One-Step conversion to a disubstituted cyclopentenone from 2-Deoxy-D-Glucose and application to synthesis of prostaglandin e1 methyl ester

Article abstract of DOI:10.1246/bcsj.20180241

We have developed a facile one-step conversion of 2-deoxy-D-glucose to form a disubstituted cyclopentenone through catalyst-free hydrothermal reaction under mild conditions. The use of 2-deoxy-D-glucose in one-pot conversion is to provide the formation of a carbon five-membered ring instead of the common biomass-derived furans such as furfural, 5-HMF, etc. The cyclopentenone has a potential to be a building block for the preparation of chemical products. As one example, we successfully demonstrated the synthesis of prostaglandin E₁ methyl ester.

Full text of DOI:10.1246/bcsj.20180241

Document type: Article
Selected Paper
One-Step Conversion to a Disubstituted Cyclopentenone
from 2-Deoxy-D-Glucose and Application to Synthesis
of Prostaglandin E1 Methyl Ester
Takaaki Kamishima,1,2 Toshiyuki Nonaka,2 Toshihiro Watanabe,1
Yoshitaka Koseki,1 and Hitoshi Kasai*1
1Institute of Multidisciplinary Research for Advanced Materials (IMRAM) Tohoku University,
Aoba-ku, Sendai, Miyagi 980-8577, Japan
2FromSeeds Corporation, Aoba-ku, Sendai, Miyagi 980-0845, Japan
E-mail: hkasai@tagen.tohoku.ac.jp
Received: August 28, 2018; Accepted: September 20, 2018; Web Released: November 10, 2018
Hitoshi Kasai
Hitoshi Kasai, is a Professor at the Institute of Multidisciplinary Research for Advanced Materials, Tohoku
University. He received his Ph.D. from Tohoku University in 1996. He was promoted to Associate Professor
in 2004. He joined Precursory Research for Embryonic Science and Technology (PRESTO) in 2007–2011.
He was promoted to Professor in 2016. He is interested in organic nanomaterials including nanodrugs.
Abstract
ides such as glucose and fructose, has been made clear.1d And
We have developed a facile one-step conversion of 2-deoxy-
thus, production of new substances with higher synthetic value
from biomass resources would be surely beneficial. Therefore,
we aimed at the creation of new materials other than furans,
bioethanol and carboxylic acids which have been widely
reported, and using them for application to fine chemicals. We
have looked for procedures that could allow the preparation
of useful compounds from deoxy sugars, such as 2-deoxy-D-
glucose (2-DG) (1). The preparation methods of 1 have been
reported previously, and the overall yield is over 50% from
glucose.7 Also, 1 is one of the most easily available industrial
deoxy sugars. In addition, their transformations are much less
studied compared to those of glucose. In this paper, we describe
the first demonstration of one-step conversion to 4-hydroxy-2-
(hydroxymethyl)cyclopent-2-en-1-one (2) from 1 by hydro-
thermal treatment (Figure 1). The reactants include water and 1
without any catalyst at lower temperature and pressure than
those usually applied in general biomass conversion processes.1
Elliott et al. reported synthesis of 2 in 3.5% overall yield
through ten reaction steps from quinic acid.8 Meanwhile, our
environmentally friendly method provides 2 from an aqueous
solution of 1 in one-pot. In addition, this method significantly
enhances yield of 2 to 80%, the maximum conversion possible
from 1.
D-glucose to form a disubstituted cyclopentenone through
catalyst-free hydrothermal reaction under mild conditions. The
use of 2-deoxy-D-glucose in one-pot conversion is to provide
the formation of a carbon five-membered ring instead of the
common biomass-derived furans such as furfural, 5-HMF, etc.
The cyclopentenone has a potential to be a building block
for the preparation of chemical products. As one example, we
successfully demonstrated the synthesis of prostaglandin E1
methyl ester.
Keywords: Biomass
j
Hydrothermal reaction
j
Total synthesis
1. Introduction
Consumption of natural resources, e.g. fossil fuels, is
steadily increasing and subsequently leading to severe environ-
mental pollution among other consequences. A known alter-
native to fossil fuels is the use of degraded biomass products.
