 Hz, 1 H), 1.97–1.87 (m, 1 H), 1.85–
Hz), 129.0 (CH), 127.7 (CH), 126.3 (CH, q, J = 3.8 Hz), 126.1 (CH, q, J =
.8 Hz), 123.2 (CF , q, J = 271.7 Hz), 123.1 (CF , q, J = 271.7 Hz), 115.4
1
.64 (m, 2 H), 1.58–1.52 (m, 2 H), 1.45 (s, 3 H), 1.32 (s, 3 H).
3
3
3
13
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 152.9 (C), 145.2 (C), 134.1
3
(CH), 115.3 (CH), 114.6 (CH), 114.6 (CH), 86.6 (CH), 85.3 (CH), 73.2
(
C, q, J = 32.4 Hz), 128.3 (CH), 125.6 (CH, q, J = 3.8 Hz), 123.3 (CF , q, J =
3
(
CH), 71.9 (CH), 68.6 (CH ), 68.2 (CH ), 66.0 (CH), 64.3 (CH), 63.0 (CH),
2
2
2
71.7 Hz), 115.4 (CH), 114.6 (CH), 97.7 (C), 82.3 (CH), 72.4 (CH), 68.4
6
0.1 (CH), 58.9 (CH), 58.4 (CH), 55.7 (2 × CH ), 51.9 (C), 51.4 (C), 44.8
3
(
CH ), 66.9 (CH), 62.8 (CH), 55.7 (C), 55.7 (CH ), 51.7 (CH), 42.0 (CH ),
2
3
2
(
CH ), 41.2 (CH ), 41.0 (CH ), 37.8 (CH ), 37.2 (CH), 36.4 (CH), 34.8
2 2 2 2
41.7 (CH), 40.8 (CH ), 38.8 (CH ), 38.7 (CH ), 29.2 (CH ), 25.5 (CH ),
2 2 2 3 2
(
CH ), 34.5 (CH ), 30.4 (CH ), 30.0 (CH ), 25.5 (CH ), 25.1 (CH ).
2
2
2
2
2
2
2
0.5 (CH3).
HRMS (ESI+): m/z calcd for C27H32F NO SNa: 594.1745; found:
3
7
HRMS (ESI+): m/z calcd for C31H38F NO S Na: 712.1838; found:
3
9 2
594.1746.
712.1848.
1
1
1
(
3aR,3a S,4aS,4a S,6S,7aS,8aR)-4a -[3-(4-Methoxyphenoxy)pro-
1
1
1
(
3aR,3a S,4aS,4a S,6R,7aS,8aR)-4a -[3-(4-Methoxyphenoxy)pro-
pyl]-2,2-dimethyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}deca-
hydro-3aH-1,3-dioxa-4-azacyclopenta[def]fluoren-6-ol (34c)
pyl]-2,2-dimethyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}deca-
hydro-3aH-1,3-dioxa-4-azacyclopenta[def]fluorene-6-carbonitrile
To a solution of 33c (1.93 g, 3.38 mmol) in acetone (140 mL) was add-
ed anhyd CuSO (1.8 g, 11.3 mmol) and PPTS (850 mg, 3.38 mmol) at
r.t. and the solution was stirred for 16 h at the same temperature. The
solution was evaporated and the residue was partitioned between
EtOAc and aq NaHCO . The aqueous phase was extracted with EtOAc
(
35c)
To a solution of 54c (1.83 g, 2.52 mmol) in DMSO (30 mL) was added
8-crown-6 (4.36 g, 16.5 mmol) and KCN (4.36 g, 66.7 mmol) at r.t.
and the solution was stirred for 5 h at 80 °C. After cooling to r.t., EtOAc
and aq NaHCO3 were added. The resulting solution was extracted
with EtOAc. The organic phase was washed with brine, dried (Na2-
SO ), and filtered. The filtrate was concentrated in vacuo and the re-
sidual oil was purified by flash column chromatography (SiO ; n-hex-
ane–EtOAc, 3:1 → 2:1) to afford 35c (1.69 g, 97%) as a white amor-
phous solid; [α]D –79.4 (c = 1.00, CHCl3).
4
1
3
and the combined organic phases were washed with brine, dried
(
Na SO ), and filtered. The filtrate was concentrated in vacuo and the
2 4
4
residue was purified by flash column chromatography (SiO ; n-hex-
ane–EtOAc, 1:1) to give 34c (1.65 g, 80%) as a white amorphous solid;
2
2
27
[
α]D
–43.4 (c = 1.00, CHCl3).
27
IR (film): 3504, 2939, 1508, 1470, 1403, 1355, 1323, 1232, 1166,
107, 1062, 948, 826 cm .
IR (film): 3483, 2990, 2939, 1508, 1468, 1403, 1383, 1350, 1323,
232, 1172, 1132, 1062, 943, 828 cm .
–1
1
1
–1
1
1
H NMR (400 MHz, CDCl ): δ = 8.13 (d, J = 8.5 Hz, 2 H), 7.72 (d, J = 8.5
Hz, 2 H), 6.85–6.77 (m, 4 H), 5.89 (d, J = 6.4 Hz, 1 H), 4.42 (dd, J = 6.4,
,4 Hz, 1 H), 4.03 (dd, J = 10.5, 8.2 Hz, 1 H), 3.87 (t, J = 6.0 Hz, 2 H), 3.77
s, 3 H), 3.42–3.30 (m, 1 H), 2.33 (dd, J = 6.4, 6.4 Hz, 1 H), 2.20 (ddd, J =
4.0, 7.8, 4.4 Hz, 1 H), 2.13–2.07 (m, 1 H), 1.94 (d, J = 14.0 Hz, 1 H),
.91–1.50 (m, 9 H), 1.45 (s, 3 H), 1.31 (s, 3 H).
3
H NMR (400 MHz, CDCl ): δ = 8.13 (d, J = 8.3 Hz, 2 H), 7.73 (d, J = 8.3
Hz, 2 H), 6.85–6.76 (m, 4 H), 5.89 (d, J = 6.4 Hz, 1 H), 4.45 (dd, J = 6.4,
.0 Hz, 1 H), 4.10 (dd, J = 10.1, 8.2 Hz, 1 H), 3.90–3.83 (m, 2 H), 3.77 (s,
H), 2.82–2.75 (m, 1 H), 2.43 (dd, J = 6.4, 6.4 Hz, 1 H), 2.31–2.20 (m, 2
H), 2.09 (ddd, J = 13.3, 11.5, 3.2 Hz, 1 H), 2.00–1.65 (m, 8 H), 1.46 (s, 3
3
4
(
1
1
5
3
H), 1.29 (s, 3 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

M
Synthesis
Y. Ochi et al.
Paper
13
C NMR (100 MHz, CDCl ): δ = 153.8 (C), 153.0 (C), 145.3 (C), 134.3
2.66 (m, 1 H), 2.30–2.20 (m, 1 H), 2.22 (d, J = 8.2 Hz, 1 H), 2.05–1.92
3
(
C, q, J = 32.4 Hz), 128.3 (CH), 125.8 (CH, q, J = 3.8 Hz), 123.2 (CF , q, J =
(m, 2 H), 1.90–1.85 (m, 1 H), 1.85–1.46 (m, 8 H), 0.92 (s, 9 H), 0.07 (s,
3
271.7 Hz), 120.8 (C), 115.5 (CH), 114.6 (CH), 97.8 (C), 82.5 (CH), 72.6
3 H), 0.05 (s, 3 H).
(
4
2
CH), 68.4 (CH ), 60.0 (CH), 55.7 (CH ), 55.6 (C), 55.4 (CH), 41.8 (CH ),
13
2
3
2
C NMR (100 MHz, CDCl ): δ = 154.0 (C), 152.7 (C), 145.4 (C), 134.6
3
1.3 (CH ), 40.2 (CH), 31.5 (CH ), 30.9 (CH ), 29.3 (CH ), 24.8 (CH ),
2
2
2
3
2
(C, q, J = 32.4 Hz), 134.0 (CH), 127.6 (CH), 126.5 (CH, q, J = 2.9 Hz),
124.4 (CH), 123.0 (CF , q, J = 271.7 Hz), 121.6 (C), 118.4 (CH ), 115.3
4.0 (CH), 20.5 (CH3).
3
2
HRMS (ESI+): m/z calcd for C31H35F N O SNa: 643.2066; found:
(CH), 114.7 (CH), 72.3 (CH), 68.1 (CH ), 61.7 (CH), 55.7 (CH ), 52.5
3
2
6
2
3
643.2058.
(CH), 50.9 (C), 39.0 (CH ), 38.2 (CH ), 36.3 (CH), 34.2 (CH ), 28.7 (CH ),
2 2 2 2
2
8.1 (CH ), 25.8 (CH ), 25.7 (CH ), 19.0 (CH), 18.0 (C), –4.6 (CH ), –5.0
2
2
3
3
1
1
(CH3).
