A rapid and diverse construction of 6-substituted-5,6-dihydro-4-hydroxy-2- pyrones through double Reformatsky reaction

Article abstract of DOI:10.1016/j.tet.2013.10.079

A rapid and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through a double Reformatsky reaction of aldehydes to δ-hydroxy-β-ketoesters followed by lactonization is described. Due to the high functional group tolerance and reaction site discrimination between aldehyde, nitrile, and ester groups in the substrate, the protocol can provide the dihydropyrones with bromo, nitro, carboxylic acid, and β-ketoester groups, which are suitable for the further derivatizations. Furthermore, the protocol has been successfully applied to the rapid total synthesis of naturally occurring Yangonin.

Full text of DOI:10.1016/j.tet.2013.10.079

Tetrahedron 69 (2013) 10921e10926
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A rapid and diverse construction of 6-substituted-5,6-dihydro-4-
hydroxy-2-pyrones through double Reformatsky reaction
*
Masahiro Mineno , Yasuhiro Sawai, Kazuaki Kanno, Naotaka Sawada, Hideya Mizufune
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome, Yodogawa-ku,
Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2013
Received in revised form 21 October 2013
Accepted 23 October 2013
Available online 30 October 2013
A rapid and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
through a double Reformatsky reaction of aldehydes to d-hydroxy-b-ketoesters followed by lactonization
is described. Due to the high functional group tolerance and reaction site discrimination between al-
dehyde, nitrile, and ester groups in the substrate, the protocol can provide the dihydropyrones with
bromo, nitro, carboxylic acid, and b-ketoester groups, which are suitable for the further derivatizations.
Furthermore, the protocol has been successfully applied to the rapid total synthesis of naturally occurring
Yangonin.
Keywords:
5,6-Dihydro-4-hydroxy-2-pyrones
Double Reformatsky reaction
Lactonization
Ó 2013 Elsevier Ltd. All rights reserved.
Kavalactones
1. Introduction
6-Substituted-5,6-dihydro-2-pyrone is an important structural
moiety found in a wide variety of biologically active natural prod-
ucts. In particular, those with hydroxy or alkoxy groups at the C-4
position are common in various types of natural sources. For ex-
ample, Mescengricin is known as an inhibitor of L-glutamate exci-
totoxicity in neutrons,1 and Jerangolid A and D are known to exhibit
antifungal activity (Fig. 1).2 In addition, Piper methysticin (kava), an
extract from roots that has been traditionally used as a folk medi-
cine or a ceremonial drink in the South Pacific Islands for thousands
of years, contains various 6-substituted-5,6-dihydro-4-methoxy-2-
pyrones such as (þ)-Kavain and (þ)-Methysticin (Fig. 1).3,4 The
kavalactones display various and important biological properties
such as anxiolytic, anticonvulsive, muscle-relaxing, sedative, and
analgesic effects.3
Furthermore, in recent years, several synthetic 6-substituted-5,6-
dihydro-4-hydroxy-2-pyrones have also been reported to demon-
strate an array of biological properties, including as a non-peptide
HIV protease inhibitor 1 (Tipranavir),5 and an inhibitor of unde-
caprenyl pyrophosphate synthetase 2 (Fig. 2).6 Many researchers
have been attracted by these intriguing biological properties and
have found that simple changes in the substitution pattern often
lead to diverse biological activities.7 As a result, much effort has been
Fig. 1. Naturally occurring 5,6-dihydro-2-pyrones.
* Corresponding author. Tel.: þ81 6 6300 6784; fax: þ81 6 6300 6251; e-mail
address: masahiro.mineno@takeda.com (M. Mineno).
Fig. 2. Synthetic 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.079

10922
M. Mineno et al. / Tetrahedron 69 (2013) 10921e10926
devoted to the development of the synthetic methodologies for
6-substituted-5,6-dihydro-4-hydroxy-2-pyrones and the deriva-
tives.4e13 In particular, various synthetic protocols7d,m,9a,10b,e,13b,c,f,g
for the 6-aryl-substituted compounds have been reported as his-
torical backgrounds of discovery of HIV protease inhibitor and the
structural similarity to naturally occurring 6-aryl-2-pyrones7a,g,j,14
such as Anibine and 4-methoxyparacotoin.15
Table 1
Divergent synthesis of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones via double
Reformatsky reactiona
Among known synthetic works on 6-substituted-5,6-dihydro-4-
hydroxy-2-pyrones and their derivatives, the most common syn-
Run
1
Substrate
Product
Isolated yield (%)
thetic approach in drug discovery chemistry is lactonization of
d-
hydroxy- -ketoesters, which are prepared via the reaction of ace-
b
toacetates with aldehydes in the presence of NaH and n-BuLi
(Weiler’s dianion method) (Scheme 1).5e8 Although this approach
is facile and straightforward, the highly reactive reagents, such as n-
BuLi and NaH, could limit the scope of available substrates due to
poor functional group tolerance.16 While other methods utilizing
dienes (Chan’s diene,9 Brassard’s diene,4e,i,10 and their analogous
dienes),4g,11 diketene12 or other acetoacetate equivalents13c,f,g have
been reported, they are considered to be less convenient to rapidly
provide a wide range of this class of molecules, due to the need to
prepare the reagents or cryogenic reaction conditions.
81
2b
85
3
4
73
79
Scheme 1. Common approach to 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones.
