Synthetic Studies on FNC-RED and Its Analogues Containing an All syn-Cyclopentanetetrol Moiety

Article abstract of DOI:10.1021/acs.joc.9b02101

FNC-RED exhibits innate immune receptor Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) stimulatory activity. We have developed a divergent synthetic route to FNC-RED derivatives containing various alkyl side chains. Key features of the

Full text of DOI:10.1021/acs.joc.9b02101

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Note
Synthetic Studies on FNC-RED and Its Analogues
Containing an All syn-Cyclopentanetetrol Moiety
Shinsuke Inuki, Keisuke Sato, Naoto Zui, Ryosuke Yamaguchi, Takanori Matsumaru, and Yukari Fujimoto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02101 • Publication Date (Web): 11 Sep 2019
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The Journal of Organic Chemistry
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Synthetic Studies on FNC-RED and Its Analogues
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Containing an All syn-Cyclopentanetetrol Moiety
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Shinsuke Inuki,†, ‡ Keisuke Sato,† Naoto Zui,† Ryosuke Yamaguchi,† Takanori Matsumaru,† and Yukari
Fujimoto*,†
†Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama,
Kanagawa 223-8522, Japan
‡Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 Japan
fujimotoy@chem.keio.ac.jp.
TOC:
HO
OR2
N
O
OH
OH
Stepwise cross-coupling
reactions
R3
Z
Y
HO
R1
O
R2O
+
Construction of all syn-
cyclopentanetetrol moiety
HO
O
R2O
N
R1 X
+
FNC-RED derivatives
Abstract: FNC-RED exhibits innate immune receptor Toll-like receptor 4 (TLR4)/myeloid
differentiation factor-2 (MD2) stimulatory activity. We have developed a divergent synthetic route to
FNC-RED derivatives containing various alkyl side chains. Key features of the synthetic study include
stepwise palladium catalyzed cross-coupling reactions and the construction of an all syn-
cyclopentanetetrol moiety.
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FNC-RED1 is a reduced derivative of funiculosin, an unusual secondary metabolite isolated from
Penicillium funiculosum THOM reported by Ando and co-workers in 1969 (Figure 1).2-3 FNC-RED consists
of a unique hydroxy-2-pyridinone core structure containing an all syn-cyclopentanetetrol moiety, which
is the common structure of funiculosin. Recently, we have reported that FNC-RED and its derivatives are
recognized by the innate immune receptor Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2
(MD2), and induce NF-kB activation via murine TLR4/MD2, although naturally occurring funiculosin
exhibits no TLR4/MD2 stimulatory activity. FNC-RED and its variants contain saturated and branched-
alkyl side chains, and were obtained through the reduction of funiculosin extracted from the soil
bacterium. Among the derivatives containing several kinds of alkyl side chains, FNC-RED was shown to
be the strongest activator of NF-kB, indicating that the structures of the alkyl side chain of funiculosin
derivatives might be a key to its modulation of TLR4/MD2 recognition. Numerous studies have revealed
that TLR4/MD2 signaling is involved in various metabolic or autoimmune disorders.4 Therefore,
TLR4/MD2 modulators have recently garnered attention as potential therapeutic agents, and several
TLR4/MD2 activators and inhibitors have been developed.5-7 Total synthesis of funiculosin has not been
reported to date, and even the synthetic studies for its derivatives are scarce. Williams group performed
synthetic studies on funiculosin, and accomplished the synthesis of its methoxy derivatives through the
elegant late-stage construction of a pyridinone core structure.8-9 Several groups have reported the total
syntheses of the related natural products featuring the central 4-hydroxy-2-pyridinone core structure,10
such as tenellin,11 sambutoxin12 or apiosporamide.13
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HO
OH
OH
HO
HO
N
O
FNC-RED
HO
OH
OH
HO
O
H
O
H
HO
N
Funiculosin
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The Journal of Organic Chemistry
Figure 1. Structures of FNC-RED and funiculosin.
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Herein, we planned to develop a concise and divergent synthetic route to FNC-RED and its derivatives
for the purposes of structure–activity relationship (SAR) studies, in particular, focusing on the
derivatization of alkyl side chains for the exploration of novel TLR4/MD2 modulators. The synthetic
strategy toward FNC-RED and its derivatives is shown in Scheme 1. We expected late stage cross
coupling reactions (Suzuki-Miyaura coupling etc.) to introduce various alkyl side chains (R1 groups) to
hydroxy-2-pyridinone containing all syn-cyclopentanetetrol fragments 2. The all syn-cyclopentanetetrol
moiety linked to the 4-hydroxy-2-pyridinone 2 would be synthesized through a cross-coupling reaction,
such as Heck type reaction or Stille coupling reaction, between the cyclopentenone derivative 3 and the
hydroxy-2-pyridinone core 4, followed by functionalization of the cyclopentenone portion. Central
challenges to accomplish the synthesis are the development of efficient C-C bond formation reactions of
the hydroxy-2-pyridinone core with the cyclopentenone 3 and alkyl side chains (R1 groups), and the
construction of an all syn-cyclopentanetetrol moiety linked to the 4-hydroxy-2-pyridinone.
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O
R3
R2O
R2O
R2O
HO
R2O
OR2
OR2
OH
OH
R1
X
(R3 = H or Sn)
3
HO
R1
O
Y
+
OR2
R2O
HO
N
N
O
Cross-coupling
reaction
(Suzuki
Cross-coupling
reaction
(Heck type or
Stille coupling
reaction etc.)
