Efficient synthesis of karrikinolide via Cu(II)-catalyzed lactonization

Article abstract of DOI:10.1016/j.tet.2010.11.108

The efficient total synthesis of karrikinolide (KAR₁), a potent plant growth regulator discovered in smoke from burning plant material, is described. 3-Hydroxy-4-pyranone, prepared from d-xylose, was subjected to a Cu(II)-catalyzed transesterification-Wittig lactonization to afford the dihydrofuropyran in good yield. Finally, radical bromination, followed by olefin formation, provided KAR₁ in acceptable yield.

Full text of DOI:10.1016/j.tet.2010.11.108

Tetrahedron 67 (2011) 971e975
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Tetrahedron
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Efficient synthesis of karrikinolide via Cu(II)-catalyzed lactonization
,
,b,
Kazumasa Matsuo a b, Mitsuru Shindo a
*
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
b Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2010
Received in revised form 27 November 2010
Accepted 30 November 2010
Available online 7 December 2010
The efficient total synthesis of karrikinolide (KAR1), a potent plant growth regulator discovered in smoke
from burning plant material, is described. 3-Hydroxy-4-pyranone, prepared from D-xylose, was subjected
to a Cu(II)-catalyzed transesterificationeWittig lactonization to afford the dihydrofuropyran in good
yield. Finally, radical bromination, followed by olefin formation, provided KAR1 in acceptable yield.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
et al. synthesized 1 via the intramolecular Wittig reaction with thi-
oketone in poor yield;3a Goddard-Boger et al. utilized
D-xylose as
Karrikinolide, 3-methyl-2H-furo[2,3-c]pyran-2-one (1), and
analogous compoundshave beenisolated fromplant-derived smoke
and are responsible for promoting seed germination of a wide range
of plant species at extraordinarily low concentrations, some as low
as nanomolar (Fig. 1).1 Although the role of smoke in germination
and its potential applications have been reviewed and the re-
lationship between karrikinolides and storigolactone has been dis-
cussed, the mechanistic details of the bioactivity have not yet been
elucidated.2 Since smoke contains only a small amount of karriki-
nolide, this compound has to be supplied by organic synthesis for
studies. So far, several reports on the total synthesis of karrikinolides
have appeared in the literature, including the following:3 Flematti
a carbon source to prepare KAR2, which led to KAR1;3b Xu et al.
synthesized KAR2 from a butenolide that led to KAR1; Tanabe et al.
prepared the butenolide via Ti-crossed aldol addition (Scheme 1).
Since the direct lactonization of 2-hydroxy-4-pyrone seems to be
difficult, efficient construction of the lactone would be a point. These
efforts motivated us to find a more efficient synthetic method to
provide an adequate supply of KAR1 for an SAR study.4
Recently, wehavedevelopedacatalytictransesterificaitoneWittig
lactonization reaction forming a butenolide in one pot (Scheme 2),5
which is expected to be very useful for the synthesis of the karriki-
nolides. Herein, we report an efficient synthesis of karrikinolide
(KAR1) (1) using our new lactonization reaction as the key step.
2. Results and discussion
First, we attempted the lactonization of the acyloin 3, easily
prepared from kojic acid (2),6 using the Wittig reagent 5 and the Cu
(II) salt 4 as the catalyst in the presence of Oxone and molecular
ꢀ
sieves 4 A under air. However, the reaction did not proceed at all
even at higher temperature, probably due to the low nucleophi-
licity of the enol in 3 (Scheme 3).7 In the initial transesterification
between 5a and 3, the nucleophilic hydroxyl must be a more re-
active alcoholic hydroxyl group.
We then decided to use the
strate for the lactonization (Scheme 4). 3,4-Di-O-acetyl-
(9), prepared from
-xylose in three steps,8 was subjected to
a
-hydroxy enone 11 as the sub-
D
-xylal
D
methanolysis to give the diol 10. Its allylic alcohol was selectively
oxidized with PDC in the presence of acetic acid to afford 11 in
moderate yield.9 The Cu(II) catalyzed Wittig lactonization of 11 in
the presence of Oxone was carried out at 60 ꢀC under air to pro-
vide the lactone 12 in good yield. Attempts to oxidize 12 by allylic
radical bromination, followed by elimination, resulted in low
Fig. 1. Karrikinolides and strigol.
