The first asymmetric total synthesis of lycoposerramine-R

Article abstract of DOI:10.1039/c5ob00827a

The first asymmetric total synthesis of lycoposerramine-R, a Lycopodium alkaloid possessing a novel skeleton, was accomplished by a strategy featuring the stereoselective intramolecular aldol cyclization giving a cis-fused 5/6 bicyclic skeleton and a new method for the construction of the pyridone ring via the aza-Wittig reaction.

Full text of DOI:10.1039/c5ob00827a

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DOI: 10.1039/C5OB00827A
Organic & Biomolecular Chemistry
PAPER
First asymmetric total synthesis of lycoposerramine-R
Hiroaki Ishida, Shinya Kimura, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama*
Received 00th January 20xx,
Accepted 00th January 20xx
The first asymmetric total synthesis of lycoposerramine-R, a Lycopodium alkaloid possessing a novel skeleton, was
accomplished by a strategy featuring the stereoselective intramolecular aldol cyclization giving a cis–fused 5/6 bicyclic
skeleton and a new method for the construction of the pyridone ring via the aza-Wittig reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
reported by Bisai and Sarpong,3s the asymmetric total synthesis
has never been accomplished and the absolute configuration of
the natural product has not been clarified thus far. Herein, we
Introduction
The club moss, Lycopodium, is a rich source of complex
alkaloids, the so-called Lycopodium alkaloids,1 which have a
report the first asymmetric total synthesis of lycoposerramine-R
variety of biological activities, such as acetylcholine esterase (1) involving such key steps as the intramolecular aldol
(AchE) inhibitory activity2 and neurite outgrowth promotion,
and are anticipated to treat Alzheimer’s disease, to improve
geriatric memory loss and so on. Furthermore, Lycopodium
the aza-Wittig reaction, which confirmed the absolute
alkaloids have complex skeletons and unique structures, and
have continued to attract the attention of researchers in the
cyclization to give a cis-fused 5/6 bicycle skeleton, and a newly
developed procedure for the construction of a pyridone ring via
configuration of the natural product.
fields of natural product chemistry, synthetic chemistry, and
medicinal chemistry.3
Results and discussion
These several years, we have engaged in the chemical and
synthetic researches on Lycopodium alkaloids.4 As one of these
The retrosynthetic analysis of (–)-lycoposerramine-R (1) is
studies, we have reported the isolation and structure elucidation
outlined in Scheme 1. We envisioned that the pyridone ring
could be constructed at the last stage. Tricyclic key
intermediate 2 could be derived from diketone 3 by regio- and
of lycoposerramine-R (1) from Lycopodium serratum in 2009.4f
Lycoposerramine-R (1) is characterized by a novel skeleton
consisting of a fused tetracyclic ring system possessing four
asymmetric centers, a pyridone ring, and a cis-fused 5/6 ring
(Fig. 1)
O
1
O
5
Construction of
pyridone ring
HN
5
Recently, we have reported the total synthesis of (±)-
lycoposerramine-R (1) via the Diels-Alder reaction, the
stereoselective introduction of a methyl group, the regio- and
stereoselective reductive amination, and the construction of a
pyridone ring.4a Although the total synthesis of (±)-1 was also
12
7
8
H
15
N
12
9
7
8
13
H
Me
H
H
N
9
H
13
15
H
Me
H
H
2
(–)-lycoposerramine-R (1)
O
Stereoselective
Cu-mediated
1,4-addition
1
Regio- and
stereoselective
reductive
NBnCbz
HN
5
O
and cyclization
O
amination
13
12
7
8
4
12
H
N
9
5
7
15
13
15
H
H
Me
H
Me
H
3
(–)-lycoposerramine-R (1)
Fig. 1 Structure of lycoposerramine-R (1).
O
O
Introduction
of C3 unit
PhS
CbzBnN
15
Me
Me
4
5
Scheme 1. Retrosynthetic analysis of lycoposerramine-R (1).
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J. Name., 2013, 00, 1-3 | 1
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stereoselective reductive amination. Diketone 3 could be
Journal Name
Having succeeded in the synthesis of diketoneV3ie,wwAreticlteuOrnnleinde
obtained from enone 4 via a stereoselective copper-mediated our attention to the construction of tricyclic key intermediate 2
DOI: 10.1039/C5OB00827A
conjugated addition and a stereoselective intramolecular aldol (Scheme 3). Reductive amination of diketone 3 followed by
cyclization. Enone
4
could be derived from known Cbz protection afforded desired key intermediate 2, which was
cyclized between the C-13 carbonyl group and nitrogen, and its
phenylsulfide 55 via the introduction of a C3 unit.
Our project began with the synthesis of diketone 3 (Scheme regioisomer 13, which was cyclized between the C-4 carbonyl
2). We initially prepared known phenylsulfide 5, which was group and nitrogen, in the ratio of 3.6:1.7 The structures
synthesized from commercially available (R)-pulegone (6) including the stereochemistry of the aminomethine position of 2
through epoxidation, followed by treatment with sodium and 13 were respectively elucidated by X-ray crystallographic
thiophenolate in two steps. Alkylation of the enolate of 5, analysis after conversion into para-bromobenzamide
which was prepared by treatment with sodium hydride, with derivatives 14 and 15.8
iodide 7 afforded phenylsulfenyl ketone 8 as a diastereomeric
mixture (dr = 3:1) in 81% yield. Oxidation of 8 with m-CPBA
at –78 °C followed by treatment at room temperature gave
enone 4. Stereoselective installation of a C3 unit at the β
position of the α,β-unsaturated carbonyl group in 4 was
NBnCbz
achieved by the copper-mediated conjugated addition of acetal-
O
O
4
containing Grignard reagent 9 to enone 4 to yield a mixture of
cyclohexanone 10 and silyl enol ether 11. Treatment of crude
10 and 11 with aqueous hydrogen chloride at 50 °C gave cis-
fused 5/6 bicyclic compound 12 in 81% yield (two steps)
having the correct configuration of the quaternary stereocenter
at C-12 via intramolecular aldol cyclization.6 Oxidation of 12
with Dess-Martin reagent afforded diketone 3 in 91% yield.
13
Me
H
3
1) Pd/C, H2, MeOH, rt, 4 h
2) NaBH(OAc)3, AcOH, THF
rt, 1.5 h
3) CbzCl, Na2CO3, CH2Cl2, H2O
rt, 15.5 h
1) H2O2 aq., KOH
MeOH, rt, 4 h
quant.
2) PhSH, NaH, THF
reflux, 21 h, 95%
Cbz
H
Cbz
N
Me
O
O
O
N
O
4
13
H
PhS
Me
13
4
Me
Me
Me
Me
H
H
6
5
CbzBnN
I
H
O
4
O
7
m-CPBA
CH2Cl2
O 13
Me
NaH, DMF
CbzBnN
PhS
H
N
rt, 17 h
81%, dr = 3:1
rt, 57 h
58%
13
N
H
H
Me
Cbz
4
H
Me
Cbz
8
H
2
13
(16% in 3 steps)
O
(57% in 3 steps)
O
BrMg
1) Pd/C, H2
1) Pd/C, H2
9
MeOH, rt, 1 h
2) p-BrBzCl, Et3N
THF, rt, 13.5 h
MeOH, rt, 1 h
2) p-BrBzCl, Et3N
THF, rt, 1 h
O
CuBr·Me2S, TMSCl
DMAP, THF
CbzBnN
–78 °C, 25 h
57% in 2 steps
87% in 2 steps
Me
H
4
O
4
13
O
Me
O
OTMS
Me
H
N
13
H
N
H
CbzBnN
O
CbzBnN
O
H
Me
Bz-p-Br
4
p-Br Bz
H
Me
14
15
O
O
10
11
4
NBnCbz
NBnCbz
13
DMP
CH2Cl2
13
O
13
O
13
2N HCl, THF HO
O
4
4
4
50 °C, 17 h
rt, 70 min
91%
12
81%
in 2 steps
dr = 1:1
Me
Me
Scheme 3. Synthesis of tricyclic key intermediate 2.