On the other hand, we have been recently engaged in de-
veloping a double Reformatsky reaction that can readily provide
d-
hydroxy- -ketoesters with various functional groups via tandem
b
addition of two molecules of zinc alkanoate to a carbonyl com-
pound.17 Beneficial aspects of the reaction are its mild reaction
condition and the moderate nucleophilicity of the organozinc re-
agent, which both contribute to high functional group tolerance.
Consequently, we expected that a sequence of the double Refor-
matsky reaction and a lactonization would be a novel rapid syn-
thetic procedure to give 6-substituted-5,6-dihydro-4-hydroxy-2-
pyrones with high molecular diversity (Scheme 2). Herein, we de-
scribe an efficient protocol for the rapid and diverse construction of
6-substituted-5,6-dihydro-4-hydroxy-2-pyrones and its applica-
tion to naturally occurring kavalactones.
5
6
82
86
7
8
47
69
9
59
Scheme 2. Synthetic protocol for 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones via
double Reformatsky reaction.
a
Reaction condition: (1)
3 (2.5 mmol), ethyl bromozincacetate (5.0 equiv),
TMEDA (2.0 equiv), THF, 50 ꢀC, 1e5 h under N2, (2) aq NaOH (2.0 equiv), (3) aq HCl
(3.0 equiv).
b
Reaction condition: (1) 3b (1.25 mmol), ethyl bromozincacetate (10.0 equiv),
2. Results and discussion
TMEDA (4.0 equiv), THF, 50 ꢀC, (2) aq NaOH (4.0 equiv), (3) aq HCl (6.0 equiv).
c
Isolated as ketoeenol tautomers of 3-oxopropanoate. The ratio of keto tautomer
to enol tautomer is 9:1, as judged by 1H NMR.
To establish this protocol, benzaldehyde (3a) was initially
employed as a model substrate (Table 1, run 1). The reaction of 3a

M. Mineno et al. / Tetrahedron 69 (2013) 10921e10926
10923
with ethyl bromozincacetate in THF in the presence of TMEDA was
carried out at 50 ꢀC for 3 h. In order to easily isolate the pyrone from
the reaction mixture after the subsequent lactonization, un-
necessary zinc species were removed by extraction with ethyl ac-
etate and aq citric acid. After the organic layer was concentrated,
lactonization was smoothly accomplished by a successive treat-
ment of aq NaOH and HCl. As a consequence, 4a, a key synthetic
intermediate of 2,6 was obtained as crystals directly from the re-
action mixture. Encouraged by this result, the reactions with other
aldehydes possessing various functional groups were performed.
Initially, the products from p-terephthalaldehyde (3b), p-cyano-
benzaldehyde (3c), and p-formylbenzoate (3d) were compared
(runs 2e4). In our previous paper, we disclosed that the double
Reformatsky reaction proceeds differently for aldehydes, nitriles,
5,6-dicyano-p-benzoquinone (DDQ) in THF was conducted. Finally,
Yangonin was isolated in 47% yield from 3j.
Scheme 4. Synthesis of Yangonin.
3. Conclusion
and esters: for example, aldehydes are readily converted to
d-hy-
An efficient and rapid synthetic protocol for biologically im-
portant 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through
a sequence of double Reformatsky reaction and lactonization has
been developed. The reaction system offers high functional group
tolerance, due to the moderate nucleophilicity of the organozinc
reagent. Additionally, the different transformations of aldehydes,
nitriles, and esters, enable diverse functionalizations of the prod-
ucts. Therefore, the present strategy provides a powerful tool for
the preparation of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
with high molecular diversity. Furthermore, the protocol has been
successfully applied to the rapid total synthesis of naturally oc-
curring Yangonin. Further expansion of the scope of the protocol,
including asymmetric reaction, is currently underway.
droxy- -ketoesters, whereas nitriles are just converted to
b
b-
ketoesters, and esters remain unchanged.17 In fact, the reaction
with 3b readily afforded the di-5,6-dihydro-4-hydroxy-2-pyrone
substituted product (4b) (run 2). Meanwhile, the reaction of 3c
gave 4c in good yield, in which the formyl moiety is transferred to
the 5,6-dihydro-4-hydroxy-2-pyrone structure, while the nitrile
moiety is converted to a b
-ketoester (run 3).18 More interestingly,
application of 3d to this reaction provided 4d with the 5,6-dihydro-
4-hydroxy-2-pyrone moiety and carboxylic acid derived from
unreacted ester (run 4). Thus, the present synthetic protocol can
discriminate between aldehydes, nitriles, and esters to provide
various functional groups. Also, functional groups such as bromide
or nitro groups were tolerated (3e and 3f), which allows an op-
portunity for further functionalizations (runs 5 and 6). The reaction
can also be applied to hetero arylaldehydes (run 7). Other than
arylaldehydes, the reaction with alkenylaldehyde (3h) and alky-
laldehyde (3i) gave the corresponding adducts 4h and 4i (runs 8
and 9). It is noteworthy from a practical perspective that all the
products were readily isolated as crystals, directly from the reaction
mixture.
4. Experimental section
4.1. General
All chemicals were obtained from commercial suppliers and
used without further purification. NMR was recorded on a 500 MHz
spectrometer with tetramethylsilane as an internal standard. High-
resolution mass spectra (HRMS) were measured by ESI-Orbitrap
mass spectrometer.
Furthermore, the successful application to an alkenylaldehyde
can lead to the rapid synthesis of kavalactones, such as (ꢁ)-Kavain
by the methylation of 4h (Scheme 3).