* Corresponding author. E-mail address: shindo@cm.kyushu-u.ac.jp (M. Shindo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.108

972
K. Matsuo, M. Shindo / Tetrahedron 67 (2011) 971e975
Scheme 1.
Scheme 2.
Scheme 3.
yields, because considerable amounts of byproducts (12-Br, 1-Br,
12-Br0, and 12-diBr) were formed via allylic bromination at the
terminal methyl group. Since the terminal methylene radical 12a0
would be highly stabilized by the conjugated dienyl group com-
pared to the endo-radical 12b0, these byproducts were preferen-
tially generated (Fig. 2). We also tried dehydrobromination of
12-diBr to result in decomposition. Therefore, the desired product
1, which would be generated from 12-Br, was converted into 1-Br,
while 12-diBr would be formed from 12-Br0. Dehydrogenation of
12 with PdeC did not work at all.
Since it seems to be very difficult to obtain 1 from 12 in good
yield, we then decided to use another type of ketone as a precursor
of the lactonization. To prevent the generation of the terminal
methylene radical, we prepared an unconjugated acyloin 13 as the
substrate by the Michael addition of thiophenol to 11 (Scheme 5).10
Due to its instability, the acyloin 13 was subjected to lactonization

K. Matsuo, M. Shindo / Tetrahedron 67 (2011) 971e975
973
Scheme 4.
without purification to afford the butenolide 14 as a diastereomeric
mixture in 50% yield for the two steps. The structure of one di-
astereomer (trans form) was confirmed by the X-ray crystallo-
graphic analysis (Fig. 3).
Fig. 2. Possible radical intermediates.
Fig. 3. X-ray crystal structure of trans-14.
The radical allylic bromination of 14 with NBS initiated by AIBN
in CCl4 under high dilution successfully afforded the endo-bromi-
nated product 15 in good yield as a single isomer. Both the cis and
trans isomers of 14 were converted into the same isomer of 15, the
stereochemistry of which is not known. Finally, 15 was treated with
p-TsOH in toluene under reflux to furnish karrikinolide (KAR1) (1)
in 76% yield (Scheme 6).
Scheme 5.

974
K. Matsuo, M. Shindo / Tetrahedron 67 (2011) 971e975
1H); 13C NMR (100 MHz, CDCl3)
d: 20.9 (q), 21.1 (q), 63.4 (d), 63.6 (t),
67.2 (d), 97.4 (d), 148.0 (d), 169.8 (s), 169.9 (s); IR (neat): 2968, 1732,
1645, 1373, 1224, 1095 cmꢁ1; MS (FAB) m/z: 201 ([MþH]þ); HRMS
(FAB) calcd for C9H13O5 ([MþH]þ): 201.0763, found: 201.0761.
4.1.2.
D
-Xylal (10). A solution of the acetate 9 (0.4 g, 2.0 mmol) in
MeOH (10 mL) was treated with MeONa (11.0 mg, 0.2 mmol) and
the reaction mixture was stirred for 4 h at room temperature. After
the mixture was evaporated, the residue was purified by silica-gel
column chromatography (80% EtOAcehexane) to give 10 (0.21 g,
Scheme 6.
92% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d: 1.73 (d,
3. Conclusion
J¼5.6 Hz, 1H), 1.93 (d, J¼4.0 Hz, 1H), 3.79e3.84 (m, 1H), 3.97 (dd,
We have achieved an efficient synthesis of karrikinolide (KAR1)
by using the Wittig lactonization in 7.3% overall yield in nine steps
in which purification was performed in only six steps. SAR studies
for the potential plant growth regulator are now in progress.
J¼8.4, 4.4 Hz, 1H), 4.01e4.03 (m, 2H), 4.92 (ddd, J¼6.0, 4.4, 1.6 Hz,
1H), 6.52 (d, 1.73, J¼6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d: 64.8
(d), 65.9 (t), 68.5 (d), 101.0 (d), 146.5 (d); IR (neat): 3352, 2924, 1651,
1454, 1242, 1084, 1033, 995 cmꢁ1; MS (EI) m/z: 116 (Mþ), 73 (100%);
HRMS (EI) calcd for C5H8O3 (Mþ): 116.0473, found: 116.0478.