H
H
3
12
Scheme 2. Synthesis of diketone 3.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
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DOI: 10.1039/C5OB00827A
O
4
a. Michael addition/condensation/decarboxylation by Smith
1) KOH, EtOH
reflux, 12 h
allylMgBr
THF
O
H2N
O
O
4
H2N
O
H
O
N
H
Me
O
HN
rt, 3 h
91%
2) CbzCl
Na2CO3
CH2Cl2, H2O
rt, 20 h
78%
in 2 steps
O
H
Me
H
Me
H
N
H
Cbz
H
H
H
H
CO2Me
H
Me
Me
H
CO2Me
H
2
N
H
H
H
16
N
N
H
H
lyconadin A
b. Michael addition/condensation/elimination of sulfoxide by Fukuyama
O
S
O
HO
5
1
2
1
4
2
5
Ph
NH2
O
O
SOCl2, pyridine
CH2Cl2
NH2
O
H
Me
4
O
HN
H
Me
H
Me
Ph
H
N
H
H
S
N
H
H
H
0 °C, 2 h;
rt, 3 h
89%
O
H
Me
Cbz
H
H
H
Cbz
HN
H
H
H
H
N
H
HN
H
Me
17
18
lyconadin C
c. Tandem Curtius rearrangement/6π-electrocyclization by Waters
i) 9-BBN, THF
rt, 2.5 h;
ii) BH3·THF
rt, 9.5 h;
O
HO
O
1) Jones' reagent
acetone
–40 °C, 1 h
C
CO2H
H
Me
1
HN
H
Me
N
5
2
4
H
Me
OH
H
H
H
H
iii) H2O2 aq.
2N NaOH aq.
rt, 7.5 h
74%
(one pot)
H
N
2) Et3N, Et2O
0 °C, 15 min;
DPPA
HN
H
H
H
HN
H
HN
H
H
Me
Cbz
lyconadin C
H
0 °C, 1 h
19
Scheme 5. Previous pyridone ring construction strategies in
Lycopodium alkaloid synthesis.
O
3) PPh3
toluene
rt, 1 h;
O
1
O
1
N
5
5
R
reflux, 12 h
compared with that in the synthesis of racemic 1. Further, in
dehydration of 17, slow addition of the reagent (SOCl2) and
prolongation of the reaction time increased the yield (65% ⇒
89%) as well. Further, the yield of the hydroboration-oxidation
steps for the preparation of 19 could be greatly increased (from
39% to 74%) by careful addition of the oxidant (see
Experimental section). At the final stage, the construction of the
pyridone ring was accomplished by the aza-Wittig reaction.
Thus, Jones’ oxidation of diol 19 followed by the in situ
formation of acyl azide 21,11 treatment with triphenyl
phosphine, heating in toluene, and auto-oxidation of resultant
dihydropyridone 22 produced pyridone 23 in 53% yield from
diol 19 (Scheme 4). Finally, deprotection of the Cbz group in
23 gave (–)-lycoposerramine-R (1). Synthetic 1 was identical in
all respects with the natural product, including the optical
H
N
H
N
H
Me
Cbz
H
H
Cbz
H
22
Me
R = OH: 20
R = N3: 21
O
O
Pd/C
H2, 1 atm
MeOH
HN
HN
rt, 2 h
quant.
53%
in 3 steps
H
H
N
N
H
H
H
Cbz
H
H
Me
Me
(–)-lycoposerramine-R (1)
23
Scheme 4. Synthesis of (–)-lycoposerramine-R (1).
property: synthetic, [α]26 –26.1 (c 0.03, CHCl3); natural,
D
[α]25 –23.9 (c 0.21, CHCl3). Therefore, the absolute
D
configuration of lycoposerramine-R was established, as shown
in formula 1.
With optically active key intermediate 2 in hand, we next
focused on the construction of the pyridone ring. In our
previous study4a on the racemic synthesis of 1, 2 was converted
into 5-oxocarboxylic acid 20 (Scheme 4), which was then
treated with NH2OMe·HCl to afford pyridone 23. However, the
conversion yield was very low (12% yield in two steps).
Previously reported procedures for the construction of the
pyridone ring in Lycopodium alkaloid syntheses (Scheme 5),
Conclusions
In summary, the first asymmetric total synthesis of
lycoposerramine-R (1) was achieved in 19 steps and 4.7%
overall yield starting from (R)-pulegone (6). The synthesis
involved the stereoselective intramolecular aldol cyclization
giving the cis-fused 5/6 bicyclic skeleton and a new method for
the construction of the pyridone ring via the aza-Wittig reaction.
namely,
(a)
Michael
addition,
condensation,
and
decarboxylation by Smith,9 (b) Michael addition, condensation,
and elimination of sulfoxide by Fukuyama,3d and (c) tandem
Curtius rearrangement and 6π-electrocyclization by Waters,10
were inapplicable to our system. Therefore, we made efforts to
improve the reaction conditions for the preparation of 5-
oxocarboxylic acid 20 from 2 as well as to develop a new and
efficient method for construction of the pyridone ring by
utilizing 20 as the intermediate.
Experimental section
General
Reagents and solvents were purified by standard means or used
without further purification. CH2Cl2, Et3N, MeOH, EtOH,
pyridine, and toluene were distilled from CaH2. Acetone and
We found that in the preparation of 16 from 2 the addition of
allyl magnesium bromide two times (each 1.2 equivalents of
reagent) improved the conversion yield (85% ⇒ 91%)
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DMF were distilled after treatment with MS4Å. Anhydrous THF and at 55 °C) δ: 7.37-7.20 (10H, overlapped), 5.18 (2H, s), 4.48 (2H,
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Et2O were used as supplied by Kanto Chemical Co., Inc. in the s), 3.55 (2H, q, J = 5.8 Hz), 3.41 (2H, DbOr-I:s1)0, .130.0391/C(51OHB,00b8r-2s7)A,
highest purity. IR spectra were recorded on a JASCO FT/IR- 1.67 (2H, quin, J = 5.8 Hz). 13C NMR (CDCl3, 100 MHz, at
230 spectrophotometer. UV spectra were recorded in MeOH on 55 °C) δ: 157.2, 137.7, 136.6, 128.6, 128.5, 128.1, 127.9, 127.6,
1
a JASCO V-560 instrument. H and 13C NMR spectra were 127.4, 67.6, 59.0, 50.6, 43.3, 30.6. IR (ATR) ν max cm-1: 3412,
recorded on JEOL JNM ECP-400, JNM ECP-600, JNM ECS- 2947, 1675, 1420, 1232, 1120, 1057. HR-MS (ESI): calcd for
400, and ECA-600 with CDCl3 as solvent and tetramethylsilane C18H21NO3Na [M+Na]+: 322.1419, found: 322.1392.