Z
Y
R1 = alkyl side chains
1
2
N
O
coupling etc.)
4
(Y, Z = halogens)
Scheme 1. Retrosynthetic analysis of FNC-RED derivative 1.
Our synthesis began with the preparation of the all syn-cyclopentenediol 3 as shown in Scheme 2. The
known iodide 614 was readily prepared via the cyclopentenone 5 starting from D-(–)-ribose, by following
the published procedure.15 The reaction of 6 with (n-Bu3Sn)2 or (Me3Sn)2 in the presence of Pd(PPh3)4
afforded the coupling precursors 7 and 8, respectively.16 Next, we prepared 4-hydroxy-2-pyridinone 11
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as shown in Scheme 3. 2-Pyridinone derivative 10 was easily accessible from commercially available 4-
chloropyridine N-oxide 9.17-18 The selective stepwise bromination and iodination gave the desired
coupling precursor 11 in high yield.19
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9
(n-Bu3Sn)2
Pd(PPh3)4
Toluene, 85°C
R1
SnR2
3
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HO
O
O
O
OH
or
6 steps
HO
D-ribose
OH
(Me3Sn)2
Pd(PPh3)4
Toluene, 100°C
O
O
O
O
(R1 = H)
(R1 = I)
7
8
(R2 = n-Bu): 21%
(R2 = Me): 72%
5
6
ref. 14
Scheme 2. Synthesis of cyclopentene fragments 7 and 8
Cl
OBn
Br
OBn
1) NBS
CH2Cl2
I
N
O
N
O
N
O
2) NIS
TFA
MeCN
3 steps
9
10
11
81% (2 steps)
Scheme 3. Synthesis of 4-hydroxy-2-pyridinone derivative 11
With the requisite coupling precursors in hand, we went on to investigate the palladium catalyzed
coupling reaction between the cyclopentenone derivative and the hydroxy-2-pyridinone core. Initially, we
examined the Heck type reaction between the cyclopentenone 5 and 4-hydroxy-2-pyridinone 11.20 To
achieve the efficient conversion to the desired compound, the selective oxidative addition of the iodide
group to the palladium catalyst should be required. Balme group developed the site-selective Suzuki
coupling reaction of 3-bromo-5-iodo-2-pyridone, resulting from the lower capability of the C–Br bond to
oxidative addition to palladium than the C–I bond.19 Cho group and Sarpong group reported that the
regioselective Stille coupling reactions of 3,5-dibromo-2-pyrone depending on the reaction conditions.21-
22 All our initial attempts to carry out the Heck type reaction failed to produce the desired coupling product
in a reasonable yield. Thus, we next investigated the Stille coupling reaction of stannane 7 with
dihalopyridinone 11 (Table 1). The reaction of the stannane 7 with 11, Pd(PPh3)4 and CuI in DMF at 85 ℃
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provided the desired compound 12 in moderate yield (61%, entry 1).23-24 Changing the palladium source
to PdCl2(MeCN)2 or PdCl2(dppf) did not improve the yield of the desired products (entries 2 and 3). The
addition of LiCl also did not have a positive effect on the reaction course (entry 4). The use of substrate
8 lead to a slight increase in the yield to 63% (entry 5).
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Table 1. Optimization of Stille coupling reaction
SnR2
3
OBn
O
O
OBn
N
I
Br
O
Pd catalysts
O
Br
O
+
additive, CuI, DMF
N
O
O
O
(R2 = n-Bu)
(R2 = Me)
12
7
8
11
entrya sub. Pd catalyst additive yield (%)b
1
2
7
7
7
7
8
Pd(PPh3)4
PdCl2(MeCN)2
PdCl2(dppf)
Pd(PPh3)4
-
61
9
-
3
-
LiCl
-
22
4 c
5
ND d
63
Pd(PPh3)4
a Reactions were carried out with 1.0 equiv of 7 or 8, 2.0 equiv of 11, 10 mol % of Pd catalysts, 1.0 equiv
of CuI in DMF at 85 ℃. b Isolated yields. c Reactions were carried out with 4.0 equiv of LiCl, 10 mol %
of Pd catalysts and 1.0 equiv of CuI in DMF. d ND = Not detected.
Next, we focused on the construction of the requisite all cis-cyclopentyl moiety (Scheme 4). The selective
reduction of the carbonyl group with NaBH4 in the presence of CeCl3∙7H2O gave the alcohol 13, which
was protected with the TES group. The use of BH3∙SMe2 allowed the regio- and stereoselective
introduction of the hydroxyl group to the cyclopentane ring in moderate yield (51%). The oxidation of
the resulting alcohol 15 gave the corresponding ketone. A subsequent reduction with NaBH4 proceeded
selectively from the less-hindered convex face to furnish the desired functionalized cyclopentyl moiety
with an all-syn configuration. The configuration of the functionalized cyclopentyl moiety was confirmed
by X-ray crystallographic analysis of its derivative 17.
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O
O
OBn
N
1
2
3
4
OBn
N
NaBH4
CeCl3·7H2O
TESCl
imidazole
O
O
Br
O
Br
O
12
TESO
HO
MeOH, 0 °C
91%
DMF, 0 °C
96%
13
14
5
6
7
8
9
O
O
OH
OH
BH3·SMe2
THF, 0 °C
1) DMP
CH2Cl2
OBn
N
OBn
O
O
Br
O
Br
then
6M NaOH aq.