(
2S,2aR,2a S,3R,4aS,6R,7aS)-2-Allyl-3-hydroxy-2a -[3-(4-methoxy-
phenoxy)propyl]-1-{[4-(trifluoromethyl)phenyl]sulfonyl}decahy-
HRMS (ESI+): m/z calcd for C37H49F N O SSiNa: 741.2981; found:
3 2 5
dro-1H-cyclopenta[cd]indole-6-carbonitrile (36)
741.3003.
To a solution of 35c (1.21 g, 4.01 mmol) in CH Cl (60 mL) was added
2
2
1
allyltrimethylsilane (6.30 mL, 39.6 mmol) and BF ·OEt (2.90 mL, 22.9
(2S,2aR,2a S,3R,4aS,6R,7aS)-2-Allyl-3-[(tert-butyldimethylsi-
3
2
1
mmol) at –78 °C. After stirring for 10 min at –78 °C, the mixture was
stirred for 30 min at 0 °C. The reaction was quenched with aq NaH-
CO . The resulting solution was extracted with CH Cl . The organic
lyl)oxy]-2a -[3-(4-methoxyphenoxy)propyl]decahydro-1H-cyclo-
penta[cd]indole-6-carbonitrile (37)
3
2
2
To a solution of 55 (1.84 g, 2.56 mmol) in MeOH (200 mL) was added
Mg (6.00 g, 247 mmol) at r.t. and the solution was heated at 40 °C for
h. After cooling to r.t., EtOAc was added and then the solution was
concentrated. The residue was partitioned between EtOAc and H O.
The organic phase was washed with brine, dried (Na SO ), and fil-
tered. The filtrate was concentrated in vacuo and the residue was pu-
phase was washed with brine, dried (Na SO ), and filtered. The fil-
2
4
trate was concentrated in vacuo and the residual oil was purified by
3
flash column chromatography (SiO ; n-hexane–EtOAc, 1:1) to afford
2
2
27
3
6 (1.13 g, 96%) as a white amorphous solid; [α]D –0.812 (c = 1.00,
2
4
CHCl3).
IR (film): 3504, 2947, 2388, 2241, 1508, 1366, 1402, 1323, 1231,
rified by flash column chromatography (SiO ; n-hexane–EtOAc, 2:1)
to afford 37 (1.26 g, 96%) as a pale yellow oil; [α]D +5.47 (c = 1.00,
2
–1
27
1161, 1134, 1062, 923, 827 cm
.
1
CHCl
3
).
H NMR (400 MHz, CDCl ): δ = 8.04 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2
3
Hz, 2 H), 6.90–6.76 (m, 4 H), 5.63 (dddd, J = 16.9, 11.5, 3.2, 1.8 Hz, 1
H), 5.10 (dd, J = 11.5, 0.9 Hz, 1 H), 5.06 (dd, J = 16.9, 0.9 Hz, 1 H), 4.68
IR (film): 3464, 2929, 2856, 2237, 1639, 1508, 1470, 1413, 1359,
–1
1231, 1143, 1044, 914, 835, 776 cm
.
(
(
(
1
1
dd, J = 10.1, 3.2 Hz, 1 H), 4.24–4.10 (m, 1 H), 3.96–3.85 (m, 2 H), 3.77
s, 3 H), 3.65–3.60 (m, 1 H), 2.78 (dd, J = 15.3, 2.1 Hz, 1 H), 2.70–2.63
m, 1 H), 2.52–2.10 (m, 2 H), 2.28 (d, J = 7.8 Hz, 1 H), 2.04 (d, J = 4.1 Hz,
1
H NMR (400 MHz, CDCl ): δ = 6.83 (s, 4 H), 5.70 (dddd, J = 17.0, 13.4,
.2, 1.4 Hz, 1 H), 5.07 (dd, J = 8.2, 1.4 Hz, 1 H), 5.02 (dd, J = 17.0, 1.4 Hz,
H), 4.05 (ddd, J = 10.8, 8.0, 2.8 Hz, 1 H), 3.91 (t, J = 6.2 Hz, 2 H), 3.77
3
8
1
H), 2.02–2.00 (m, 1 H), 1.97–1.86 (m, 1 H), 1.82–1.57 (m, 8 H).
(s, 3 H), 3.66 (dd, J = 6.9, 6.9 Hz, 1 H), 3.36–3.32 (m, 1 H), 3.22 (dddd, J
3
C NMR (100 MHz, CDCl ): δ = 154.0 (C), 152.7 (C), 145.2 (C), 134.7
= 12.4, 12.4, 2.8, 2.8 Hz, 1 H), 2.14–2.05 (m, 2 H), 2.02–1.86 (m, 5 H),
3
(C, q, J = 33.4 Hz), 133.7 (CH), 127.6 (CH), 126.7 (CH, q, J = 2.9 Hz),
1.85–1.68 (m, 4 H), 1.65–1.51 (m, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H), 0.03
1
23.2 (CF , q, J = 271.7 Hz), 121.6 (C), 118.7 (CH ), 115.3 (CH), 114.7
(s, 6 H).
3
2
(
5
CH), 71.9 (CH), 68.1 (CH ), 61.7 (CH), 60.2 (CH), 55.7 (CH ), 52.1 (CH),
13
2
3
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 152.9 (C), 136.2 (CH), 123.8
3
1.7 (C), 38.4 (CH ), 37.9 (CH ), 36.4 (CH), 34.2 (CH ), 28.8 (CH ), 28.1
2
2
2
2
(C), 117.2 (CH ), 115.4 (CH), 114.7 (CH), 72.9 (CH), 68.8 (CH ), 59.0
(CH), 58.5 (CH), 55.7 (CH ), 54.3 (CH), 48.6 (C), 41.0 (CH ), 39.6 (CH ),
2
2
(CH ), 25.8 (CH ), 19.0 (CH).
2
2
3
2
2
HRMS (ESI+): m/z calcd for C31H35F N O SNa: 627.2117; found:
36.3 (CH), 35.3 (CH ), 31.7 (CH ), 29.4 (CH ), 26.3 (CH ), 25.8 (CH ),
2 2 2 2 2
3
2
5
627.2091.
18.2 (CH), 18.0 (C), –4.7 (CH ), –4.9 (CH ).
3
3
HRMS (ESI+): m/z calcd for C30H47N O Si: 511.3356; found: 511.3354.
2
3
1
(
2S,2aR,2a S,3R,4aS,6R,7aS)-2-Allyl-3-[(tert-butyldimethylsilyl)-
1
oxy]-2a -[3-(4-methoxyphenoxy)propyl]-1-{[4-(trifluorometh-
yl)phenyl]sulfonyl}decahydro-1H-cyclopenta[cd]indole-6-carbo-
nitrile (55)
1
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-2-Allyl-3-[(tert-butyldi-
1
methylsilyl)oxy]-6-cyano-2a -[3-(4-methoxyphenoxy)pro-
pyl]decahydro-1H-cyclopenta[cd]indole-1-carboxylate (38)
To a solution of 36 (2.00 g, 3.30 mmol) in CH Cl (60 mL) were added
2
2
To a solution of 37 (1.74 g, 3.41 mmol) and Et N (1.43 mL, 10.2 mmol)
in DMF (20.0 mL) was added N-(tert-butoxycarbonyloxy)succinimide
3
2.6-lutidine (6.90 mL, 59.6 mmol) and tert-butyldimethylsilyl trifluo-
romethanesulfonate (1.53 mL, 6.60 mmol) at 0 °C. After stirring for 1
(1.47 g, 6.82 mmol) at r.t. and the solution was heated at 40 °C for 3 h.
h at the same temperature, aq NaHCO was added. The resulting solu-
3
After cooling to 0 °C, EtOAc and aq NaHCO were added. The resulting
3
tion was extracted with CH Cl . The organic phase was washed with
2
2
solution was extracted with EtOAc. The organic phase was washed
with brine, dried (Na SO ), and filtered. The filtrate was concentrated
brine, dried (Na SO ), and filtered. The filtrate was concentrated in
2
4
2
4
vacuo and the residual oil was purified by flash column chromatogra-
in vacuo and the residue was purified by flash column chromatogra-
phy (SiO ; n-hexane–EtOAc, 20:1 → 1:1) to afford 55 (2.20 g, 93%) as a
2
phy (SiO ; n-hexane–EtOAc, 5:1) to give 38 (1.91 g, 92%) as a white
2
27
white amorphous solid; [α]D –5.20 (c = 1.00, CHCl3).
27
amorphous solid; [α]D +17.9 (c = 1.00, CHCl3).
IR (film): 2952, 2857, 2239, 1508, 1471, 1402, 1323, 1232, 1163,
IR (film): 2932, 2857, 2362, 2238, 1695, 1508, 1472, 1394, 1232,
–1
1135, 1062, 835, 778 cm
.
–1
1174, 1130, 1045, 884, 835, 776 cm
.