(1H, 0.00 ppm), CDCl3 (13C, 77.0 ppm) as internal standard. To a solution of the above alcohol (21.6 g, 72.2 mmol) in
The NMR peak assignments reported herein were confirmed by CH2Cl2 (722 mL) at 0 °C were added PPh3 (22.7 g, 86.6 mmol),
COSY, HMQC, HMBC, and differential NOE experiments. J imidazole (5.90 g, 86.6 mmol), and iodine (22.0 g, 86.6 mmol).
values are given in Hz. HRESIMS spectra were recorded on a After stirring at room temperature for 70 min under argon
Thermo Fisher Scientific Exactive spectrometer. Optical atmosphere, the reaction mixture was quenched by adding
rotations were measured with a JASCO P-1020 polarimeter. X- saturated aqueous NaHCO3 solution, and the resultant mixture
ray crystallographic analyses were conducted on a Rigaku R- was diluted with CHCl3. The organic phase was separated, and
AXIS RAPID imaging plate diffractometer using a graphite the aqueous phase was extracted three times with CHCl3. The
monochromator with Cu-Kα radiation at 93 K. Melting points combined organic extracts were washed with brine, dried over
were measured with a Yanagimoto Micro Melting Point MgSO4, filtered, and concentrated under reduced pressure. The
Apparatus 1631A. TLC was performed on precoated silica gel crude material was purified by silica gel flash column
60 F254 plates (Merck, 0.25 mm thick). Column chromatography (EtOAc/n-hexane = 15:85) to afford 7 (26.2 g,
1
chromatography was carried out on silica gel 60 [Kanto 89%) as a yellow oil. H NMR (CDCl3, 400 MHz, at 55 °C) δ:
Chemical Co., Inc., 40-50 µm (for flash column 7.32-7.23 (10H, overlapped, PhCH2OCO- and PhCH2N-), 5.18
chromatography)] and Chromatorex NH [Fuji Silysia Chemical (2H, s, PhCH2OCO-), 4.51 (2H, s, PhCH2N-), 3.32 (2H, t, J =
Ltd., 100-200 mesh (for amino-silica gel column 6.8 Hz), 3.07 (2H, br-t, J = 6.8 Hz), 2.03 (2H, br-s). 13C NMR
chromatography)]. Medium pressure liquid chromatography (CDCl3, 100 MHz, at 55 °C) δ: 156.5, 137.7, 136.7, 128.7,
(MPLC) was performed using C. I. G. prepacked column CPS- 128.5, 128.1, 128.0, 127.7, 127.5, 67.4, 51.2, 47.5, 32.2, 2.3. IR
HS-221-05 (Kusano Kagakukikai, SiO2).
(ATR) νmax cm-1: 3029, 2948, 1692, 1417, 1228, 1097. HR-MS
(ESI): calcd for C18H20NO3INa [M+Na]+: 432.0436, found:
432.0399.
Benzyl benzyl(3-iodopropyl)carbamate (7)
To a solution of 3-amino-1-propanol (26.9 g, 358 mmol) in
MeOH (90 mL) at 0 °C were added HC(OMe)3 (39.2 mL, 358 Benzyl
benzyl(3-((4R)-4-methyl-2-oxo-1-
mmol) and benzaldehyde (36.3 mL, 358 mmol). The reaction (phenylthio)cyclohexyl)propyl)carbamate (8)
mixture was warmed to room temperature under argon To a solution of 5 (4.38 g, 19.9 mmol) in DMF (60 mL) at
atmosphere. After stirring at the same temperature for 3.5 h, –40 °C was added solid NaH (958 mg, 60% in oil, 23.9 mmol)
NaBH4 (14.9 g, 393 mmol) was added at 0 °C. Then, the in portions over 20 min with extensive gas evolution. After 3 h,
reaction mixture was stirred for 10 h at room temperature. After a solution of 7 (24.5 g, 59.9 mmol) in DMF (60 mL) was
quenching the reaction mixture by adding H2O at 0 °C, the dropped over 1.5 h at –40 °C. The cooling bath was removed
resultant mixture was concentrated under reduced pressure and and the reaction mixture was stirred for 17 h at room
then diluted with CHCl3. The organic phase was separated, and temperature. The reaction mixture was diluted with saturated
the aqueous phase was extracted three times with CHCl3. The aqueous NH4Cl solution and EtOAc. The organic phase was
combined organic extracts were washed with brine, dried over separated, and the aqueous phase was extracted three times with
MgSO4, filtered, and concentrated under reduced pressure. The EtOAc. The combined organic extracts were washed with brine,
crude material was used in the next reaction without further dried over MgSO4, filtered, and concentrated under reduced
purification. To a solution of the crude material in CH2Cl2 (358 pressure. The crude material was purified by silica gel flash
mL) and H2O (247 mL) was added K2CO3 (59.3 g, 429 mmol) column chromatography (EtOAc/n-hexane = 15:85) to afford 8
at 0 °C. After the reaction mixture was stirred vigorously at (8.08 g, 81%, dr = 3:1) as a yellow oil. Compund 8 (3 : 1
1
room temperature for 10 min under argon atmosphere, CbzCl mixture of diastereomers): H NMR (CDCl3, 600 MHz, at
(51.0 mL, 358 mmol) was added at 0 °C over 60 min. After 55 °C, 8-major* : 8-minor**) δ: 7.31-7.20 (30H, overlapped,
stirring at room temperature for 12 h under argon atmosphere, PhCH2OCO- and PhCH2N- and PhS-), 5.172 (2H, s,
the reaction mixture was diluted with CH2Cl2 and H2O. The PhCH2OCO-)**, 5.166 (2H, s, PhCH2OCO-)*, 4.47 (2H, s,
organic phase was separated, and the aqueous phase was PhCH2N-)*, 4.45 (2H, s, PhCH2N-)**, 3.23-3.04 (6H,
extracted three times with CH2Cl2. The combined organic overlapped), 2.26 (2H, m), 2.11 (2H, m), 2.03 (2H, br-s), 1.91
extracts were washed with brine, dried over MgSO4, filtered, (2H, br-s), 1.79 (2H, br-s), 1.63 (4H, br-s), 1.53-1.42 (6H,
and concentrated under reduced pressure. The crude material overlapped), 1.05 (3H, d, J = 5.5 Hz, H-16)**, 0.92 (3H, d, J =
was purified by silica gel flash column chromatography 6.9 Hz, H-16)*. 13C NMR (CDCl3, 150 MHz, at 55 °C) δ: 207.6,
(EtOAc/n-hexane
=
50:50)
to
afford
N- 206.9, 156.5, 156.4, 138.1, 138.0, 137.01, 136.99, 136.5, 136.0,
(benzyl)benzyloxycarbonyl 3-amino-1-propanol12 (104.5 g, 135.4, 130.8, 130.5, 129.3, 129.2, 129.03, 128.96, 128.9,
98% in two steps) as a colorless oil. 1H NMR (CDCl3, 400 MHz, 128.82, 128.77, 128.61, 128.59, 128.5, 128.0, 127.9, 127.7,
4 | J. Name., 2012, 00, 1-3
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127.40, 127.35, 67.3, 61.7, 60.1, 50.8, 46.8, 46.0, 41.2, 37.3, Crude 10 and 11 were used in the next reaction wVitiehwoAurtticfleuOrtnhliener
DOI: 10.1039/C5OB00827A
35.8, 34.6, 33.5, 31.9, 31.8, 31.6, 29.8, 28.0, 27.9, 26.6, 22.4, purification. To a solution of crude 10 and 11 in THF (80 mL)
22.2, 22.0, 19.7. IR (ATR) ν max cm-1: 3067, 3030, 2950, 2861, was added 2N aqueous HCl (20 mL) at 0 °C. The reaction
1766, 1694, 1418, 1230, 1212, 1115. HR-MS (ESI): calcd for mixture was stirred for 17 h at 50 °C under argon atmosphere.
