Dibromomethane as one-carbon source in organic synthesis: total synthesis of (±)-canadensolide

Article abstract of DOI:10.1016/j.tet.2006.07.066

A diastereoselective total synthesis of (±)-canadensolide is described. The key step is to introduce the α-methylene group by the ozonolysis of mono-substituted alkenes followed by reaction with a preheated mixture of CH₂Br₂-Et₂

Full text of DOI:10.1016/j.tet.2006.07.066

Tetrahedron 62 (2006) 9713–9717
Dibromomethane as one-carbon source in organic
synthesis: total synthesis of ( )-canadensolide
a
Yung-Son Hona,b, and Cheng-Han Hsieh
*
aDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 62102, Taiwan, ROC
bInstitute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
Received 19 May 2006; revised 20 July 2006; accepted 21 July 2006
Available online 17 August 2006
Abstract—A diastereoselective total synthesis of (ꢀ)-canadensolide is described. The key step is to introduce the a-methylene group by the
ozonolysis of mono-substituted alkenes followed by reaction with a preheated mixture of CH2Br2–Et2NH.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Penicillium canadense, Xylaria obovata, and Sporothrix
sp., respectively. They are closely related natural products
that differ simply in the length of their side chain (Fig. 1).
The interest in these compounds lies not only in their sig-
nificant biological activities but also their unique stereo-
chemical features. The fungicidal activity of canadensolide
(7), the phytotoxic activity of xylobovide (8), and the anti-
bacterial, fungicidal, algicidal, and herbicidal activities of
sporothriolide (9) are noteworthy. These compounds con-
tain all cis stereochemistry of the three adjacent methine
protons and the alkyl substituent is interestingly situated in
the sterically less accessible concave face. These structures
have received considerable attention as synthetic targets,
with several reported total syntheses of canadensolide,8,9
xylobovide,10 and sporothriolide11 appearing in the
literature.
We have reported that the ozonolysis of mono-substituted
alkenes 1 followed by reaction with a preheated mixture of
CH2Br2–Et2NH affords a-substituted acroleins 2 in good
yields.1 The a-substituted acroleins 2 were easily oxidized
by NaClO2 and then treated with CH2N2 to give a-
substituted acrylate 3 in excellent yields (Scheme 1).2 This
methodology was also applied to prepare the a-methylene
lactones with different ring sizes from the corresponding
alkenol.3
H
OMe
O
1. NaClO2
2. CH2N2
1. O3, CH2Cl2
R
R
O
2. [CH2Br2, Et2NH]
R
1
2
3
In continuation of our interest in the synthetic applications of
the a-methylenation methodology in natural product synthe-
sis,4 we want to develop a general synthetic pathway, which
is applicable to prepare natural products 7–9. In this article,
our effort in the stereoselective total synthesis of canadenso-
lide (7) will be described.
Scheme 1.
Various bioactive a-methylene-g-butyrolactones and bislac-
tones have been isolated from microorganisms and some
specific examples are shown in Figure 1.4 The structures
4–6 contain a-methylene, b-carboxylic acid, and g-alkyl
groups in different chain lengths. Both the b- and g-substit-
uents are trans to each other. We have successfully applied
the methodology described in Scheme 1 in the total synthesis
of the (ꢀ)- and (ꢁ)-methylenolactocin (4).4
O
O
O
O
R
β
β
H
H
H
H
Naturally occurring bislactones such as canadensolide (7),5
γ
γ
O
O
xylobovide (8),6 and sporothriolide (9)7 are metabolites of
R
O
HO
Canadensolide 7
Xylobovide 8
R = n-C4H9
R = n-C2H5
R = n-C6H13
(-)-Methylenolactocin 4
R = n
-C5H11
R = n-C11H23 trans-Nephrosterinic acid 5
(-)-Protolichesterinic acid 6
Sporothriolide 9
R = n-C13H27
Keywords: Canadensolide; a-Methylene-g-butyrolactones; Bislactones;
a-Methylenation.