4. Experimental
4.1.3. (R)-3-Hydroxy-2H-pyran-4-one (11). PDC (0.66 g, 1.7 mmol)
was added to a solution of the diol 10 (163 mg, 1.4 mmol) in EtOAc
(18 mL) and anhydrous AcOH (0.37 mL). The mixture was stirred
vigorously for 16 h at room temperature and filtered through a pad
of Celite, and the residue was washed with EtOAc. After evapo-
ration of the filtrate, the residue was purified by silica-gel column
chromatography (35% EtOAcehexane) to give 11 (60.7 mg, 38%) as
4.1. General procedures
1H NMR and 13C NMR were measured in CDCl3 solution using
a JEOL JNM AL-400 (1H NMR at 400 MHz, 13C NMR at 100 MHz) and
a JNM ECA-600 spectrometer (1H NMR at 600 MHz, 13C NMR at
150 MHz) with the reference standards (1H NMR at 0.00 ppm (TMS),
13C NMR at 77.03 ppm (CDCl3)) unless otherwise noted. Chemical
shifts are reported in parts per million. Peak multiplicities are in-
dicated with the following abbreviations: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. IR spectra were recorded
on Shimazu FT/IR-8300 spectrometers. Mass spectra and high res-
olution mass spectra were obtained on a JEOL JMS-700. Elemental
analyses were performed with a YANACO 026 CHN analyzer. Melting
points were measured with an SRS Opti Melt MPA 100 apparatus and
are uncorrected. Analytical TLC was performed on precoated plates
(0.25 mm, silica gel Merck 60 F254). Column chromatography was
performed on silica gel (Kanto Chemical Co., Inc.). Preparative HPLC
was performed on Kanto Mightysil Si60, with a system utilizing
a JASCO PU-2087 plus Intelligent Pump with Dynamic Mixer MX-
2080.32, UV-2075 plus Intelligent UV/vis Detector, and RI-2031 plus
Intelligent RI Detector. All reactions were performed under an air
atmosphere unless otherwise noted, and dichloromethane (CH2Cl2),
diethyl ether (Et2O), and tetrahydrofuran (THF) were purchased
from Kanto Chemical Co., Inc.; all other solvents were distilled. Un-
less otherwise noted, reagents were obtained from chemical sources
and used without further purification.
a colorless oil. 1H NMR (400 MHz, CDCl3)
d: 3.55 (s, 1H), 4.04 (dd,
J¼14.4, 10.8 Hz, 1H), 4.37 (dd, J¼14.4, 6.4 Hz, 1H), 4.65 (dd, J¼10.8,
6.4 Hz, 1H), 5.46 (d, J¼6.0 Hz, 1H), 7.38 (d, 6.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d: 67.3 (d), 71.3 (t), 103.7 (d), 164.9 (d), 193.8 (s);
IR (neat): 3352, 2883, 1681, 1593, 1415, 1265, 1199, 1122, 1033,
1003, 922, 887, 848 cmꢁ1; MS (EI) m/z: 114 (Mþ), 71 (100%); HRMS
(EI) calcd for C5H6O3 (Mþ): 114.0317, found: 114.0314.
4.1.4. 3-Methyl-5-(phenylthio)-4,5,7,7a-tetrahydro-2H-furo[2,3-c]
pyran-2-one (14). To a dry THF solution (100 mL) of 11 (1.14 g,
10 mmol) at 0 ꢀC, was added Cs2CO3 (3.9 g, 12 mmol), followed by
the addition of PhSH (3.08 mL, 30 mmol) under an Ar atmosphere.
The reaction was monitored by thin-layer chromatography (TLC)
until the starting material disappeared. After 30 min, the reaction
was quenched with water and extracted with CH2Cl2. The solvent
was evaporated under reduced pressure to give 13. To a solution of
the crude product 13 in toluene (100 mL) was added the Cu(II)
catalyst 4 (210 mg, 0.5 mmol), the Wittig reagent 5a (6.33 g,
ꢀ
15 mmol), molecular sieves 4 A (5.0 g), and Oxone (9.2 g, 30 mmol).
