Total synthesis of (S)-(+)-ent-phomapyrones B and surugapyrone B

Article abstract of DOI:10.1002/jhet.3845

Phomapyrone B (1), the 2-pyrones isolated from the phytopathogenic fungus Leptosphaeria maculans, has been synthesized as the enantiomeric form starting from (S)-2-methylbutanol (4). Surugapyrone B (3) isolated from Streptmyces sp. USF-6280 as an antioxidant has also been synthesized as a natural form. The absolute configuration of phomapyrone B (1) was estimated to be the (R)-form and that of surugapyrone B (3) being the (S)-form. A series of 2-pyrone derivatives 17 have been synthesized through the established procedure and their DPPH radical-scavenging activities have also been evaluated.

Full text of DOI:10.1002/jhet.3845

Received: 27 August 2019
DOI: 10.1002/jhet.3845
Revised: 9 November 2019
Accepted: 17 November 2019
A R T I C L E
Total synthesis of (S)-(+)-ent-phomapyrones B and
surugapyrone B
Hiroaki Ohmukai1 | Yasumasa Sugiyama2 | Akira Hirota3
Mitsunori Kirihata1 | Shinji Tanimori1
|
1Department of Applied Biological
Abstract
Sciences, Graduate School of Life and
Environmental Sciences, Osaka Prefecture
University, Osaka, Japan
2Department of Food and Health
Sciences, Jissen Women's University,
Hino, Tokyo, Japan
3School of Food and Nutritional Sciences,
University of Shizuoka, Shizuoka, Japan
Phomapyrone B (1), the 2-pyrones isolated from the phytopathogenic fungus
Leptosphaeria maculans, has been synthesized as the enantiomeric form
starting from (S)-2-methylbutanol (4). Surugapyrone B (3) isolated from
Streptmyces sp. USF-6280 as an antioxidant has also been synthesized as a nat-
ural form. The absolute configuration of phomapyrone B (1) was estimated to
be the (R)-form and that of surugapyrone B (3) being the (S)-form. A series of
2-pyrone derivatives 17 have been synthesized through the established proce-
dure and their DPPH radical-scavenging activities have also been evaluated.
Correspondence
Shinji Tanimori, Department of Applied
Biological Sciences, Graduate School of
Life and Environmental Sciences, Osaka
Prefecture University, 1-1 Gakuencho,
Nakaku, Sakai, Osaka 599-8531, Japan.
Email: tanimori@bioinfo.osakafu-u.ac.jp
Funding information
JSPS KAKENHI, Grant/Award Number:
Grant Number 17K07776
1 | INTRODUCTION
first total syntheses of (S)-(+)-ent-phomapyrone B (ent-1)
and (S)-(+)-ent-phomapyrones C (ent-2) (surugapyrone B
Phomapyrones B (1) and C (2) were isolated from the
phytopathogenic fungus Leptosphaeria maculans, the
asexual stage of Phoma linyum, as weakly virulent (also
called avirulent) isolates of this pathogen, and their pla-
nar structures being determined by Pedras and coworkers
in 1994.[1] We also isolated the related novel 2-pyrones,
surugapyrone A and B (3), from the Streptomyces
coelicoflavus strain USF-6280 as antioxidants in 2007[2] in
which surugapyrone B (3) was identified as the antipode
of phomapyrone C (2) based on the optical rotation sign.
Later, the absolute stereochemistry of these natural prod-
ucts was elucidated based on our asymmetric synthesis in
2011.[3] Recently, phomapyrone C was also isolated from
a marine-derived Nocardiopsis strain and the absolute
configuration was determined based on the Mosher
method by Zhang and coworkers,[4] which is consistent
with our result.[3] More recently, Dickschat reported the
(3)) and proposed their absolute configurations,[5]
which also agreed with the previous results.[3,4] However,
the synthesis of (S)-(+)-ent-phormapyrone C (ent-2,
surugapyrone B) has shown a lower enantioselectivity
caused by a partial racemization (19% ee).[5] In this
paper, we report the enantioselective synthesis of (S)-
(+)-ent-phomapyrone B (ent-1) and surugapyrone B (3)
from readily available chiral sources. In addition, the syn-
theses of a series of unnatural 2-pyrone derivatives
17a-h[6] and their antioxidant activities have also been
documented (Figure 1).
Dickschat recently achieved the short step total
synthesis of (S)-(+)-ent-phomapyrone B (ent-1) from
the commercially-available 4-hydroxy-3,6-dimethyl-2H-
pyran-2-one through the protection, aldol reaction, oxida-
tion followed by deprotection in the overall yield of 34%
in four steps (Figure 2).[5]
J Heterocycl Chem. 2019;1–11.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
OHMUKAI ET AL.
2 | RESULTS AND DISCUSSION
reagent to afford the carboxylic acid 4 in 74% yield.[8]
Conversion of 4 into the acid chloride 5[9] followed by
condensation with malonic acid mono-ethyl ester 6[10] in
the presence of n-butyl lithium provided the chiral β-keto
ester 7 in 68% yield.[11] Subsequently, the ketone carbonyl
group of 7 was protected as ethylene acetal to give com-
pound 8,[12] which was condensed with the dianion
derived from ethyl 2-methyl-3-oxobutanoate 9 to form
the enol 10 in 63% yield. The enol 10 was saponified with
potassium hydroxide in ethanol to generate the bis-
potassium salt 11 in 77% yield. Finally, the desired (S)-
(+)-ent-phormapyrone B (ent-1) was obtained by the
treatment of 11 with trifluoroacetic acid in trifluoroacetic
anhydride at 0ꢀC to afford the α-pyrone 12, which was
followed by the hydrolysis of the acetal with hydrochloric
acid.[13] The spectral data of the synthetic (S)-(+)-ent-
Our synthetic route to (S)-(+)-ent-phomapyrone B (ent-
1), which constitutes the construction of whole carbon
skeleton of phomapyrone B via the condensation of the
acid chloride 5 with malonic acid mono-ethyl ester
followed Claisen condensation starting from the chiral
alcohol 3 and subsequent cyclization into 2-pyrone, is
summarized in Scheme 1. The commercially-available
(S)-2-methyl-1-butanol (3)[7] was oxidized with Jones'
1
phomapyrone (ent-1) (mp, H- and 13C-NMR) are identi-
cal for those reported in the lit.[1] except for the
FIGURE 1 Structures of phomapyrones B (1), C (2) and
surugapyrone B (3)
optical rotation sign ([α]D28 + 18.7 (c 0.14, CHCl3); lit.[1]
FIGURE 2 Previous synthesis of (S)-
(+)-ent-phomapyrone B (ent-1)
SCHEME 1 Total synthesis of (S)-(+)-ent-phomapyrone B (1)

OHMUKAI ET AL.
3
[α]D−18.6 (c 0.14, CHCl3) for the natural phomapyrone,
lit.[5][α]D20 + 18.7 (c 0.99, CHCl3) for the synthetic (S)-
(+)-ent-phomapyrone), which strongly suggests that the
products. The values of the DPPH radical-scavenging
activities of some selected 2-pyrone compounds are sum-
marized in Table 1.
natural phormapyrone
configuration at the side chain chiral center.