* Corresponding author. Tel.: +886 5 2720411x66412; fax: +886 5
2721040; e-mail: cheysh@ccu.edu.tw
Figure 1. Natural products with b,g-disubstituted-a-methylene-g-butyro-
lactone moiety and a-methylene-furofurandione moiety.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.066

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Y.-S. Hon, C.-H. Hsieh / Tetrahedron 62 (2006) 9713–9717
2. Results and discussions
a preheated mixture of CH2Br2 and Et2NH afforded acrolein
15 in 70% yield. The acrolein 15 was oxidized by sodium
chlorite in the presence of a chlorine scavenger (i.e.,
2-methyl-2-butene) to give the corresponding acrylic acid,
which was subsequently treated with CH2N2 to give methyl
acrylate 16 in 79% yield. Acid-catalyzed cyclization of
methyl acrylate 16 in methanol gave cis-b,g-disubstituted-
2.1. The retrosynthetic analysis of bislactone-type
natural product
The retrosynthetic analysis of bislactone-type natural prod-
uct A is shown in Figure 2. The bislactone A should be easily
prepared by the bislactonization of the diester B. The methyl
1
g-butyrolactone 17, which was confirmed by the H NMR
O
O
OP'
O
MeO
Sequential
O
Our
P'O
H
P'O
R
Bis-Lactonization
Protocol
H
OMe
H
H
H
R
H
R
CO2Me
OP
CO2Me
O
R
O
A
OP
OP
O
C
B
C
Diastereoselective
Aldol Reaction
O
OH
Diastereoselective
OSiR"3
Dianion Alkylation
R
R
+
H
OMe
OMe
OP
OP
D
E
F
Figure 2. Retrosynthetic analysis of the total synthesis of bislactone natural products.
acrylate B should be easily prepared from allylacetate C by
our methodology as shown in Scheme 1. The stereoselective
introduction of the a-stereogenic center of compound C
from the allylation of the dianion of b-hydroxy ester D is
a well known procedure in the literature.12 The syn-b-
hydroxy-g-alkoxy ester D formed from the Lewis acid-
catalyzed addition of the silyl enol ether F to a-alkoxy
aldehyde E via chelation-controlled intermediate should be
a diastereoselective process (Fig. 2).13
of the crude product. However, we found that compound
17 undergoes isomerization to the endocyclic olefin 18 dur-
ing the silica gel column chromatography. Fortunately, the
debenzylation of the crude product 17 with a stoichiometric
15
amount of SnCl4 was tried and canadensolide (7) was
isolated in 77% yield for two steps as a white solid. Presum-
ably, the isomerization to the extended conjugated product is
a facile process only for the monocyclic compound 17 but
not the bicyclic compound 7.
2.2. The total synthesis of canadensolide
3. Conclusions
The readily available a-benzyloxyhexanal (10)14 undergoes
aldol additions with trimethylsilyl ketene acetal 11 catalyzed
by TiCl4 at ꢁ78 ꢂC to give the chelation-controlled 1,2-
asymmetric induction13 syn product 12 in 77% yield
(Scheme 2). Essentially only one of two possible diastereo-
mers is formed. The allylation of b-hydroxy ester 12 follow-
ing the procedure of Frater12 gave the 2,3-anti-b-hydroxy
ester 13 in 61% yield. The acetylation of the secondary alco-
hol 13 gave the corresponding acetate 14 in 91% yield. The
ozonolysis of terminal olefin 14 followed by addition of
The special features of our synthetic design are described as
follows. The relative stereochemistry of g- and d-substitu-
ents was established by the TiCl4-catalyzed aldol reaction
via chelation-controlled intermediate. The relative stereo-
chemistry of b- and g-substituents was established by the
stereoselective allylation of the dianion of b-hydroxy ester
12. Furthermore, the a-methylene-g-butyrolactone moiety
was derived from the corresponding terminal alkene by the
methodology developed in our laboratory (Fig. 3). We
O
OH
OH
OTMS
ii
CO2Me
i
n-C4H9
n-C4H9
CO2Me
n-C4H9
+
H
77%
61%
OMe
11
OBn
OBn
OBn
10
12
13
OAc
OAc
OAc
n-C4H9
CO2Me
CO2Me
iii
91%
iv
70%
v
n-C4H9
CO2Me
CHO
n-C4H9
CO2Me
79%
OBn
OBn
OBn
O
14
15
16
O
O
Me
O
H
O
O
vii
vi
H
H
H
H
77% from 16
CO2Me
17
n-C4H9
CO2Me
18
n-C4H9
O
7
n-C4H9
O
OBn
OBn
viii
90% from 16
Scheme 2. Reagents and conditions: (i) TiCl4, ꢁ78 ꢂC, CH2Cl2, 8 h; (ii) (a) 2.2 equiv LDA, ꢁ78 ꢂC, 6 h; (b) H2C]CHCH2Br; (iii) Ac2O, Et3N, cat. DMAP;
(iv) (a) O3, CH2Cl2, ꢁ78 ꢂC; (b) preheated mixture of Et2NH and CH2Br2, 2 h; (v) (a) NaClO2, t-BuOH, NaH2PO4$2H2O, MeCH]CMe2, 8 h; (b) CH2N2; (vi)
cat. MeCOCl, MeOH, 24 h; (vii) SnCl4, CH2Cl2, reflux, 2.5 h; (viii) silica gel column chromatography.