1
H NMR (400 MHz, CDCl ): δ = 8.03 (d, J = 8.2 Hz, 2 H), 7.83 (d, J = 8.2
1
3
H NMR (400 MHz, CDCl ): δ = 6.82 (s, 4 H), 5.67 (dddd, J = 18.4, 13.4,
3
Hz, 2 H), 6.85–6.76 (m, 4 H), 5.60 (dddd, J = 16.5, 10.1, 3.2, 1.8 Hz, 1
H), 5.08 (d, J = 10.1 Hz, 1 H), 5.04 (d, J = 16.5 Hz, 1 H), 4.64 (dd, J = 10.8,
7
4
3
.3, 2.3 Hz, 1 H), 5.05 (d, J = 15.6 Hz, 1 H), 5.04 (d, J = 12.4 Hz, 1 H),
.43 (ddd, J = 8.2, 4.1, 2.3 Hz, 1 H), 4.04 (ddd, J = 13.2, 8.2, 7.3 Hz, 2 H),
.91 (t, J = 6.0 Hz, 2 H), 3.76 (s, 3 H), 3.58 (dd, J = 3.2, 2.7 Hz, 1 H), 2.68
3
3
.0 Hz, 1 H), 4.04 (ddd, J = 17.8, 8.2, 2.8 Hz, 1 H), 3.95–3.85 (m, 2 H),
.77 (s, 3 H), 3.68–3.63 (m, 1 H), 2.82 (dd, J = 15.4, 2.1 Hz, 1 H), 2.74–
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

N
Synthesis
Y. Ochi et al.
Paper
13
(dddd, J = 12.4, 12,4, 3.0, 3.0 Hz, 1 H), 2.36–2.20 (m, 2 H), 2.07 (dd, J =
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.6 (C), 152.8 (C), 122.7
3
7
6
.3, 2.3 Hz, 1 H), 2.02–1.90 (m, 2 H), 1.85–1.70 (m, 3 H), 1.69–1.54 (m,
H), 1.47 (s, 9 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
(C), 115.4 (CH), 114.7 (CH), 80.9 (C), 72.9 (CH), 68.4 (CH ), 59.6 (CH),
2
59.5 (CH), 55.7 (CH), 55.3 (CH ), 54.6 (C), 50.6 (CH ), 38.9 (CH ), 38.0
3
2
2
1
3
(CH
2
), 36.8 (CH), 34.3 (CH
2
), 28.8 (CH
2
), 28.7 (CH
2
), 28.4 (CH
3
), 25.8
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.5 (C), 152.8 (C), 134.7
3
(
CH ), 25.8 (CH ), 19.5 (CH), 18.0 (C), –4.5 (CH ), –4.8 (CH ).
(CH), 123.0 (C), 117.2 (CH ), 115.4 (CH), 114.6 (CH), 79.7 (C), 72.6
2
3
3
3
2
(
CH), 68.5 (CH ), 60.5 (CH), 57.0 (CH), 55.7 (CH ), 53.6 (CH), 50.2 (C),
HRMS (ESI+): m/z calcd for C34H54N O SiNa: 637.3649; found:
2 6
2
3
3
2
9.2 (CH ), 38.6 (CH ), 36.7 (CH), 34.8 (CH ), 29.3 (CH ), 29.0 (CH ),
637.3658.
2
2
2
2
2
8.4 (CH ), 25.8 (CH ), 25.8 (CH ), 19.1 (CH), 18.0 (C), –4.6 (CH ), –4.9
3
2
3
3
(
CH3).
1
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-[(tert-Butyldimethylsi-
1
HRMS (ESI+): m/z calcd for C35H54N O SiNa: 633.3700; found:
lyl)oxy]-6-cyano-2a -[3-(4-methoxyphenoxy)propyl]-2-[2-(N-
2
5
633.3719.
methyl-2-nitrophenylsulfonamido)ethyl]decahydro-1H-cyclopen-
ta[cd]indole-1-carboxylate (40)
1
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-[(tert-Butyldimethylsi-
To a solution of 39 (470 mg, 0.764 mmol) in toluene (11.0 mL) was
added N-methyl-2-nitrobenzenesulfonamide (181 mg, 0.840 mmol),
1
lyl)oxy]-6-cyano-2a -[3-(4-methoxyphenoxy)propyl]-2-(2-oxoeth-
yl)decahydro-1H-cyclopenta[cd]indole-1-carboxylate (56)
PPh
.993 mmol, 2.2 M in toluene) at 0 °C. The solution was stirred for 1 h
at r.t. To this solution was added CH Cl and aq NaHCO . The resulting
3
(260 mg, 0.993 mmol) and diethyl azadicarboxylate (451 μL,
0
To a solution of 38 (820 mg, 1.34 mmol) in 1.4-dioxane (70.0 mL) and
H O (23.0 mL) was added 2.6-lutidine (1.37 mL, 11.8 mmol), NaIO
2
2
3
2
4
solution was extracted with CH Cl . The organic phase was washed
(
5.73 g, 26.8 mmol), and OsO4 (33.6 mL, 1.34 mmol, 0.04 M in t-
BuOH) at 0 °C. The mixture was stirred for 3 h at r.t. After cooling to
°C, CH Cl and aq NaHCO3 were added. The resulting solution was
2
2
with brine, dried (Na SO ), and filtered. The filtrate was concentrated
2
4
in vacuo and the residue was purified by flash column chromatogra-
0
2
2
phy (SiO ; n-hexane–EtOAc, 5:1 → 2:1) to give 40 (600 mg, 97%) as a
extracted with CH Cl . The organic phase was washed with brine,
2
2
2
26
white amorphous solid; [α]D
+13.5 (c = 1.00, CHCl3).
dried (Na SO ), and filtered. The filtrate was concentrated in vacuo
2
4
and the residue was purified by flash column chromatography (SiO2;
IR (film): 2932, 2857, 2238, 1692, 1545, 1508, 1471, 1367, 1231,
1169, 1126, 1042, 835, 776 cm .
–1
n-hexane–EtOAc, 2:1) to give 56 (730 mg, 89%) as a white amorphous
27
solid; [α]D
+30.6 (c = 1.00, CHCl3).
1
H NMR (400 MHz, CDCl ): δ = 7.96 (m, 1 H), 7.68–7.59 (m, 2 H), 7.58
3
IR (film): 2932, 2857, 2238, 1725, 1697, 1508, 1471, 1393, 1366,
(m, 1 H), 6.84 (s, 4 H), 4.30 (m, 1 H), 4.07 (ddd, J = 10.5, 6.4, 6.4 Hz, 1
H), 3.94 (t, J = 5.7 Hz, 2H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.23 (ddd, J =
13.1, 13.1, 4.1 Hz, 1 H), 3.07 (ddd, J = 13.1, 12.8, 5.3 Hz, 1 H), 2.89 (s, 3
H), 2.68 (dddd, J = 13.0, 13.0, 2.8, 2.8 Hz, 1 H), 2.03–1.92 (m, 4 H),
–1
1231, 1172, 1127, 1043, 836, 776 cm .
1
H NMR (400 MHz, CDCl ): δ = 9.70 (t, J = 2.5 Hz, 1 H), 6.83 (s, 4 H),
3
4.80 (m, 1 H), 4.09 (ddd, J = 10.5, 6.9, 6.9 Hz, 1 H), 3.92 (t, J = 5.7 Hz, 2
1.87–1.61 (m, 7 H), 1.61–1.51 (m, 3 H), 1.46 (s, 9 H), 0.85 (s, 9 H), 0.04
H), 3.77 (s, 3 H), 3.69 (m, 1 H), 2.74–2.64 (m, 2 H), 2.54 (ddd, J = 14.6,
(
s, 3 H), 0.02 (s, 3 H).
5
0
.5, 2.5 Hz, 1 H), 2.04–1.93 (m, 3 H), 1.88–1.58 (m, 9 H), 1.47 (s, 9 H),
.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.3 (C), 152.9 (C), 148.1
3
1
3
(C), 133.5 (CH), 132.6 (C), 131.6 (CH), 130.7 (CH), 124.1 (CH), 122.9
C), 115.5 (CH), 114.7 (CH), 80.1 (C), 72.6 (CH), 68.5 (CH ), 60.1 (CH),
C NMR (100 MHz, CDCl ): δ = 200.2 (CH), 154.0 (C), 153.1 (C), 152.8
3
(
(C), 122.7 (C), 115.5 (CH), 114.7 (CH), 80.8 (C), 72.6 (CH), 68.4 (CH2),
2
5
5.7 (CH ), 55.3 (CH), 54.9 (CH), 50.5 (C), 47.3 (CH ), 39.1 (CH ), 36.9
6
0.4 (CH), 56.1 (CH), 55.7 (CH ), 53.3 (CH), 50.2 (C), 49.0 (CH ), 39.1
3
2
2
3
2
(
(
(
CH), 34.6 (CH ), 34.6 (CH ), 34.6 (CH ), 32.9 (CH ), 29.1 (CH ), 28.4
(CH ), 36.9 (CH), 35.5 (CH ), 29.4 (CH ), 29.4 (CH ), 28.4 (CH ), 25.7
3 2 2 2 2
2
2
2
2
3
CH ), 25.8 (CH ), 25.7 (CH ), 19.3 (CH), 17.9 (C), –4.5 (CH ), –4.9
(CH ), 25.7 (CH ), 19.2 (CH), 17.9 (C), –4.6 (CH ), –5.0 (CH ).