B
(1) possesses an (R)-
The ED50 value of ent-phomapyrone C (surugapyrone
B) (2) was 3.6 mM. The ED50 values of the 2-pyrones
substituted by electron withdrawing groups on the aro-
matic ring (17e and 17f) were higher than that of ent-
phomapyrone C. Some 2-pyrones substituted by electron
donating groups on the aromatic ring (17c and 17d)
showed lower values than that of ent-phomapyrone
C. Typically, the value of 2-pyrone 17c substituted by the
p-methoxy phenyl group was half the value of ent-
phomapyrone C.
Surugapyrone B (3) with the chiral sec-butyl side
chain has been synthesized in a similar manner as shown
in Scheme 2. Fisher esterification of the carboxylic acid
4 afforded the ester 13 in 64% yield. The ester 13 was con-
densed with the dianion derived from the β-keto ester
9 to give the enol 14, which was saponified without isola-
tion to provide the bis-potassium salt 15 in 34% yield.
Finally, acid treatment of 15 in the presence of
trifluoroacetic acid in trifluoroacetic anhydride provided
the desired surugapyrone B (3) in 79% yield. The spectral
data of the synthetic 3 (mp, 1H- and 13C-NMR, [α]D) were
identical to those reported in the literature,[2] which indi-
cated that the natural surugapyrone B possesses the
(S)-configuration at the side chain chiral center. The ste-
reochemistry was also clarified by Dickschat and
coworkers based on their total synthesis of (S)-(+)-ent-
3 | CONCLUSIONS
In conclusion, we have accomplished the total synthesis
of the fungitoxic 2-pyrone natural products (S)-(+)-ent-
phomapyrones B (ent-1) and surugapyrone B (3) as their
enantiomeric and natural forms, respectively, from a
readily available chiral material in a straightforward
manner without the loss of chirality. Although the pre-
sent method requires more steps than the previous
synthesis,[5] it would be easier to synthesize the related
α-pyrones derivatives with a variety of side chains.[1,2,4]
The absolute configurations of the natural products were
clearly elucidated in this study along with the previous
studies.[3–5] A series of 2-pyrone derivatives focused on
the C-6 substitution have been synthesized and the pre-
liminary studies of the DPPH radical-scavenging activi-
ties have been performed. Further studies directed
toward the synthesis of the 2-pyrone derivatives focusing
on the C-3 substitution are now under investigation.
phormapyron
C
(2)
(surugapyrone
B)
from
(S)-2-methylbutyraldehyde by the Mukaiyama aldol reac-
tion, Dess-Martin oxidation and subsequent treatment
with DBU, in which a partial racemization through the
base-catalyzed cyclization stage was observed.[5]
Finally, a preliminary investigation of the antioxidant
activities of the 2-pyrone compounds was performed
based on the DPPH radical-scavenging activities.[14] The
2-pyrone compounds 17a-17j were synthesized based on
the Claisen condensation in 3 to 36% yields as shown in
Scheme 3. The reasons for the lower yields of these trans-
formations are attributed to the lower reactivity of these
aromatic esters along with the higher polarity of the
SCHEME 2 Total synthesis of surugapyrone B (3)

4
OHMUKAI ET AL.
SCHEME 3 Synthesis of a series of 2-pyrone compounds 17
TABLE 1 DPPH radical-scavenging activity of 2-pyrone derivatives 17
4 | EXPERIMENTAL
4.1 | General information
DMSO-d6 solution using 400 and 100 MHz spectrometers,
respectively. The proton chemical shifts (δ) are relative to
tetramethylsilane (TMS, δ = 0.0) as the internal standard
and expressed in parts per million. The spin multiplicities
are given as s (singlet), d (doublet), t (triplet), and m
(multiplet) as well as br (broad). The coupling constants
(J) are given in hertz. The infrared spectra were recorded
by a FT-IR spectrometer. The melting points were deter-
mined using a Büchi melting point B-540 apparatus and
are uncorrected. MS spectra were obtained by a mass
Unless stated otherwise, the reactions were monitored by
thin layer chromatography (TLC) on silica gel plates
(60 Å, F254), visualizing with ultraviolet light or iodine
spray. Column chromatography was performed on silica
gel (60-120 mesh) using hexane and ethyl acetate. The
1H- and 13C-NMR spectra were determined in a CDCl3 or

OHMUKAI ET AL.
5
spectrometer. The HRMS was determined using a JEOL
JMS-700 mass spectrometer. The optical rotations were
measured by a JASCO DIP-360 polarimeter.
n-BuLi (13.5 mL, 20.0 mmol, 1.6M) was slowly added and
the mixture stirred for 15 min at –78ꢀC. (S)-2-Methylbutyryl
chloride 5 (0.54 g, 0.60 mL, 5.0 mmol) was dropwise added
and stirred for 5 h at room temperature. The reaction was
then quenched by the addition of 1N HCl (10 mL). The resi-
due was diluted with diethyl ether (10 mL). The organic
layer was separated. The water layer was extracted with
diethyl ether (10 mL × 3) and the combined organic layer
was washed with saturated aqueous NaHCO3 (30 mL) and
brine (30 mL) and dried over anhydrous Na2SO4, then fil-
tered. The filtrate was concentrated in vacuo, and the crude
product was purified by silica gel column chromatography
(eluting with 10% EtOAc in hexane) to give the β-keto ester
7 (0.58 g, 68%) as a yellow oil: Rf 0.62 (hexane:EtOAc = 4:1);
½αꢁD = +19.7 (c 0.3, CHCl3); H-NMR (CDCl3): δ 0.88 to
0.92 (3H, m, –CHCH2CH3), 1.15 (3H, t, J = 6.3 Hz, –
OCH2CH3), 1.28 (3H, d, J = 6.6 Hz, –CHCH3), 1.41 to
1.74 (2H, m, –CHCH2CH3), 2.56 to 2.61 (1H, m, –
CHCH2CH3), 3.48 (2H, s, –COCH2CO–), 4.17 to 4.22 (2H,
m, –OCH2CH3); 13C-NMR (CDCl3): δ 11.4, 14.1, 15.5,
25.6, 47.7, 48.0, 61.3, 167.4, 206.6.
4.2 | (S)-2-methylbutanoic acid (4)[8]
To a stirred and cooled (0ꢀC) solution of (S)-2-methyl-
1-butanol 3 (20.6 g, 0.23 mmol) in acetone (200 mL),
Jones' CrO3 reagent3 (2.69M, 110 mL, 0.30 mmol) was
dropwise added at 0ꢀC and the mixture stirred for 2 h at
room temperature. The reaction was then quenched by
the addition of 2-propanol and the mixture concentrated
in vacuo. The residue was diluted with water and
extracted with diethyl ether. The organic phase was
washed with dilute HCl (10%) and brine, dried over
MgSO4, and concentrated. The residue was distilled to
give 20.1 g (85%) of (S)-4 as a colorless oil: Rf 0.34 (hex-
13
1
23
ane:EtOAc = 3:1); ½αꢁD = +19.2 (c 1.15, CHCl3) (lit.[7]
23
½αꢁD = +19.8 (c 1.15, CHCl3)); IR: νmax = 2962 (br s, OH),
1708 (br s, C=O), 1462, 1418, 1287, 1230, 1155, 1089,
943, 772, 631 cm‑1; 1H-NMR (CDCl3): δ 0.95 (3H,
t, J = 7.6 Hz, –CHCH2CH3), 1.18 (3H, d, J = 6.8 Hz,
–CHCH3), 1.42 to 1.77 (2H, m, –CHCH2CH3), 2.36 to 2.45
(1H, sextet, J = 6.8 Hz, –CHCH2CH3), 11.8 (1H, br s,
–CO2H); 13C-NMR (CDCl3): δ 11.5, 16.3, 26.5, 40.8, 183.5.