Y.-S. Hon, C.-H. Hsieh / Tetrahedron 62 (2006) 9713–9717
9715
3.37 (td, J¼6.1 and 4.1 Hz, 1H, –CHOBn), 2.70 (d,
J¼5.8 Hz, 1H, OH), 2.53–2.55 (m, 2H, –CH2CO2Me),
1.32–1.67 (m, 6H), 0.91 (t, J¼7.0 Hz, 3H, –CH2CH3); 13C
NMR (CDCl3, 100 MHz) d 172.8, 138.2, 128.3, 127.8,
127.7, 80.8, 72.2, 69.0, 51.6, 38.0, 29.4, 27.6, 22.8, 13.9;
IR (thin film, NaCl plates): 3471, 2953, 2930, 2859, 1736,
1455, 1437, 1275, 1170, 1072, 736, 699 cmꢁ1; FAB Mass
(m/z): 281 (M++l, 30), 280 (M+, 0.2), 263 (4), 249 (2), 173
(12), 91 (100); HRMS calcd for C16H24O4: 280.1675, found:
280.1673.
The
β- and γ-chiral centers are set by
stereoselective
α
-allylation of
β-hydroxy ester.
O
α
O
The γ- and δ-chiral centers
are set by chelation-controlled
aldol reaction.
From terminal alkene
H
R
H
O
γ
β
by our α-methylenation
δ O
methodology.
Xylobovide (8) and sporothriolide (9) should also be prepared with
this synthetic methodology by changing the R group of compound 10.
Figure 3. Summary of the special features of our natural product synthesis.
4.3. (2R*,3S*,4S*)-2-Allyl-4-(benzyloxy)-3-hydroxy-
octanoic acid methyl ester (13)
complete the total synthesis of canadensolide (7) in nine op-
eration steps in 18% overall yield starting from a-benzyloxy
aldehyde 10.