4.2. Preparation of ethyl bromozincacetate (THF solution)
Under N2 atmosphere, to a 200 mL round-bottom flask were
added zinc powder (11.5 g, 175.8 mmol, 2.0 equiv) and dry THF
(44 mL). TMSCl (0.96 g, 8.8 mmol, 0.1 equiv) was added to the
suspension. The suspension was warmed to 40e50 ꢀC. Ethyl bro-
moacetate (14.7 g, 88.2 mmol, 1.0 equiv) in THF (110 mL) was added
dropwise to the suspension. After insoluble matter precipitated, the
light yellow supernatant solution was decanted and used for sub-
sequent experiments.
Scheme 3. Synthesis of (ꢁ)-Kavain.
To further demonstrate the synthetic utility of this protocol,
a rapid total synthesis of Yangonin was investigated. Yangonin is
one of the major components of kava extract as well as (þ)-Kavain
and (þ)-Methysticin, and it is reported to show a promising TNF-
4.3. Synthesis of 6-substituted-5,6-dihydro-4-hydroxy-2-
pyrones
a
release inhibitory activity.3e The intriguing biological activities
4.3.1. General procedure: 6-substituted-5,6-dihydro-4-hydroxy-2-
pyrones. Under N2 atmosphere, to a 100 mL round-bottom flask
were added ca. 0.54 mol/L ethyl bromozincacetate (THF solution)
(23.3 mL, ca. 12.5 mmol, 5 equiv), TMEDA (0.75 mL, 5 mmol,
2.0 equiv), and aldehydes (3) (2.5 mmol, 1.0 equiv). The solution
was warmed to 50 ꢀC and stirred for 1e5 h. After cooling to ambient
temperature, the mixture was diluted with EtOAc (50 mL). The
solution was successively washed with 20% aq citric acid (25 mL),
10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL), and water (25 mL). The
organic layer was concentrated in vacuo to give the crude oil. The
crude oil was stirred in 0.2 N aq NaOH (25 mL) at ambient tem-
perature. After being stirred for 30 min, 0.2 N aq HCl (35 mL) was
added dropwise to the solution, and the solution was stirred at
have aroused the interest of synthetic chemists to explore new
synthetic pathways.4a,b,d,h,j,k Among various synthetic pathways
that have been reported, our double Reformatsky reaction based
methodology appeared to offer the most rapid synthesis of Yan-
gonin (Scheme 4). Initially, commercially available 4-methoxy
cinnamaldehyde (3j) was converted to the corresponding
d-hy-
droxy- -ketoester, with almost full conversion, under the double
b
Reformatsky reaction condition. After simple acidic workup to
purge zinc species, lactonization was smoothly accomplished with
potassium carbonate in methanol as reported in the literature.4g
After the solvent was switched to acetone, methylation was car-
ried out with Me2SO4. Subsequently, oxidation with 2,3-dichloro-

10924
M. Mineno et al. / Tetrahedron 69 (2013) 10921e10926
ambient temperature for 1 h. The precipitate was collected by fil-
tration and washed with water 2 mL, and dried in vacuo at 50 ꢀC to
give a crystalline solid.
procedure, and isolated as an off-white solid (504.0 mg, 86% yield).
Mp 152e154 ꢀC (decomp.); 1H NMR (500 MHz, DMSO-d6)
2.71
d
(dd, J¼17.3, 4.4 Hz, 1H), 2.81 (ddd, J¼17.3, 11.7, 1.6 Hz,1H), 5.04e5.13
(m, 1H), 5.60e5.71 (m, 1H), 7.75 (m, 2H), 8.28 (m, 2H), 11.70 (br s,
4.3.1.1. 4-Hydroxy-6-phenyl-5,6-dihydro-2H-pyran-2-one
(4a). The title compound was prepared according to the general
procedure, and isolated as an off-white solid (385.1 mg, 81% yield).
1H); 13C NMR (125 MHz, DMSO-d6)
d 33.9, 75.0, 90.8, 123.6, 127.5,
146.5,147.3,166.1,172.5; HRMS (ESI-Orbitrap) m/z calcd for [MþH]þ
C11H9NO5 236.0553; found 236.0556.
Mp 124e125 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.80e3.00 (m, 2H),
3.49 (d, J¼18.9 Hz, 1H), 3.68 (d, J¼19.2 Hz, 1H), 5.71 (dd, J¼10.2,
3.6 Hz, 1H), 7.33e7.52 (m, 5H). Analysis of the spectroscopic data
matched reported data.13d
4.3.1.7. 4-Hydroxy-6-(thiophen-3-yl)-5,6-dihydro-2H-pyran-2-
one (4g). The title compound was prepared according to the gen-
eral procedure, and isolated as an off-white solid (230.3 mg, 47%
yield). Mp 118e119 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.89e3.08 (m,
4.3.1.2. 6,60-Benzene-1,4-diylbis(4-hydroxy-5,6-dihydro-2H-py-
ran-2-one) (4b). The title compound was prepared according to the
general procedure (p-terephthalaldehyde (3b) (167.7 mg,
1.25 mmol), Reformatsky reagent (23.5 mL, 10 equiv), TMEDA
(0.75 mL, 4 equiv)) and isolated as an off-white solid (322.2 mg, 85%
2H), 3.44 (d, J¼19.2 Hz, 1H), 3.61 (d, J¼19.2 Hz 1H), 5.78e5.84 (m,
1 H), 7.12 (dd, J¼5.0, 1.6 Hz, 1H), 7.32e7.36 (m, 1H), 7.42 (dd, J¼5.0,
2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 44.1, 47.0, 72.9, 123.0,
125.3, 127.7, 137.8, 166.8, 199.3; HRMS (ESI-Orbitrap) m/z calcd for
[MþH]þ C9H8O3S 197.0267; found 197.0266.