C31H35NO3SNa [M+Na]+: 524.2235, found: 524.2203. [α]27
–26 (c 0.98, CHCl3).
After cooling to room temperature, the reaction mixture was
extracted three times with EtOAc. The combined organic
extracts were washed with saturated aqueous NaHCO3 and
D
Benzyl
(R)-benzyl(3-(4-methyl-6-oxocyclohex-1-en-1- brine, dried over MgSO4, filtered, and concentrated under
yl)propyl)carbamate (4)
reduced pressure. The crude material was purified by silica gel
To a solution of 8 (133 mg, 0.265 mmol) in CH2Cl2 (1.7 mL) at flash column chromatography (EtOAc/n-hexane = 40:60) to
–78 °C was added a solution of m-CPBA (59.3 mg, 0.265 afford 12 (752.8 mg, 81% in 2 steps, dr = 1:1) as a brown oil.
mmol) in CH2Cl2 (1.0 mL) over 10 min. The mixture was Compound 12 (a less polar isomer): 1H NMR (CDCl3, 400
warmed to room temperature over 1 h and then stirred for 57 h MHz, at 55 °C) δ: 7.32-7.21 (10H, overlapped, PhCH2OCO-
under argon atmosphere, whereupon the solution became and PhCH2N-), 5.16 (2H, br-s, PhCH2OCO-), 4.51 (1H, br-d, J
homogeneous. The reaction mixture was diluted with aqueous = 6.2 Hz, H-4), 4.46 (2H, br-s, PhCH2N-), 3.20 (2H, br-t, J =
10% w/w NaHSO3 solution. The organic phase was separated, 7.0 Hz, H-9), 2.28 (1H, m), 2.15 (1H, br-d, J = 9.9 Hz), 2.02-
and the aqueous phase was extracted five times with EtOAc. 1.94 (2H, overlapped), 1.88 (1H, m), 1.78 (1H, m), 1.67 (1H,
The combined organic extracts were washed with brine, dried br-d, J = 13.2 Hz), 1.54-1.42 (5H, overlapped), 1.35-1.21 (3H,
over MgSO4, filtered, and concentrated under reduced pressure. overlapped), 0.97 (3H, d, J = 5.9 Hz, H-16). 13C NMR (CDCl3,
The crude material was purified by silica gel flash column 100 MHz, at 55 °C) δ: 214.9, 156.6, 138.0, 136.9, 128.6, 128.5,
chromatography (EtOAc/n-hexane = 20:80) to afford 4 (59.8 128.0, 127.9, 127.7, 127.4, 74.5, 67.3, 62.0, 50.6, 47.8, 47.2,
mg, 58%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz, at 44.3, 34.1, 33.4, 32.4, 29.6, 29.1, 27.1, 22.2. IR (ATR) ν max cm-
55 °C) δ: 7.31-7.21 (10H, overlapped, PhCH2OCO- and 1: 3467, 2950, 2925, 2869, 1688, 1685, 1454, 1421, 1231, 1119.
PhCH2N-), 6.57 (1H, br-s, H-7), 5.16 (2H, s, PhCH2OCO-), HR-MS (ESI): calcd for C28H35NO4Na [M+Na]+: 472.2464,
4.49 (2H, s, PhCH2N-), 3.21 (2H, br-s), 2.44 (1H, br-d, J = 15.0 found: 472.2446. [α]28D = +47 (c 0.75, CHCl3).
Hz), 2.32 (1H, br-d, J = 16.5 Hz), 2.12-1.92 (5H, overlapped),
1.63 (2H, br-t, J = 7.2 Hz), 1.01 (3H, d, J = 6.6 Hz, H-16). 13C Benzyl
benzyl(3-((3aS,6R,7aR)-6-methyl-3,4-
NMR (CDCl3, 150 MHz, at 55 °C) δ: 199.1, 144.3, 138.8, dioxooctahydro-3aH-inden-3a-yl)propyl)carbamate (3)
138.0, 137.7, 137.0, 128.6, 128.53, 128.46, 128.0, 127.9, 127.3, To a solution of 12 (857.3 mg, 1.91 mmol) in CH2Cl2 (9.6 mL)
67.2, 50.4, 46.7, 46.3, 34.4, 31.7, 30.6, 26.7, 21.1. IR (ATR) ν was added a solution of Dess-Martin reagent (1.70 g, 3.81
max cm-1: 3030, 2952, 2924, 2871, 1694, 1670, 1454, 1419, 1216, mmol) in CH2Cl2 (9.5 mL) at 0 °C. The reaction mixture was
1119. HR-MS (ESI): calcd for C25H29NO3Na [M+Na]+: warmed to room temperature under argon atmosphere. After
414.2045, found: 414.2023. [α]28D –16 (c 0.46, CHCl3).
stirring at the same temperature for 70 min, the reaction
mixture was quenched by adding saturated aqueous Na2S2O3
Benzyl
benzyl(3-((3aS,6R,7aR)-3-hydroxy-6-methyl-4- solution, and the resultant mixture was diluted with CHCl3. The
organic phase was separated, and the aqueous phase was
oxooctahydro-3aH-inden-3a-yl)propyl)carbamate (12)
To a stirred mixture containing 201 mg (8.28 mmol) of fresh extracted three times with CHCl3. The combined organic
magnesium turnings in THF (10 mL) was added a small iodine extracts were washed with brine, dried over MgSO4, filtered,
crystal under argon atmosphere. Then, over a period of 30 min, and concentrated under reduced pressure. The crude material
a solution of 2-(2-bromoethyl)-1,3-dioxolane (824 mg, 4.55 was purified by silica gel flash column chromatography
mmol) in THF (10 mL) was added to the mixture, the (EtOAc/n-hexane = 30:70) to afford 3 (780.9 mg, 91%) as a
1
temperature of which was maintained below 25 °C by using a pale yellow oil. H NMR (CDCl3, 600 MHz, at 55 °C) δ: 7.32-
cooling bath. The resulting Grignard reagent mixture was 7.22 (10H, overlapped, PhCH2OCO- and PhCH2N-), 5.17 (2H,
continuously stirred for 1 h at room temperature before being s, PhCH2OCO-), 4.48 (2H, s, PhCH2N-), 3.23 (2H, br-s, H-9),
transferred into a stirred precooled mixture of 4-DMAP (556 2.36-2.32 (2H, overlapped), 2.20 (2H, m), 2.04 (2H, m), 1.87
mg, 4.55 mmol) and CuBr·Me2S (430 mg, 2.07 mmol) in THF (1H, br-s), 1.70-1.47 (5H, overlapped), 1.26 (2H, m), 1.00 (3H,
(30 mL) at –78 °C via a cannula. After the resulting reaction d, J = 6.2 Hz, H-16). 13C NMR (CDCl3, 150 MHz, at 55 °C) δ:
mixture was stirred at –78 °C for 1 h, TMSCl (0.58 mL, 4.55 214.4, 208.4, 156.6, 138.0, 137.0, 128.63, 128.62, 128.5, 128.0,
mmol) and a solution of 4 (810 mg, 2.07 mmol) in THF (20 127.9, 127.4, 67.3, 66.6, 50.4, 47.0, 46.9, 42.3, 35.9, 33.2, 30.2,
mL) were added dropwise, respectively, at the same 29.7, 28.8, 24.0, 21.6. IR (ATR) ν max cm-1: 2952, 1748, 1698,
temperature. The reaction mixture was stirred at –78 °C for 25 1508, 1457, 1222. HR-MS (ESI): calcd for C28H33NO4Na
h under argon atmosphere and finally quenched by the addition [M+Na]+: 470.2307, found: 470.2327. [α]28 +49 (c 0.18,
D
of saturated aqueous NH4Cl solution. The resultant mixture was CHCl3).