Currently biomass resources are converted to products by
chemical methods using sub- and supercritical fluids,1 acids,2
catalysts3 or enzymes.4 Many compounds can be obtained via
initial production of glucose from crops such as sugarcane and
corn, including ethanol,5 carboxylic acids,4b,6 furfural,2b,4a etc.
Due to enormous previous efforts, the syntheses of almost all
products that can be obtained from direct conversion of
cellulosic-biomass resources, especially natural monosacchar-
2. Experimental
Materials.
2-Deoxy-D-glucose was purchased from
Carbosynth Limited, phosphorus tribromide (PBr3), chlorotri-
Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan | 1691

Previous work
300, 300 mL, Swagelok, Co.) and sealed tightly. The reactor
was placed in a pre-heated dry oven (DO-450PA, AS ONE Co.)
at 140 °C, and left standing without stirring at the same
temperature. After 22 hours, it was taken out of the oven and
cooled in water rapidly to terminate the reaction. The reaction
mixture including the solid removed from the reactor was
frozen for aggregation. The mixture, thawed at room tempera-
ture, was filtered twice (retained particle diameter, 1.0 and 0.2
¯m) and the solid (insoluble char) was removed. Concentration
in vacuo to remove water gave a residue as a brown paste. The
activated basic alumina with the same amount of residue and
10 w/v % distilled water were added to the residue and stirred
at 50 °C. After 5 hours, the resultant mixture was diluted with
2-propanol (25 mL © 4) and filtered (filter paper, 0.4 ¯m) to
remove the alumina. In this case, the alumina was used not only
for isomerization but also for purification. Concentration in
vacuum gave the racemic 2 (6.3 g, 49.2 mmol, 80%) as a single
isomer. TLC (EtOAc): Rf = 0.22; 1H NMR (400 MHz, acetone-
d6): δ 2.18 (dd, J = 2.0, 18.4 Hz, 1H), 2.72 (dd, J = 6.0,
18.4 Hz, 1H), 4.21 (s, 2H), 4.91-4.92 (m, 1H), 7.36-7.37 (m,
1H) ppm; 13C NMR (100 Mz, acetone-d6): δ 45.9, 56.8, 68.6,
147.6, 157.7, 205.4 ppm; IR(neat): 1701, 3276 cm¹1; HR-MS
(ESI-TOF): m/z calcd. for C6H9O3 ([M + H]+), 129.0546;
found, 129.0552; (R)-2, [α]D26 = +33.0 (c = 1.0 in ethanol).
The optical rotation was in agreement with those previously
published;8 (S)-2, [α]D18 = ¹34.3 (c = 1.0 in ethanol).
Compound 4: PBr3 (59 ¯L, 0.62 mmol) was added to a
stirred solution of (R)-2 (227 mg, 1.77 mmol) in THF (5.9 mL)
at 0 °C, and the mixture was stirred at the same temperature.
After 5 min, Et3N (0.49 mL, 3.54 mmol) and HNEt2 (0.37 mL,
3.54 mmol) were added to the same pot, and the mixture was
stirred at room temperature for 15 min. Finally, TESCl (0.39
mL, 2.30 mmol) was added to the reaction mixture, and further
stirred 30 min at room temperature (If the reaction is stopped
halfway or does not proceeded, the temperature is set above
30 °C.) All reactions were monitored by TLC (AcOEt). The
reaction was quenched with saturated H2O. The resulting
mixture was extracted with AcOEt (2 © 10 mL). The combined
extracts were washed with brine (10 mL) then dried with
MgSO4. Concentration in vauco afforded a residue, which was
purified by column chromatography (hexane/EtOAc 1:1 ¼
Non-food based
biomass
O
O
O
O
HO
Ref.1-6
Furfural
O
5-HMF
Glucose
Ref.7
HO
Bioethanol
e. g.