30% H2O2 aq.
2) NaBH4
MeOH
–10 °C
TESO
TESO
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N
O
15
16
51%
72% (2 steps)
O
OH
OBn
N
O
TBAF
Br
O
THF, 0 °C
HO
88%
17
17
ORTEP of
Scheme 4. Synthesis of hydroxy-2-pyridinone containing the all cis-tetrahydroxycyclopentyl fragment 17
Finally we examined the introduction of alkyl side chains to the 4-hydroxy-2-pyridinone core structure,
and the conversion to the funiculosin derivatives containing various alkyl side chains (Scheme 5). After
several investigations, we found that the TES protection of the hydroxyl group was needed to achieve the
palladium cross-coupling reaction efficiently to connect with the alkyl side chains. The reaction of the
TES protected derivative 18 with alkenyl pinacol boronates, Pd(OAc)2, and XPhos provided the desired
compound 19a,25 and 19b, which were readily converted into the FNC-RED derivative 21a and 21b by
the removal of acetal and Bn groups and the reduction of olefin group.
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The Journal of Organic Chemistry
R3
O
B
1
2
3
4
5
6
7
O
O
O
OTES
OBn
OTES
OBn
TESCl
imidazole
Pd(OAc)2
XPhos
O
O
R3
Br
O
16
DMF
96%
K3PO4·nH2O
THF, 60 °C
TESO
TESO
N
N
O
(R3 = n-C8H17): 65%
(R3 = n-C10H21): 68%
18
19a
8
19b
9
10
11
12
13
14
15
16
17
18
HO
HO
HO
OH
OH
OBn
N
TFA/THF/H2O
(1:3:3), 60 C
OH
HO
R3
Pd(OH)2/C, H2
MeOH
R4
O
HO
HO
O
N
(R3 = n-C8H17): 68%
(R3 = n-C10H21): 68%
(R4 = n-C10H21): 79%
(R4 = n-C12H25): quant.
20a
21a
21b
20b
Scheme 5. Synthesis of funiculosin derivatives containing alkyl side chains
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In conclusion, we have developed an efficient synthetic route to FNC-RED derivatives containing alkyl
side chains through the stepwise cross-coupling reaction using palladium catalysts and the construction
of a functionalized cyclopentyl moiety with an all-syn configuration. This synthetic route takes an
advantage of the late-stage introduction of the alkyl side chains into the pyridinone core, paving the way
to the divergent synthesis of FNC-RED derivatives.
Experimental Section
General Methods. All moisture-sensitive reactions were performed using syringe-septum cap
techniques under an argon atmosphere and all glassware was dried in an oven at 80 °C for 2 h prior to
use. Reactions at –78 °C employed a CO2–MeOH bath. An oil bath was used for conventional heating.
Analytical thin layer chromatography (TLC) was performed on Silica gel 60 F254 Plates (Merck, 0.25 mm
thickness). For flash chromatography, Silica gel 60 N [spherical neutral (Kanto Chemical Co., 40-50 m)]
was employed. All NMR spectral data were recorded on a JEOL ECX-400 spectrometer for 1H (400 MHz)
13
and C{1H} (100 MHz). Chemical shifts are reported in  (ppm) relative to TMS in CDCl3 as internal
standard (1H NMR) or the residual CHCl3 signal (13C NMR). 1H NMR spectra are tabulated as follows:
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chemical shift, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
number of protons, and coupling constant(s). Exact mass (HRMS) spectra were recorded on an
electronspray ionization quadrupole time of flight (ESI-QTOF) mass spectrometer (micrOTOF-QII-HC;
BRUKER).
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(3aR,6aR)-2,2-Dimethyl-5-(tributylstannyl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one (7).
To a dried round-bottom flask equipped with a stir bar were added 6 (154 mg, 0.548 mmol) and Pd(PPh3)4
(127 mg, 0.110 mmol). After the flask was sealed and evacuated then backfilled argon, toluene (5.0 mL)
and (n-Bu3Sn)2 (0.548 mL, 1.10 mmol) were added to the flask. After being stirred for 12 h at 85 ˚C, the
mixture quenched with H2O. The whole was extracted three times with EtOAc. The combined organic
layers were dried over Na2SO4. The filtrate was concentrated under reduced pressure, which was purified
by flash chromatography over silica gel with n-hexane-EtOAc (9:1) to give 7 as pale yellow oil (51.6 mg,
21% yield): 1H NMR (400MHz, CDCl3) δ: 7.65 (d, J = 2.2 Hz, 1H), 5.22 (dd, J = 5.5, 2.2 Hz, 1H), 4.43
(d, J = 5.5 Hz, 1H), 1.53-1.45 (m, 6H), 1.40 (s, 3H), 1.38 (s, 3H), 1.31-1.28 (m, 6H), 1.05-1.02 (m, 6H),
0.87 (t, J = 7.0 Hz, 9H); 13C{1H} NMR (100MHz, CDCl3) δ: 207.9, 168.4, 151.1, 115.1, 80.8, 76.7, 29.0
(3C), 27.5, 27.2 (3C), 26.5, 13.6 (3C), 9.5 (3C). HRMS (ESI-QTOF): calcd C20H36NaO3Sn [M + Na]+,
467.1584; found [M + Na]+, 467.1578.