3
3
2
3
2
3
3
3
CH3).
HRMS (ESI+): m/z calcd for C34H52N O SiNa: 635.3492; found:
6
2
6
HRMS (ESI+): m/z calcd for C41H60N O SSiNa: 835.3748; found:
35.3509.
4
9
835.3735.
1
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-[(tert-Butyldimethylsi-
lyl)oxy]-6-cyano-2-(2-hydroxyethyl)-2a -[3-(4-methoxyphen-
oxy)propyl]decahydro-1H-cyclopenta[cd]indole-1-carboxylate
1
1
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-[(tert-Butyldimethylsi-
1
lyl)oxy]-6-formyl-2a -[3-(4-methoxyphenoxy)propyl]-2-[2-(N-
methyl-2-nitrophenylsulfonamido)ethyl]decahydro-1H-cyclopen-
ta[cd]indole-1-carboxylate (57)
(39)
To a solution of 56 (685 mg, 1.12 mmol) in MeOH (20.0 mL) was add-
ed NaBH4 (96.0 mg, 2.46 mmol) at 0 °C. The solution was stirred for
To a solution of 40 (544 mg, 0.669 mmol) in toluene (14.0 mL) was
added DIBAL-H (1.0 M in toluene, 1.34 mL, 1.34 mmol) at –78 °C. The
solution was stirred for 1 h at the same temperature. To this solution
was added H O carefully. The resulting solution was extracted with
CH Cl . The organic phase was washed with brine, dried (Na SO ),
and filtered. The filtrate was concentrated in vacuo and the residue
was purified by flash column chromatography (SiO ; n-hexane–
EtOAc, 2:1 → 5:1) to give 57 (510 mg, 93%) as a pale yellow amor-
3
0 min at the same temperature. To this solution was added CH Cl
2 2
and aq NaHCO . The resulting solution was extracted with CH Cl . The
3
2
2
organic phase was washed with brine, dried (Na SO ), and filtered.
2
2
4
The filtrate was concentrated in vacuo and the residue was purified
2
2
2
4
by flash column chromatography (SiO ; n-hexane–EtOAc, 1:1) to give
2
3
9 (510 mg, 74%) as a white amorphous solid; [α]D26 +7.71 (c = 1.00,
2
CHCl3).
26
phous solid; [α]D +13.9 (c = 0.600, CHCl3).
IR (film): 3481, 2932, 2857, 2238, 1692, 1508, 1472, 1393, 1366,
–1
IR (film): 2930, 2857, 2390, 1722, 1693, 1546, 1508, 1470, 1366,
231, 1169, 1126, 1043, 835, 776 cm .
1
313, 1231, 1173, 1128, 1044, 836, 776 cm .
–1
1
1
H NMR (400 MHz, CDCl ): δ = 6.83 (s, 4 H), 4.61 (br s, 1 H), 4.07 (ddd,
3
1
H NMR (400 MHz, CDCl ): δ = 9.69 (s, 1 H), 7.97 (m, 1 H), 7.70–7.60
m, 2 H), 7.59 (m, 1 H), 6.83 (s, 4 H), 4.33 (m, 1 H), 4.08 (ddd, J = 10.5,
.4, 6.4 Hz, 1 H), 3.93 (t, J = 5.7 Hz, 2 H), 3.77 (s, 3 H), 3.64 (m, 1 H),
.24 (ddd, J = 13.1, 13.1, 4.1 Hz, 1 H), 3.09 (ddd, J = 13.1, 12.7, 4.6 Hz, 1
J = 6.4, 6.4, 10.6 Hz, 1 H), 3.92 (t, J = 6.0 Hz, 2 H), 3.77 (s, 3 H), 3.68–
3
(
6
3
3.45 (m, 4 H), 2.70 (dddd, J = 12.4, 12.4, 2.5, 2.5 Hz, 1 H), 2.10–1.91 (m,
3
H), 1.89–1.49 (m, 11 H), 1.46 (s, 9 H), 0.91 (s, 9 H), 0.07 (s, 6 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

O
Synthesis
Y. Ochi et al.
Paper
1
H), 2.90 (s, 3 H), 2.50 (m, 1 H), 2.05–1.70 (m, 7 H), 1.70–1.50 (m, 6 H),
H NMR (400 MHz, CDCl ): δ = 7.96 (m, 1 H), 7.70–7.65 (m, 2 H), 7.59
3
1
3
.44 (s, 9 H), 1.32 (ddd, J = 13.3, 13.3, 2.7 Hz, 1 H), 0.86 (s, 9 H), 0.05 (s,
H), 0.02 (s, 3 H).
(m, 1 H), 6.83 (s, 4 H), 4.38 (m, 1 H), 4.21 (ddd, J = 8.0, 8.0, 8.0 Hz, 1 H),
3.92 (t, J = 6.2 Hz, 2 H), 3.77 (s, 3 H), 3.60 (m, 1 H), 3.52–3.42 (m, 2 H),
3.36 (ddd, J = 13.3, 8.2, 8.2 Hz, 1 H), 3.19 (ddd, J = 13.3, 8.2, 4.1 Hz, 1
H), 2.92 (s, 3 H), 2.49 (br s, 1 H), 2.10 (dd, J = 7.3, 1.8 Hz, 1 H), 2.05–
13
C NMR (100 MHz, CDCl ): δ = 204.7 (CH), 153.9 (C), 153.3 (C), 153.0
3
(C), 148.1 (C), 133.4 (CH), 132.7 (C), 131.5 (CH), 130.7 (CH), 124.1
1.93 (m, 2 H), 1.85–1.51 (m, 11 H), 1.46 (s, 9 H), 1.28 (m, 1 H), 1.10
(CH), 115.5 (CH), 114.7 (CH), 79.6 (C), 72.8 (CH), 68.7 (CH ), 60.9 (CH),
2
(ddd, J = 14.2, 11.9, 2.8 Hz, 1 H).
5
5.7 (CH ), 55.5 (CH), 55.2 (CH), 51.3 (C), 47.3 (CH ), 40.2 (CH), 39.5
3
2
13
(
(
(
CH ), 37.2 (CH), 34.9 (CH ), 34.6 (CH ), 33.7 (CH ), 28.4 (CH ), 28.4
CH ), 25.8 (CH ), 25.8 (CH ), 25.0 (CH ), 17.9 (C), –4.5 (CH ), –4.9
CH3).
C NMR (100 MHz, CDCl ): δ = 153.8 (C), 153.5 (C), 153.0 (C), 148.2
2
2
3
2
2
3
(C), 133.6 (CH), 131.8 (C), 131.6 (CH), 130.8 (CH), 124.1 (CH), 115.5
(CH), 114.7 (CH), 79.6 (C), 72.3 (CH), 68.9 (CH ), 68.1 (CH ), 61.7 (CH),
3
3
2
2
3
2
2
5
5.7 (CH ), 54.9 (CH), 54.1 (CH), 52.4 (C), 47.1 (CH ), 38.8 (CH ), 37.9
HRMS (ESI+): m/z calcd for C41H61N O10SSiNa: 838.3745; found:
3
2
2
3
(CH), 35.3 (CH ), 34.4 (CH ), 31.8 (CH ), 29.2 (CH), 28.9 (2 × CH ), 28.6
838.3752.
2
3
2
2
(CH ), 26.0 (CH ).
3
2
1
HRMS (ESI+): m/z calcd for C35H49N O10SNa: 726.3036; found:
726.3032.