yield). Mp 180e181 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 2.60 (dd,
J¼17.3, 4.1 Hz, 2H), 2.83 (ddd, J¼17.2, 11.8, 1.6 Hz, 2H), 4.96e5.19 (m,
4.3.1.8. 4-Hydroxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-py-
ran-2-one (4h). The title compound was prepared according to the
general procedure, and isolated as an off-white solid (370.3 mg, 69%
2H), 5.48 (dd, J¼12.0, 4.1 Hz, 2H), 7.50 (s, 4H), 11.58 (br s, 2H); 13C
NMR (125 MHz, DMSO-d6)
d 34.1, 75.8, 90.8, 126.5, 139.1, 166.6,
172.7; HRMS (ESI-Orbitrap) m/z calcd for [MþH]þ C16H14O6
yield). Mp 118e119 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.74 (dd, J¼18.3,
303.0863; found 303.0864.
9.8 Hz, 1H), 2.88 (dd, J¼18.3, 3.5 Hz, 1H), 3.50 (d, J¼19.2 Hz, 1H),
3.60 (d, J¼19.2 Hz, 1H), 5.34 (d, J¼1.6 Hz, 1H), 6.23 (dd, J¼15.8,
6.0 Hz, 1H), 6.71e6.81 (m, 1H), 7.28e7.44 (m, 5H); 13C NMR
4.3.1.3. Ethyl 3-(4-(4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)
phenyl)-3-oxopropanoate (4c). The title compound was prepared
according to the general procedure, and isolated as a white solid
(557.7 mg, 73% yield as ketoeenol tautomers of the 3-
oxopropanoate; the ratio of keto tautomer to enol tautomer is
9:1, as judged by 1H NMR). Mp 100e101 ꢀC; (keto tautomer) 1H
(125 MHz, CDCl3)
d 43.5, 47.1, 75.4, 123.8, 126.8, 126.9, 128.8, 128.9,
134.3, 135.1, 166.8, 199.3; HRMS (ESI-Orbitrap) m/z calcd for
[MþH]þ C13H13O3 217.0859; found 217.0860.
4.3.1.9. 4-Hydroxy-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-
one (4i). The title compound was prepared according to the general
procedure, and isolated as an off-white solid (366.0 mg, 59% yield).
NMR (500 MHz, DMSO-d6)
d
1.19 (t, J¼7.1 Hz, 3H), 2.61e2.73 (m,
1H), 2.75e2.88 (m,1H), 4.13 (q, J¼6.9 Hz, 2H), 4.21 (s, 2H), 5.07 (br s,
1H), 5.52e5.63 (m, 1H), 7.64 (m, 2H), 8.00 (m, 2H), 11.54e11.77 (m,
Mp 100e101 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.01 (dddd, J¼14.4,
1H); 13C NMR (125 MHz, DMSO-d6)
d
13.9, 33.9, 45.5, 60.6, 75.4,
90.7, 126.5, 128.6, 135.5, 144.7, 166.4, 167.6, 172.5, 193.0. (enol tau-
tomer) 1H NMR (500 MHz, DMSO-d6)
8.9, 7.6, 4.1 Hz, 1H), 2.18 (m, 1H), 2.51 (dd, J¼18.3, 11.7 Hz, 1H), 2.69
(dd, J¼18.3, 2.5 Hz, 1H), 2.80e2.88 (m, 1H), 2.88e2.97 (m, 1H), 3.44
(d, J¼18.9 Hz, 1H), 3.55 (d, J¼18.6 Hz, 1H), 4.59 (m, 1H), 7.19e7.26
d
1.28 (t, J¼7.1 Hz, 3H), 2.37
(m, 1H), 2.60 (s, 1H), 2.66e2.67 (m, 1H), 2.82e2.84 (m, 1H), 4.25 (q,
J¼6.9 Hz, 2H), 5.60 (m, 1H), 5.99 (s, 1H), 7.56e7.60 (m, 1H),
7.67e7.68 (m, 1H), 7.89e7.93 (m, 2H), 12.62 (s, 1H); 13C NMR
(m, 3H), 7.30e7.36 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 30.8, 36.2,
43.6, 47.1, 74.3, 126.5, 128.5, 128.8, 140.0, 167.1, 199.7; HRMS (ESI-
Orbitrap) m/z calcd for [MþH]þ C13H15O3 219.1016; found 219.1015.
(125 MHz, DMSO-d6) d 14.0, 33.8, 60.3, 75.2, 87.5, 118.5, 127.1, 132.4,
136.5, 144.4, 166.1, 169.9, 172.6, 192.9. HRMS (ESI-Orbitrap) m/z
4.3.2. 4-Methoxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-2-
one ((ꢁ)-Kavain) (Scheme 3). To a 25 mL round-bottom flask were
added 4-hydroxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-
2-one (4h) (216.1 mg, 1.0 mmol), powdered potassium carbonate
calcd for [MþH]þ C16H17O6 305.1020; found 305.1022.