The mixture was stirred at 60 ꢀC for 6 h under air. The resulting
mixture was filtered through a pad of Celite, and the solvent was
evaporated under reduced pressure. The residue was purified with
column chromatography (5e15e25% EtOAcehexane) to give 14a
(0.63 g, 24% for two steps) and 14b (0.67 g, 26% for two steps) as
colorless needles.
4.1.1. 3,4-Di-O-acetyl- D-Xylose(106.6 mmol,16.0 g) was
-xylal (9)7.
D
acetylated with acetic anhydride (80 mL) and pyridine (133 mL) at
room temperature for 6 h. Methanol was added to the mixture and
then removed in vacuo. Toluene was added to the residue, and the
mixture was evaporated. The residue was dissolved in dichloro-
methane (427 mL), and HBr (30% in acetic acid, 97 mL) was added at
trans Isomer 14a: colorless needles (EtOAcehexane): mp
93e94ꢀC;1HNMR(400MHz, CDCl3)
d
:1.86(s, 3H), 2.62(d, J¼12.0Hz,
1H), 3.10e3.16 (m, 2H), 4.57e4.60 (m, 2H), 4.73 (br t, J¼7.8 Hz, 1H),
7.26e7.35 (m, 3H), 7.51e7.53 (m, 2H); 13C NMR (100 MHz, CDCl3)
0
ꢀC. After 3 h at 0 ꢀC, the mixture was diluted with chloroform,
washed with water, saturated aqueous NaHCO3, and brine, dried
with MgSO4, and concentrated in vacuo. The resulting bromide 8
was dissolved in acetic acid (350 mL) and was added to the sus-
pension of Zn dust (1.06 mmol, 69.3 g) and CuSO4eH2O (21.3 mmol,
5.3 g) in water (71 mL) with stirring. After 2.5 h at 0 ꢀC, the mixture
was filtered through Celite. The filtrate was poured into saturated
aqueous NaHCO3 and extracted with chloroform. The combined
organic phases were washed with saturated aqueous NaHCO3 and
brine, then dried, and concentrated. The residue was purified by
silica-gel column chromatography (20% EtOAcehexane) to give 5
(13.8 g, 65% for three steps) as a colorless oil. 1H NMR (400 MHz,
d:
8.5 (q), 34.0 (t), 72.0 (t), 74.9 (d), 84.7 (d),121.7 (s),128.3 (d),129.1 (d),
132.39 (s), 132.44 (d), 157.4 (s), 173.8 (s); IR (KBr): 1763, 1747, 1693,
1477,1039 cmꢁ1; MS (FAB) m/z: 263 ([MþH]þ); HRMS (FAB) calcd for
C14H15O3S ([MþH]þ): 263.0742, found: 263.0743. The stereochem-
istry was determined by X-ray crystal structure analysis: CCDC
793254 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (þ44)1223 336 033; or deposit@ccdc.cam.ac.uk.
cis Isomer 14b: colorless needles (EtOAcehexane): mp
CDCl3)
d
: 2.07 (s, 3H), 2.10 (s, 3H), 3.96 (dd, J¼12.0, 1.2 Hz, 1H), 4.20
98e99 ꢀC; 1H NMR (600 MHz, CDCl3)
(dddd, J¼14.4, 7.2, 1.8, 1.8 Hz, 1H), 3.15 (d, J¼14.4 Hz, 1H), 3.97 (dd,
d
: 1.92 (t, J¼1.8 Hz, 3H), 3.04
(ddd, J¼12.0, 3.2, 1.2 Hz, 1H), 4.95e5.00 (m, 3H), 6.60 (d, J¼5.2 Hz,

K. Matsuo, M. Shindo / Tetrahedron 67 (2011) 971e975
975
J¼10.2, 10.2 Hz, 1H), 4.25 (dd, J¼10.2, 6.6 Hz, 1H), 4.77 (br t,
J¼8.4 Hz, 1H), 5.78 (d, J¼6.6 Hz, 1H), 7.26e7.33 (m, 3H), 7.40e7.42
of Basic and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN). K.M. additionally acknowledges the support of
the JSPS.