(3aR,6aR)-2,2-Dimethyl-5-(trimethylstannyl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one
(8). To a dried round-bottom flask equipped with a stir bar were added 6 (427 mg, 1.53 mmol) and
Pd(PPh3)4 (176 mg, 0.153 mmol). After the flask was sealed and evacuated then backfilled argon, toluene
(7.5 mL) and (Me3Sn)2 (1.0 g, 3.05 mmol) were added to the flask. After being stirred for 12 h at 100 ˚C,
the mixture was diluted with H2O. The whole was extracted three times with EtOAc. The combined
organic layers were dried over Na2SO4. The filtrate was concentrated under reduced pressure, which was
purified by flash chromatography over silica gel with n-hexane-EtOAc (7:1) to give 8 as white solid (348
mg, 72% yield): 1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J = 1.5 Hz, 1H), 5.24-5.20 (m, 1H), 4.45 (d, J =
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5.8 Hz, 1H), 1.41 (s, 3H), 1.39 (s, 3H), 0.29 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ: 207.6, 167.9,
151.0, 115.3, 80.5, 76.7, 27.3, 26.2, –9.8 (3C); HRMS (ESI-QTOF) (m/z) calcd for C11H18NaO3Sn [M +
Na]+ 341.0170, found 341.0178.
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7
8
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4-(Benzyloxy)-3-bromo-5-iodo-1-methylpyridin-2(1H)-one (11). To a stirred solution of 10 (2.76 g,
12.8 mmol) in CH2Cl2 (132 mL) was added N-bromosuccinimide (2.74 g, 15.4 mmol) at 0 ˚C. After being
stirred for 4.0 h at room temperature, the mixture was diluted with saturated Na2S2O3 (aq). and CH2Cl2.
The whole was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4. The
filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash
chromatography over silica gel with CH2Cl2-acetone (4:1) to give a bromide as blown solid (3.47 g). To
a stirred solution of the bromide (3.47 g) in MeCN (57 mL) was added N-iodesuccinimide (3.19 g, 14.2
mmol) and trifluoroacetic acid (0.271 mL, 3.54 mmol) at 0 ˚C. After being stirred for 17 h at room
temperature, the mixture was diluted with saturated Na2S2O3 (aq) and CH2Cl2. The whole was extracted
twice with CH2Cl2. The combined organic layers were washed with 1 M NaOH (aq). The organic layer
was dried over Na2SO4. The filtrate was concentrated under reduced pressure to give 11 as blown solid
without further purification (4.34 g, 81% yield): 1H NMR (400 MHz, CDCl3) δ: 7.66 (s, 1H), 7.62-7.34
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(m, 5H), 5.12 (s, 2H), 3.58 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ: 163.3, 160.2, 142.4, 135.2,
128.8, 128.7 (2C), 128.5 (2C), 108.0, 74.6, 65.8, 38.3; HRMS (ESI-QTOF) (m/z) calcd for
C13H11BrINNaO2 [M + Na]+ 441.8910, found 441.8907.
General Procedure for Stille Cross-coupling Reaction: 4-(benzyloxy)-3-bromo-5-[(3aR,6aR)-2,2-
dimethyl-4-oxo-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-5-yl]-1-methylpyridin-2(1H)-one (12)
(Table 1, entry 5). To a dried round-bottom flask equipped with stir bar were added 8 (100 mg, 0.32
mmol), 11 (265 mg, 0.63 mmol), Pd(PPh3)4 (36.5 mg, 0.032 mmol) and CuI (60.0 mg, 0.32 mmol). After
the flask was sealed and evacuated then backfilled argon, deoxidized DMF (3 mL) was added to the flask.
After being stirred for 6.0 h at 85 ˚C, the mixture was diluted with H2O. The whole was extracted twice
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with Et2O. The combined organic layers were dried over Na2SO4. The filtrate was concentrated under
reduced pressure, which was purified by flash chromatography over 10% w/w anhydrous K2CO3-silica
with CH2Cl2-acetone (9:1) to give 12 as white solid (89.0 mg, 63% yield): 1H NMR (400MHz, CDCl3) δ:
8.16 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.45-7.34 (m, 5H), 5.11 (dd, J = 5.6, 2.4 Hz, 1H), 5.02 (d, J = 10.2
Hz, 1H), 4.90 (d, J = 10.2 Hz, 1H), 4.49 (d, J = 5.6 Hz, 1H), 3.64 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H);
13C{1H} NMR (100MHz, CDCl3) δ: 201.3, 163.4, 160.0, 155.0, 138.6, 135.1, 134.3, 128.9 (3C), 128.7
(2C), 115.4, 108.7, 106.8, 76.7, 76.2, 75.1, 38.8, 27.4, 26.0; HRMS (ESI-QTOF) (m/z) calcd for
C21H20BrNNaO5 [M + Na]+ 468.0417, found 468.0414.