4.3.1.4. 4-(4-Hydroxy-6-oxo-5,6-dihydro-2H-pyran-2-yl)benzoic
acid (4d). The title compound was prepared according to the gen-
eral rocedure, and isolated as a brownish white solid (461.0 mg, 79%
yield). Mp 212e213 ꢀC (decomp.); 1H NMR (500 MHz, DMSO-d6)
(276.4 mg, 2.0 mmol, 2.0 equiv), dimethyl sulfate (190 mL, 2.0 mmol,
2.0 equiv), and acetone (2 mL). The reaction mixture was stirred at
ambient temperature overnight and then diluted with EtOAc
(10 mL). The solution was washed with 0.5 N aq HCl (10 mL). The
aqueous layer was extracted with EtOAc (4 mLꢂ2). The combined
organic layer was concentrated in vacuo to give the crude solid. The
crude solid was purified by flash chromatography (50% EtOAc/
Hexane) to give the title compound as an off-white solid (178.8 mg,
d
2.61e2.70 (m, 1H), 2.74e2.87 (m, 1H), 5.07 (d, J¼1.3 Hz, 1H),
5.41e5.64 (m, 1H), 7.61 (m, 2H), 7.99 (m, 2H), 11.53e11.77 (m, 1H),
12.86e13.10 (m, 1H); 13C NMR (125 MHz, DMSO-d6)
34.0, 75.5,
d
90.8, 126.3, 129.5, 130.6, 143.9, 166.4, 166.9, 172.6; HRMS (ESI-Orbi-
trap) m/z calcd for [MþH]þ C12H10O5 235.0601; found. 235.0601.
78% yield). Mp 145e146 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.55 (dd,
4.3.1.5. 6-(4-Bromophenyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-
one (4e). The title compound was prepared according to the gen-
eral procedure, and isolated as an off-white solid (548.3 mg, 82%
J¼17.2, 4.3 Hz, 1H), 2.67 (ddd, J¼17.0, 10.7, 1.6 Hz, 1H), 3.77 (s, 3H),
5.07 (dddd, J¼10.6, 6.2, 4.4, 1.6 Hz, 1H), 5.20 (d, J¼1.6 Hz, 1H),
6.23e6.30 (m, 1H), 6.71e6.77 (m, 1H), 7.26e7.30 (m, 1H), 7.31e7.36
(m, 2H), 7.37e7.41 (m, 2H); HRMS (ESI-Orbitrap) m/z calcd for
[MþH]þ C14H15O3 231.1016; found 231.1015. Analysis of the spec-
troscopic data matched reported data.3e,4g
yield). Mp 125e126 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.83 (dd,
J¼18.4, 10.9 Hz, 1H), 2.95 (dd, J¼18.3, 3.2 Hz, 1H), 3.51 (d, J¼19.2 Hz,
1H), 3.69 (d, J¼18.9 Hz, 1H), 5.67 (dd, J¼10.9, 3.3 Hz, 1H), 7.29 (m,
2H), 7.58 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 45.1, 47.0, 75.8,
123.4, 127.5, 132.4, 135.6, 166.5, 198.8; HRMS (ESI-Orbitrap) m/z
calcd for [MþH]þ C11H10BrO3 268.9808 (79Br) and 270.9787 (81Br);
found 268.9811 (79Br) and 270.9790 (81Br).
4.3.3. 4-Methoxy-6-[(E)-2-(4-methoxyphenyl)ethenyl]-2H-pyran-2-
one (Yangonin) (Scheme 4). To a 100 mL round-bottom flask were
added ethyl bromozincacetate (THF solution) (23.5 mL, ca.
12.5 mmol, 5 equiv), TMEDA (0.75 mL, 5 mmol, 2.0 equiv), and 4-
methoxycinnamaldehyde (3j) (406.0 mg, 2.5 mmol, 1.0 equiv). The
yellow solution was warmed to 50 ꢀC and stirred for 5 h. After
4.3.1.6. 4-Hydroxy-6-(4-nitrophenyl)-5,6-dihydro-2H-pyran-2-
one (4f). The title compound was prepared according to the general

M. Mineno et al. / Tetrahedron 69 (2013) 10921e10926
10925
Howe, W. J.; Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury, G. E.; Wilson,
G. J.; Shiou, L.; Zipp, G. L.; Wilkinson, K. F.; Rush, B. D.; Ruwart, M. J.; Koep-
linger, K. A.; Zhiyang, Z.; Cole, S.; Zaya, R. M.; Kakuk, T. J.; Janakiramn, M. N.;
Watenpaugh, K. D. J. Med. Chem. 1996, 39, 4349; (c) For the example without
using Weiler’s dianion, see: Trost, B. M.; Anderson, N. G. J. Am. Chem. Soc.
2002, 124, 14320.
cooling to ambient temperature, the mixture was diluted with
EtOAc (50 mL). The solution was successively washed with 20% aq
citric acid (25 mL), 10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL), and
water (25 mL). The organic layer was concentrated in vacuo to give
an orange oil. Methanol (2 mL) and powdered potassium carbonate
(862.5 mg, 6.3 mmol, 2.5 equiv) were added to the oil, and the
mixture was warmed to 50 ꢀC and stirred for 3 h. After cooling to
ambient temperature, the mixture was concentrated in vacuo. Ac-
6. Hurley, T. M.; Peukert, S.; Wattanasin, S. PCT Int. Appl WO/2008/14311.
7. For the application of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones to
the drug discovery study, all of which utilize Weiler’s dianion method, see:
(a) Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Borchardt, A.; Dragovich, P.;
Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.; Parge, H.; Love, R.; Hickey, M.; Doan,
C.; Shi, S.; Duggal, R.; Lewisc, C.; Fuhrmana, S. Bioorg. Med. Chem. Lett.