n-Butyllithium (4.9 mL, 7.85 mmol, 1.6 M in hexane) was
added to a stirring solution of diisopropylamine (1.10 mL,
7.85 mmol) in THF (12 mL) at ꢁ78 ꢂC. To the LDA solu-
tion, b-hydroxy ester 11 (1.0 g, 3.57 mmol) in 5 mL of
THF was added at ꢁ78 ꢂC and stirred at this temperature
for 1 h. At ꢁ78 ꢂC, a mixture of allyl bromide (0.37 mL,
4.27 mmol) and HMPA (1.2 mL) in THF (4.8 mL) was
added to the reaction mixture. After stirring at ꢁ78 ꢂC for
1 h, the reaction mixture was partitioned between 40% ethyl
acetate/petroleum ether and saturated aqueous NH4Cl. The
combined organic phase was dried (Na2SO4), concentrated,
and chromatographed on silica gel column to afford product
13 (698 mg, 2.44 mmol) in 61% yield as a colorless oil. TLC
Rf¼0.58 (hexane/EtOAc¼5:l). 1H NMR (CDCl3, 400 MHz)
d 7.29–7.37 (m, 5H, Ph-H), 5.62–5.73 (m, 1H, –CH]CH2),
5.01–5.07 (m, 2H, –CH]CH2), 4.66 (ABq, J¼11.4 Hz, 1H,
–CH2Ph), 4.42 (ABq, J¼11.4 Hz, 1H, –CH2Ph), 3.70 (ddd,
J¼9.4, 5.8, and 2.7 Hz, 1H, –CHOH), 3.54 (s, 3H, OMe),
3.38 (ddd, J¼7.7, 5.2, and 2.6 Hz, 1H, –CHOBn), 2.85 (d,
J¼9.5 Hz, 1H, OH), 2.64 (dt, J¼9.0 and 5.8 Hz, 1H,
–CHCO2Me), 2.22–2.41 (m, 2H, –CH2CH]CH2), 1.29–
1.64 (m, 6H), 0.91 (t, J¼7.0 Hz, 3H, –CH2CH3); 13C
NMR (CDCl3, 100 MHz) d 174.8, 138.1, 134.7, 128.4,
127.9, 127.7, 117.2, 79.3, 72.8, 71.5, 51.6, 48.5, 33.8,
29.3, 27.6, 22.9, 14.0; IR (thin film, NaCl plates): 3481,
2953, 2932, 2861, 1736, 1455, 1437, 1267, 1195, 1167,
1069, 916, 734, 699 cmꢁ1; FAB Mass (m/z): 321 (M++l,
31), 320 (M+, 0.2), 281 (28), 213 (32), 207 (21), 147 (28),
91 (100), 73 (42); HRMS calcd for C19H28O4: 320.1988,
found: 320.1990.
Our synthetic design should be extendable to the total syn-
thesis of xylobovide (8) and sporothriolide (9) by replacing
the a-substituent of compound 10 from n-butyl to ethyl and
n-hexyl, respectively.
4. Experimental
4.1. General
All reactions were carried out under nitrogen. Unless other-
wise noted, materials were obtained from commercial sup-
pliers and used without further purification. Melting points
were determined by using a Thomas–Hoover melting point
1
apparatus and were uncorrected. The H and 13C NMR
spectra were recorded on a Bruker Avance DPX400 spec-
trometer, and chemical shifts were given in parts per million
downfield from tetramethylsilane (TMS). IR spectra were
taken with a Perkin–Elmer 682 spectrophotometer and only
noteworthy absorptions were listed. Mass spectra were
measured on a Micromass Trio-2000 GC–MS spectrometer
(National Chiao-Tung University) by electronic impact at
70 eV (unless otherwise indicated). High Resolution Mass
Spectroscopy (HRMS) was measured on a Finnigan/Thermo
Quest MAT (National Chung Hsing University) mass spec-
trometer. 3-Nitrobenzyl alcohol (NBA) was used as FAB
Mass matrix. Compound 10 was prepared by the reported
procedure.14
4.2. (3S*,4S*)-4-(Benzyloxy)-3-hydroxyoctanoic acid
methyl ester (12)
4.4. (2R*,3S*,4S*)-3-Acetoxy-2-allyl-4-(benzyloxy)octa-
noic acid methyl ester (14)
To a mixture of aldehyde 10 (1.2 g, 5.82 mmol) and enol
silyl ether 11 (1.02 g, 6.98 mmol) in 23 mL of CH2Cl2 was
added TiCl4 (6.4 mmol, 6.4 mL, 1.0 M in CH2Cl2) by
syringe pump at ꢁ78 ꢂC over 1 h. The reaction mixture
was warmed to rt and continued to stir for another 8 h.