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4-(Benzyloxy)-3-bromo-5-[(3aS,4S,6aR)-4-hydroxy-2,2-dimethyl-3a,6a-dihydro-4H-
cyclopenta[d][1, 3] dioxol-5-yl]-1-methylpyridin-2(1H)-one (13). To a stirred solution of 12 (247 mg,
0.55 mmol) and CeCl3·7H2O (617 mg, 1.65 mmol) in MeOH (5 mL) was added NaBH4 (31.4 mg, 0.83
mmol) at 0 ˚C. After being stirred for 5 minutes, the mixture was diluted with saturated NH4Cl (aq). The
whole was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4. The
filtrate was concentrated under reduced pressure to give a residue, which was purified by flash
chromatography over silica gel with CH2Cl2-acetone (6:1) to give 13 as white solid (226 mg, 91% yield):
1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.50-7.33 (m, 5H), 6.30 (s, 1H), 5.04-4.94 (m, 3H), 4.78-
4.68 (m, 2H), 3.63 (s, 3H), 2.97 (d, J = 8.8 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ: 164.0, 159.9, 138.9, 137.5, 135.4, 128.8 (2C), 128.7 (2C), 128.6 (2C), 112.3, 111.0, 109.0,
82.4, 76.2, 74.5, 74.3, 38.7, 27.7, 26.3; HRMS (ESI-QTOF) (m/z) calcd for C21H22BrNNaO5 [M + Na]+
470.0574, found 470.0582.
4-(Benzyloxy)-3-bromo-5-{(3aR,4S,6aR)-2,2-dimethyl-4-[(triethylsilyl)oxy]-3a,6a-dihydro-4H-
cyclopenta[d][1,3] dioxol-5-yl}-1-methylpyridin-2(1H)-one (14). To a stirred solution of 13 (225 mg,
0.50 mmol) and imidazole (154 mg, 2.26 mmol) in DMF (6.6 mL) was added chlorotriethylsilane (253
L, 1.50 mmol) at 0 ˚C. After being stirred for 3.0 h at room temperature, the mixture was diluted with
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The Journal of Organic Chemistry
saturated NaHCO3 (aq). The whole was extracted three times with Et2O. The combined organic layers
were dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue,
which was purified by flash chromatography over silica gel with CH2Cl2-acetone (9:1) to give 14 as
colorless oil (270 mg, 96% yield): 1H NMR (400MHz, CDCl3) δ: 7.48 (s, 1H), 7.44-7.30 (m, 5H), 6.00-
5.98 (m, 1H), 5.03 (d, J = 10.7 Hz, 1H), 4.91 (d, J = 10.7 Hz, 1H), 4.89-4.85 (m, 1H), 4.67 (m, 1H), 4.57
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(m, 1H), 3.60 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 0.89 (t, J = 8.0 Hz, 9H), 0.62-0.56 (m, 6H); C{1H}
NMR (100 MHz, CDCl3) δ: 163.8, 160.2, 139.8, 137.0, 135.6, 129.4, 128.9 (2C), 128.7, 128.5 (2C),
112.0, 111.7, 108.4, 81.7, 78.3, 75.6, 75.0, 38.3, 27.6, 26.5, 6.7 (3C), 4.9 (3C); HRMS (ESI-QTOF) (m/z)
calcd for C27H36BrNNaO5Si [M + Na]+ 584.1438, found 584.1440.
4-(Benzyloxy)-3-bromo-5-{(3aR,4S,5S,6S,6aR)-4-hydroxy-2,2-dimethyl-6-[(triethylsilyl)oxy]
tetrahydro-4H-cyclopenta[d][1, 3]dioxol-5-yl}-1-methylpyridin-2(1H)-one (15). To a stirred solution
of 14 (270 mg, 0.48 mmol) in THF (2.7 mL) was added BH3·SMe2 (2.0 M in THF solution, 0.14 mL, 0.27
mmol) at 0 ˚C. After being stirred for 5.0 h at this temperature and 2.0 h at room temperature, the mixture
was diluted with 6 M NaOH (aq), H2O and 30% H2O2 (aq). After being stirred overnight at room
temperature, the mixture was diluted with H2O. The whole was extracted three times with Et2O. The
combined organic layers were washed with saturated NH4Cl (aq). The organic layer was dried over
Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with CH2Cl2-acetone (4:1) to give 15 as colorless oil (144 mg,
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51% yield): H NMR (400 MHz, CDCl3) δ: 7.45–7.40 (m, 6H), 5.21 (d, J = 11.2 Hz, 1H), 5.15 (d, J =
11.2 Hz, 1H), 4.40 (d, J = 8.0, 4.2 Hz, 1H), 4.37-4.33 (m, 1H), 4.29–4.25 (m, 1H), 3.85 (dd, J = 4.2 Hz,
1H), 3.61 (s, 3H), 2.99 (dd, J = 10.2, 4.2 Hz, 1H), 1.71 (d, J = 4.9 Hz, 1H), 1.46 (s, 3H), 1.31 (s, 3H) ,
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0.82 (t, J = 8.0 Hz, 9H), 0.51-0.33 (m, 6H); C{1H} NMR (100 MHz, CDCl3) δ: 165.0, 160.3, 137.5,
136.2, 128.8, 128.8 (2C), 128.5 (2C), 114.0, 111.7, 106.7, 85.1, 79.8, 78.9, 75.3, 72.2, 47.9, 38.6, 26.1,
25.2, 6.7 (3C), 4.7 (3C); HRMS (ESI-QTOF) (m/z) calcd for C27H38BrNNaO6Si [M + Na]+ 602.1544,
found 602.1553.