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-[(tert-Butyldimethylsi-
3
1
lyl)oxy]-6-(hydroxymethyl)-2a -[3-(4-methoxyphenoxy)propyl]-
2
-[2-(N-methyl-2-nitrophenylsulfonamido)ethyl]decahydro-1H-
1
1
cyclopenta[cd]indole-1-carboxylate (41)
tert-Butyl (2S,2aR,2a S,4aS,6R,7aS)-6-Formyl-2a -[3-(4-methoxy-
phenoxy)propyl]-2-[2-(N-methyl-2-nitrophenylsulfonamido)eth-
yl]-3-oxodecahydro-1H-cyclopenta[cd]indole-1-carboxylate (43)
To a solution of 57 (1.41 g, 1.73 mmol) in THF (10.0 mL) and MeOH
(10.0 mL) was added NaBH (130 mg, 3.46 mmol) at 0 °C. The solution
4
was stirred for 1 h at the same temperature. To this solution were
added CH Cl and aq NH Cl. The resulting solution was extracted with
To a solution of 42 (510 mg, 0.725 mmol) in CH Cl (25.0 mL) was
2
2
added NaHCO3 (1.90 g, 22.6 mmol) and Dess–Martin periodinane
(677 mg, 1.56 mmol) at 0 °C, and the solution was stirred for 3 h at
the same temperature. To this solution was added CH Cl and H O
2
2
4
CH Cl . The organic phase was washed with brine, dried (Na SO ),
2
2
2
4
and filtered. The filtrate was concentrated in vacuo and the residue
2
2
2
was purified by flash column chromatography (SiO ; n-hexane–
and then the resulting solution was extracted with CH Cl . The organ-
2
2 2
EtOAc, 1:1) to give 41 (1.37 g, 97%) as a pale yellow amorphous solid;
ic phase was washed with brine, dried (Na SO ), and filtered. The fil-
2 4
trate was concentrated in vacuo and the residue was purified by flash
27
[α]D +20.9 (c = 1.70, CHCl3).
column chromatography (SiO ; n-hexane–EtOAc, 1:2) to afford 43
IR (film): 3464, 2930, 2857, 1681, 1545, 1508, 1471, 1366, 1231,
2
27
–1
(497 mg, 98%) as a white amorphous solid; [α]
D
+16.3 (c = 1.00,
1169, 1125, 1042, 971, 898, 835, 776 cm .
CHCl3).
1
H NMR (400 MHz, CDCl ): δ = 7.97 (m, 1 H), 7.70–7.60 (m, 2 H), 7.58
3
IR (film): 2933, 2360, 1737, 1687, 1545, 1508, 1468, 1368, 1232,
(m, 1 H), 6.84 (s, 4 H), 4.32 (m, 1 H), 4.07 (ddd, J = 9.6, 7.3, 7.3 Hz, 1 H),
–1
1
166, 1125, 1038, 982, 826, 760 cm .
3.93 (t, J = 6.2 Hz, 2 H), 3.76 (s, 3 H), 3.57 (m, 1 H), 3.53–3.40 (m, 2 H),
3.22 (ddd, J = 12.8, 12.8, 4.3 Hz, 1 H), 3.18–3.00 (m, 2 H), 2.90 (s, 3 H),
2.00–1.84 (m, 3 H), 1.84–1.51 (m, 10 H), 1.44 (s, 9 H), 1.27 (ddd, J =
13.3, 13.3, 6.4 Hz, 1 H), 1.08 (ddd, J = 14.2, 11.9, 2.7 Hz, 1 H), 0.86 (s, 9
1
H NMR (400 MHz, CDCl ): δ = 9.70 (s, 1 H), 7.96 (m, 1 H), 7.70–7.64
3
(m, 2 H), 7.58 (m, 1 H), 6.82 (s, 4 H), 4.00–3.91 (m, 2 H), 3.86 (m, 1 H),
3.76 (s, 3 H), 3.60 (br s, 1 H), 3.38 (m, 1 H), 3.14 (ddd, J = 15.6, 10.1, 5.5
Hz, 1 H), 2.94 (s, 3 H), 2.77–2.61 (m, 2 H), 2.60–2.20 (m, 3 H), 2.13 (dd,
J = 18.5, 6.0 Hz, 1 H), 2.18–1.53 (m, 9 H), 1.46 (s, 9 H).
H), 0.04 (s, 3 H), 0.01 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 153.9 (C), 153.3 (C), 153.1 (C), 148.1
3
13
(C), 133.4 (CH), 132.8 (C), 131.5 (CH), 130.7 (CH), 124.1 (CH), 115.5
C NMR (100 MHz, CDCl ): δ = 217.1 (C), 202.3 (CH), 153.9 (C), 153.5
3
(
CH), 114.7 (CH), 79.3 (C), 73.0 (CH), 68.9 (CH ), 68.1 (CH ), 61.8 (CH),
(C), 152.9 (C), 148.2 (C), 133.5 (CH), 132.1 (C), 131.6 (CH), 130.7 (CH),
2
2
5
5.7 (CH ), 55.4 (CH), 55.4 (CH), 51.2 (C), 47.5 (CH ), 39.7 (CH ), 37.9
124.1 (CH), 115.5 (CH), 114.7 (CH), 80.4 (C), 68.3 (CH ), 60.2 (CH),
3
2
2
2
(
(
CH), 35.1 (CH ), 34.6 (CH ), 33.5 (CH ), 29.4 (CH), 28.8 (2 × CH ), 28.5
58.3 (CH), 58.2 (CH), 55.7 (CH ), 52.1 (C), 47.1 (CH ), 44.0 (CH ), 41.1
2
3
2
2
3
2
2
CH ), 26.0 (CH ), 25.8 (CH ), 18.0 (C), –4.4 (CH ), –4.8 (CH ).
(CH), 35.1 (CH ), 34.6 (CH ), 33.6 (CH ), 32.3 (CH ), 28.4 (CH ), 24.8
3
2
3
3
3
3 2 2 2 3
3
(
CH ), 22.6 (CH). One sp carbon signal missing, possibly due to
HRMS (ESI+): m/z calcd for C41H63N O10SSiNa: 840.3901; found:
8
2
3
broadening.
40.3923.
HRMS (ESI+): m/z calcd for C35H45N O10SNa: 722.2723; found:
3
1
722.2705.
tert-Butyl (2S,2aR,2a S,3R,4aS,6R,7aS)-3-Hydroxy-6-(hydroxy-
1
methyl)-2a -[3-(4-methoxyphenoxy)propyl]-2-[2-(N-methyl-2-ni-
1
1
trophenylsulfonamido)ethyl]decahydro-1H-
cyclopenta[cd]indole-1-carboxylate (42)
tert-Butyl (2S,2aR,2a S,4S,4aS,6S,7aS,8S)-8-Hydroxy-2a -[3-(4-
methoxyphenoxy)propyl]-2-[2-(N-methyl-2-nitrophenylsulfon-
amido)ethyl]-3-oxodecahydro-1H-4,6-methanocyclopenta[cd]in-
dole-1-carboxylate (44)
To a solution of 41 (650 mg, 0.795 mmol) in DMF (4.50 mL) was added
tris(dimethylamino)sulfonium difluorotrimethylsilicate (1.20 g, 4.36
mmol) in DMF (3.00 mL) at r.t. The solution was stirred for 3 h at the
same temperature. To this solution was added CH Cl and H O. The
To a solution of 43 (497 mg, 0.710 mmol) in MeOH (27.0 mL) was
added KOH (8.70 mL, 15.5 mmol, 10% w/w in MeOH) at 0 °C and the
2
2
2
resulting solution was extracted with CH Cl . The organic phase was
solution was stirred for 1.5 h at r.t. To this solution was added CH Cl2
2
2
2
washed with brine, dried (Na SO ), and filtered. The filtrate was con-
and aq NH Cl at 0 °C and then the resulting solution was extracted
2
4
4
centrated in vacuo and the residue was purified by flash column chro-
with CH Cl . The organic phase was washed with brine, dried
2
2
matography (SiO ; n-hexane–EtOAc, 0:1) to afford 42 (540 mg, 97%)
as a pale yellow amorphous solid, [α]D +13.6 (c = 1.00, CHCl3).
(Na SO ), and filtered. The filtrate was concentrated in vacuo and the
2
2 4
27
residue was purified by flash column chromatography (SiO ; n-hex-
2
ane–EtOAc, 1:3) to afford 44 (490 mg, 98%) as a white amorphous sol-
IR (film): 3444, 2932, 1671, 1543, 1508, 1456, 1405, 1367, 1347,
27
–1
id; [α]
D
+40.1 (c = 1.00, CHCl ).
3
1231, 1165, 1137, 1041, 826, 758 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

P
Synthesis
Y. Ochi et al.
Paper
1
1
IR (film): 3466, 2946, 2391, 1731, 1683, 1544, 1508, 1455, 1370,
1
tert-Butyl (2S,2aR,2a S,4S,4aS,6S,7aS,8S)-8-(Benzoyloxy)-2a -[3-(4-
methoxyphenoxy)propyl]-2-[2-(N-methyl-2-nitrophenylsulfon-
amido)ethyl]-3-oxodecahydro-1H-4,6-methanocyclopenta[cd]in-
dole-1-carboxylate (58)
348, 1231, 1164, 1132, 1033, 826, 760 cm–1
.