2006, 16, 4834; (b) de Aguiar Amaral, P.; Bergold, A. M.; Eifler-Lima, V. L. J.
Pharm. Pharm. Sci. 2005, 8, 69; (c) de Souza, L. C.; Feitosa dos Santos, A.;
Sant’Ana, A. E. G.; de Oliveira Imbroisi, D. Bioorg. Med. Chem. Lett. 2004, 14,
5859; (d) de Souza, L. C.; Soares de Araujo, S. M.; de Oliveira Imbroisi, D.
Bioorg. Med. Chem. 2004, 12, 865; (e) Aristoff, P. A.; Gammill, R. B.; Johnson,
P. D.; Piper, R. C.; Romero, D. L.; Skulnick, H. I.; Strohbach, J. W.; Thaisri-
vongs, S.; Tommasi, R. A.; Turner, S. R.; Yang, C.; Zhang, Q. Eur. Pat. Appl.
EP20020002073; (f) Chen, S.; Mccleary, J.; Sun, L. PCT Int. Appl WO/2003/
072103. (g) Boyer, F. E.; Vara Prasad, J. V. N.; Domagala, J. M.; Ellsworth, E.
L.; Gajda, C.; Hagen, S. E.; Markoski, L. J.; Tait, B. D.; Lunney, E. A.; Palovsky,
A.; Ferguson, D.; Graham, N.; Holler, T.; Hupe, D.; Nouhan, C.; Tummino, P.
J.; Urumov, A.; Zeikus, E.; Zeikus, G.; Gracheck, S. J.; Sanders, J. M.; Van-
derRoest, S.; Brodfuehrer, J.; Iyer, K.; Sinz, M.; Gulnik, S. V.; Erickson, J. W.
J. Med. Chem. 2000, 43, 843; (h) Vara Prasad, J. V. N.; Boyer, F. E.; Doma-
gala, J. M.; Ellsworth, E. L.; Gadja, C.; Hamilton, H. W.; Hagen, S. E.; Mar-
koski, L. J.; Steinbaugh, B. A.; Tait, B. D.; Humblet, C.; Lunney, E. A.;
Pavlovsky, A.; Rubin, J. R.; Ferguson, D.; Graham, N.; Holler, T.; Hupe, D.;
Nouhan, C.; Tummino, P. J.; Urumov, A.; Zeikus, E.; Zeikus, G.; Grachech, S.
J.; Saunders, J. M.; VanderRoest, S.; Brodfuehrer, J.; Iyer, K.; Sinz, M.;
Gulnik, S. V.; Erickson, J. W. Bioorg. Med. Chem. 1999, 7, 2775; (i) Ellsworth,
E. L.; Lunney, E.; Tait, B. D. U.S. Pat. Appl. 5,789,440. (j) Tait, B. D.; Hagen,
S.; Domagala, J.; Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Vara Prasad, J.
V. N.; Ferguson, D.; Graham, N.; Hupe, D.; Nouhan, C.; Tummino, P. J.;
Humblet, C.; Lunney, E. A.; Pavlovsky, A.; Rubin, J.; Gracheck; Baldwin, E.
T.; Bhat, T. N.; Erickson, J. W.; Gulnik, S. V.; Liu, B. J. Med. Chem. 1997, 40,
3781; (k) Hagen, S. E.; Vara Prasad, J. V. N.; Boyer, F. E.; Domagala, J. M.;
Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Markoski, L. J.; Steinbaugh, B.
A.; Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.; Hupe, D.;
Nouhan, C.; Gracheck, S. J.; Saunders, J. M.; Vander Roest, S. J. Med. Chem.
1997, 40, 3707; (l) Thaisrivongs, S.; Romero, D. L.; Tammasi, R. A.; Jana-
kiraman, M. N.; Strohbach, J. W.; Turner, S. R.; Biles, C.; Morge, R. R.;
Johnson, P. D.; Aristoff, P. A.; Tomich, P. K.; Lynn, L. C.; Horng, M.-M.;
Chong, K.-T.; Hinshaw, R. R.; Howe, W. J.; Finzel, B. C.; Watenpaugh, K. D. J.
Med. Chem. 1996, 39, 4630; (m) Tummino, P. J.; Vara Prasad, J. V. N.; Fer-
guson, D.; Nouhan, C.; Graham, N.; Domagala, J. M.; Ellsworth, E. L.; Gajda,
C.; Hagen, S. E.; Lunney, E. A.; Para, K. S.; Tait, B. D.; Pavlovsky, A.;
Erickson, J. W.; Gracheck, S.; McQuade, T. J.; Hupe, D. J. Bioorg. Med. Chem.
1996, 4, 1401; (n) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J.
, Jr.; Deana, A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, J. D.;
Smith, R. L.; Willard, A. K. J. Med. Chem. 1985, 28, 347; (o) Dugger, R. W.;
Heathcock, C. H. J. Org. Chem. 1980, 45, 1181.
etone (2 mL) and dimethyl sulfate (597 mL, 6.3 mmol, 2.5 equiv)
were added to the mixture, and the mixture was stirred at ambient
temperature overnight. The mixture was diluted with EtOAc
(24 mL). The solution was neutralized with 0.5 N aq HCl. The
aqueous layer was separated and washed with ethyl acetate
(4 mLꢂ2). The combined organic layer was concentrated in vacuo.