O
Levulinic acid
This work
HO
O
Catalyst-free
Hydrothermal reaction
O
OH
OH
HO
H2O
OH
HO
2
2-Deoxy-D-gulcose (1)
Figure 1. Strategy of biomass utilization.
ethylsilane (TESCl), trimethylamine (Et3N), 4-dimethylamino-
pyridine (DMAP), diethylamine (HNEt2), methyl 6-bromo-
hexanoate, sodium iodide (NaI), triethylborane (Et3B), tri-
butyltin hydride (n-Bu3SnH) methanol (MeOH) and anhydrous
solvents for organic synthesis, including CH2Cl2, tetrahydro-
furan (THF), and diethyl ether (Et2O) were purchased from
Wako Pure Chemical Industries, pyridinium p-toluenesulfonate
(PPTS) was purchased from Tokyo Chemical Industry Co., (S)-
(¹)-1-octyn-3-ol (97% ee), lithium 2-thienylcyanocuprate and
aluminum oxide, activated, basic, Brokmann Grade I (Al2O3)
were obtained from Sigma-Aldrich. Silica gel plates (60F-254)
for thin layer chromatography were purchased from Merck.
Silica gel 60N (230-400 mesh) for flash chromatography was
purchased from Kanto Chemical. All reagents were used
without further purification. All reactions were carried out in
flame-dried glassware under a nitrogen atmosphere with dry
solvents. Unless stated otherwise, commercial grade reagents
were used without further purification. Reactions were moni-
tored by analytical thin layer chromatography (TLC) carried
out on 0.25 mm E. Merck silica gel plates (60F-254). Visual-
ization of the developed chromatograms was performed by UV
absorbance and aqueous cerium ammonium molybdate. Flash
chromatography was performed on Kanto Chemical silica gel
60N (230-400 mesh) with the indicated solvent systems.
Instruments. Optical rotations were recorded on a Jasco
DIP-1000 polarimeter. Infrared spectra (IR) were recorded on
a Jasco FT/IR-4100 spectrometer using ATR. Nuclear mag-
netic resonance (NMR) spectra were recorded on a Bruker
AVANCE-400 III spectrometer and calibrated using residual
undeuterated solvent as an internal reference (CDCl3 at δ 7.26
ppm for 1H, δ 77.16 for 13C NMR, (CD3)2CO (Acetone-d6) at δ
2:1) to give 4 (219 mg, 0.734 mmol, 42%) as a pale yellow oil.
26
TLC (hexane:EtOAc, 1:2 v/v): Rf = 0.40 (broad); [α]D
=
1
+18.7 (c = 1.0 in CHCl3); H NMR (400 Mz, CDCl3) δ 0.65
(dd, J = 8.0, 15.8 Hz, 6H), 0.96-1.04 (m, 15H), 2.32 (dd,
J = 2.0, 18.4 Hz, 1H), 2.47-2.53 (m, 4H), 2.77 (dd, J = 6.0,
18.2 Hz, 1H), 3.15-3.25 (m, 2H), 4.90-4.92 (m, 1H), 7.24-7.25
(m, 1H) ppm; 13C NMR (100 Mz, CDCl3) δ 4.8, 6.9 12.1, 45.9,
47.4, 47.5, 68.8, 145.1, 158.9, 206.2 ppm; IR(neat): 1147,
1716, 2960 cm¹1; HR-MS (ESI-TOF): m/z C16H32NO4Si
([M + H]+) calcd. for 298.2197, found 298.2196.
2.05 ppm for H, δ 29.8, 206.3 for 13C NMR). High-resolution
1
mass spectrometry (HR-MS) was performed using a Bruker
MicrOTOF-Q II-S1 using electrospray ionization (ESI). High
performance liquid chromatography (HPLC) was performed
using YMC LC-Forte/R100. Gas chromatography (GC) was
performed using an Agilent Technologies 7890B/5977A MSD.
Compound 6: n-BuLi (1.55 M, 0.25 mL, 0.39 mmol) was
added to a stirred solution of vinyl iodide (145 mg, 0.39 mmol)
prepared from (S)-(¹)-1-octyn-3-ol in Et2O (1.3 mL) at ¹78 °C
under argon atmosphere. After 2 hours, lithium 2-thienyl-
cyanocuprate (0.25 M, 1.57 mL, 0.39 mmol) was added to the
reaction and stirring further continued for 30 minutes at the
Experimental Produces.