4.5 | (S)-(2-sec-Butyl-[1,3]dioxolan-2-yl)-
acetic acid ethyl ester (8)[12]
Triethylorthoformate (0.78 g, 0.87 mL, 5.20 mmol) and
ethylene glycol (0.32 g, 0.29 mL, 5.20 mmol) were
dropwise added to a solution of the β-keto ester 7 (0.30 g,
1.70 mmol) and p-toluenesulfonic acid (33 mg, 0.17 mmol)
in anhydrous toluene (10 mL) at room temperature under
a nitrogen atmosphere, then the mixture was stirred for
24 h at room temperature. The mixture was concentrated
in vacuo to give a residue, which was purified by silica gel
column chromatography (stepwise: 3% EtOAc in hexane
to 5% EtOAc in hexane) to give the protected β-keto ester
8 (0.31 g, 82%) as a yellow oil: Rf 0.49 (hexane:
4.3 | (S)-2-Methylbutyryl chloride (5)[9]
Under a nitrogen atmosphere, SOCl2 (0.72 g, 1.2 mL,
16.5 mmol) and a drop of DMF was slowly added to (S)-
2-methylbutanoic acid 4 (1.92 g, 1.80 mL, 16.0 mmol) at
0ꢀC and the mixture stirred for 2 h at 55ꢀC. After cooling,
the excess SOCl2 was eliminated under reduced pressure
(bath temperature: 30ꢀC) leaving a residue, which was
purified by distillation under reduced pressure (bath tem-
perature: 50ꢀC) to give (S)-2-methylbutyryl chloride
5 (1.26 g, 62%) as a colorless oil:
12
EtOAc = 4:1); ½αꢁD = −8.8 (c 0.31, CHCl3); 1H-NMR
(CDCl3): δ 0.92 (3H, t, J = 7.3 Hz, –CHCH2CH3), 0.95
(3H, d, J = 6.8 Hz, –CHCH3), 1.01 to 1.1 (1H, m, –
CHCH2CH3), 1.27 (3H, t, J = 7.1 Hz, –OCH2CH3), 1.67 to
1.80 (2H, m, –CHCH2CH3), 2.67 (2H, s, –CH2CO–), 3.94
to 4.02 (4H, m, –OCH2CH2O–), 4.12 (2H, q, J = 7.1 Hz, –
OCH2CH3); 13C-NMR (CDCl3): δ 12.2, 13.4, 14.2, 23.6,
40.0, 42.5, 60.5, 65.3, 65.4, 111.9, 170.0.
13
20
½αꢁD = +16.5 (c 0.55, CHCl3) (lit.[8] ½αꢁD = +17.2
(neat)); 1H-NMR (CDCl3) δ 0.98 (3H, t, J = 7.3 Hz,
–CHCH2CH3), 1.28 (3H, d, J = 3.4 Hz, –CHCH3), 1.56 to
1.89 (2H, m, –CHCH2CH3), 2.79 to 2.86 (1H, m,
–CHCH2CH3); 13C-NMR (CDCl3): δ11.1, 16.5, 26.5,
52.9, 177.7.
4.4 | (S)-4-Methyl-3-oxo-hexanoic acid
ethyl ester (7)[11]
4.6 | (S)-6-(2-sec-Butyl-[1,3]dioxolan-2-yl)-
5-hydroxy-2-methyl-3-oxo-hex-4-enoic acid
ethyl ester (10)[13]
Under a nitrogen atmosphere, to a stirred solution of mono-
ethyl malonate 6 (0.98 g, 1.10 mL, 10.0 mmol) and
4,4-bipyridine (1 mg) in anhydrous THF (50 mL) at ‑78ꢀC,
Ethyl 2-methyl acetoacetate 9 (0.67 g, 0.66 mL, 4.7 mmol)
was dropwise added to a solution of sodium hydride

6
OHMUKAI ET AL.
(0.21 g, 5.10 mmol, 60%) in anhydrous THF (20 mL) at
0ꢀC under a nitrogen atmosphere. After 15 min of stirring
at 0ꢀC, n-BuLi (2.90 mL, 4.70 mmol, 1.6M) was slowly
added. After 15 min of stirring at 0ꢀC, the protected
β-keto ester 8 (0.31 g, 1.43 mmol) in anhydrous THF
(2 mL) was dropwise added, then the mixture was stirred
at 0ꢀC for 3 h. The reaction was then quenched by the
addition of 1N HCl (20 mL). The residue was diluted with
water (5 mL) and diethyl ether (5 mL). The organic
layer was separated. The water layer was extracted with
diethyl ether (10 mL × 3) and the combined organic layer
was washed with brine (20 mL) and dried over anhy-
drous Na2SO4, then filtered. The filtrate was
concentrated in vacuo, and the crude product was puri-
fied by silica gel column chromatography (stepwise: 3%
EtOAc in hexane to 7% EtOAc in hexane) to give the
δ-enol-β-keto ester 10 (0.47 g, 63%) as a yellow oil: Rf
4.8 | (S)-6-(2-sec-Butyl-[1,3] dioxolan-
2-ylmethyl)-4-hydroxy-3-methyl-pyran-
2-one (12)
Under a nitrogen atmosphere, to a solution of the
bis-potassium salt 11 (0.15 g, 0.42 mmol) in
trifluoroacetic anhydride (2.5 mL), trifluoroacetic acid
(0.11 g, 0.070 mL, 0.94 mmol) was dropwise added at
−20ꢀC and stirred for 12 h at 0ꢀC. The excess TFA/TFAA
was eliminated under reduced pressure. The remaining
traces of TFA could be azeotropically removed with tolu-
ene and the crude product was poured into water, then
the mixture was filtered under reduced pressure with
water to give the protected α-pyrone 12 (75 mg, 70%) as a
white solid: Rf 0.18 (hexane:EtOAc = 1:1); Mp: 148.9ꢀC
12
to 150.4ꢀC; ½αꢁD = −7.9 (c 0.14, CHCl3); IR: νmax 2967,
2886, 2682, 1634, 1576, 1414, 1258, 1173, 1126, 1038,
847 cm‑1; 1H-NMR (CD3OD): δ 0.90 to 0.98 (6H, m,
–CHCH2CH3 and –CHCH3), 1.05 to 1.13 (1H, m,
–CHCH2CH3), 1.58 to 1.75 (2H, m, –CHCH2CH3), 1.85
(3H, s, pyrone –CH3), 2.78 (2H, s, –CH2CO–), 3.81 to 3.90
(4H, m, –OCH2CH2O–), 6.11 (1H, s, pyrone H); 13C-NMR
(CD3OD): δ 8.2, 12.6, 13.9, 25.0, 39.2, 44.0, 66.4, 66.5,
99.5, 104.1, 113.7, 160.7, 167.6, 169.1; FAB-MS m/z (%)
269 ([M+H]+, 15), 129 (36), 89 (21), 77 (13); HRMS-FAB
m/z [M+H]+ calcd for C14H21O5: 269.1389, found
269.1399.