THF (8 mL) and DDQ (483.2 mg, 2.2 mmol, 0.9 equiv) were added to
the mixture, the mixture was stirred reflux for 30 min (HPLC assay
yield: 87%). After cooling to ambient temperature, the mixture was
concentrated in vacuo. Toluene (20 mL) was added to the mixture,
and the mixture was warmed to 100 ꢀC and stirred for 1.5 h. After
cooling to ambient temperature, the precipitates were filtered off.
The filtrate was concentrated in vacuo. The crude oil was purified
by flash chromatography (EtOAc/hexane) to give the title com-
pound as an orange solid (303.5 mg, 47% yield). Mp 152e153 ꢀC; 1H
NMR (500 MHz, CDCl3)
d
3.81 (s, 3H), 3.83 (s, 3H), 5.46 (d, J¼2.5 Hz,
1H), 5.89 (d, J¼2.2 Hz, 1H), 6.44 (d, J¼16.1 Hz, 1H), 6.87e6.92 (m,
2H), 7.40e7.47 (m, 3H). HRMS (ESI-Orbitrap) m/z calcd for [MþH]þ
C14H15O3 259.0965; found 259.0962. Analysis of the spectroscopic
data matched reported data.3e
Acknowledgements
We thank Dr. Masahiro Kajino, Mr. Hideo Hashimoto, Mr. Yoi-
chiro Ishimaru, and Dr. David Cork for helpful discussions.
References and notes
1. Kin, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1997,
38, 3431.
2. (a) Knauth, P.; Reichenbach, H. J. Antibiot. 2000, 53, 1182; (b) Reichenbach, H.;
€
Hofle, G.; Gerth, K.; Washausen, P. PCT Int. Appl. WO/1997/31912. (c) Gerth, K.;
€
Washausen, P.; Hofle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 71; (d)
Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt, A. L.; Blair, B.;
Kantor, G.; von Strandmann, M. J. Antibiot. 1977, 30, 371; (e) Connor, D. T.;
Greenough, R. C.; von Strandtmann, M. J. Org. Chem. 1977, 42, 3664; (f) For
a total synthesis of Jerangolid A, see: Hanessian, S.; Focken, T.; Oza, R. Org. Lett.
8. Other examples of diverse synthesis using Weiler’s dianion method, see: (a)
Peterson, J. R.; Winter, T. J.; Miller, C. P. Synth. Commun. 1988, 18, 949; (b)
Groutas, W. C.; Huang, T. L.; Stamga, M. A.; Brubaker, M. J.; Moi, M. K. J. Het-
erocycl. Chem. 1985, 22, 433.
9. (a) Villano, R.; Acocella, M. R.; Massa, A.; Palombi, L.; Scettri, A. Tetrahedron Lett.
2007, 48, 891; (b) Villano, R.; Acocella, M. R.; Massa, A.; Palombi, L.; Scettri, A.
Tetrahedron: Asymmetry 2006, 17, 3332; (c) Hagiwara, H.; Kimura, K.; Uda, H. J.
Chem. Soc., Perkin Trans. 1 1992, 693; (d) Hagiwara, H.; Kimura, K.; Uda, H. J.
Chem. Soc., Chem. Commun. 1986, 860.
ꢀ
ꢁ
2010, 12, 3172; (g) For a total synthesis of Jerangolid D, see: Pospísl, J.; Marko, I.
E. J. Am. Chem. Soc. 2007, 129, 3516.
3. (a) Tanaka, A.; Hamada, N.; Fujita, Y.; Itoh, T.; Nozawa, Y.; Iinuma, M.; Ito, M.
Bioorg. Med. Chem. 2010, 18, 3133; (b) Lasme, P.; Davrieux, F.; Montet, D.; Lebot,
V. J. Agric. Food Chem. 2008, 56, 4976; (c) Bilia, A. R.; Scalise, L.; Bergonzi, M. C.;
^ ꢁ
Vincieri, F. F. J. Chromatogr., B 2004, 812, 203; (d) Cote, C. S.; Kor, C.; Cohen, J.;
10. (a) Lin, L.; Fan, Q.; Qin, B.; Feng, X. J. Org. Chem. 2006, 71, 4141; (b) Fan, Q.; Lin,
L.; Liu, J.; Huang, Y.; Feng, X. Eur. J. Org. Chem. 2005, 3542; (c) Du, H.; Zhao, D.;
Ding, K. Chem.dEur. J. 2004, 10, 5964; (d) Fan, Q.; Lin, L.; Liu, J.; Huang, Y.;
Feng, X.; Zhang, G. Org. Lett. 2004, 6, 2185; (e) Pierres, C.; George, P.; Hijfte, L.
V.; Ducep, J.-B.; Hibert, M.; Mann, A. Tetrahedron Lett. 2003, 44, 3645; (f)
Auclair, K. Biochem. Biophys. Res. Commun. 2004, 322, 147; (e) Hashimoto, T.;
Suganuma, M.; Fujiki, H.; Yamada, M.; Kohno, T.; Asakawa, Y. Phytomedicine
2003, 10, 309; (f) Younis, Y. M.; Al-Shaihry, S. S. Aust. J. Chem. 2000, 53, 589; (g)
Scherer, J. Adv. Ther. 1998, 15, 261.
4. For the kavalactones synthesis, see: (a) Soldi, C.; Moro, A. V.; Pizzolatti, M. G.;
€
Blaser, E.; Kolar, P.; Fenske, D.; Goesmann, H.; Waldmann, H. Eur. J. Org. Chem.