Optimized Procedure for
Catalyst-Free Hydrothermal Reaction and Isomerization:
A solution of 2-DG (1) (10 g, 60.9 mmol) in distilled water
(250 mL) was poured into a tube bomb reactor (304L-HDF4-
same temperature to allow formation of mixed cuprate 5.9e
A
solution of 4 (106 mg, 0.35 mmol) in Et2O (1.5 mL) was added
1692 | Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan

dropwise at ¹78 °C. The mixture was stirred for 20 min at the
same temperature. The reaction was quenched with saturated
aqueous NH4Cl. The resulting mixture was extracted with
hexane (2 © 10 mL). The combined extracts were washed with
brine (10 mL) then dried with Na2SO4. Concentration in vauco
afforded a residue, which was purified by column chromatog-
raphy (hexane/EtOAc 60:1 ¼ 40:1) to give 6 (114 mg, 0.243
mmol, 70%) as a colorless oil. TLC (hexane:EtOAc, 20:1 v/v):
Rf = 0.33; [α]D22 = ¹40.8 (c = 0.30 in CHCl3); 1H NMR
(400 Mz, CDCl3) δ 0.56-0.62 (m, 12H), 0.88 (t, J = 6.8 Hz,
3H), 0.93-0.97 (m, 18H), 1.26-1.51 (m, 8H), 2.34 (dd, J =
6.4, 17.8 Hz, 1H), 2.63 (dd, J = 6.4, 17.8 Hz, 1H), 3.30-3.33
(m, 1H), 4.10-4.15 (m, 2H), 5.24-5.25 (m, 1H), 5.45-5.65
(m, 2H), 6.12-6.13 (m, 1H) ppm; 13C NMR (100 Mz, CDCl3)
δ 4.9, 5.1, 6.9, 7.0, 14.2, 22.8, 25.2, 32.0, 38.7, 47.1, 54.6,
72.79, 72.83, 77.4, 119.5, 127.6, 137.7, 146.8, 203.7 ppm;
IR(neat): 1149, 1427, 1731, 2360, 2954 cm¹1; HR-MS (ESI-
TOF): m/z C26H48O3Si2Na ([M + Na]+) calcd. for 487.3034,
found 487.3029.
Conversion to 2 from IV: An aqueous solution (3 w/v %)
of IV prepared form tri-O-acetyl-D-glucal11 was poured into a
sealed reactor and sealed tightly. The rector was placed in a
previously heated dry oven at 160 °C and left standing without
stirring at same temperature. After 4 hours, the reactor was
taken out of the oven and cooled in water rapidly to terminate
the reaction. The resulting mixture was filtered to remove the
solid. Concentration in vacuo gave a crude residue as a brown
1
paste. The ratio of 2/3 was 1:0.4 according to H NMR mea-
surements (see Supporting Information).
GC-FID Measurements:
Column, HP-INNOWAX
19091N-113; injection, 250 °C; Detection (FID), 250 °C;
presser, 88.0 kP; He flow late, 2.5 mL min¹1; linear velocity,
42 cm sec¹1; split flow late, 14 mL min¹1, conditions; 80 °C
(2 min)-(10 °C min¹1)-100 °C
(2 min)-(10 °C min¹1)-245 °C
(5 min); retention time, 2 and 3, 22.0 min.
HPLC Measurements:
CHIRAL ART Cellulose-SC
(5 ¯m, º 30.0 I.D. © 250 mm YMC CO., LTD.); column tem-
perature, room temperature; mobile phase, hexane/i-propanol
(v/v) = 50/50 for 20 min; flow rate, 13 mL min¹1; sample
concentration, 5 mg mL¹1; injection volume, 4.5 mL; UV
absorbance was monitored at 220 nm; retention times, (S)-2,
12.9 min; (R)-2, 14.4 min.