12
0.51 (hexane:EtOAc = 3:1); ½αꢁD = −7.8 (c 0.3, CHCl3);
IR: νmax = 2973, 2886, 1738, 1610, 1458, 1309, 1193, 1086,
1
1034 cm‑1; H-NMR (CDCl3): δ 0.91 (3H, t, J = 7.3 Hz,
–CH(CH3)CH2CH3), 0.95 (3H, d, J = 5.9 Hz, –CH(CH3)
CH2CH3), 1.02 to 1.1 (1H, m, –CHCH2CH3), 1.27 (3H, t,
J = 7.1 Hz, –OCH2CH3), 1.39 (3H, d, J = 7.3 Hz,
–COCHCH3CO–), 1.63 to 1.72 (2H, m, –CHCH2CH3),
2.62 (2H, s, –CH2C(OH)=), 3.37 (1H, q, J = 7.3 Hz,
–COCHCH3CO–), 3.94 (4H, s, –OCH2CH2O–), 4.16 (2H,
q, J = 7.1 Hz, –OCH2CH3), 5.72 (1H, s, HOC=CHCO–);
13C-NMR (CDCl3): δ 12.2, 13.5, 13.8, 14.0, 23.8, 42.7, 43.0,
49.4, 61.3, 65.3, 65.4, 100.8, 112.8, 170.8, 188.2, 192.5;
FAB-MS m/z (%) 315 ([M+H]+, 4), 305 (7), 257 (4),
171 (16), 129 (100), 113 (4), 57 (6); HRMS-FAB m/z
[M+H]+ calcd for C16H27O6: 315.1808, found 315.1755.
4.9 | (S)-(+)-ent-Phomapyrone B
(ent-1)[1,5]
Under a nitrogen atmosphere, 10% HCl (0.2 mL) was
dropwise added to a solution of the protected α-pyrone 12
(60 mg, 0.22 mmol) in MeOH (1.2 mL) at 0ꢀC, then the
mixture was stirred for 24 h at room temperature. The
reaction was then quenched by the addition of 10% aque-
ous NaHCO3 and converted to pH 5 to 6. The water layer
was extracted with diethyl ether (5 mL × 3) and dried
over anhydrous Na2SO4, then filtered. The filtrate was
concentrated in vacuo, and the crude product was crystal-
lized from MeOH to give (S)-(+)-ent-phomapyrone B
(ent-1) (29 mg, 58%) as white crystals: Rf 0.18 (hexane:
4.7 | Bis-potassium salt of (S)-6-
(2-sec-butyl-[1,3]dioxolan-2-yl)-5-
hydroxy-2-methyl-3-oxo-hex-4-enoic
acid (11)
Under a nitrogen atmosphere, a solution of potassium
hydroxide (0.18 g, 2.70 mmol, 85%) in anhydrous EtOH
(1.1 mL) was stirred at room temperature. After 15 min,
the δ-enol-β-keto ester 10 (0.15 g, 0.49 mmol) in anhy-
drous EtOH (1 mL) was dropwise added at room temper-
ature and stirred for 3 h at room temperature. The
mixture was filtered under reduced pressure with diethyl
ether. The solvent was eliminated under reduced pres-
sure to give the bis-potassium salt 11 (0.15 g, 90%) as a
white solid, which was used without purification in the
next reaction.
23
EtOAc = 1:1); Mp: 139.2 to 139.5ꢀC; ½αꢁD = +18.7 (c 0.14,
20
CHCl3) (lit.[1] ½αꢁD = −18.6 (c 0.14, CHCl3), lit.[5]
20
1
½αꢁD + 18.7 (c 0.99, CHCl3)); H-NMR (CD3OD): δ 0.89
(3H, t, J = 7.6 Hz, –CHCH2CH3), 1.11 (3H, d, J = 6.8 Hz,
–CHCH3), 1.40 to 1.75 (2H, m, –CHCH2CH3), 1.94 (3H, s,
pyrone –CH3,), 2.54 to 2.62 (1H, ddq, J = 6.8 Hz,
–CHCH2CH3), 3.60 (2H, s, –COCH2), 6.16 (1H, s, pyrone

OHMUKAI ET AL.
7
H), 9.07 (1H, br s, pyrone –OH); 13C-NMR (CD3OD): δ
8.2, 11.5, 15.5, 25.6, 45.2, 48.1, 99.7, 103.5, 155.5, 165.2,
167.2, 208.4; FAB-MS m/z (%) 225 ([M+H]+, 100),
154 (14), 141 (17), 107 (6), 85 (10), 77 (6), 57 (20); HRMS-
FAB m/z [M+H]+ calcd for C12H17O4: 225.1127, found
225.1125.
(20 mL), dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated in vacuo, and the crude product
was purified by silica gel column chromatography (step-
wise: 4% EtOAc in hexane to 7% EtOAc in hexane) to
give the δ-enol β-keto ester 14 as a brown oil (0.44 g),
which was used without purification in the next reaction:
Rf 0.64 (hexane:EtOAc = 3:1).
4.10 | (S)-Ethyl-2-methylbutanoate
(13)[15,16]
4.12 | Bis potassium salt of (S)-
5-hydroxy-2,6-dimethyl-3-oxo-oct-4-enoic
acid (15)[18]
Under a nitrogen atmosphere, to a stirred and cooled
solution of (S)-2-methylbutanoic acid 4 (3.0 g, 3.20 mL,
29.0 mmol) and 3 Å MS (3.0 g) in anhydrous EtOH
(40 mL), sulfuric acid (0.6 mL) was slowly dropwise
added at 0ꢀC, then the mixture was heated at reflux for
3 h. After cooling, diethyl ether (20 mL) was added. The
residue was washed with aqueous NaHCO3 (20 mL × 2)
and aq. CaCl2 (20 mL × 4) and dried over anhydrous
Na2SO4, and filtered. The filtrate was concentrated in
vacuo to give (S)-ethyl 2-methylbutanoate 13 (2.43 g,
64%) as a colorless oil: Rf 0.33 (hexane:EtOAc = 3:1);
Under nitrogen atmosphere, a solution of potassium
hydroxide (1.0 g, 18.0 mmol, 85%) in anhydrous EtOH
(6 mL) was stirred at room temperature. After 15 min,
δ-enol-β-keto ester 14 (0.44 g) in anhydrous EtOH (2 mL)
was dropwise added at room temperature and the mix-
ture was stirred for 30 min at room temperature. The res-
idue was stored for 12 h at ‑20ꢀC. The mixture was then
filtered under reduced pressure with diethyl ether. The
solvent was eliminated under reduced pressure to give
the bis-potassium salt 15 (0.39 g, 34%, from 13) as a white
solid, which was used without purification in the nest
reaction: Rf 0.19 (CHCl3:MeOH = 1:9).
23
24
½αꢁD = +18.6 (c 1.15, CHCl3) (lit.[14] ½αꢁD = +17.8 (neat));
IR: νmax 2972, 1733 (s, C=O), 1461, 1376, 1262, 1187,
1152, 1088, 1032, 757 cm‑1; 1H-NMR (CDCl3): δ 0.91 (3H,
t, J = 7.3 Hz, –CHCH2CH3), 1.14 (3H, d, J = 5.6 Hz,
–CHCH3), 1.26 (3H, t, J = 4.6 Hz, –OCH2CH3), 1.4 to 1.73
(2H, m, –CHCH2CH3), 2.33 to 2.38 (1H, m, –CHCH2CH3),
4.11 to 4.12 (2H, m, –OCH2CH3); 13C-NMR (CDCl3):
δ 11.6, 14.3, 16.6, 26.8, 41.1, 60.0, 176.8. The oil was used
without purification in the next reaction.