1
H NMR (400 MHz, CDCl ): δ (3:2 mixture of rotamers) = 8.00–7.91
3
(m, 1 H), 7.68–7.60 (m, 2 H), 7.58–7.52 (m, 1 H), 6.84 (s, 4 H), 4.05–
3
=
3
.94 (m, 3 H), 3.85 (m, 3/5 1 H), 3.80–3.73 (m, 3 H + 2/5 1 H), 3.63 (t, J
9.1 Hz, 2/5 1 H), 3.47 (t, J = 9.1 Hz, 3/5 1 H), 3.41–3.25 (m, 1 H),
.22–3.08 (m, 1 H), 2.94 (s, 3/5 3 H), 2.92 (s, 2/5 3 H), 2.84–2.72 (m, 3
To a solution of 44 (460 mg, 0.657 mmol) in pyridine (8.0 mL) was
added benzoyl chloride (152 μL, 1.31 mmol) at 0 °C and the solution
was stirred for 1 h at r.t. To this solution was added CH
NaHCO at 0 °C and then the resulting solution was extracted with
CH Cl
(Na SO
Cl and aq
2
2
H), 2.69–2.36 (m, 3 H), 2.17–2.10 (m, 1 H + 3/5 1 H), 2.6–1.84 (m, 4 H
3
+
1
3/5 1 H), 1.78–1.43 (m, 1 H), 1.70 (br s, 3/5 1 H), 1.67 (br s, 2/5 1 H),
.44 (s, 2/5 9 H), 1.42 (s, 3/5 9 H), 0.38 (m, 1 H).
2
2
(3 ×). The organic phase was washed with brine, dried
), and filtered. The filtrate was concentrated in vacuo and the
2
4
1
3
residue was purified by flash column chromatography (SiO
2
; n-hex-
C NMR (100 MHz, CDCl ): δ (mixture of rotamers) = 218.0 (C), 217.6
3
ane–EtOAc = 4:1 → 1:2) to afford 58 (486 mg, 92%) as a white amor-
(C), 154.5 (C), 154.1 (C), 153.9 (2 C), 153.0 (2 C), 148.3 (C), 148.1 (C),
26
phous solid; [α]D +88.1 (c = 1.50, CHCl3).
1
1
8
33.6 (CH), 133.4 (CH), 132.2 (C), 131.6 (CH), 130.7 (CH), 130.6 (CH),
24.2 (CH), 124.1 (CH), 115.5 (CH), 114.7 (CH), 84.5 (CH), 84.4 (CH),
0.3 (C), 79.9 (C), 68.5 (2 × CH ), 60.9 (CH), 60.8 (CH), 60.5 (CH), 59.2
IR (film): 3471, 2952, 1736, 1716, 1687, 1545, 1508, 1453, 1369,
–1
1273, 1231, 1168, 1110, 1069, 1026, 953, 826, 760 cm .
2
(
5
(
2
CH), 58.2 (CH), 58.1 (CH), 57.4 (CH), 57.0 (CH), 55.8 (CH ), 54.0 (C),
1
3
H NMR (400 MHz, CDCl ): δ (3:2 mixture of rotamers) = 8.10–7.92
3
3.0 (C). 47.8 (2 × CH ), 39.3 (CH), 39.2 (CH), 38.9 (CH), 38.7 (CH), 35.0
2
(m, 3 H), 7.70–7.52 (m, 4 H), 7.50–7.27 (m, 2 H), 6.92–6.80 (m, 4 H),
5.10–5.00 (m, 1 H), 4.20–3.70 (m, 3 H), 3.75 (s, 3 H), 3.67 (t, J = 9.2 Hz,
2/5 1 H), 3.50 (t, J = 9.2 Hz, 3/5 1 H), 3.45–3.25 (m, 1 H), 3.22–2.84 (m,
3 H), 2.94 (s, 3/5 3 H), 2.92 (s, 2/5 3 H), 2.78–2.55 (m, 1 + 3/5 2 H),
2.55–2.40 (m, 1 + 2/5 1 H), 2.15–1.35 (m, 7 + 2/5 1 H), 1.45 (s, 3.8 H),
2 × CH ), 34.0 (2 × CH ), 32.9 (CH ), 31.8 (CH ), 30.4 (CH ), 29.6 (CH ),
3 2 2 2 2 2
8.5 (2 × CH ), 27.8 (CH ), 27.7 (CH ), 24.6 (CH ), 24.4 (CH ).
3 2 2 2 2
HRMS (ESI+): m/z calcd for C35H45N O10SNa: 722.2723; found:
7
3
22.2701.
1
.43 (s, 5.2 H), 0.60 (m, 1 H).
1
1
13
tert-Butyl (2S,2aR,2a S,4S,4aS,6S,7aS,8R)-8-Hydroxy-2a -[3-(4-
methoxyphenoxy)propyl]-2-[2-(N-methyl-2-nitrophenylsulfon-
amido)ethyl]-3-oxodecahydro-1H-4,6-methanocyclopenta[cd]in-
dole-1-carboxylate (45)
C NMR (100 MHz, CDCl ): δ (mixture of rotamers) = 216.5 (C), 216.2
3
(C), 165.5 (2 C), 154.3 (C), 154.0 (C), 153.8 (2 C), 153.0 (2 C), 148.3 (2
C), 133.5 (CH), 133.4 (CH), 133.1 (2 × CH), 132.1 (2 C), 131.6 (2 × CH),
130.6 (CH), 130.5 (CH), 130.1 (2 C), 130.0 (2 × CH), 128.4 (2 × CH),
1
8
24.1 (CH), 124.0 (CH), 115.5 (2 × CH), 114.7 (2 × CH), 85.8 (2 × CH),
0.3 (C), 80.0 (C), 68.4 (2 × CH ), 60.4 (CH), 59.2 (CH), 57.9 (CH), 57.8
To a solution of 43 (30.0 mg, 0.0429 mmol) in THF (3.0 mL) was added
DBU (30.0 μL, 0.201 mmol) at 0 °C and the solution was stirred for 15
min at r.t. To this solution were added CH Cl and aq NH Cl at 0 °C and
2
(
CH), 57.6 (2 × CH), 57.3 (CH), 57.1 (CH), 55.7 (2 × CH ), 54.2 (C), 53.1
3
2
2
4
(C), 47.9 (2 × CH ), 39.4 (CH), 39.3 (CH), 36.7 (CH), 36.5 (CH), 35.2
then the resulting solution was extracted with CH Cl (3 ×). The or-
2
2
2
(CH ), 35.1 (CH ), 33.9 (2 × CH ), 33.1 (CH ), 32.1 (CH ), 30.3 (CH ),
ganic phase was washed with brine, dried (Na SO ), and filtered. The
3 3 2 2 2 2
2
4
29.4 (CH ), 28.4 (2 × CH ), 28.3 (CH ), 28.0 (CH ), 24.5 (CH ), 24.3
filtrate was concentrated in vacuo and the residue was purified by
2 3 2 2 2
(
CH2).
PTLC (SiO ; n-hexane–EtOAc, 1:3) to afford 44 (8.1 mg, 27%) as a pale
2
27
yellow gum and 45 (20.2 mg, 67%) as a white amorphous solid; [α]D
27.6 (c = 1.25, CHCl3).
IR (film): 3479, 2938, 1730, 1682, 1544, 1508, 1456, 1369, 1231,
HRMS (ESI+): m/z calcd for C42H49N O11SNa: 826.2986; found:
826.2996.
3
+
–1
1
1
1
167, 1127, 1102, 1036, 826, 760 cm
.
tert-Butyl (2S,2aR,2a S,4S,4aS,6S,7aS,8S)-8-(Benzoyloxy)-2a -(3-hy-
droxypropyl)-2-[2-(N-methyl-2-nitrophenylsulfonamido)ethyl]-
3
1
H NMR (400 MHz, CDCl ): δ = 8.00–7.92 (m, 1 H), 7.71–7.62 (m, 2 H),
3
-oxodecahydro-1H-4,6-methanocyclopenta[cd]indole-1-carbox-
7.60–7.52 (m, 1 H), 6.83 (s, 4 H), 4.18 (d, J = 10.5 Hz, 1 H), 4.10–3.92
ylate (46)
(m, 2 H), 3.90–3.60 (m, 4.6 H), 3.51 (t, J = 8.7 Hz, 0.7 H), 3.45–3.25 (m,
1.7 H), 3.25–3.10 (m, 1.4 H), 3.00–2.85 (m, 3 H), 2.80 (dd, J = 10.5, 8.3
To a solution of 58 (760 mg, 0.946 mmol) in MeCN (20.0 mL) and H O
2
Hz, 1 H), 2.70 (dd, J = 8.2, 5.5, 1.6 Hz, 1.6 H), 2.60–2.50 (m, 1.7 H),
(5.0 mL) was added cerium(IV) ammonium nitrate (570 mg, 1.04
mmol) at 0 °C and the solution was stirred for 2.5 h at the same tem-
2
1
.44–2.30 (m, 0.7 H), 2.25–2.15 (m, 1 H), 2.00–1.70 (m, 4.5 H), 1.55–
.50 (m, 3 H), 1.50–1.35 (m, 10 H), 1.15–1.10 (m, 1 H).
perature. To this solution was added CH
and then the resulting solution was extracted with CH
organic phase was washed with brine, dried (Na SO ), and filtered.