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tetrahydro-4H-cyclopenta[d][1,3] dioxol-5-yl}-1-methylpyridin-2(1H)-one (16). To a stirred solution
of 15 (21.5 mg, 0.0370 mmol) in CH2Cl2 (0.50 mL) was added Dess-Martin periodinane (27.9 mg, 0.066
mmol) at room temperature. After being stirred for 9.0 h at this temperature, the mixture was diluted with
saturated Na2S2O3 (aq) and saturated NaHCO3 (aq). The whole was extracted twice with CH2Cl2. The
combined organic layers were washed with saturated NaHCO3 (aq). The organic layer was dried over
Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue. To a stirred solution
of the residue in MeOH (0.60 mL) was added NaBH4 (8.4 mg, 0.22 mmol) at –10 ˚C. After being stirred
for 1.5 h at this temperature, the mixture was diluted with saturated NH4Cl (aq). The whole was extracted
three times with Et2O. The combined organic layers were washed with saturated NH4Cl (aq). The organic
layer was dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue,
which was purified by flash chromatography over silica gel with CH2Cl2-acetone (5:1) to give 16 as
colorless oil (15.4 mg, 72% yield): 1H NMR (400 MHz, CDCl3) δ: 8.02 (s, 1H), 7.41-7.29 (m, 5H), 5.21
(d, J = 10.7 Hz, 1H), 5.09 (d, J = 10.7 Hz, 1H), 4.37 (dd, J = 7.8, 5.8 Hz, 1H), 4.20 (dd, J = 7.8, 4.8 Hz,
1H), 3.79-3.72 (m, 2H), 3.60 (s, 3H), 2.84 (d, J = 9.8 Hz, 1H), 2.51 (d, J = 3.4 Hz, 1H), 1.52 (s, 3H), 1.37
(s, 3H), 0.81 (t, J = 7.8 Hz, 9H), 0.51-0.33 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ: 164.5, 160.2,
139.6, 136.1, 128.9, 128.8 (2C), 128.7 (2C), 114.6, 111.6, 106.2, 80.9, 79.5, 75.7, 74.7, 73.1, 43.2, 38.7,
25.9, 25.3, 6.7 (3C) 4.7 (3C); HRMS (ESI-QTOF) (m/z) calcd for C27H38BrNNaO6Si [M + Na]+ 602.1544,
found 602.1538.
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4-(Benzyloxy)-3-bromo-5-[(3aR,4R,5R,6S,6aS)-4,6-dihydroxy-2,2-dimethyltetrahydro-4H-
cyclopenta[d][1,3]dioxol-5-yl]-1-methylpyridin-2(1H)-one (17). To a stirred solution of 17 (38.2 mg,
0.085 mmol) in THF (0.74 mL) was added TBAF (1.0 M THF solution, 0.26 mL, 0.26 mmol) at 0 ˚C.
After being stirred for 1.5 h at room temperature, the mixture was diluted with saturated NaHCO3 (aq).
The whole was extracted three times with Et2O. The combined organic layers were dried over Na2SO4.
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The Journal of Organic Chemistry
The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash
chromatography over silica gel with CH2Cl2-acetone (3:1) to give 17 as white solid (26.9 mg, 88% yield)
Recrystallization from CH2Cl2–hexane gave pure 17 as colorless crystals: 1H NMR (400 MHz, CDCl3) δ:
7.99 (s, 1H), 7.41–7.35 (m, 5H), 5.19 (s, 2H), 4.41-4.38 (m, 2H), 3.84–3.80 (m, 2H), 3.63 (s, 3H), 2.65
(d, J = 5.4 Hz, 2H), 2.62 (t, J = 3.8 Hz, 1H), 1.59 (s, 3H), 1.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ: 164.3, 160.3, 139.5, 136.1, 128.9, 128.8 (2C), 128.6 (2C), 114.8, 111.1, 106.0, 79.8 (2C), 75.6, 72.5
(2C), 43.2, 38.9, 25.8, 24.9; HRMS (ESI-QTOF) (m/z) calcd for C21H24BrNNaO6 [M + Na]+ 488.0679,
found 488.0671.
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4-(Benzyloxy)-3-bromo-5-{(3aR,4S,5r,6R,6aS)-2,2-dimethyl-4,6-bis[(triethylsilyl)oxy]tetrahydro-
4H-cyclopenta[d][1,3]dioxol-5-yl}-1-methylpyridin-2(1H)-one (18). To a stirred solution of 16 (103
mg, 0.178 mmol) and imidazole (54.4 mg, 0.799 mmol) in DMF (0.59 mL) was added chlorotriethylsilane
(0.0890 mL, 0.533 mmol) at 0 ˚C. After being stirred for 1.5 h at room temperature, the mixture was
diluted with saturated NaHCO3 (aq). The whole was extracted four times with Et2O. The combined
organic layers were dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by flash chromatography over silica gel with CH2Cl2-acetone (19:1) to
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give 18 as yellow oil (101 mg, 82% yield): H NMR (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.41-7.32 (m,
5H), 5.11 (s, 2H), 4.27-4.24 (m, 2H), 3.65 (s, 3H), 3.61-3.57 (m, 2H), 2.81 (t, J = 5.0 Hz, 1H), 1.46 (s,
3H), 1.33 (s, 3H), 0.83 (t, J = 8.1 Hz, 18H), 0.49-0.42 (m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ:
164.6, 160.1, 141.8, 136.1, 128.9 (3C), 128.7 (2C), 114.3, 110.7, 105.5, 81.1 (2C), 75.6, 73.0 (2C), 43.0,
38.4, 26.2, 26.1, 6.8 (6C), 4.7 (6C); HRMS (ESI- QTOF) (m/z) calcd for C33H52BrNNaO6Si2 [M + Na]+
716.2414, found 716.2409.