The reaction mixture was neutralized slowly by saturated
aqueous NaHCO3 at 0 ꢂC and extracted with CH2Cl2. The
organic layer was dried over Na2SO4, filtered, and concen-
trated to give the crude product. The crude product was
purified by silica gel column chromatography to give
b-hydroxy ester 12 (1.26 g, 4.49 mmol) as a pale yellow
To a solution of the alcohol 13 (500 mg, 1.56 mmol), N,N-di-
methylaminopyridine (DMAP, 19.0 mg, 0.156 mmol) and
Et3N (0.26 mL, 1.87 mmol) in 3.1 mL of CH2Cl2 was added
acetic anhydride (0.17 mL, 1.87 mmol) at rt and stirred for
2 h. The reaction mixture was concentrated and chromato-
graphed on silica gel column to afford the acetate 14
(515 mg, 1.42 mmol) in 91% yield as a pale yellow oil.
TLC Rf¼0.67 (hexane/EtOAc¼3:l). 1H NMR (CDCl3,
400 MHz) d 7.28–7.37 (m, 5H, Ph-H), 5.67–5.69 (m, 1H,
–CH]CH2), 5.24 (dd, J¼8.3 and 3.7 Hz, 1H, –CHOAc),
4.99–5.03 (m, 2H, –CH]CH2), 4.64 (ABq, J¼11.7 Hz,
1H, –CH2Ph), 4.54 (ABq, J¼11.7 Hz, 1H, –CH2Ph), 3.64
(s, 3H, OMe), 3.52 (td, J¼6.4 and 3.7 Hz, 1H, –CHOBn),
2.96 (td, J¼8.3 and 6.3 Hz, 1H, –CHCO2Me), 2.24–2.28
(m, 2H, –CH2CH]CH2), 2.03 (s, 3H, –COCH3), 1.28–1.51
1
oil in 77% yield. Rf¼0.39 (hexane/EtOAc¼5:l); H NMR
(CDCl3, 400 MHz) d 7.28–7.38 (m, 5H, Ph-H), 4.64 (ABq,
J¼11.4 Hz, 1H, –CH2Ph), 4.51 (ABq, J¼11.4 Hz, 1H,
–CH2Ph), 4.08–4.14 (m, 1H, –CHOH), 3.68 (s, 3H, OMe),

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Y.-S. Hon, C.-H. Hsieh / Tetrahedron 62 (2006) 9713–9717
(m, 6H), 0.88 (t, J¼7.2 Hz, 3H, –CH2CH3); 13C NMR
(CDCl3, 100 MHz) d 172.9, 169.9, 138.0, 134.2, 128.3,
127.9, 127.7, 117.3, 77.3, 73.4, 71.7, 51.4, 46.5, 32.8,
29.2, 27.4, 22.6, 20.8, 13.8; IR (thin film, NaCl plates):
2954, 2935, 2871, 1746, 1455, 1436, 1372, 1233, 1169,
1026, 918, 736, 699 cmꢁ1; EI Mass (m/z): 362 (M+, 1),
255 (74), 177 (24), 155 (20), 143 (65), 135 (40), 123 (45),
105 (93), 91 (100), 77 (49), 55 (19); HRMS calcd for
C21H30O5: 362.2093, found: 362.2101.
with 2 N HCl and extracted with two 5 mL portions of ether.
The combined ether layers were washed with 6 mL of water,
dried with Na2SO4, concentrated to give the crude carbox-
ylic acid. To a solution of a-substituted acrylic acid in
2 mL of CH2Cl2 was added a solution of CH2N2 in ethyl
ether at rt. The progress of the reaction should be monitored
carefully by TLC. Excess of the CH2N2 will cause further
1,3-dipolar cycloaddition on the double bond. The reaction
mixture was concentrated and the residue was chromato-
graphed on silica gel column to give methyl acrylate 16
(171 mg, 0.42 mmol) as a pale yellow oil in 79% yield.