Cl
and aq NaHCO
at 0 °C
2
2
3
13
2
Cl (3 ×). The
2
C NMR (100 MHz, CDCl ): δ = 220.4 (C), 154.7 (C), 153.9 (C), 153.0
3
2
4
(
(
C), 148.2 (C), 133.5 (CH), 133.4 (CH), 132.1 (C), 131.6 (CH), 130.7
CH), 130.6 (CH), 124.1 (CH), 115.5 (CH), 114.7 (CH), 80.3 (C), 79.9 (C),
The filtrate was concentrated in vacuo and the residue was purified
by flash column chromatography (SiO ; n-hexane–EtOAc, 1:1 → 1:3)
2
7
7.3 (CH), 77.2 (CH), 68.4 (CH ), 59.0 (CH), 57.8 (CH), 56.3 (CH), 55.7
2
to afford 46 (590 mg, 89%) as a white amorphous solid; [α]D27 +67.7
(
CH ), 55.0 (C), 50.3 (CH), 50.2 (CH), 47.8 (CH ), 40.7 (CH), 40.6 (CH),
3
2
(
c = 1.00, CHCl3).
3
2
2
5.2 (CH), 35.1 (CH), 33.8 (CH ), 32.9 (CH ), 31.8 (CH ), 29.7 (CH ),
2 2 2 2
8.5 (CH ), 25.9 (CH ), 25.8 (CH ), 25.4 (CH ), 24.5 (CH ), 24.4 (CH ),
IR (film): 3503, 2944, 1735, 1716, 1683, 1543, 1454, 1369, 1274,
3
2
2
2
2
2
–1
4.3 (CH2).
1166, 1112, 1068, 985, 852, 760 cm
1H NMR (400 MHz, CDCl
): δ (2:1 mixture of rotamers) = 8.00–7.91
(m, 3 H), 7.74–7.52 (m, 4 H), 7.47–7.40 (m, 2 H), 5.08–5.02 (m, 1 H),
.92 (d, J = 9.2 Hz, 2/3 1 H), 3.84–3.75 (m, 1 H + 1/3 1 H), 3.73–3.60
m, 1 H + 1/3 1 H), 3.50–3.30 (m, 1 H + 2/3 1 H), 3.15–2.84 (m, 3 H),
.
HRMS (ESI+): m/z calcd for C35H45N O10SNa: 722.2723; found:
3
3
722.2742.
3
(
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

Q
Synthesis
Y. Ochi et al.
Paper
2
2
2
.95 (s, 2/3 3 H), 2.94 (s, 1/3 3 H), 2.75–2.62 (m, 2 H + 2/3 1 H), 2.55–
.38 (m, 1 H + 1/3 1 H), 1.98–1.55 (m, 7 H), 1.46 (s, 1/3 9 H), 1.43 (s,
/3 9 H), 0.66–0.53 (m, 1 H).
vacuo. The residual oil containing 48 was dissolved in MeCN (40.0
mL) and treated with K PO (200 mg, 0.941 mmol) and thiophenol
3
4
(230 μL, 2.26 mmol) at room temperature. After stirring for 2 h at r.t.,
AcOH (320 μL) was added and then the reaction mixture was heated
at 50 °C for 18 h. After cooling to r.t., the solution was concentrated in
vacuo and the residue was purified by flash column chromatography
13
C NMR (100 MHz, CDCl ): δ (mixture of rotamers) = 216.7 (C), 216.4
3
(
(
C), 165.5 (2 C), 154.2 (C), 153.9 (C), 148.2 (2 C), 133.7 (CH), 133.6
CH), 133.1 (2 × CH), 131.9 (C), 131.8 (C), 131.7 (2 × CH), 130.6 (CH),
(
SiO ; CHCl –MeOH, 5:1) to give 49 (49.0 mg, 89% for 2 steps) as a
130.4 (CH), 130.1 (C), 129.5 (2 × CH), 128.4 (2 × CH), 124.1 (CH), 124.1
2 3
27
white solid; mp 212.2–213.0 °C; [α]D
+156 (c = 1.75, CHCl3).
(
CH), 85.8 (CH), 85.7 (CH), 80.2 (C), 80.0 (C), 62.6 (2 × CH ), 59.4 (CH),
2
5
8.4 (CH), 58.2 (CH), 58.0 (CH), 57.5 (CH), 57.5 (CH), 57.3 (CH), 57.0
IR (film): 3421, 2943, 1722, 1451, 1274, 1177, 1110, 1068, 984, 855
cm .
–1
(CH), 54.4 (C), 53.3 (C), 48.0 (2 × CH ), 39.2 (CH), 39.0 (CH), 36.7 (CH),
2
3
3
6.5 (CH), 35.5 (CH ), 35.3 (CH ), 33.1 (CH ), 33.0 (CH ), 32.9 (CH ),
1
3
3
2
2
2
H NMR (400 MHz, CDCl ): δ = 7.98 (dd, J = 7.6, 1.4 Hz, 2 H), 7.55 (dd,
3
1.9 (CH ), 30.5 (CH ), 29.6 (CH ), 28.4 (2 × CH ), 28.1 (CH ), 27.8
2
2
2
3
2
J = 7.6, 7.6 Hz, 1 H), 7.42 (dd, J = 7.6, 7.6 Hz, 2 H), 5.02 (s, 1 H), 3.70 (t,
J = 8.2 Hz, 1 H), 3.51–3.43 (m, 1 H), 3.00–2.90 (m, 2 H), 2.71–2.57 (m,
2 H), 2.56–2.46 (m, 2 H), 2.45 (s, 3 H), 2.41 (d, J = 6.4 Hz, 1 H), 2.38–
2.30 (m, 1 H), 2.22 (ddd, J = 15.6, 9.9, 9.9 Hz, 1 H), 2.10–1.93 (m, 2 H),
(CH ), 27.5 (CH ), 27.3 (CH ).
2 2 2
HRMS (ESI+): m/z calcd for C35H43N O10SNa: 720.2567; found:
3
720.2587.
1.80–1.70 (m, 3 H), 0.99 (dd, J = 15.6, 10.1 Hz, 1 H).
1
13
tert-Butyl (2S,2aR,2a S,4S,4aS,6S,7aS,8S)-8-(Benzoyloxy)-2-[2-(N-
C NMR (100 MHz, CDCl ): δ = 219.9 (C), 165.5 (C), 133.0 (CH), 130.2
3
1
methyl-2-nitrophenylsulfonamido)ethyl]-3-oxo-2a -(3-oxopro-
pyl)decahydro-1H-4,6-methanocyclopenta[cd]indole-1-carboxyl-
(C), 129.6 (CH), 128.4 (CH), 86.4 (CH), 76.5 (CH), 65.1 (CH), 63.2 (CH),
61.2 (CH), 60.8 (CH), 54.4 (C), 42.7 (CH ), 42.6 (CH ), 42.0 (CH), 38.5
3
2
ate (47)
(CH), 35.8 (CH ), 28.1 (CH ), 26.6 (CH ), 24.5 (CH ), 23.4 (CH ).
2 2 2 2 2
To a solution of 46 (550 mg, 0.788 mmol) in CH Cl (600 mL) was add-
2
2
HRMS (ESI+): m/z calcd for C24H29N O 393.2178; found: 393.2180.
2 3
ed NaHCO3 (1.10 g, 13.1 mmol), Dess–Martin periodinane (401 mg,
.946 mmol) at 0 °C. After stirring for 1 h at r.t., H O was added at the
0
2
Lycopalhine A (2)
same temperature. The resulting solution was extracted with CH Cl
2
2
To a solution of 49 (20.0 mg, 0.0509 mmol) in MeOH (1.0 mL) was
(
(
3 ×). The combined organic phases were washed with brine, dried
Na SO ), and filtered. The filtrate was concentrated in vacuo and the
added K CO (20 mg 0.145 mmol) at 0 °C. After stirring for 3 h at r.t.,
2
3
2
4
the solution was concentrated in vacuo and the residue was purified
by PTLC (NH silica gel; CHCl –MeOH, 10:1) to give lycopalhine A (2)
and epi-lycopalhine A (50) (13.0 mg, 89%) as a colorless gum; [α]
residue was purified by flash column chromatography (SiO ; n-hex-
2
27
2
3
ane–EtOAc, 1:2) to give 47 (540 mg, 98%) as a colorless oil; [α]D
76.7 (c = 1.75, CHCl3).
IR (film): 3854, 2968, 1718, 1685, 1544, 1453, 1369, 1273, 1167,
25
D
+
6
15
+
105 (c = 0.200, MeOH) {Lit. [α]D +89.1 (c = 0.17, MeOH)}.
–1
IR (film): 3411, 2940, 1714, 1659, 1454, 1367, 1300, 1177, 1048,
1
111, 1069, 985, 852, 759 cm .
–1
1
026, 854 cm .