Compound 8: Triethylborane (47 ¯L, 0.047 mmol) was
added to a stirred solution of 6 (210 mg, 0.47 mmol), 7 (358
mg, 1.40 mmol) and tributyltin hydride (0.38 mL, 1.40 mmol)
in toluene (1.5 mL) at ¹20 °C under argon atmosphere. The
mixture was stirred for 3 hours at the same temperature.
Concentration in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 50:1 ¼ 20:1) to
give 8 (158 mg, 0.262 mmol, 56%) as a colorless oil. TLC
(hexane:EtOAc, 10:1 v/v): Rf = 0.40; [α]D22 = ¹29.0 (c =
Optical Resolution via HPLC: CHIRAL ART Cellulose-
SC (5 ¯m, º 30.0 I.D. © 250 mm, YMC CO., LTD.); col-
umn temperature, room temperature; mobile phase, hexane/
¹1
i-propanol (v/v) = 50/50 for 20 min; flow rate, 13 mL min
sample amount, 1.0 g; sample concentration, 40 mg mL
;
;
¹1
1
0.24 in CHCl3); H NMR (400 Mz, CDCl3) δ 0.55-0.62 (m,
injection volume, 2.0 mL at a time; UV absorbance was moni-
tored at 220 nm; collection, (S)-2, 492 mg, 14.7 min; (R)-2, 489
mg, 17.8 min.
12H), 0.88 (t, J = 6.8 Hz, 3H), 0.92-0.99 (m, 18H), 1.21-1.63
(m, 18H), 1.91-1.97 (m, 1H), 2.18 (dd, J = 8.0, 18.4 Hz, 1H),
2.28 (t, J = 7.6 Hz, 2H), 2.42-2.49 (m, 1H), 2.62 (ddd, J =
1.2, 7.2, 18.2 Hz, 1H), 3.66 (s, 3H), 4.1-4.13 (m, 2H), 5.49-
5.61 (m, 2H) ppm; 13C NMR (100 Mz, CDCl3) δ 4.9, 5.1, 6.7,
6.9, 7.1, 14.2, 22.8, 25.1, 25.2, 26.8, 28.0, 29.1, 29.3, 29.7,
32.0, 34.2, 38.7, 51.6, 53.2, 53.9, 73.0, 77.4, 129.0, 136.3,
174.4, 216.5 ppm; HR-MS (ESI-TOF): m/z C33H64O5Si2Na
([M + Na]+) calcd. for 619.4184, found 619.4203.
3. Results and Discussion
Hydrothermal conversion of glucose, fructose, cellulose, etc.
into products has been investigated under sub- (150-374 °C)
and supercritical (374-500 °C) conditions.1,12 Since the tem-
perature ramping rate and the reaction time greatly affect the
yield of the product and quantity of by-products, there are still
many difficulties in the conversion of saccharides into products
using batch reaction systems. On the other hand, flow reaction
systems have been recently used for controlling the reaction
conditions.13 However, this equipment must strictly manage
reaction time at high temperatures and pressures, so other solu-
tions are essential. We have found that 2 can be obtained from
2-DG (1) by hydrothermal reaction at 160 °C or lower without
any catalyst. Since the retro-aldol reaction of 1 is suppressed
under these conditions, the dehydration reactions of 1 and its
intermediates are selectively enhanced. We have also optimized
the reaction conditions to achieve the highest yield, as follows.