TLC Rf¼0.6 (hexane/EtOAc¼3:l). 1H NMR (CDCl3,
400 MHz) d 7.27–7.35 (m, 5H, Ph-H), 6.38 (s, 1H,
–C]CH2), 5.90 (s, 1H, –C]CH2), 5.59 (dd, J¼9.0 and
3.4 Hz, 1H, –CHOAc), 4.51 (ABq, J¼11.5 Hz, 1H,
–CH2Ph), 4.41 (ABq, J¼11.5 Hz, 1H, –CH2Ph), 4.17 (d,
J¼9.0 Hz, 1H, –CHCO2Me), 3.68 (s, 3H, OMe), 3.65 (s,
3H, OMe), 3.49 (td, J¼6.4 and 3.4 Hz, 1H, –CHOBn),
2.05 (s, 3H, –COCH3), 1.28–1.35 (m, 6H), 0.86 (t,
J¼7.1 Hz, 3H, –CH2CH3); 13C NMR (CDCl3, 100 MHz)
d 171.1, 170.0, 166.0, 138.1, 135.2, 128.8, 128.1, 127.5,
127.4, 77.9, 72.9, 71.6, 52.1, 47.2, 29.0, 27.4, 22.5, 20.8,
13.8; IR (thin film, NaCl plates): 2953, 2932, 2860, 1748,
4.5. (2S*,3R*,4R*)-3-Acetoxy-4-(benzyloxy)-2-
(1-formylvinyl)octanoic acid methyl ester (15)
A two-necked flask fitted with a glass tube to admit ozone,
a CaCl2 drying tube, and a magnetic stirring bar were
charged with terminal alkene 14 (400 mg, 1.10 mmol) in
CH2Cl2 (20 mL). The flask was cooled to ꢁ78 ꢂC and ozone
was bubbled through the solution. When the solution turned
blue, ozone addition was stopped. Nitrogen was passed
through the solution until the blue color was discharged. A
mixture of Et2NH (0.62 mL, 16.7 mmol) and CH2Br2
(1.2 mL, 5.6 mmol) was heated to 55 ꢂC for 1.5 h to give
a yellow solution and then cooled to rt. To a solution of ozon-
ide in CH2Cl2 generated above was added a preheated mix-
ture of Et2NH and CH2Br2 at ꢁ78 ꢂC. After the addition, the
cooling bath was removed and the reaction mixture was
stirred at rt. The reaction was complete in 2.5 h and the re-
action mixture was concentrated. To the crude mixture, ether
was added and most of the ammonium salts were precipi-
tated out. After filtration, the filtrate was concentrated, chro-
matographed on the silica gel column to give the desired
acrolein 15 (290 mg, 0.77 mmol) in 70% yield as a pale
yellow oil; TLC Rf¼0.32 (hexane/EtOAc¼5:l). 1H
NMR (CDCl3, 400 MHz) d 9.40 (s, 1H, CHO), 7.26–7.35
(m, 5H, Ph-H), 6.59 (s, 1H, –C]CH2), 6.14 (s, 1H,
–C]CH2), 5.52 (dd, J¼8.8 and 3.8 Hz, 1H, –CHOAc),
4.49 (ABq, J¼11.5 Hz, 1H, –CH2Ph), 4.42 (ABq,
J¼11.5 Hz, 1H, –CH2Ph), 4.20 (d, J¼8.8 Hz, 1H,
–CHCO2Me), 3.64 (s, 3H, OMe), 3.44 (ddd, J¼7.2, 5.5,
and 3.8 Hz, 1H, –CHOBn), 2.05 (s, 3H, –COCH3), 1.28–
1.49 (m, 6H), 0.87 (t, J¼7.0 Hz, 3H, –CH2CH3); 13C
NMR (CDCl3, 100 MHz) d 191.9, 170.7, 169.9, 144.2,
137.9, 136.5, 128.2, 127.7, 127.5, 77.8, 72.7, 71.6, 52.1,
43.2, 29.1, 27.5, 22.5, 20.8, 13.8; IR (thin film, NaCl plates):
2955, 2934, 2870, 1747, 1696, 1455, 1435, 1372, 1232,
1168, 1027, 914, 734, 699 cmꢁ1; FAB Mass (m/z): 376
(M+, 1), 316 (17), 284 (88), 270 (16), 230 (51), 210 (65),
199 (81), 177 (90), 157 (98), 139 (91), 125 (95), 109 (22),
91 (100), 65 (84), 55 (27); HRMS calcd for C21H29O6
(M++1): 377.1964, found: 377.1956.
1455, 1436, 1372, 1229, 1172, 1027, 917, 736, 699 cmꢁ1
;
EI Mass (m/z): 406 (M+, 5), 375 (18); HRMS calcd for
C22H30O7: 406.1992, found: 406.1990.