4-(Benzyloxy)-3-[(E)-dec-1-en-1-yl]-5-{(3aR,4S,5r,6R,6aS)-2,2-dimethyl-4,6-
bis[(triethylsilyl)oxy]tetrahydro-4H-cyclopenta[d] [1,3] dioxol-5-yl}-1-methylpyridin-2(1H)-one
(19a). To a dried flask equipped with a stirring bar was added 18 (7.04 mg, 10.1 µmol), Pd(OAc)2 (450
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µg, 2.00 µmol), XPhos (1.92 mg, 4.03 µmol) and K3PO4·nH2O (12.8 mg, 60.4 µmol). After the flask was
sealed and evacuated then backfilled argon, 1-decenylboronate pinacol ester (9.65 mg, 36.3 mmol) in
anhydrous THF (0.336 mL) were added to the flask. After being stirred for 12 h at 60 °C, the mixture was
extracted three times with Et2O. The combined organic layers were dried over Na2SO4. The filtrate was
concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography
over silica gel with CH2Cl2-acetone (15:1) to give 19a as yellow oil (4.89 mg, 65% yield): 1H NMR (400
MHz, CDCl3) δ: 7.77 (s, 1H), 7.39-7.36 (m, 3H), 7.31-7.29 (m, 2H), 7.15-7.08 (m, 1H), 6.52 (d, J = 16.1
Hz, 1H), 4.86 (s, 2H), 4.29-4.28 (m, 2H), 3.63-3.61 (m, 2H), 3.56 (s, 3H), 2.83 (t, J = 4.6 Hz, 1H), 2.25
(dt, J = 7.2 Hz, 2H), 1.48 (s, 3H), 1.34 (s, 3H), 1.30-1.24 (m, 12H), 0.84 (t, J = 8.0 Hz, 21 H), 0.49-0.43
(m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ: 162.9, 162.6, 140.4, 136.6 (2C), 128.7 (2C), 128.6, 128.5
(2C), 120.8, 116.0, 114.5, 110.1, 81.3 (2C), 75.9, 73.3 (2C), 42.6, 37.7, 34.7, 31.9, 29.6, 29.5, 29.4, 29.3,
26.4, 26.2, 22.7, 14.1, 6.8 (6C), 4.8 (6C); HRMS (ESI-QTOF): calcd C43H71NNaO6Si2 [M + Na]+
776.4718, found 776.4720.
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4-(Benzyloxy)-5-{(3aR,4S,6R,6aS)-2,2-dimethyl-4,6-bis[(triethylsilyl)oxy]tetrahydro-4H-
cyclopenta[d][1,3]dioxol-5-yl}-3-[(E)-dodec-1-en-1-yl]-1-methylpyridin-2(1H)-one (19b). By a
procedure identical with that described for synthesis of 19a from 18, the compound 18 (24.8 mg, 0.0357
mmol) was converted into 19b as yellow oil (17.5 mg, 68% yield): 1H NMR (400 MHz, CDCl3) δ: 7.76
(s, 1H), 7.41-7.28 (m, 5H), 7.12 (dt, J = 16.0, 7.0 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 4.86 (s, 2H), 4.30-
4.27 (m, 2H), 3.64-3.60 (m, 2H), 3.56 (s, 3H), 2.84-2.81 (m, 1H), 2.29-2.21 (m, 2H), 1.48 (s, 3H), 1.36-
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1.22 (m, 19H), 0.90-0.80 (m, 21H), 0.51-0.42 (m, 12H); C{1H} NMR (100 MHz, CDCl3) δ: 162.9,
162.6, 140.4, 136.6 (2C), 128.7 (2C), 128.6, 128.5 (2C), 120.8, 116.0, 114.5, 110.1, 81.3 (2C), 75.9, 73.3
(2C), 42.6, 37.7, 34.7, 31.9, 29.7, 29.6, 29.5, 29.4 (3C), 26.4, 26.2, 22.7, 14.1, 6.8 (6C), 4.8 (6C); HRMS
(ESI- QTOF) (m/z) calcd for C45H75NNaO6Si2 [M + Na]+ 804.5025, found 804.5031.
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The Journal of Organic Chemistry
4-(Benzyloxy)-3-[(E)-dec-1-en-1-yl]-1-methyl-5-[(1r,2R,3R,4S,5S)-2,3,4,5-
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tetrahydroxycyclopentyl]pyridin-2(1H)-one (20a). To a stirred solution of 19a (4.21 mg, 5.59 µmol) in
THF (0.420 mL) and H2O (0.420 mL) was added trifluoroacetic acid (0.140 mL) at 0 ˚C. After being
stirred for 3.0 h at 60 °C, the mixture was diluted with saturated NaHCO3 (aq). The whole was extracted
three times with CH2Cl2. The combined organic layers were dried over Na2SO4. The filtrate was
concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography
over silica gel with CHCl3-MeOH (5:1) to give 20a as yellow oil (1.85 mg, 68% yield): 1H NMR (400
MHz, CDCl3) δ: 7.80 (s, 1H), 7.38-7.36 (m, 3H), 7.30-7.28 (m, 2H), 7.12-7.04 (m, 1H), 6.49 (d, J = 16.2
Hz, 1H), 4.95 (s, 2H), 4.11-4.06 (m, 2H), 3.85-3.82 (m, 2H), 3.56 (s, 3H), 3.40-3.35 (m, 2H), 3.27 (d, J =
4.9 Hz, 2H), 2.44 (t, J = 3.3 Hz, 1H), 2.25 (dt, J = 7.2, 7.2 Hz, 2H), 1.50-1.43 (m, 2H), 1.28-1.25 (m,
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10H), 0.86 (t, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ: 163.0, 162.9, 137.9, 136.7, 136.1,
128.8 (2C), 128.7, 128.0 (2C), 120.4, 117.6, 110.5, 75.6, 74.7 (2C), 69.9 (2C), 40.0, 38.1, 34.7, 31.9, 29.7,
29.5, 29.4, 29.3, 22.7, 14.1; HRMS (ESI- QTOF) (m/z) calcd for C28H39NNaO6 [M + Na]+ 508.2675,
found 508.2678.