Table 1 shows the conditions for conversion of 1 into 2. In our
experiments, we fixed the concentration of the reactants, and
varied the reaction time and temperature. The reaction of 1 was
conducted in a tube bomb reactor with an inner volume of
150 mL. An aqueous solution (100 mL) of 1 (3.0 g) was loaded
into the reactor. The reactor was sealed and placed in a constant
temperature drying oven controlled at the reaction tempera-
ture (140 °C and 160 °C). After the reaction, the reactor was
removed from the oven and rapidly quenched in an ice-water
bath. The reaction mixture was filtered with a 0.22 ¯m mem-
PGE1-Methyl Ester (9): PPTS (0.63 mg, 2.5 ¯mol) was
added to a stirred solution of 8 (50.0 mg, 0.084 mmol) in
acetone (0.83 mL) and water (0.17 mL). After 6 hours stirring
at room temperature, acetone was removed in vacuo and the
residue was extracted with EtOAc (2 © 10 mL). The combined
extracts were washed with brine (5 mL) then dried with
MgSO4. Concentration in vauco afforded a residue, which was
purified by column chromatography (Et2O/MeOH 50:1) to
give 9 (25.2 mg, 0.0684 mmol, 82%) as a colorless oil. TLC
(Et2O:MeOH, 50:1 v/v): Rf = 0.23; [α]D22 = ¹46.8 (c = 0.93
in MeOH), [lit [α]D22 = ¹55.6 (c = 0.33 in MeOH)]; H NMR
1
(400 Mz, CDCl3) δ 0.89 (t, J = 6.4 Hz, 3H), 1.21-1.69 (m,
18H), 1.96-2.04 (m, 1H), 2.17-2.38 (m, 5H), 2.73 (ddd, J =
1.2, 7.2, 18.4 Hz, 1H), 3.22 (brs, 1H), 3.66 (s, 3H), 4.01-4.14
(m, 2H), 5.52-5.70 (m, 2H) ppm; 13C NMR (100 Mz, CDCl3) δ
14.2, 22.8, 25.0, 25.3, 26.7, 27.8, 29.0, 29.5, 31.8, 34.1, 37.5,
46.0, 51.6, 54.6, 54.9, 72.0, 73.1, 131.9, 136.9, 174.5, 214.8
ppm; HR-MS (ESI-TOF): m/z C21H36O5Na ([M + Na]+)
calcd. for 391.2455, found 391.2459. The spectroscopic data
and the optical rotation were in agreement with those previ-
ously published.10
Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan | 1693

Table 1. Investigation of reaction condition(a)
O
O
OH
OH
Hydrothermal
reaction
O
HO
OH
OH
+
O
O
O
OH
160°C, 4 h
HO
OH
Conditions
H2O
IV
OH
OH
2
3
+
HO
2/3 = 1 : 0.4
HO
OH
OH
2
3
2-DG (1)
Scheme 2. Conversion to 2 and 3 from intermediate IV.
Ratio of 2 and 3 was determined by H NMR analysis.
1
Entry
Temp.(°C)
Time (h)
Yield (%)(b)
Ratio (2:3)(c)
1
2
3
4
5
6
7
160
160
160
140
140
140
140
7
14
28
14
28
56
94
74
63
37
67
80
55
41
1 : 0.3
-
-
-
1 : 0.3
-
-
O
OH
HO
cat. H2O
Activated Al2O3
(R)-2 >99%ee
HPLC
2 + 3
2
50 °C, 5 h
(a) Unless stated otherwise, reactions were performed as
O
1
follows: 2-DG ( ) (3.0 g) in H2O (100 mL) at indicated
2
temperature and for indicated time without stirring. (b) Yield of
OH
including 3 was determined by GC-FID analysis. (c) Ratio of 2
and 3 was determined by 1H NMR analysis.
HO
(S)-2
>99%ee
Scheme 3. Isomerization by alumina and purification via
HPLC.
HO
HO
O
OH
OH
OH
a
b
O
HO
CHO
HO
reaction was stopped for 1 hour at 160 °C, presence of the inter-
mediate IV in the reaction solution was confirmed by 1H NMR
measurements. Therefore, we have synthesized the intermediate
IV by a known method11 and performed its hydrothermal rea-
OH OH
I
OH
OH
2-DG (1)
II
c
1
ction at 160 °C. Monitoring the reaction by TLC and H NMR
H2O
O
measurements, we found that IV completely disappeared in
4 hours and the mixture of 2 and 3 was produced as mentioned
in Table 1 (Scheme 2). Unfortunately, the isomers were not
separable by silica gel column chromatography. Several
methods of isomerization of substituted cyclopentenones have
been previously reported. A method of isomerization using
activated alumina was applied due to simplicity of the proc-
ess.14 An amount of activated basic alumina equivalent in
weight was added to the mixture of 2 and 3 together with a
small amount of water and the resultant mixture was heated at
50 °C for the isomerization of 3 to 2, accompanied by the
removal of alumina from the reaction mixture to give a single
isomer 2 as a racemate (Scheme 3). The product was purified
via high-performance liquid chromatography (HPLC) to yield
(R)-2 and (S)-2 separately (see Supporting Information). The
optical rotation of (R)-2, [α]D26 = +33.0 (c = 1.0 in ethanol), a
HO
HO
O
OH
OH
OH
O
d
b
OH
OH
V
a
IV
III
O
O
O
e
HO
c
OH
OH
OH
OH
HO
VI
3
2
Scheme 1. Reaction mechanism: (a) Ring opening; (b)
Dehydration; (c) Cyclization; (d) Dehydration/Hydration;
(e) Equilibrium reaction.