4.13 | Surugapyrone B (3)[1,2,5]
Under a nitrogen atmosphere, to a solution of the bis-
potassium salt 15 (0.39 g, 1.40 mmol) in trifluoroacetic
anhydride (7.1 mL), trifluoroacetic acid (0.37 g, 0.24 mL,
3.3 mmol) was dropwise added at ‑20ꢀC and stirred for
4 h at 0ꢀC. The excess TFA/TFAA was removed under
reduced pressure. The remaining traces of TFA could be
azeotropically removed with toluene and the crude prod-
uct was purified by silica gel preparative TLC (MeOH:
CHCl3 = 1:9) to give surugapyrone B (3) (202 mg, 79%) as
a white crystal: Rf 0.46 (MeOH:CHCl3 = 1:9); Mp: 126.2 to
4.11 | (S)-5-Hydroxy-2,6-dimethyl-3-oxo-
oct-4-enoic acid ethyl ester (14)[17]
Ethyl 2-methylacetoacetate
9
(1.22 g, 1.20 mL,
8.20 mmol) was dropwise added to a solution of sodium
hydride (0.36 g, 9.00 mmol, 60%) in anhydrous THF
(28 mL) at 0ꢀC under nitrogen atmosphere. After 15 min
of stirring at 0ꢀC, n-BuLi (5.6 mL, 9.00 mmol, 1.6M) was
slowly added. After 15 min of stirring at 0ꢀC, ethyl (S)-
2-methylbutanoate 13 (0.49 g, 0.57 mL, 4.10 mmol) was
dropwise added and stirred at 0ꢀC for 15 min. The reac-
tion was then quenched by the addition of concentrated
HCl (2 mL). The residue was diluted with water (6 mL)
and diethyl ether (10 mL). The organic layer was sepa-
rated. The water layer was extracted with diethyl ether
(10 mL × 3) and the combined organic layer was washed
with saturated aqueous NaHCO3 (20 mL) and brine
23
20
127.8ꢀC; ½αꢁD = +20.5 (c 0.28, CHCl3) (lit.[1] ½αꢁD = −16.1
20
(c 0.28, CHCl3) for phormapyrone C. ½αꢁD = +22.2
(c 0.135, CHCl3) for surugapyrone B[2]); IR: νmax 2969,
2933, 2694, 1641, 1574, 1409, 1239, 1158, 849 cm‑1; H-
1
NMR (CDCl3): δ 0.87 (3H, t, J = 7.3Hz, –CHCH2CH3),
1.18 (3H, d, J = 6.8Hz, –CHCH3) 1.46 to 1.73 (2H, m,
–CHCH2CH3), 1.97 (3H, s, pyrone –CH3), 2.46 (1H, sex-
tet, J = 6.8Hz, –CHCH3), 6.20 (1H, s, pyrone –H), 10.37
(1H, br s, pyrone –OH); 13C-NMR (CDCl3): δ 8.1, 11.5,
17.8, 27.4, 39.6, 98.6, 100.0, 167.0, 167.3, 168.7; EI-MS m/
z (%) 182 (M+, 52), 154 (15), 125 (100), 97 (8), 69 (19),

8
OHMUKAI ET AL.
56 (4); EI-HRMS calcd for C10H14O3 (M+) 182.0943,
found 182.0925.
(226 mg, 36%) was obtained as a white solid: Rf 0.59
(CHCl3:MeOH = 1:9); IR: νmax 3080, 2938, 2667, 1620,
1562, 1494, 1460, 1398, 1283, 1253, 1155, 1125, 1057,
1
1024, 748 cm‑1; Mp: 215ꢀC to 215.6ꢀC; H-NMR(DMSO):
4.14 | 4-Hydroxy-3-methyl-
6-phenylpyrone (17a)[17–19]
δ 1.84 (3H, s, pyrone CH3), 3.92 (3H, s, OCH3), 7.07 (1H,
s, pyrone H), 7.10 (1H, dd, Ph, J = 7.6 Hz, J = 8.0 Hz),
7.20 (1H, d, Ph, J = 8.4 Hz), 7.47 (1H, dd, Ph, J = 7.6 Hz,
J = 8.4 Hz), 7.74 (1H, d, Ph, J = 8.0 Hz), 11.26 (1H, br s,
pyrone OH); 13C-NMR (DMSO): δ 8.6, 55.9, 98.3, 102.6,
112.4, 119.5, 120.8, 127.9, 131.7, 153.6, 157.0, 164.4, 164.9;
EI-MS m/z (%) 232 (M+, 92), 204 (54), 177 (11), 135 (100),
92 (12), 77 (22), 69 (7); EI-HRMS calcd for C13H12O4
(M+) 232.0736, found 232.0668.
According to the procedure for the synthesis of the keto ester
14, ethyl benzoate (0.85 g, 0.81 mL, 5.70 mmol) was reacted
with the dianion prepared from ethyl 2-methylacetoacetate
(1.1 g, 1.1 mL, 7.5 mmol), sodium hydride (0.36 g, 8.2 mmol,
60%), and n-butyllithium (4.7 mL, 7.7 mmol, 1.6M). After
work-up followed by chromatography on silica gel (stepwise:
4% EtOAc in hexane to 7% EtOAc in hexane), the keto ester
16 (0.65 mg) was obtained as a yellow oil, which was directly
used in the next step.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (0.65 g) was
treated with potassium hydroxide (1.0 g, 15 mmol, 85%)
in anhydrous methanol (6 mL). After work-up, the resid-
ual solid was treated with trifluoroacetic acid (0.45 g,
0.3 mL, 4.0 mmol) in trifluoroacetic anhydride (3 mL).
After work-up followed by recrystallization from metha-
nol, 2-pyrone 17a (58 mg, 5%) was obtained as a white
solid: Rf 0.59 (CHCl3:MeOH = 1:9); Mp: 275.0ꢀC to
275.8ꢀC (lit.[18] Mp: 270-273ꢀC); 1H-NMR (DMSO): δ 1.83
(3H, s, pyrone CH3), 6.70 (1H, s, pyrone H), 7.49 to 7.53
(3H, m, Ph), 7.73 to 7.75 (2H, m, Ph), 11.35 (1H, bs,
pyrone OH); 13C-NMR (DMSO): δ 8.7, 97.9, 98.5, 125.1
(2 × C), 129.2(2 × C), 130.6, 131.2, 156.6, 164.3, 164.9.