diluted with EtOAc. The organic phase was separated, and the
aqueous phase was extracted three times with EtOAc. The Benzyl
(4aR,7aS,9R,10aS)-9-methyl-5-
combined organic extracts were washed with brine, dried over oxodecahydrocyclopenta[e]quinoline-1(2H)-carboxylate (2)
MgSO4, filtered, and concentrated under reduced pressure. and
benzyl
(4aR,6aR,8R)-8-methyl-10-
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
oxodecahydroindeno[1,7a-b]pyridine-4(1H)-carboxylate
(13)
213.4, 155.4, 137.3, 128.3, 127.8, 127.6, 66.6, 65.V6ie,w5A5r.ti0cl,e 4O8nl.in2e,
46.7, 44.8, 34.2, 33.5, 30.0, 27.1, 24.8,D2O2I.:21,0.12013.98/.CI5ROB(0A08T2R7A)
To a solution of 3 (98.3 mg, 0.220 mmol) in MeOH (2.2 mL) νmax cm-1: 2948, 2925, 2869, 2847, 1699, 1687, 1497, 1342,
was added 10% Pd/C (23.4 mg, 0.022 mmol) at room 1256, 1109. HR-MS (ESI): calcd for C21H27NO3Na [M+Na]+
temperature under argon atmosphere. Then, the reaction 364.1889; found 364.1880. [α]21D +116 (c 0.38, CHCl3).
mixture was vigorously stirred for 4 h at room temperature
under 1.0 atm pressure of hydrogen atmosphere. The reaction (4aR,7aS,9R,10aS)-1-(4-Bromobenzoyl)-9-
mixture was filtered through a pad of Celite®, and the filtrate methyldecahydrocyclopenta[e]quinolin-5(2H)-one (14)
was concentrated under reduced pressure to afford the crude To a solution of 2 (2.0 mg, 5.86 µmol) in MeOH (1.0 mL) was
product as a pale yellow oil, which was used in the next added 10% Pd/C (0.6 mg, 0.586 µmol) at room temperature
reaction without further purification. To a solution of the above under argon atmosphere. Then, the reaction mixture was
product and AcOH (13 µL, 0.220 mmol) in THF (2.2 mL) was vigorously stirred for 1 h at room temperature under 1.0 atm
added NaBH(OAc)3 (58.6 mg, 0.268 mmol) at 0 °C. After pressure of hydrogen atmosphere. The reaction mixture was
stirring at room temperature for 1.5 h under argon atmosphere, filtered through a pad of Celite®, and the filtrate was
the reaction mixture was quenched by adding 1N aqueous concentrated under reduced pressure to afford the crude product
NaOH at 0 °C, and the resultant mixture was diluted with as a pale yellow oil, which was used in the next reaction
EtOAc. The organic phase was separated, and the aqueous without further purification. To a solution of the crude material
phase was extracted five times with EtOAc. The combined in THF (0.5 mL) were added Et3N (2 µL, 12.9 µmol) and p-
organic extracts were washed with brine, dried over MgSO4, bromobenzoyl chloride (1.5 mg, 6.45 µmol) at 0 °C. After
filtered, and concentrated under reduced pressure. The crude stirring at room temperature for 1 h under argon atmosphere,
material was used in the next reaction without further the reaction mixture was diluted with CHCl3 and saturated
purification. To a solution of the crude material in CH2Cl2 (2.2 aqueous NaHCO3 solution. The organic phase was separated,
mL) and H2O (2.2 mL) was added Na2CO3 (233.2 mg, 2.20 and the aqueous phase was extracted three times with CHCl3.
mmol) at 0 °C. After stirring vigorously at room temperature The combined organic extracts were washed with brine, dried
for 10 min under argon atmosphere, CbzCl (94 µL, 0.660 over MgSO4, filtered, and concentrated under reduced pressure.
mmol) was added at 0 °C. After stirring at room temperature for The crude material was purified by silica gel flash column
15.5 h under argon atmosphere, the reaction mixture was chromatography (EtOAc/n-hexane = 50:50) to afford 14 (2.0
diluted with CHCl3 and H2O. The organic phase was separated, mg, 87% in
2
steps) as colorless platelet crystals.
and the aqueous phase was extracted three times with CHCl3. Recrystallization of 14 from a mixed solvent of EtOAc/n-
The combined organic extracts were washed with brine, dried hexane under ambient temperature gave a suitable crystal for X-
1
over MgSO4, filtered, and concentrated under reduced pressure. ray analysis. H-NMR (400 MHz, CDCl3) δ: 7.50 (2H, d, J =
The crude material was purified by silica gel flash column 8.8 Hz, BrC6H4CO-), 7.40 (2H, d, J = 8.8 Hz, PhCH2OCO-),
chromatography (EtOAc/n-hexane = 17:83) to afford 2 (42.6 3.86 (1H, ddd, J = 13.2, 3.3, 3.3 Hz, H-9), 3.60 (1H, dd, J =
mg, 57% in 3 steps) as a pale yellow oil and 13 (12.2 mg, 16% 13.4, 3.5 Hz, H-13), 2.94 (1H, ddd, J = 13.5, 13.5, 3.3 Hz, H-9),
in 3 steps) as a pale yellow oil. Compound 2: 1H NMR (CDCl3, 2.40-2.32 (3H, overlapped), 2.20-2.09 (4H, overlapped), 2.04
400 MHz) δ: 7.40-7.26 (5H, overlapped, PhCH2OCO-), 5.24 (1H, br-dd, J = 12.4, 4.0 Hz), 1.73-1.60 (2H, overlapped), 1.56-
(1H, d, J = 12.6 Hz, PhCH2OCO-), 5.10 (1H, d, J = 12.6 Hz, 1.33 (4H, overlapped), 1.04 (3H, d, J = 7.3 Hz, H-16). 13C-
PhCH2OCO-), 4.35 (1H, m, H-9), 3.37 (1H, dd, J = 13.5, 3.7 NMR (150 MHz, CDCl3) δ: 217.8, 170.6, 138.2, 131.4, 128.1,
Hz, H-13), 2.74 (1H, ddd, J = 13.0, 13.0, 2.6 Hz, H-9), 2.42 122.7, 58.9, 53.1, 49.9, 40.8, 34.8, 34.5, 34.0, 32.4, 27.6, 23.3,
(1H, ddd, J = 13.5, 13.5, 4.0 Hz), 2.36-2.30 (2H, overlapped), 21.9, 16.7. IR (ATR) νmax cm-1: 2961, 2929, 2856, 1724, 1644,
2.17-2.06 (3H, overlapped), 2.04 (1H, m), 1.94 (1H, m), 1.71 1585, 1435, 1365, 1115. HR-MS (ESI): calcd for C20H25NO2Br
(1H, m), 1.52-1.24 (5H, overlapped), 1.01 (3H, d, J = 7.3 Hz, [M+H]+ 390.1069; found 390.1064. [α]21D –44 (c 0.54, CHCl3).
H-16). 13C NMR (CDCl3, 100 MHz) δ: 217.5, 155.9, 137.5, m.p.: 158.8-159.2 °C (plate).