brane filter. The products in the filtered solution were identified
by GC-FID.
matched previous report for (R)-2, [α]D = +50 (c = no data in
19
ethanol),8 but the sign of optical rotation of (S)-2, [α]D
=
Under high yield conditions (Entry 1 and 5), a crude mixture
2 and its isomer 3 was obtained and the ratio of 2/3 was 1:0.3
according to H NMR measurements (see Supporting Informa-
¹34.3 (c = 1.0 in ethanol) was opposite. We strongly believe
that 2 has potential to be a key building block for the pre-
paration of chemical products such as natural products,
pharmaceuticals, flavors, etc.14,15 In particular, many natural
products which have physiological activity having C4-position
substituted cyclopentenones as a central block or segments
are known. As one example for application to the synthesis
of natural products, we focused on prostaglandins which are
currently produced enzymatically by using cyclooxygenase
type I (COX-I) and type II (COX-II).16 A lot of prostaglandins
and derivatives have been synthesized and used as drugs.9
Herein, we have demonstrated that 2 is a useful compound for
achieving formal synthesis of prostaglandin E1 (PGE1)
1
tion). The following reaction mechanism could be the reason
for the resultant isomers (Scheme 1). At the beginning,
unsaturated ketone is formed by dehydration (I ¼ II); and the
followed cyclization results in IV (II ¼ III ¼ IV). After that,
the furan ring is opened by hydration and cyclized to form
a carbon five-membered ring (IV ¼ V ¼ VI ¼ 3). Finally, in
the presence of water, an equilibrium reaction occurs between
2 and 3, however, the amount of 2 is higher due to its ther-
modynamic stability. This hypothesis was verified from the
experimental results described below. When the hydrothermal
1694 | Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan

ed by Sato et al.9d Therefore, we followed this synthetic
approach: the two-component coupling process of Sato et al.
Cuprate (5) was prepared from (S)-1-octyn-3-ol (97% ee)9e and
(2-thieny)Cu(CN)Li reacted with 4 to produce the adduct
6.9d,9e,18 The conjugated adduct 8 was produced from 6 and the
known α-chain unit (7) by radical reaction.19 According to the
report of Sato et al., stereoselectivity was poor under heating.
Furthermore, when tris(trimethylsilyl)silane or Et3SiH were
used as a hydride source, the substrate decomposed. Therefore,
we carried out the reaction using n-tributyltin at low temper-
ature, to obtain 8 stereoselectively. However, the chemi-
cal yield was moderate (56%) due to decomposition of product.
The yield was further decreased when the reaction time was
extended. On the other hand, when the reaction time was
shortened, 6 remained. Finally, desilylation under mild condi-
tions produced PGE1 methyl ester (9). Its spectroscopic prop-
erties were identical with those described previously.10 As
reported by Spur et al, PGE1 can be prepared from 9.18 In addi-
tion, we believe that 6 could be also reacted with organo-
metallic reagents as reported previously.20
O
O
(a)
OH
NEt2
One-Pot
Operation
HO
TESO
(R)-2
4
(b) ω-chain (5)
O
(c) α-chain (7)
TESO
OTES
O
O
6
OMe
TESO
OTES
8
O
O
(d)
OMe
HO
OH
PGE1 methyl ester (9)
13.5% overall
4. Conclusion
O
O
from (R)-2
In conclusion, we have developed a novel method which
avoids the use of catalysts, high pressure and high tempera-
ture, and produced 2 from 2-DG (1) in a one-pot operation. In
addition, the reaction mechanism under hydrothermal treatment
was elucidated. The key intermediate 4 obtained from (R)-2
was used to prepare PGE1 methyl ester (9). We also believe that
if 2 were to be widely known, there could be more valua-
ble and useful products produced from 2 as a building block.