4.16 | 4-Hydroxy-6-(4-methoxyphenyl)-
3-methylpyrone (17c)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl 4-methoxybenzoate (0.75 g, 0.68 mL,
4.2 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (1.1 g, 1.1 mL, 7.5 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-butyllithium
(4.7 mL, 7.7 mmol, 1.6M). After work-up followed by chro-
matography on silica gel (stepwise: 4% EtOAc in hexane to
10% EtOAc in hexane), the keto ester 16c (0.36 g) was
obtained as a yellow oil, which was directly used in the
next step.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (0.36 g) was
treated with potassium hydroxide (0.60 g, 9.1 mmol, 85%)
in anhydrous methanol (4 mL). After work-up, the resid-
ual solid was treated with trifluoroacetic acid (0.45 g,
0.3 mL, 4 mmol) in trifluoroacetic anhydride (5 mL). After
work-up followed by recrystallization from methanol,
2-pyrone 17c (134 mg, 21%) was obtained as a yellow
solid: Rf 0.59 (CHCl3:MeOH = 1:9); Mp: 260.0ꢀC to
260.5ꢀC; IR: νmax 3097, 2918, 2650, 1628, 1559, 1402, 1249,
4.15 | 4-Hydroxy-6-(2-methoxyphenyl)-
3-methylpyrone (17b)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl 2-methoxybenzoate (0.78 g, 0.67 mL,
4.2 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (1.1 g, 1.1 mL, 7.5 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 7% EtOAc in hexane), the keto ester
16 (572 mg) was obtained as a yellow oil, which was
directly used in the next step.
1
1157, 1027, 871, 747 cm‑1; H-NMR (DMSO): δ 1.81 (3H,
s, pyrone CH3), 3.80 (3H, s, OCH3), 6.56 (1H, s, pyrone H)
7.04 (2H, d, Ph, J = 8.8 Hz), 7.69 (2H, d, Ph, J = 8.8 Hz),
11.26 (1H, br s, pyrone OH); 13C-NMR (DMSO ): δ 8.7,
55.4, 96.2, 97.4, 114.5(2 × C), 123.6, 126.7(2 × C), 156.8,
161.1, 164.4, 165.2; EI-MS m/z (%) 232 (M+, 100), 204 (66),
177 (17), 135 (58), 109 (7), 69 (9), 64 (3); EI-HRMS calcd
for C13H12O4 (M+) 232.0736, found 232.0714.
According to the procedure for the synthesis of
(S)-(+)-phomapyrone
C (2), the above keto ester
(572 mg) was treated with potassium hydroxide (0.89 mg,
14.0 mmol, 85%) in anhydrous methanol (4 mL). After
work-up, the residual solid was treated with
trifluoroacetic acid (0.45 g, 0.3 mL, 4.0 mmol) in
trifluoroacetic anhydride (5 mL). After work-up followed
by recrystallization from methanol, 2-pyrone 17b
4.17 | 6-(3-Methylphenyl)-4-hydroxy-
3-methylpyrone (17d)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl 3-methylbenzoate (0.50 g, 0.51 mL,

OHMUKAI ET AL.
9
3.9 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (0.51 g, 0.51 mL, 3.9 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 10% EtOAc in hexane), the keto ester
16d (0.22 g) was obtained as a yellow oil, which was
directly used in the next step.
pyrone CH3), 6.44 (1H, s, pyrone H), 7.44 (1H, dt, Ph,
J = 1.6 Hz, J = 8.0 Hz), 7.51 (1H, t, Ph J = 7.6 Hz), 7.58
(1H, dd, Ph, J = 1.6 Hz, J = 7.6 Hz), 7.76 (1H, d, Ph,
J = 8.0 Hz), 11.49 (1H, br s, pyrone OH); 13C-NMR
(DMSO): δ 8.6, 98.7, 102.9, 120.9, 128.2, 131.0, 132.0,
133.3, 133.6, 156.6, 164.2, 164.4; EI-MS m/z (%) 280 (M+,
100), 254 (72), 201 (63), 183 (41), 173 (34), 155 (19),
69 (37), 57 (7); EI-HRMS calcd for C12H9O3Br (M+)
279.9735, found 279.9734.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (0.22 g) was
treated with potassium hydroxide (0.60 g, 9.1 mmol, 85%)
in anhydrous methanol (4 mL). After work-up, the resid-
ual solid was treated with trifluoroacetic acid (0.45 g,
0.3 mL, 4 mmol) in trifluoroacetic anhydride (5 mL).
After work-up followed by recrystallization from metha-
nol, 2-pyrone 17d (67 mg, 8%) was obtained as a yellow
solid: Rf 0.75 (CHCl3:MeOH = 1:9); Mp: 193.7ꢀC to
194.2ꢀC; IR: νmax 3725, 2613, 1553, 1335, 1142,
4.19 | 6-(4-Chlorophenyl)-4-hydroxy-
3-methylpyrone (17f)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl 4-chlorobenzoate (0.77 g, 3.4 mmol) was
reacted with the dianion prepared from ethyl
2-methylacetoacetate (0.51 g, 0.51 mL, 3.9 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 7% EtOAc in hexane), the keto ester
16f (351 mg) was obtained as a yellow oil, which was
directly used in the next step.
1
789, 641 cm‑1; H-NMR (DMSO): δ 1.85 (3H, s, pyrone
CH3), 2.38 (3H, s, CH3), 6.69 (1H, s, pyrone H), 7.32 (1H,
d, Ph, J = 7.6 Hz), 7.40 (1H, t, Ph, J = 7.6 Hz), 7.5 to 7.6
(2H, m, Ph), 11.33 (1H, br s, pyrone OH); 13C-NMR
(DMSO): δ 8.7, 21.0, 97.8, 98.4, 122.2, 125.4, 129.0, 131.1,
131.2, 138.5, 156.7, 164.3, 164.8; FAB-MS m/z (%) 217 ([M
+H]+, 10) 195 (100), 178 (8), 165 (26), 164 (9); HRMS-
FAB m/z [M+H]+ calcd for C13H13O3: 217.0865, found
217.0906.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (351 mg)
was treated with potassium hydroxide (0.60 g, 9.1 mmol,
85%) in anhydrous methanol (4 mL). After work-up, the
residual solid was treated with trifluoroacetic acid
(0.45 g, 0.3 mL, 4 mmol) in trifluoroacetic anhydride
(5 mL). After work-up followed by recrystallization from
methanol, 2-pyrone 17f (30 mg, 3%) was obtained as a
white solid. Rf 0.7 (CHCl3:MeOH = 1:9); IR: νmax 3723,
2636, 1619, 1552, 1497, 1390, 1151, 820, 744, 641 cm‑1;
4.18 | 6-(2-Bromophenyl)-4-hydroxy-
3-methylpyrone (17e)[17,18]
According to the procedure for the synthesis of the keto
ester 14, 2-bromobenzoyl chloride (0.77 g, 3.4 mmol) was
reacted with the dianion prepared from ethyl
2-methylacetoacetate (0.51 g, 0.51 mL, 3.9 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6 M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 7% EtOAc in hexane), the keto ester
16e (320 mg) was obtained as a yellow oil, which was
directly used in the next step.
1
Mp: 254.5ꢀC to 256.3ꢀC; H-NMR (DMSO): δ 1.82 (3H, s,
pyrone CH3), 6.69 (1H, s, pyrone H), 7.55 (2H, d, Ph,
J = 8.4 Hz), 7.74 (2H, d, Ph, J = 8.4 Hz), 11.36 (1H, br s,
pyrone OH); 13C-NMR (DMSO): δ 8.7, 98.3, 98.8, 126.8
(2 × C), 129.2 (2 × C), 130.0, 135.2, 155.3, 164.1, 164.7;
FAB-MS m/z (%) 237 ([M+H]+, 34), 236 (11), 165 (6),
89 (21), 77 (16); HRMS-FAB m/z [M+H]+ calcd for
C12H10O3Cl: 237.0319, found 237.0308.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (0.32 g) was
treated with potassium hydroxide (0.60 g, 9.1 mmol, 85%)
in anhydrous methanol (4 mL). After work-up, the resid-
ual solid was treated with trifluoroacetic acid (0.45 g,
0.3 mL, 4 mmol) in trifluoroacetic anhydride (3 mL).