128.3, 127.8, 127.5, 66.5, 58.1, 53.1, 48.5, 40.6, 34.72, 34.68,
34.6, 33.4, 27.8, 23.2, 21.5, 16.6. IR (ATR) νmax cm-1: 1731, (4aR,6aR,8R)-4-(4-Bromobenzoyl)-8-
1711, 1683. HR-MS (ESI): calcd for C21H27NO3Na [M+Na]+ methyldecahydroindeno[1,7a-b]pyridin-10(1H)-one (15)
364.1889; found 364.1871. [α]27 –28 (c 0.110, CHCl3). To a solution of 13 (38.0 mg, 0.112 mmol) in MeOH (1.1 mL)
D
1
Compound 13: H-NMR (600 MHz, CDCl3) δ: 7.39-7.26 (5H, was added 10% Pd/C (11.9 mg, 0.011 mmol) at room
overlapped, PhCH2OCO-), 5.20 (1H, d,
J = 12.7 Hz, temperature under argon atmosphere. Then, the reaction
PhCH2OCO-), 5.14 (1H, d, J = 12.7 Hz, PhCH2OCO-), 4.35 mixture was vigorously stirred for 1 h at room temperature
(1H, br-d, J = 13.7 Hz), 2.76 (1H, dd, J = 12.7, 7.2 Hz), 2.66 under 1.0 atm pressure of hydrogen atmosphere. The reaction
(1H, ddd, J = 13.1, 13.1, 3.1 Hz), 2.42 (1H, br-s), 2.28 (1H, br- mixture was filtered through a pad of Celite®, and the filtrate
d, J = 13.1 Hz), 2.22 (1H, br-s), 2.16 (1H, d, J = 13.1 Hz), 2.12 was concentrated under reduced pressure to afford the crude
(1H, br-d, J = 13.1 Hz), 2.09-2.02 (2H, overlapped), 1.75 (2H, product as a pale yellow oil, which was used in the next
overlapped), 1.60 (1H, ddd, J = 14.4, 11.7, 4.8 Hz), 1.52-1.39 reaction without further purification. To a solution of the crude
(3H, overlapped), 1.35 (1H, ddd, J = 13.0, 13.0, 3.8 Hz), 1.00 material in THF (1.1 mL) were added Et3N (35 µL, 0.246
(3H, d, J = 6.2 Hz, H-16). 13C-NMR (150 MHz, CDCl3) δ: mmol) and p-bromobenzoyl chloride (27.0 mg, 0.123 mmol) at
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
0 °C. After stirring at room temperature for 13.5 h under argon Benzyl
ARTICLE
(4aR,5S,7aS,9R,10aS)-5-allyl-5-hydroxy-9-
View Article Online
DOI: 10.1039/C5OB00827A
atmosphere, the reaction mixture was diluted with CHCl3 and methyldecahydrocyclopenta[e]quinoline-1(2H)-carboxylate
saturated aqueous NaHCO3 solution. The organic phase was (17)
separated, and the aqueous phase was extracted three times with Compound 16 (50.2 mg, 0.182 mmol) was dissolved in a
CHCl3. The combined organic extracts were washed with brine, solution of KOH (102.1 mg, 1.82 mmol) in EtOH (1.8 mL) at
dried over MgSO4, filtered, and concentrated under reduced 0 °C under argon atmosphere. The reaction mixture was
pressure. The crude material was purified by silica gel flash refluxed for 12 h. After the reaction mixture was concentrated,
column chromatography (EtOAc/n-hexane = 50:50) to afford the resultant crude material was dissolved in 10%
15 (25.0 mg, 57% in 2 steps) as colorless platelet crystals. MeOH/CH2Cl2 and H2O, and then the resultant mixture was
Recrystallization of 15 from a mixed solvent of EtOAc/n- extracted five times with 10% MeOH/CH2Cl2. The combined
hexane under ambient temperature gave a suitable crystal for X- organic extracts were dried over MgSO4, filtered, and
1
ray analysis. H-NMR (400 MHz, CDCl3) δ: 7.50 (2H, d, J = concentrated under reduced pressure to afford the crude product
8.8 Hz, PhCH2OCO-), 7.43 (2H, br-d, J = 8.1 Hz, PhCH2OCO-), as a pale yellow oil, which was used in the next reaction
4.08 (1H, br-s), 2.97 (1H, dd, J = 12.4, 7.0 Hz), 2.73 (1H, ddd, without further purification. To a solution of the crude material
J = 13.5, 13.5, 3.6 Hz), 2.34 (1H, br-d, J = 11.0 Hz), 2.25-2.05 in CH2Cl2 (3.6 mL) and H2O (1.8 mL) was added Na2CO3
(5H, overlapped), 1.77-1.39 (8H, overlapped), 1.01 (3H, d, J = (192.9 mg, 1.82 mmol) at 0 °C. After the reaction mixture was
6.6 Hz, H-16). 13C-NMR (150 MHz, CDCl3) δ: 213.8, 170.6, stirred vigorously at room temperature for 10 min under argon
137.7, 131.2, 129.1, 123.4, 66.2, 55.6, 48.5, 48.2, 44.9, 33.7, atmosphere, CbzCl (78 µL, 0.546 mmol) was added at 0 °C,
33.2, 30.1, 27.0, 24.9, 22.2, 21.9. IR (ATR) νmax cm-1: 2944, and the reaction mixture was stirred for another 20 h at room
2909, 2884, 1701, 1638, 1586, 1459, 1439, 1376, 1358, 1260. temperature. After adding CHCl3 and saturated aqueous
HR-MS (ESI): calcd for C20H25NO2Br [M+H]+ 390.1069; NaHCO3 solution, the resultant mixture was extracted three
found 390.1056. [α]21 +70 (c 0.59, CHCl3). m.p.: 148.0- times with CHCl3. The combined organic extracts were washed
D
148.5 °C (plate).
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by silica gel
flash column chromatography (EtOAc/n-hexane = 5:95) to give
17 (54.5 mg, 78% in 2 steps) as a colorless oil. 1H NMR
(1R,4aR,5S,7aS,9R,10aS)-5-Allyl-9-methyldecahydro-2H-
5,1-(epoxymethano)cyclopenta[e]quinolin-12-one (16)
To a stirred solution of 2 (141.2 mg, 0.414 mmol) in THF (4.2 (CDCl3, 400 MHz) δ: 7.39-7.28 (5H, overlapped, PhCH2OCO-),
mL) was slowly added allylmagnesium bromide (1.0 M in Et2O, 5.95 (1H, dddd, J = 17.2, 10.3, 7.0, 7.0 Hz, H-2), 5.16 (1H, d, J
0.50 mL, 0.50 mmol) at 0 °C under argon atmosphere, and the = 12.4 Hz, PhCH2OCO-), 5.13 (1H, d, J = 12.4 Hz,
resultant mixture was stirred at room temperature. After 1 h 45 PhCH2OCO-), 5.01 (1H, br-dd, J = 10.3, 2,2 Hz, H-1), 4.92 (1H,
min, 2 still remained in the reaction mixture. To the reaction br-dd, J = 16.8, 2.2 Hz, H-1), 4.29 (1H, dd, J = 13.5, 6.2 Hz, H-
mixture was slowly introduced an additional amount of 9), 4.01 (1H, br-s, -OH), 3.36 (1H, dd, J = 13.5, 5.1 Hz, H-13),
allylmagnesium bromide (1.0 M in Et2O, 0.50 mL, 0.50 mmol) 3.16 (1H, ddd, J = 13.2, 13.2, 6.6 Hz, H-9), 3.04 (1H, ddd, J =
at 0 °C under argon atmosphere, and the resultant mixture was 13.2, 13.2, 4.0 Hz), 2.25 (1H, m), 2.20 (2H, d, J = 7.0 Hz),
stirred for an additional 1 h 15 min at room temperature. After 1.99-1.71 (7H, overlapped), 1.51-1.21 (5H, overlapped), 1.01
adding saturated aqueous NH4Cl solution at 0 °C, the resultant (3H, d, J = 7.0 Hz, H-16). 13C NMR (CDCl3, 150 MHz) δ:
mixture was extracted three times with EtOAc. The combined 156.0, 136.5, 135.9, 128.6, 128.1, 127.9, 116.5, 85.0, 67.0, 61.7,
organic extracts were washed with brine, dried over MgSO4, 51.4, 49.9, 47.3, 46.6, 37.9, 37.8, 34.5, 33.2, 27.0, 26.6, 24.3,
filtered, and concentrated under reduced pressure. The crude 19.6. IR (ATR) ν max cm-1: 3421, 2955, 2927, 1675, 1481, 1438,
material was purified by silica gel flash column 1385, 1358, 1281, 1239, 1213, 1161, 1120, 1095, 1027, 911.