Currently, we are pursuing the conversion of products closer to
biomass origin, such as glucose, into 2 to obtain large-scale
processes for industrial applications. In addition, development
of optical resolution method without using chiral HPLC is
promoted for reduce the manufacturing costs is under way.
These accomplishments demonstrate an example of the con-
scious use of an unnatural sugar. In addition, we proved that it
is possible to create a more valuable compound by modifying
some functional groups rather than directly utilizing biomass
resources such as glucose. We are convinced that pushing
forward research on conversion of modified sugars will lead to
discovery of more valuable compounds in the field of biomass
chemistry.
OH
Ref.17
HO
OH
PGE1
S
O
I
Li2(NC)Cu
OMe
α-chain (7)
ω-chain (5)
OTES
Scheme 4. Synthesis of prostaglandin E1 methyl ester (9).
Reagents and Conditions: (a) Phosphorus tribromide
(PBr3), THF, 0 °C, 15 min; diethylamine, trimethylamine,
room temperature (r.t.), 15 min; TESCl (TES = triethyl-
silyl), r.t., 30 min (42%, one-pot, 3 steps); (b) ω-chain (5),
Et2O, ¹78 °C, 20 min (70%); (c) α-chain (7), Triethyl-
borane (Et3B), n-Bu3SnH, toluene, ¹20 °C, 3 h (56%); (d)
Pyridinium p-toluenesulfonate (PPTS), acetone-H2O (4:1),
r.t., 6 h (82%).
(Scheme 4). 2 has two allyl-alcohol substituents: 2-hydroxyl-
methyl and 4-hydroxyl groups. First, we attempted to synthe-
size the core frame 4 step by step, but it was impossible to
isolate each of them because of instability of the intermediates.
Therefore, 4 was synthesized in a one-pot operation. This reac-
tion is made up of three stages, 1) regioselective primary
bromination with the minimum required amount of phosphous
tribromide, 2) replacement of diethylamino and bromo groups,
and 3) silylation of the secondary hydroxyl group. In this reac-
tion, the second stage is particularly interesting. This conver-
sion proceeds by double Michael addition and E1cb elimina-
tion.9d,17 As a result, we have successfully obtained 4 in 42%
overall yield from (R)-2 without any evaporation or solvent
exchange. In addition, 4 was synthesized without isomerization
under the same condition by using (R)-2 obtained via optical
resolution of 2 by HPLC. The key intermediate 4 is fairly
similar to the key compound in the synthesis of PGE1 report-
We would like to thank Emeritus Profs. Masahiro Hirama,
Hachiro Nakanishi, Kunio Arai, and Assoc. Prof. Hiroshi Tada
of Tohoku University and Dr. Hideo Hattori of FromSeeds Co.,
who provided fruitful discussion. We are very grateful to Prof.
Fumi Nagatsugi, Prof. Hidetoshi Oikawa, Assoc. Prof. Ilya D.
Gridnev, Assistant Prof. Anh T. N. Dao of Tohoku University
and Dr. Kiyotaka Hatakeda of AIST, for their help on the
compound measurements. This work was performed under the
Cooperative Research Program of Network Joint Research
Center for Materials and Devices.
Supporting Information
1
Copies of the H NMR, 13C NMR, HPLC analysis and GC-
FID analysis of materials. This material is available on http://
dx.doi.org/10.1246/bcsj.20180241.
Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan | 1695

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1696 | Bull. Chem. Soc. Jpn. 2018, 91, 1691–1696 | doi:10.1246/bcsj.20180241
© 2018 The Chemical Society of Japan