Correia, C. R. D. Eur. J. Org. Chem. 2012, 3607; (b) Moro, A. V.; Cardoso, F. S. P.;
1999, 329; (g) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 5058; (h)
Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 4647; (i) Togni, A. Or-
ganometallics 1990, 9, 3106; (j) Midland, M. M.; Afonso, M. M. J. Am. Chem. Soc.
1989, 111, 4368; (k) Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106,
4294.
ꢀ
ꢁ
Correia, C. R. D. Org. Lett. 2009, 11, 3642; (c) Pospísl, J.; Marko, I. E. Tetrahedron
Lett. 2008, 49, 1523; (d) Amral, P. A.; Gouault, N.; Roch, M. L.; Efifler-Lima, V. L.;
David, M. Tetrahedron Lett. 2008, 49, 6607; (e) Lin, L.; Chen, Z.; Yang, X.; Liu, X.;
Feng, X. Org. Lett. 2008, 10, 1311; (f) Sabitha, G.; Sudhakar, K.; Yadav. Tetrahedron
Lett. 2006, 47, 8599; (g) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.;
Carroll, K. A.; Alphen, S. V. Org. Lett. 2004, 6, 2317; (h) Lygo, B. Tetrahedron 1995,
51, 12859; (i) Castellino, S.; Sims, J. J. Tetrahedron Lett. 1984, 25, 4059; (j) Israili,
Z. H.; Smissman, E. E. J. Org. Chem. 1976, 41, 4070; (k) Suzuki, E.; Hamajima, R.;
Inoue, S. Synthesis 1975, 192; (l) Klohs, M. W.; Keller, K.; Williams, R. E. J. Org.
Chem. 1959, 24, 1829.
11. Castellino, S.; Sims, J. J. Tetrahedron Lett. 1984, 25, 2307.
12. Izawa, T.; Mukaiyama, T. Chem. Lett. 1975, 161.
13. Other examples of the diverse synthesis of 4-hydroxy-6-substituted-5,6-
dihydro-2-pyrones and their analogues, see: (a) Andersh, B.; Nguyen, E. T.;
Van Hoveln, R. J.; Kemmerer, D. K.; Baudo, D. A.; Graves, J. A.; Roark, M. E.;
Bosma, W. B. J. Org. Chem. 2013, 78, 4563; (b) Andersh, B.; Gereg, J.; Amanuel,
M.; Stanley, C. Synth. Commun. 2008, 38, 482; (c) Creech, G. S.; Kwon, O. Org.
Lett. 2008, 10, 429; (d) Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169; (e) Audrain,
H.; Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 11543; (f) Fan, R.; Hudlicky, T.
Tetrahedron Lett. 1989, 30, 5533; (g) Shandala, M. Y.; Ayoub, M. T.; Mohammad,
M. J. J. Heterocycl. Chem. 1984, 21, 1755.
5. (a) Turner, S. R.; Strohbach, J. W.; Tommasi, R. A.; Aristof, P. A.; Johnson, P. D.;
Skulnick, H. I.; Dolak, L. A.; Seest, E. P.; Tomich, P. K.; Bohanon, M. J.; Horng,
M.-M.; Lynn, J. C.; Cong, K.-T.; Hinshaw, R. R.; Watenpaugh, K. D.; Janakiraman,
M. N.; Thaisrivongs, S. J. Med. Chem. 1998, 41, 3467; (b) Thaisrivongs, S.;
Skulnick, H. I.; Turner, S. R.; Strohbach, J. W.; Tommasi, R. A.; Johnson, P. D.;
Aristoff, P. A.; Judge, T. M.; Gammill, R. B.; Morris, J. K.; Romines, K. R.;
Chrusciel, R. A.; Hinshaw, R. R.; Chong, K.-T.; Tarpley, W. G.; Poppe, S. M.;
Slade, D. E.; Lynn, J. C.; Horn, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L. A.;
14. (a) Vara Prasad, J. V. N.; Lunney, E. A.; Ferguson, D.; Tummino, P. J.; Rubin, J. R.;
Reyner, E. L.; Stewart, B. H.; Guttendorf, R. J.; Domagala, J. M.; Suvorov, L. I.;

10926
M. Mineno et al. / Tetrahedron 69 (2013) 10921e10926
Gulnik, S. V.; Topol, I. A.; Bhat, T. N.; Erickson, J. W. J. Am. Chem. Soc. 1995, 117,
16. For the pioneering works, see: (a) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52,
2157; (b) Huckin, S. N.; Weiler, L. Tetrahedron Lett. 1971, 50, 4835; (c) For a re-
view see: Langer, P.; Friberg, W. Chem. Rev. 2004, 104, 4125.
17. Mineno, M.; Sawai, Y.; Kanno, K.; Sawada, N.; Mizufune, H. J. Org. Chem. 2013,
78, 5843.
11070; (b) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.; Ortwine, D. F.; Dunbar,
J. B., Jr.; Ferguson, D.; Tummino, P. J.; Hupe, D.; Tait, B. D.; Domagala, J. M.;
Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. M. A.; Baldwin, J. E. T.; Erickson, J. W.;
Sawyer, T. K. J. Am. Chem. Soc. 1994, 116, 6989.
15. Mors, W. B.; Gottlieb, O. R.; Djerassi, C. J. Am. Chem. Soc. 1957, 117, 4507.
18. Hydrolysis of b-ketoesters was hardly observed.