chromatography (EtOAc/n-hexane = 30:70) to afford 16 (103.6 HR-MS (ESI): calcd for C24H33NO3Na [M+Na]+: 406.2358,
1
mg, 91%) as a colorless solid. H NMR (CDCl3, 600 MHz) δ: found: 406.2341. [α]28D –64 (c 0.29, CHCl3)
6.05 (1H, dddd, J = 17.2, 9.6, 5.5, 5.5 Hz, H-2), 5.20 (1H, d, J =
9.6 Hz, H-1), 5.12 (1H, d, J = 17.2 Hz, H-1), 3.96 (1H, dd, J = Benzyl
(4aS,7aR,9R,10aS)-5-allyl-9-methyl-
13.1, 6.9 Hz, H-9), 3.12 (1H, ddd, J = 13.1, 13.1, 4.1 Hz, H-9), 3,4,7,7a,8,9,10,10a-octahydrocyclopenta[e]quinoline-1(2H)-
2.94 (1H, dd, J = 13.1, 6.9 Hz, H-13), 2.60 (1H, ddd, J = 14.4, carboxylate (18)
4.8, 2.0 Hz), 2.28-2.24 (2H, overlapped), 2.03-1.95 (4H, To a stirred solution of 17 (9.9 mg, 0.026 mmol) in CH2Cl2 (0.5
overlapped), 1.93-1.85 (2H, overlapped), 1.77 (1H, m), 1.69 mL) were added pyridine (32 µL, 0.387 mmol) and SOCl2 (4.0
(1H, m), 1.62 (1H, m), 1.48 (1H, dd, J = 13.7, 8.2 Hz), 1.44- µL, 0.052 mmol) at 0 °C under argon atmosphere. After stirring
1.34 (2H, overlapped), 1.31 (1H, m), 1.01 (3H, d, J = 6.9 Hz, for 2 h at 0 °C and for 3 h at room temperature, the reaction
H-16). 13C NMR (CDCl3, 150 MHz) δ: 161.6, 133.2, 118.8, mixture was concentrated. The crude material was purified by
95.1, 60.9, 54.6, 45.7, 43.4, 40.3, 37.3, 34.12, 34.06, 31.1, 27.2, silica gel flash column chromatography (EtOAc/n-hexane =
1
24.6, 24.5, 23.0. IR (ATR) ν max cm-1: 2923, 1696, 1508, 1474, 5:95) to afford 18 (8.4 mg, 89%) as a colorless oil. H NMR
1344, 1245, 1218, 1185, 1062, 1006, 956, 920, 865, 836. HR- (CDCl3, 600 MHz) δ: 7.39-7.28 (5H, overlapped, PhCH2OCO-),
MS (ESI): calcd for C16H25NNa [M–CO2+Na]+: 254.1885, 5.87 (1H, dddd, J = 17.2, 10.3, 6.9, 6.9 Hz), 5.35 (1H, br-s),
found: 254.1877. [α]24D +30 (c 0.07, CHCl3).
5.12 (1H, d, J = 12.4 Hz, PhCH2OCO-), 5.05 (1H, d, J = 12.4
Hz, PhCH2OCO-), 4.99 (1H, dd, J = 10.3, 1.4 Hz, H-1), 4.95
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ARTICLE
Journal Name
(1H, dd, J = 17.2, 1.4 Hz, H-1), 4.47 (1H, br-dd, J = 13.1, 4.8 extracted five times with 10% MeOH/CHCl3. TVhieew cArotimclebOinnleinde
DOI: 10.1039/C5OB00827A
Hz, H-9), 3.35 (1H, dd, J = 13.7, 3.4 Hz, H-13), 3.04 (1H, br-d, organic extracts were dried over MgSO4, filtered, and
J = 17.9 Hz), 2.84 (1H, dd, J = 13.1, 13.1, 2.7 Hz, H-9), 2.84 concentrated under reduced pressure to afford the crude product
(1H, m), 2.47 (1H, m), 2.26 (1H, ddd, J = 13.1, 13.1, 4.8 Hz), as a green solid, which was used in the next reaction without
2.06 (1H, m), 2.00-1.93 (3H, overlapped), 1.78 (1H, m), 1.62 further purification. To a solution of the crude material in Et2O
(1H, br-d, J = 15.8 Hz), 1.56-1.38 (3H, overlapped), 1.23 (1H, (1.0 mL) was added Et3N (3 µL, 0.019 mmol) at 0 °C. After
m), 0.99 (3H, d, J = 6.9 Hz, H-16). 13C NMR (CDCl3, 150 stirring at 0 °C for 15 min under argon atmosphere,
MHz) δ: 154.6, 147.5, 137.2, 136.7, 128.4, 128.0, 127.8, 125.6, diphenylphosphoryl azide (4.0 mL, 0.019 mmol) was added to
115.4, 66.5, 59.8, 53.3, 48.6, 44.7, 39.9, 35.6, 35.3, 34.5, 34.1, the reaction mixture at 0 °C and the reaction mixture was
27.6, 23.6, 18.1. IR (ATR) ν max cm-1: 2959, 2940, 2917, 1706, stirred for 1 h at the same temperature. After adding Et2O and
1457, 1437, 1376, 1264, 1236, 1173, 1069, 909. HR-MS (ESI): saturated aqueous NaHCO3 solution, the resultant mixture was
calcd for C24H32NO2 [M+H]+: 366.2433, found: 366.2416. extracted three times with Et2O. The combined organic extracts
[α]26D –28 (c 0.10, CHCl3).
were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure at ambient temperature.
Benzyl
(4aS,5S,6S,7aR,9R,10aS)-6-hydroxy-5-(3- To a solution of the crude material in toluene (0.5 mL) was
hydroxypropyl)-9-methyldecahydrocyclopenta[e]quinoline-
1(2H)-carboxylate (19)
added PPh3 (3.3 mg, 0.013 mmol) at 0 °C. The reaction mixture
was stirred for 1 h at room temperature and refluxed for 12 h.