1
H NMR (400 MHz, CDCl ): δ (2:1 mixture of rotamers) = 9.90 (s, 2/3 1
3
1
H NMR (400 MHz, pyridine-d ): δ = 4.46 (dd, J = 11.0, 5.5 Hz, 0.2 H,
5
H), 9.88 (s, 1/3 1 H), 8.00–7.88 (m, 3 H), 7.75–7.65 (m, 2 H), 7.65–7.52
minor isomer), 4.29 (s, 1 H), 3.95–3.89 (m, 0.2 H, minor isomer), 3.81
(
3
m, 2 H), 7.47–7.40 (m, 2 H), 5.04 (s, 1 H), 3.91 (d, J = 10.0 Hz, 2/3 1 H),
.81 (d, J = 10.0 Hz, 1/3 1 H), 3.67 (dd, J = 8.6, 8.6 Hz, 1/3 1 H), 3.50 (dd,
J = 9.2, 9.2 Hz, 2/3 1 H), 3.46–3.30 (m, 1 H), 3.15–3.00 (m, 2 H), 2.95 (s,
(dd, J = 10.1, 7.4 Hz, 0.2 H, minor isomer), 3.65 (dd, J = 10.1, 6.4 Hz, 1
H), 3.59–3.54 (m, 1 H), 3.05 (d, J = 8.2 Hz, 1 H), 2.98 (ddd, J = 12.8, 9.2,
3.2 Hz, 1 H), 2.84 (ddd, J = 10.6, 7.8, 2.5 Hz, 0.2 H, minor isomer),
2.63–2.55 (m, 0.2 H, minor isomer), 2.57 (dd, J = 9.9, 9.9 Hz, 1 H),
2.47–2.22 (m, 6 H), 2.45 (s, 3 H), 2.16 (ddd, J = 11.5, 4.6, 4.6 Hz, 1 H),
2.07 (ddd, J = 15.6, 9.6, 9.6 Hz, 1 H), 1.87 (ddd, J = 11.9, 11.9, 7.4 Hz, 1
2
1
/3 3 H), 2.94 (s, 1/3 3 H), 2.90–2.58 (m, 5 H + 2/3 1 H), 2.55–2.41 (m,
H + 1/3 1 H), 2.22–2.17 (m, 1 H), 2.02–1.92 (m, 2 H), 1.75–1.49 (m, 3
H), 1.45 (s, 1/3 9 H), 1.43 (s, 2/3 9 H), 0.65–0.50 (m, 1 H).
13
C NMR (100 MHz, CDCl ): δ (mixture of rotamers) = 216.1 (C), 215.7
3
H), 1.75–1.60 (m, 4 H), 1.55 (dd, J = 12.5, 7.8 Hz, 1 H), 1.35–1.25 (m,
(C), 201.2 (CH), 200.9 (CH), 165.5 (2 C), 154.2 (C), 153.9 (C), 148.3 (C),
0.2 H, minor isomer), 0.93 (dd, J = 15.1, 10.3 Hz, 1 H).
1
×
48.2 (C), 133.7 (CH), 133.6 (CH), 133.2 (2 × CH), 132.0 (2 C), 131.7 (2
CH), 130.6 (CH), 130.4 (CH), 130.0 (2 C), 129.6 (2 × CH), 128.4 (2 ×
13
C NMR (100 MHz, pyridine-d ): δ (major isomer) = 221.6 (C), 85.6
5
(CH), 77.0 (CH), 65.6 (CH), 65.3 (CH), 63.4 (CH), 61.1 (CH), 54.3 (C),
CH), 124.2 (CH), 124.1 (CH), 85.7 (CH), 85.6 (CH), 80.5 (C), 80.2 (C),
0.3 (CH), 58.6 (CH), 58.3 (CH), 57.9 (CH), 57.7 (CH), 57.5 (CH), 57.3
CH), 57.1 (CH), 53.7 (C), 52.7 (C), 47.9 (2 × CH ), 39.4 (CH), 39.2 (CH),
4
2
3.0 (CH ), 42.8 (CH ), 42.3 (CH), 41.4 (CH), 36.0 (CH ), 27.9 (CH ),
2
3
2
2
6
7.3 (CH ), 25.4 (CH ), 24.2 (CH ); δ (minor isomer) = 219.1 (C), 76.3
2
2
2
(
2
(CH), 75.5 (CH), 64.3 (CH), 62.1 (CH), 58.7 (CH), 58.2 (CH), 55.6 (C),
3
9.0 (CH ), 38.8 (CH ), 36.7 (CH), 36.5 (CH), 35.6 (CH ), 35.4 (CH ),
2
2
3
3
4
2
3.8 (CH), 42.1 (CH ), 41.0 (CH ), 37.6 (CH), 36.7 (CH ), 27.0 (CH ),
3
2
2
2
3
3.3 (CH ), 32.3 (CH ), 30.1 (CH ), 29.3 (CH ), 28.7 (CH ), 28.5 (2 ×
2
2
2
2
2
3.5 (CH ), 23.0 (CH ), 22.8 (CH ).
2
2
2
CH ), 28.3 (CH ), 28.2 (CH ), 27.8 (CH ).
3
2
2
2
HRMS (ESI+): m/z calcd for C17H25N O : 289.1916; found: 289.1902.
2
2
HRMS (ESI+): m/z calcd for C35H41N O10SNa: 718.2410; found:
3
718.2388.
1
Acknowledgment
(
2S,2aS,2a S,4S,5aS,6S,7S,10aS,10bR,13S)-8-Methyl-1-oxododeca-
1
hydro-1H-2a ,7-ethano-2,4-methanocyclopenta[cd]pyrimido[1,6-
a]indol-13-yl Benzoate (49)
Lipase QLM was kindly provided by Meito Sangyo. This work was
financially supported by JSPS KAKENHI (Grant Numbers 25221301,
26713001, 16H01141) and by the Platform Project for Supporting
Drug Discovery and Life Science Research (Platform for Drug Discov-
ery, Informatics, and Structural Life Science) from the Ministry of Ed-
ucation, Culture, Sports, Science and Technology of Japan (MEXT) as
To a solution of 47 (67.0 mg, 0.144 mmol) in CH Cl (3.0 mL) was add-
ed TFA (2.0 mL) at –78 °C. After stirring for 15 min at r.t., CH Cl and
aq NaHCO3 were added at 0 °C. The resulting solution was extracted
with CH Cl (2 ×). The combined organic phases were washed with
brine, dried (Na SO ), and filtered. The filtrate was concentrated in
2
2
2
2
2
2
2
4
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S

R
Synthesis
Y. Ochi et al.
Paper
well as the Japan Agency for Medical Research and Development
AMED).
(q) Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X.
Angew. Chem. Int. Ed. 2011, 50, 3916. (r) Canham, S. M.; France,
D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876.
(
(
6) Dong, L.-B.; Yang, J.; He, J.; Luo, H.-R.; Wu, X.-D.; Deng, X.; Peng,
L.-Y.; Cheng, X.; Zhao, Q.-S. Chem. Commun. 2012, 48, 9038.
7) Williams, B. M.; Trauner, D. Angew. Chem. Int. Ed. 2016, 55,
Supporting Information
(
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588878.
2191.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
(
8) Ochi, Y.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2016, 18, 1494.
9) Corey and co-workers reported a related reaction to form tricy-
clic lactone 60 via cleavage of a cyclopropane ring (Scheme 7):
Newhouse, T. R.; Kaib, P. S. J.; Gross, A. W.; Corey, E. J. Org. Lett.
References
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Scheme 7 Formation of tricyclic lactone 60
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19) The requisite compounds 32b and 32c were prepared from 27
in the same manner by using the corresponding sulfonamide
instead of TsNH . For details, see the experimental section.
2
(20) The use of Boc O in this transformation yielded the formation of
2
61 (Figure 2): cf. Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65,
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R
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N.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2013, 15, 2140.
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8, 9. (m) Zhang, X.-M.; Shao, H.; Tu, Y.-Q.; Zhang, F.-M.; Wang,
N
O
Ot-Bu
H
O
O
(
7
NC
6
1
S.-H. J. Org. Chem. 2012, 77, 8174. (n) Shimada, N.; Abe, Y.;
Yokoshima, S.; Fukuyama, T. Angew. Chem. Int. Ed. 2012, 51,
R = (CH2)3OPMP
Figure 2 Structure of product 61
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(21) Mitsunobu, O. Synthesis 1981, 1.
©
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S
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22) (a) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995,
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(25) Without cleavage of the benzoyl group, no epimerization at C16
was observed.
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Tran, A.; Thayumanavan, S. J. Org. Chem. 2002, 68, 1146.
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(23) The stereochemistries of 44 and 45 were determined based on
1
the coupling constants in the H NMR and NOESY experiments.
For details, see the Supporting Information.
(27) Charles, R. G. J. Org. Chem. 1957, 22, 677.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–S