(m, 2H); 13C NMR (100 MHz, CDCl3)
d: 8.5 (q), 33.5 (t), 64.6 (t), 75.4
(d), 84.0 (d), 123.1 (s), 127.7 (d), 129.2 (d), 131.3 (d), 133.6 (s), 155.0
(s), 174.0 (s); IR (KBr): 1747, 1691, 1224, 1039 cmꢁ1; MS (FAB) m/z:
263 ([MþH]þ); HRMS (FAB) calcd for C14H15O3S ([MþH]þ):
263.0742, found: 263.0743. Anal. Calcd for C14H14O3S: C, 64.10; H,
5.38. Found: C, 64.04; H, 5.39.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.108. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
4.1.5. 7a-Bromo-3-methyl-5-(phenylthio)-4,5,7,7a-tetrahydro-2H-
furo[2,3-c]pyran-2-one (15). To a solution of 14b (cis isomer)
(500 mg, 1.9 mmol) in CCl4 (380 mL) was added N-bromosuccini-
mide (388 mg, 1.25 mmol). The mixture was refluxed for 15 min,
References and notes
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9475e9480.
mosuccinimide (259 mg, 0.84 mmol) was carefully added. After
cooling to 0 ꢀC, the unreacted succinimide was removed by filtra-
tion, and the filtrate was evaporated under reduced pressure. The
residue was purified with column chromatography (5e10%
EtOAcehexane) to give 15 (551.3 mg, 85%) as a colorless oil. 1H NMR
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(600 MHz, CDCl3)
d
: 1.94 (d, J¼1.2 Hz, 3H), 3.06 (d, J¼14.4 Hz, 1H),
3.47 (dddd, J¼14.4, 6.6, 3.6, 1.8 Hz, 1H), 4.25 (d, J¼12.0 Hz, 1H), 4.28
(d, J¼12.0 Hz, 1H), 5.85 (d, J¼6.6 Hz, 1H), 7.27e7.33 (m, 3H),
7.38e7.40 (m, 2H); 13C NMR (150 MHz, CDCl3)
d: 8.6 (q), 31.6 (t),
70.7 (t), 83.9 (d), 88.0 (s), 123.7 (s), 127.8 (d), 129.3 (d), 131.1 (d),
132.9 (s), 156.0 (s), 169.7 (s); IR (CHCl3): 3018, 2359, 1782, 1689,
1440, 1273, 1224,1207, 1080, 995, 877, 788 cmꢁ1; MS (FAB) m/z: 341
(Mþ), 343 ([Mþ2]þ); HRMS (FAB) calcd for C14H14BrO3S ([MþH]þ):
340.9847, found: 340.9847.
4.1.6. Karrikinolide (3-methyl-2H-furo[2,3-c]pyran-2-one) (1)3. A
solution of 15 (3 mg, 8.8
mmol) and pTsOHeH2O (8.3 mg, 43.9 mmol)
in toluene (176 L) was refluxed for 1 h. The mixture was cooled to
m
room temperature, and saturated aqueous NaHCO3 was added. The
mixture was extracted with EtOAc, and the combined organic phase
was washed with water and brine and dried over MgSO4. The
residue was purified with column chromatography (5e35%
EtOAceHex) to give 1 (1.0 mg, 76%) as pale yellow needles
(EtOAceHex): mp 118e119 ꢀC; 1H NMR (400 MHz, CDCl3)
d
: 1.93 (s,
3H), 6.51 (s, 1H), 7.32 (s, 1H), 7.44 (s, 1H); 13C NMR (100 MHz, CDCl3)
: 7.7, 100.4, 103.5, 126.8, 139.7, 142.3, 148.0, 171.3; IR (KBr): 3088,
d
1737, 1668, 1616, 1556, 1313, 1286, 1228, 1114, 1074, 991, 881, 868,
810 cmꢁ1; MS (EI) m/z: 151 ([MþH]þ), 151 (100%); HRMS (EI) calcd
for C8H6O3 ([MþH]þ): 151.0395, found: 151.0398.
5. Matsuo, K.; Shindo, M. Org. Lett. 2010, 12, 5346e5349.
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This research was partially supported by a Grant-in-Aid for
Scientific Research (B) (22390002) and the Program for Promotion
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