4-(Benzyloxy)-3-[(E)-dodec-1-en-1-yl]-1-methyl-5-[(1r,2R,3R,4S,5S)-2,3,4,5-
tetrahydroxycyclopentyl]pyridin-2(1H)-one (20b). By a procedure identical with that described for
synthesis of 20a from 19a, the compound 19b (3.31 mg, 4.23 mol) was converted into 20b as yellow oil
(1.48 mg, 68% yield): 1H NMR (400 MHz, CDCl3) δ: 7.80 (s, 1H), 7.41-7.35 (m, 3H), 7.32-7.27 (m, 2H),
7.08 (dt, J = 16.0, 7.0 Hz, 1H), 6.48 (d, J = 16.0 Hz, 1H), 4.95 (s, 2H), 4.13-4.06 (m, 2H), 3.87-3.81 (m,
2H), 3.56 (s, 3H), 3.45-3.23 (m, 4H), 2.43 (t, J = 2.9 Hz, 1H), 2.24 (dt, J = 7.0, 7.0 Hz, 1H), 1.37-1.20
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(m, 16H), 0.91-0.84 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ: 163.0, 162.9, 137.9, 136.7, 136.1,
128.8 (2C), 128.7, 128.0 (2C), 120.4, 117.6, 110.5, 75.6, 74.7 (2C), 69.9 (2C), 40.0, 38.1, 34.7, 31.9, 29.7,
29.6 (2C), 29.4 (2C), 22.7, 14.1; HRMS (ESI- QTOF) (m/z) calcd for C30H43NNaO6 [M + Na]+ 536.2983,
found 536.2991.
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one (21a). To a stirred solution of 20a (1.01 mg, 2.06 µmol) in MeOH (1.0 mL) was added Pd(OH)2 (20%
wt on carbon, 1.00 mg) and the resulting mixture was purged with H2 gas. After being stirred for 4.0 h at
room temperature, the mixture was filtrated through membrane filter with MeOH. The filtrate was
concentrated under reduced pressure to give 21a as yellow oil (0.65 mg, 79% yield): 1H NMR (400 MHz,
CD3OD) δ: 7.50 (s, 1H), 4.11-4.04 (m, 2H), 3.98-3.91 (m, 2H), 3.40 (s, 3H), 2.95-2.88 (m, 1H), 2.43 (t, J
= 7.4 Hz, 2H), 1.24-1.16 (m, 16H), 0.80 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ: 165.4,
165.3, 138.9, 113.6, 111.3, 75.6 (2C), 73.1 (2C), 46.1, 37.8, 33.1, 30.9, 30.8 (3C), 30.5, 29.4, 25.0, 23.8,
14.5; HRMS (ESI-QTOF) (m/z) calcd C21H35NNaO6 [M + Na]+ 420.2362, found 420.2370.
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3-Dodecyl-4-hydroxy-1-methyl-5-[(1r,2R,3R,4S,5S)-2,3,4,5-tetrahydroxycyclopentyl]pyridin-
2(1H)-one (21b). By a procedure identical with that described for synthesis of 21a from 20a, the
compound 20b (2.57 mg, 5.00 mol) was converted into 21b as yellow oil (2.23 mg, quant.): 1H NMR
(400 MHz, CD3OD) δ: 7.54 (s, 1H), 4.14-4.05 (m, 2H), 4.00-3.91 (m, 2H), 3.41 (s, 3H), 2.97-2.89 (m,
1H), 2.43 (t, J = 6.2 Hz, 2H), 1.31-1.08 (m, 20H), 0.84-0.76 (m, 3H); 13C{1H} NMR (100 MHz, CD3OD)
δ: 165.3, 164.8, 139.0, 113.6, 111.1, 75.5 (2C), 73.0 (2C), 45.9, 37.9, 33.1, 30.9 (2C), 30.8 (4C), 30.5,
29.4, 24.9, 23.7, 14.4; HRMS (ESI-QTOF) (m/z) calcd for C23H39NNaO6 [M + Na]+ 448.2670 , found
448.2673.
Supporting Information Available: The Supporting Information is available free of charge on the ACS
Publications website at DOI: XXXXX.
1H and 13C NMR spectra
X-ray crystallographic data for compound 17
Acknowledgments
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The Journal of Organic Chemistry
This research was financially supported by grants from the Grant-in-Aid for Scientific Research (Nos.
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JP26282211, JP16H01162, JP17H02207, JP18H04426, JP26882036, JP16K16638). We thank Dr. Y.
Miura for assistance in confirming the structure of 17 by X-ray crystallography, and Dr. N. Sugimura and
Prof. M. Nakata (Waseda Univ.) for discussion about NMR measurements.
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