After work-up followed by recrystallization from metha-
nol, 2-pyrone 17e (106 mg, 11%) was obtained as a white
solid: Rf 0.59 (CHCl3:MeOH = 1:9); IR: νmax 2923, 2688,
1615, 1562, 1513, 1401, 1297, 1262, 1155, 1024, 833 cm‑1;
4.20 | 6-(thiophen-2-yl)-4-hydroxy-
3-methylpyrone (17g)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl thiophene-2-carboxylate (0.80 g, 0.68 mL,
5.1 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (1.1 g, 1.1 mL, 7.53 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6M). After work-up
1
Mp: 276.2ꢀC to 276.5ꢀC; H-NMR (DMSO): δ 1.83 (3H, s,

10
OHMUKAI ET AL.
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 10% EtOAc in hexane), the keto ester
16g (400 mg) was obtained as a yellow oil, which was
directly used in the next step.
163.5, 164.5; FAB-MS m/z (%) 193 ([M+H]+, 52),
192 (21), 165 (5), 120 (11), 89 (24), 77 (22), 63 (8), 51 (7);
HRMS-FAB m/z [M+H]+ calcd for C10H9O4: 193.0501,
found 193.0502.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (400 mg)
was treated with potassium hydroxide (0.48 g, 8.6 mmol,
85%) in anhydrous ethanol (4 mL). After work-up, the
residual solid was treated with trifluoroacetic acid (3.0 g,
0.2 mL, 2.7 mmol) in trifluoroacetic anhydride (5 mL).
After work-up followed by recrystallization from metha-
nol, 2-pyrone 17g (140 mg, 13%) was obtained as a red
solid: Rf 0.52 (CHCl3:MeOH = 1:9); Mp: 241.7ꢀC to
242.9ꢀC; IR: νmax 3073, 2883, 2648, 2544, 1623, 1548,
4.22 | 6-Ethyl-4-hydroxy-3-methyl-pyran-
2-one (17i)[17,18,20]
According to the procedure for the synthesis of the keto
ester 14, ethyl propanoate (0.32 g, 0.36 mL, 3.1 mmol)
was reacted with the dianion prepared from ethyl
2-methylacetoacetate (1.10 g, 1.10 mL, 7.5 mmol),
sodium hydride (0.40 g, 10.0 mmol, 60%), and n-
butyllithium (4.8 mL, 8.5 mmol, 1.6 M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to10% EtOAc in hexane), the keto ester
16i (700 mg) was obtained as a yellow oil, which was
directly used in the next step.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (700 mg)
was treated with potassium hydroxide (1.08 g, 19.3 mmol,
85%) in anhydrous ethanol (7 mL). After work-up, the
residual solid was treated with trifluoroacetic acid
(0.27 g, 0.18 mL, 2.4 mmol) in trifluoroacetic anhydride
(5 mL). After work-up followed by recrystallization from
methanol, 2-pyrone 17i (40 mg, 6%) was obtained as a
white solid: Rf 0.57 (CHCl3:MeOH = 1:9); Mp: 182.1ꢀC to
184.9ꢀC (lit.[18] Mp: 182-183ꢀC); 1H-NMR (DMSO): δ 1.08
(3H, t, J = 7.3 Hz), 1.73 (3H, s, pyrone CH3), 2.41 (2H, q,
J = 7.3 Hz), 5.95 (1H, s, pyrone H), 11.09 (1H, br s,
pyrone OH); 13C-NMR (DMSO): δ 8.3, 10.9, 25.9, 96.5,
98.3, 163.8, 165.0, 165.1.
1
1433, 1399, 1257, 1151 cm‑1; H-NMR (DMSO): δ 1.80
(3H, s, pyrone CH3), 6.55 (1H, s, pyrone H) 7.18 (1H, t,
Ph, J = 4.2 Hz), 7.60 (1H, d, Ph, J = 3.4 Hz), 7.76 (1H, d,
Ph, J = 4.9 Hz), 11.36 (1H, br s, pyrone OH); 13C-NMR
(DMSO): δ 8.7, 96.5, 98.0, 126.8, 128.7, 129.5, 134.6, 152.6,
163.7, 164.8; FAB-MS m/z (%) 209 ([M+H]+, 10),
195 (10), 165 (8), 107 (35), 89 (37), 77 (21), 65 (6), 63 (5);
HRMS-FAB m/z [M+H]+ calcd for C10H9O3S: 209.0272,
found 209.0273.
4.21 | 6-(Furan-2-yl)-4-hydroxy-3-methyl-
pyrone (17h)[17,18]
According to the procedure for the synthesis of the keto
ester 14, ethyl furan-2-carboxylate (0.70 g, 0.63 mL,
5.0 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (1.1 g, 1.1 mL, 7.53 mmol),
sodium hydride (0.36 mg, 8.2 mmol, 60%), and n-
butyllithium (4.7 mL, 7.7 mmol, 1.6M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 10% EtOAc in hexane), the keto ester
16h (450 mg) was obtained as a yellow oil, which was
used directly in the next step.
4.23 | 4-Hydroxy-6-isobutyl-3-methyl-
pyran-2-one (17j)[17,18]
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (450 mg)
was treated with potassium hydroxide (573 mg,
10.2 mmol, 85%) in anhydrous ethanol (1 mL). After
work-up, the residual solid was treated with
trifluoroacetic acid (0.45 g, 0.3 mL, 4 mmol) in
trifluoroacetic anhydride (5 mL). After work-up followed
by recrystallization from methanol, 2-pyrone 17h
(115 mg, 12%) was obtained as a yellow solid: Rf 0.51
(CHCl3:MeOH = 1:9); Mp: 224.9ꢀC to 225.6ꢀC; IR: νmax
According to the procedure for the synthesis of the keto
ester 14, ethyl 3-methylbutanoate (0.50 g, 0.57 mL,
3.8 mmol) was reacted with the dianion prepared from
ethyl 2-methylacetoacetate (1.10 g, 1.10 mL, 7.5 mmol),
sodium hydride (0.36 g, 8.2 mmol, 60%), and n-
butyllithium (4.8 mL, 8.5 mmol, 1.6 M). After work-up
followed by chromatography on silica gel (stepwise: 4%
EtOAc in hexane to 10% EtOAc in hexane), the keto ester
16j (286 mg) was obtained as a yellow oil, which was
directly used in the next step.
According to the procedure for the synthesis of (S)-
(+)-phomapyrone C (2), the above keto ester (286 mg)
was treated with potassium hydroxide (385 mg,
6.9 mmol, 85%) in anhydrous ethanol (1 mL). After
work-up, the residual solid was treated with
1
3126, 1672, 1643, 1559, 1490, 1191, 1124 cm‑1; H-NMR
(DMSO): δ 1.80 (3H, s, pyrone CH3), 6.48 (1H, s, pyrone
H), 6.6 to 6.8 (1H, m, Ph), 7.00 (1H, d, J = 3.2 Hz, Ph),
7.88 (1H, br s, Ph), 11.43 (1H, bs, pyrone OH); 13C-NMR
(DMSO): δ 8.7, 95.7, 98.2, 111.0, 112.6, 145.6, 145.7, 149.0,

OHMUKAI ET AL.