4.7. (2R*)-[(1R*)-1-(Benzyloxy)pentyl]-2,5-dihydro-4-
methyl-5-oxofuran-3-carboxylic acid methyl ester (18)
To a mixture of acetoxy-acrylate 16 (40 mg, 0.098 mmol) in
1 mL of MeOH was added a catalytic amount of acetyl chlo-
ride (2 mL, 29 mmol) and stirred at rt for 24 h. The reaction
mixture was concentrated to give the crude a-methylene-
g-butyrolactone 17. The crude product 17 was chromato-
graphed on silica gel column to give the isomerized product
18 (29.3 mg, 0.088 mmol) in 90% yield as a pale yellow oil.
TLC Rf¼0.33 (hexane/EtOAc¼10:l); 1H NMR (CDCl3,
400 MHz) d 7.14–7.35 (m, 5H, Ph-H), 5.10–5.11 (m, 1H,
CHOCO), 4.50 (ABq, J¼11.9 Hz, 1H, –CH2Ph), 4.27
(ABq, J¼11.9 Hz, 1H, –CH2Ph), 3.89 (td, J¼7.0 and
1.7 Hz, 1H, –CHOBn), 3.75 (s, 3H, OMe), 2.16 (d,
J¼2.0 Hz, 3H, ]CCH3), 1.28–1.49 (m, 6H), 0.92 (t,
J¼7.0 Hz, 3H, –CH2CH3); 13C NMR (CDCl3, 100 MHz)
d 172.8, 162.6, 144.7, 138.3, 137.8, 128.3, 127.6, 81.9,
76.4, 72.3, 52.2, 31.2, 27.9, 22.6, 13.9, 10.8; IR (thin film,
NaCl plates): 2955, 2931, 2862, 1768, 1728, 1455, 1438,
1339, 1225, 1098, 1026, 737, 699 cmꢁ1; EI Mass (m/z):
332 (M+, 1), 258 (58), 215 (88), 199 (66), 187 (69), 156
(95), 145 (52), 127 (56), 124 (88), 105 (100), 91 (97), 65
(73), 55 (63); HRMS calcd for C19H24O5: 332.1624, found:
332.1626.
4.6. (2R*)-[(1S*,2S*)-1-Acetoxy-2-(benzyloxy)hexyl]-
3-methylenesuccinic acid dimethyl ester (16)
4.8. (3aS*,6R*,6aR*)-6-Butyl-tetrahydro-3-methylene-
furo[3,4-b]furan-2,4-dione [i.e., ( )-canadensolide] (7)
To a solution of acrolein 15 (200 mg, 0.53 mmol), tert-butyl
alcohol (2.7 mL), and 2-methyl-2-butene (0.18 mL,
111.7 mg, 1.59 mmol) was added dropwise a solution of so-
dium chlorite (110.7 mg, 1.21 mmol) and sodium dihydro-
genphosphate dihydrate (163.7 mg, 1.06 mmol) in 0.8 mL
of water. The pale yellow reaction mixture was stirred at rt
for 2.5 h. The reaction mixture was concentrated, the residue
then dissolved in 1.6 mL of water, and this extracted with
6 mL of hexane. The aqueous layer was acidified to pH 3
To a solution of acetoxy-acrylate 16 (40 mg, 0.098 mmol) in
1 mL of MeOH was added a catalytic amount of acetyl chlo-
ride (2 mL, 29 mmol) and stirred at rt for 24 h. The reaction
mixture was neutralized by NaHCO3, filtered, and the filtrate
was concentrated to give the crude a-methylene-g-butyro-
lactone 17. To a solution of the crude product 17 in 2 mL
of anhydrous CH2Cl2 was added SnCl4 (0.1 mmol, 0.1 mL,

Y.-S. Hon, C.-H. Hsieh / Tetrahedron 62 (2006) 9713–9717
9717
8. The a-methylenation was the last step in the total synthesis of
canadensolide, see: (a) Al-Abed, Y.; Naz, N.; Mootoo, D.;
Voelter, W. Tetrahedron Lett. 1996, 37, 8641–8642; (b)
Nubbemeyer, U. Synthesis 1993, 1120–1128; (c) Honda, T.;
Kobayashi, Y.; Tsubuki, M. Tetrahedron 1993, 49, 1211–
1222; (d) Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron
Lett. 1990, 31, 4891–4894; (e) Tochtermann, W.; Schroeder,
G. R.; Snatzke, G.; Peters, E. M.; Peters, K.; Von Schnering,
H. G. Chem. Ber. 1988, 121, 1625–1636; (f) Tsuboi, S.;
Muranaka, K.; Sakai, T.; Takeda, A. J. Org. Chem. 1986, 51,
4944–4946; (g) Anderson, R. C.; Fraser-Reid, B. J. Org.