To a stirred solution of 18 (9.5 mg, 0.026 mmol) in THF (1.0 After adding EtOAc and saturated aqueous NaHCO3 solution,
mL) was added 9-BBN (0.5 M in THF, 156 µL, 0.078 mmol) at the resultant mixture was extracted five times with EtOAc. The
0 °C under argon atmosphere. After stirring for 2.5 h at room combined organic extracts were washed with brine, dried over
temperature, BH3·THF (1 M in THF, 156 µL, 0.078 mmol) was MgSO4, filtered, and concentrated under reduced pressure. The
added, and then the resultant mixture was stirred for 9.5 h at crude material was purified by silica gel flash column
room temperature. A mixture consisting of 30% aqueous H2O2 chromatography (MeOH/CHCl3 = 2:98) to afford 23 (2.6 mg,
1
solution (160 µL, 1.56 mmol) and 2N aqueous NaOH solution 53% in 3 steps) as a colorless oil. H NMR (CDCl3, 400 MHz)
(0.78 mL, 1.56 mmol) was added dropwise while the reaction δ: 7.39-7.25 (6H, overlapped, H-3 and PhCH2OCO-), 6.15 (1H,
temperature maintained 0 °C, and then the resultant mixture d, J = 9.1 Hz, H-2), 5.14 (1H, d, J = 12.4 Hz, PhCH2OCO-),
was stirred for 7.5 h at room temperature. Saturated aqueous 5.07 (1H, d, J = 11.8 Hz, PhCH2OCO-), 4.52 (1H, br-d, J =
Na2S2O3 solution was added to the mixture. After stirring for 40 12.0 Hz, NH), 3.41 (1H, dd, J = 13.1, 3.0 Hz, H-9), 3.09 (1H,
min at 25 °C, the mixture was extracted five times with 10% dd, J = 16.9, 6.4 Hz, H-13), 2.88 (1H, m, H-9), 2.33 (1H, d, J =
MeOH/CHCl3. The combined organic extracts were dried over 17.0 Hz), 2.26-2.16 (2H, overlapped), 2.05 (1H, br-s), 1.92 (1H,
MgSO4, filtered, and concentrated under reduced pressure. The br-d, J = 13.7 Hz), 1.77 (1H, m), 1.68-1.54 (2H, overlapped),
crude material was purified by silica gel flash column 1.47-1.35 (3H, overlapped), 1.01 (3H, d, J = 6.8 Hz, H-16). 13
C
chromatography (MeOH/CHCl3 = 5:95) to afford 19 (7.7 mg, NMR (CDCl3, 150 MHz) δ: 165.4, 154.9, 150.2, 140.6, 136.9,
1
74% in 3 steps) as a colorless oil. H NMR (CDCl3, 400 MHz) 128.4, 128.3, 128.1, 122.0, 116.1, 66.7, 59.8, 50.9, 48.7, 42.5,
δ: 7.36-7.30 (5H, overlapped, PhCH2OCO-), 5.07 (2H, s, 38.8, 35.5, 34.2, 33.0, 26.9, 22.8, 18.0. IR (ATR) ν max cm-1:
PhCH2OCO-), 4.38 (1H, m, H-9), 4.25 (1H, ddd, J = 7.4, 7.4, 2929, 1715, 1654, 1558, 1456. UV (MeOH) λmax nm: 320.5,
3.7 Hz, H-5), 3.52 (2H, m, H-1), 3.30 (1H, dd, J = 13.7, 4.1 Hz, 235.0, 203.0. HR-MS (ESI): calcd for C24H29N2O3 [M+H]+:
H-13), 2.81 (1H, ddd, J = 13.1, 13.1, 2.8 Hz, H-9), 2.67 (1H, 393.2178, found: 393.2162. [α]26 –27 (c 0.09, CHCl3).
D
ddd, J = 13.7, 13.7, 5.0 Hz), 2.18-2.12 (2H, overlapped), 2.05 *Preparation of Jones' reagent: To a solution of CrO3 (399 mg)
(1H, m), 1.92-1.68 (8H, overlapped), 1.51-1.33 (5H, in H2O (1.2 mL) were slowly added H2SO4 (0.3 mL) and H2O
overlapped), 0.99 (3H, d, J = 7.2 Hz, H-16). 13C NMR (CDCl3, (0.3 mL) at 0 °C.
150 MHz) δ: 154.4, 137.1, 128.5, 127.9, 127.8, 80.9, 66.5, 62.8,
61.5, 54.0, 49.4, 48.5, 43.0, 41.7, 39.1, 35.6, 34.1, 32.1, 30.1, (–)-Lycoposerramine-R (1)
27.8, 22.8, 17.3. IR (ATR) ν max cm-1: 3629, 3428, 2928, 1684, To a solution of 23 (1.0 mg, 2.55 µmol) in MeOH (0.5 mL) was
1457. HR-MS (ESI): calcd for C24H35NO4Na [M+Na]+: added 10% Pd/C (2.7 mg, 2.55 µmol) at room temperature. The
424.2464, found: 424.2447. [α]26 –32 (c 0.10, CHCl3).
reaction mixture was stirred for 2 h at room temperature under
1.0 atm pressure of hydrogen atmosphere. The reaction mixture
D
Benzyl
(4aS,6R,7aR,12bS)-6-methyl-10-oxo- was concentrated and the crude material was purified by amino-
2,3,4a,5,6,7,7a,8,9,10-
silica gel open column chromatography (MeOH/EtOAc = 5:95)
decahydropyrido[2',3':4,5]cyclopenta[1,2-e]quinoline-
4(1H)-carboxylate (23)
and then by amino-silica gel open column chromatography
(MeOH/CHCl3 = 5:95) to afford 1 (0.66 mg, quant.) as a
To a stirred solution of 19 (5.0 mg, 0.013 mmol) in acetone (0.3 colorless oil. Synthetic 1, [α]26 –26.1 (c 0.03, CHCl3), was
D
mL) was added Jones' reagent* at –40 °C until the color completely identical in all respects (chromatographic behavior
(orange) of the reagent persisted under argon atmosphere, and and UV, 1H NMR, 13C NMR, optical property, and mass
the reaction mixture was stirred for 1 h at the same temperature. spectra) with the natural compound.
After adding i-PrOH at –40 °C to destroy excess reagent, the
reaction mixture was concentrated. The resultant mixture was
8 | J. Name., 2012, 00, 1-3
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ARTICLE
Chem. Soc., 2014, 136, 11618-11621; (c) A. Nakayama, M.
Acknowledgements
View Article Online
Kitajima and H. Takayama, Synlett, 2012, 2014-2024; (d) K.
DOI: 10.1039/C5OB00827A
Katakawa, H. Mito, N. Kogure, M. Kitajima, S.
Wongseripipatana, M. Arisawa and H. Takayama,
Tetrahedron, 2011, 67, 6561-6567; (e) A. Nakayama, N.
Kogure, M. Kitajima and H. Takayama, Angew. Chem. Int.
Ed., 2011, 50, 8025-8028; (f) K. Katakawa, N. Kogure, M.
Kitajima and H. Takayama, Helv. Chim. Acta, 2009, 92, 445-
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Takayama, Org. Lett., 2009, 11, 5554-5557; (h) T. Tanaka, N.
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M. Kitajima and H. Takayama, Org. Lett., 2007, 9, 4069-
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This work was supported by JSPS KAKENHI Grant Numbers
25293023 and 25460005.
Notes and references
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In our previous study on racemic synthesis of 1, the
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2
3
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NR1R2
O
O
4
R1=Bn, R2=Cbz: 3
13
R1=H, R2=Cbz: 24
R1=Bn, R2=H: 25
R1=R2=H: 26
Me
H
7
8
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CCDC 1055700 contains the supplemental crystallographic
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supplemental crystallographic data of 15 for this paper.
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