11
[5] I. Burkhardt, J. S. Dickschat, Eur. J. Org. Chem. 2018, 2018,
3144–57.
trifluoroacetic acid (0.15 g, 0.10 mL, 1.3 mmol) in
trifluoroacetic anhydride (3 mL). After work-up followed
by recrystallization from methanol, 2-pyrone 17j (41 mg,
4%) was obtained as a white solid.
[6] (a) A. Fürstner, Angew Chem. Int. Ed 2018, 57, 4215–33; (b)
J. Preindl, S. Schulthoff, C. Wirtz, J. Lingnau, A. Fürstner,
Angew Chem. Int. Ed. 2017, 56, 7525–30. (c) M. Ma, M. E. Rateb,
D. Yang, J. F. Rudolf, X. Zhu, Y. Huang, L.-X. Zhao, Y. Jiang,
Y. Duan, B. Shen, J. Antibiot. 2017, 70, 200–3. (d) J. Preindl,
K. Jouvin, D. Laurich, G. Seidel, A. Fürstner, Chem. Eur. J.
2016, 22, 237–47. (e) J. S. Lee, Mar. Drugs 2015, 13, 1581–620.
(f) J. S. Yadav, B. Ganganna, P. Dutta, K. K. Singarapu, J. Org.
Chem. 2014, 79, 10762–71. (g) W. Chaładaj, M. Corbet,
A. Fürstner, Angew. Chem. Int. Ed. 2012, 51, 6929–33.
(h) I. K. Lee, B. S. Yun, J. Antibiot. 2011, 64, 349–59. (i) A. Goel,
V. J. Ram, Tetrahedron 2009, 65, 7865–913. (j) D. Song,
G. Blond, A. Fürstner, Tetrahedron 2003, 59, 6899–904.
(k) O. Geiseler, J. Podlech, Tetrahedron 2012, 68, 7280–7.
(l) D. L. Obydennov, A. I. El-Tantawya, V. Y. Sosnovskikh,
Mendeleev Commun. 2019, 29, 1–10.
Rf 0.59 (CHCl3:MeOH = 1:9); Mp: 154.3ꢀC to 155.6ꢀC;
IR: νmax 2958, 2669, 1635, 1581, 1407, 1253, 1122,
1
867 cm‑1; H-NMR (DMSO): δ 0.89 (6H, d, J = 6.8 Hz),
1.75 (3H, s, pyrone CH3), 1.88 to 1.97 (1H, sept,
J = 6.8 Hz), 2.29 (2H, d, J = 07.1 Hz), 5.98 (1H, s, pyrone
H), 11.11 (1H, br s, pyrone OH).13C-NMR (DMSO ): δ 8.4,
21.9 (2 × C), 26.4, 41.6, 69.6, 100.1, 161.6, 164.7, 165.1;
FAB-MS m/z (%) 183 ([M+H]+, 7) 154 (100), 138 (24),
124 (6); HRMS-FAB m/z [M+H]+ calcd for C10H15O3:
183.1021, found 183.1027.
[7] Purchased from Tokyo Chemical Industry Co., Ltd., Japan.
[8] T. Tashiro, K. Mori, Eur. J. Org. Chem. 1999, 1999, 2167–73.
[9] K. Krohn, H. T. Tran-Thien, J. Vitz, A. Vidal, Eur. J. Org.
Chem. 2007, 2007, 1905–11.
4.24 | Measurement of the DPPH
radical-scavenging activity[14]
An ethanol solution of a sample (2 mL) of various con-
centrations was mixed with a 0.5 mM solution of DPPH
in ethanol (1 mL) and 0.1M acetate buffer (pH 5.5,
2 mL). After standing for 45 min, the absorbance of the
mixture at 517 nm was measured. The ED50 value was
determined as the concentration of each sample required
to give 50% of the absorbance shown by a blank test.
[10] S. Niwayama, H. Cho, C. Lin, Tetrahedron Lett. 2008, 49,
4434–6.
[11] Smithkline Beecham Corporation, Patent, US2008/96921, A1,
2008.
[12] (a) H. Miyatake-Ondozabal, A. G. M. Barrett, Tetrahedron
2010, 66, 6331–4. (b) D. Ichinari, T. Ueki, K. Yoshihara,
T. Kinoshita, Chem. Commun. 1997, 1997, 1743–4.
[13] Y. Amano, M. Kinoshita, H. Akita, J. Mol. Catal. B, Enzym.
2005, 32, 141–8.
ACKNOWLEDGMENTS
[14] Y. Sugiyama, K. Yoshida, N. Abe, A. Hirota, Biosci. Biotechnol.
This study was financially supported by JSPS KAKENHI
Grant Number 17K07776. We thank Ms Akiko Oya and
Mr. Kei Watanabe (University of Shizuoka) for their gen-
erous experimental support.
Biochem. 2010, 74, 881–3.
[15] M. S. Kharasch, J. Kuderna, W. J. Nudenberg, Org. Chem.
1954, 19, 1283–9.
[16] K. Ichihara, T. Kawai, M. Kaji, M. Noda, Agric. Biol. Chem.
1976, 40, 353–8.
[17] G. Solladie, N. Gehrold, J. Maignan, Eur. J. Org. Chem. 1999,
1999, 2309–14.
[18] D. Schmidt, J. Conrad, I. Klaiber, U. Beifuss, Chem. Commun.
ORCID
Shinji Tanimori https://orcid.org/0000-0002-7468-9870
2006, 2006, 4732–4.
[19] J. Morris, G. D. Luke, D. G. Wishka, J. Org. Chem. 1996, 61,
3218–20.
REFERENCES
[1] M. S. C. Pedras, V. M. Morales, J. L. Taylor, Phytochemistry
1994, 36, 1315–8.
[20] E. Suzuki, H. Sekizaki, S. Inoue, J. Chem. Soc., Chem.
[2] (a)Y. Sugiyama, A. Oya, K. Watanabe, A. Hirota, Abstr.
Pap. 49th Sym. Chem. Nat. Products (in Japanese) 2007, 49,
323–8. (b) Y. Sugiyama, A. Oya, T. Kudo, A. J. Hirota, Antibiot.
2010, 63, 365–9.
[3] H. Ohmukai, S. Tanimori, M. Kirihata, Abstracts of Papers,
Joint Meeting of the Japan Society for Bioscience, Biotechnology,
and Agrochemistry at Kansai and Chubu Area 2011, 471, 83.
[4] H. Zhang, K. Saurav, Z. Yu, A. Mándi, T. Kurtán, J. Li,
X. Tian, Q. Zhang, W. Zhang, C. Zhang, J. Nat. Prod. 2016, 79,
1610–1618.
Commun. 1973, 16, 568.
How to cite this article: Ohmukai H,
Sugiyama Y, Hirota A, Kirihata M, Tanimori S.
Total synthesis of (S)-(+)-ent-phomapyrones B and
surugapyrone B. J Heterocycl Chem. 2019;1–11.
https://doi.org/10.1002/jhet.3845