Chem. 1985, 50, 4786–4790; (h) Sakai, T.; Yoshida, M.;
Kohmoto, S.; Utaka, M.; Takeda, A. Tetrahedron Lett. 1982,
23, 5185–5188; (i) Tsuboi, S.; Fujita, H.; Muranaka, K.;
Seko, K.; Takeda, A. Chem. Lett. 1982, 51, 1909–1912; (j)
Anderson, R. C.; Fraser-Reid, B. Tetrahedron Lett. 1978, 35,
3233–3236; (k) Kato, M.; Kageyama, M.; Tanaka, R.;
Kuwahara, K.; Yoshikoshi, A. J. Org. Chem. 1975, 40, 1932–
1941.
9. The exocyclic methylene group was introduced in the earlier
step of the total synthesis of canadensolide, see: (a)
Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.;
Thongyoo, P. J. Org. Chem. 2001, 66, 4692–4694; (b)
Lertvorachon, J.; Meepowpan, P.; Thebtaranonth, Y.
Tetrahedron 2001, 66, 14341–14358; (c) Sharma, G. V. M.;
Krishnudu, K.; Rao, S. M. Tetrahedron: Asymmetry 1995, 6,
543–548; (d) Sharma, G. V. M.; Vepachedu, S. R.
Tetrahedron 1991, 47, 519–524; (e) Carlson, R. M.; Oyler,
A. R. J. Org. Chem. 1976, 41, 4065–4069.
1 M in CH2Cl2) at rt. The solution was refluxed for 2.5 h, and
then saturated aqueous NaHCO3 was added at 0 ꢂC. The
mixture was extracted with CH2Cl2 and the organic layer
was washed with brine and dried over Na2SO4. After filtra-
tion of the mixture and evaporation of the solvent, the crude
product was purified by silica gel column chromatography
to afford 15.9 mg of canadensolide (7) as a white solid in
77% yield. TLC Rf¼0.68 (hexane/EtOAc¼l:2), mp 95.3–
1
96.7 ꢂC. H NMR (CDCl3, 400 MHz) d 6.47 (d, J¼2.0 Hz,
1H, –C]CH2), 5.16 (d, J¼1.9 Hz, 1H, –C]CH2), 5.15
(dd, J¼6.8 and 4.7 Hz, 1H, –CHOCO), 4.65 (ddd, J¼7.6,
6.6, and 4.8 Hz, 1H, –CHOCO), 4.01 (dt, J¼6.7 and 2.0 Hz,
1H, –CHCO2), 1.40–1.90 (m, 6H), 0.94 (t, J¼7.2 Hz, 3H, –
CH2CH3); 13C NMR (CDCl3, 100 MHz) d 172.1, 167.4,
129.9, 127.2, 82.8, 77.2, 46.2, 28.5, 27.5, 22.4, 13.8; IR
(thin film, NaCl plates): 2954, 2928, 2858, 1762, 1664,
1464, 1363, 1306, 1269, 1118, 1069, 934, 727 cmꢁ1; EI
Mass (m/z): 211 (M++1, 1), 156 (12), 124 (30), 110 (45),
96 (100), 85 (16), 68 (53), 55 (18); HRMS calcd for
C11H15O4 (M++1): 211.0970, found: 211.0975.
Acknowledgements
We are grateful to the National Science Council, National
Chung Cheng University, and Academia Sinica for financial
support.
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