Dibromomethane as one-carbon source in organic synthesis: Total synthesis of (±)- and (-)-methylenolactocin

Article abstract of DOI:10.1016/j.tet.2005.01.057

A general method was developed to construct monocyclic α-methylene- γ-butyrolactone moiety. The key step is to introduce the α-methylene group by the ozonolysis of mono-substituted alkenes followed by reacting with a preheated mixture of CH₂Br₂-Et₂NH. Application of this key step in the total synthesis of the (±)- and (-)-methylenolactocin was described.

Full text of DOI:10.1016/j.tet.2005.01.057

Tetrahedron 61 (2005) 2713–2723
Dibromomethane as one-carbon source in organic synthesis:
total synthesis of (G)- and (K)-methylenolactocin
a
a
Yung-Son Hon,a,b, Cheng-Han Hsieh and Yu-Wei Liu
*
aDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, ROC
bInstitute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC
Received 4 November 2004; revised 5 January 2005; accepted 7 January 2005
Abstract—A general method was developed to construct monocyclic a-methylene-g-butyrolactone moiety. The key step is to introduce the
a-methylene group by the ozonolysis of mono-substituted alkenes followed by reacting with a preheated mixture of CH2Br2–Et2NH.
Application of this key step in the total synthesis of the (G)- and (K)-methylenolactocin was described.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
monocyclic, disubstituted a-methylene-g-butyrolactones
such as (K)-methylenolactocin 8a,5 trans-nephrosterinic
acid 8b,6 and (K)-protolichesterinic acid 8c7 are noted
for their biological activities, being antibacterial,8a–h
antifungal,8b antitumor,8h and, in certain cases, growth
regulating agents.8i The characteristic features of these
natural products are described as follows. These structures
contain a-methylene, b-carboxylic acid and g-alkyl groups
in different chain length. Both the b- and g-substituents are
trans to each other for compounds 8a, 8b, and 8c, while they
are cis to each other for cis-nephrosterinic acid (8b0) and
alloprotolichesterolic acid (8c0) (Fig. 1). All these natural
products have been synthesized by different method-
ologies.9–12 In order to extend the synthetic applications of
our a-methylenation methodology, our effort to the total syn-
thesis of (K)-methylenolactocin is described in this article.
We have reported that the ozonolysis of mono-substituted
alkenes 1 followed by reacting 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. Each step
in Scheme 1 is mild so that it is suitable to prepare the
a-substituted acrylates with labile groups.2 This method-
ology was also applied to prepare the a-methylene lactones
7 with different ring size (nZ0–3) from the corresponding
alkenol 4 (Scheme 1).3
The a-methylene-g-butyrolactone moiety is a core skeleton
in many structurally complex natural products.4 The
Scheme 1.
Keywords: Ozonides; a-Methylenation; g-Butyrolactone; (K)-Methylenolactocin; (G)-Methylenolactocin.
* Corresponding author. Tel.: C886 5 2720411x66412; fax: C886 5 2721040; e-mail: cheysh@ccu.edu.tw
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.057

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Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
Et2NH1 afforded acrolein 14 in 78% yield. The acrolein 14
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 15 in 79% yield.2 Acid-
catalyzed cyclization of methyl acrylate 15 in methanol
gave cis-b,g-disubstituted lactone 16 in 82% yield. Follow-
ing the literature procedure,9l compound 16 was treated with
6 N HCl in butanone under refluxing for 2 h to give an
inseparable mixture of methylenolactocin (8a) and buteno-
lide 8a0 in a ratio of 4: 1 in 77% yield. The mole ratio was
determined by the 1H NMR integrations of the a-methylene
protons (d 6.47 and 6.02 ppm) of compound 8a and
the g-methine proton (d 5.11 ppm) of compound 8a0.
After treatment with CH2N2, their methyl esters 17 and
18 are separable and are spectroscopically identical with
previously reported samples (Scheme 2).9j,u
Figure 1. Monocyclic a-methylene-g-butyrolactone natural products.
2. Results and discussions
2.1. Retrosynthetic analysis of our design in the total
synthesis of a-methylene-b-carboxyl-g-butyrolactone
natural products
The retrosynthetic analysis of a-methylene-b-carboxyl-g-
butyrolactone A is shown in Figure 2. Several groups
reported that structure A could be derived from the
corresponding cis-isomer B via epimerization and hydroly-
sis in the same flask.9l The g-butyrolactone B should be
easily prepared from alkenol C by our methodology as
shown in Scheme 1.1 The stereoselective introduction of the
b-stereogenic center of compound C from the allylation of
the dianion of b-hydroxy ester D is a well known procedure
in the literature.13 The b-hydroxy ester D should be easily
prepared by Reformatsky reaction14a from the methyl
bromoacetate (9) and aldehyde (Fig. 2).
We failed to avoid the formation of side product 8a0 derived
from the double bond isomerization by employing the
milder reaction conditions, such as using 4 N HCl or
running the reaction at 40 8C. Therefore, if the hydrolysis
and epimerization of compound 16 were arranged at the last
two steps of the synthetic pathway, we have to face0 two
problems. One is the formation of the minor product 8a and
the other is the difficulty of separating 8a0 from the
methylenolactocin (8a). The approach of Method I led us
to accomplish the total synthesis of (G)-methylenolactocin
in six operation steps in 31% overall yield from b-hydroxy
ester 11. In addition, we learned from this approach that the
epimerization should be carried out at the earlier stage of
the synthetic pathway in order to improve the efficiency of
the synthesis.
2.2. The total synthesis of the (G)-methylenolactocin
(method I)
The known b-hydroxy ester 11 was prepared from methyl
bromoacetate (9) and n-hexanal (10) in the presence of
activated zinc in 78% yield.14b The allylation of b-hydroxy
ester 11 following the procedure of Frater13 gave the anti-b-
hydroxy ester 12 in 85% yield (Scheme 2). The acetylation
of the secondary alcohol 12 gave the corresponding acetate
13 in 96% yield. The ozonolysis of terminal olefin 13
followed by addition of a preheated mixture of CH2Br2 and
2.3. The total synthesis of the (G)-methylenolactocin
(method II)
In order to inverse the configuration of the secondary
alcohol at the early stage, anti-b-hydroxy ester 12 was
subjected to the standard Mitsunobu condition.15 Unfortu-
nately, the desired p-nitrobenzoate 19 was formed in poor
Figure 2. Retrosynthetic analysis of the methylenolactocin and its analogues.
Scheme 2. Reagents and conditions: (i) Zn, BrCH2CO2Me (9), PhH, reflux, 4 h; (ii) 2.2 equiv LDA; H2C]CHCH2Br, K78 8C, 5 h; (iii) Ac2O, cat. DMAP,
Et3N, CH2Cl2, 2 h; (iv) (a) O3, CH2Cl2, K78 8C; (b) preheated mixture of Et2NH and CH2Br2 (mol equivZ5:15), 2 h; (v) NaClO2, t-BuOH, NaH2PO4$2H2O,
MeCH]C Me2, 8 h; (vi) CH2N2; (vi) cat. MeCOCl, MeOH, 24 h; (viii) 6 N HCl, butanone, 2 h.

Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
2715
Figure 3. Proposed mechanism for the g-lactone 25 formation via p-nitrobenzoyl group migration intermediate 24B.
yield and most of the starting material 12 was recovered.
The b-hydroxy ester 12 was reduced with Dibal-H to give
the corresponding 1,3-diol 20 in 79% yield. The primary
alcohol of 1,3-diol 20 was electively protected as tert-
butyldimethylsilyl ether 21 in 97% yield. The configuration
of the secondary alcohol 21 was inversed successfully by
Mitsunobu reaction to give the corresponding p-nitrobenzo-
ate 22 in 77% yield. The ozonolysis of terminal olefin 22
followed by addition of a preheated mixture of CH2Br2 and
Et2NH afforded acrolein 23 in 68% yield. The acrolein 23
was oxidized by sodium chlorite to give the corresponding
acrylic acid, which was subsequently treated with CH2N2 to
give the methyl acrylate 24 in 70% yield. In the presence of
a catalytic amount of HCl in methanol, the methyl acrylate
24 was cyclized to trans-b,g-disubstituted lactone 25 in
77% yield. The possible mechanism for the formation of
the lactone 25 from compound 24 was proposed as follows
(Fig. 3). The tert-butyldimethylsilyl ether of compound 21
was selectively deprotected under acidic condition to give
the primary alcohol 24A. The 1,5-p-nitrobenzoyl group
migration of the intermediate 24A before the cyclization
gave the lactone 25. When the p-nitrobenzoate 25 was
hydrolyzed by ammonium hydroxide in methanol, the
corresponding primary alcohol 27 was obtained in 62%
yield. Alternatively, when the p-nitrobenzoate 25 was
treated with K2CO3 in methanol, not only the methanolysis,
but also the 1,4-addition of methanol occurred to give
the a-methoxymethyl lactone 26 in 71% yield. The
b-elimination of compound 26 with DBU (i.e. 1,8-
diazabicyclo[5.40]undec-7-ene) in refluxing benzene
afforded the a-methylene lactone 27 in 75% yield. The
primary alcohol on compound 27 was oxidized to the
corresponding carboxylic acid by Jones reagent to give
the (G)-methylenolactocin 8a in 84% yield (Scheme 3).
The exocyclic double bond of product 8a was found to be
intact during the oxidation process. The approach of
Method II led us to accomplish the total synthesis of
(G)-methylenolactocin in nine operation steps in 9.6%
overall yield from b-hydroxy ester 11.
2.4. The total synthesis of the optical active
(K)-methylenolactocin
In order to prepare the methylenolactocin in optically active
form, the optical active 1,3-diol 20 was needed. We began
with the Bu2BOTf-mediated asymmetric aldol reaction
between N-acyl oxazolidinone (K)-2816 and n-hexanal to
give syn-aldol (K)-29 in 73% yield (O95:5 diastereoselec-
tivity).17 N-Acyl oxazolidinone (K)-29 was reduced with
NaBH4 to give the corresponding 1,3-diol (K)-30. Selective
silylation at the primary alcohol of compound (K)-30
followed by acetylation gave the acetate (K)-32 in excellent
yield. The ozonolysis of terminal olefin (K)-32 followed by
addition of a preheated mixture of CH2Br2 and Et2NH
afforded acrolein (C)-33 in 86% yield. The acrolein (C)-33
was oxidized by sodium chlorite to give the corresponding
acrylic acid, which was subsequently treated with CH2N2 to
give the methyl acrylate (K)-34 in 78% yield. Acid-
catalyzed ring closure of acrylate (K)-34 in methanol gave
the corresponding a-methylene-g-butyrolactone (K)-27
in 91% yield. We believe that the formation of the lactone
(K)-27 from acrylate (K)-34 follows the similar mecha-
nism as described in Figure 3. However, under the acidic
condition, the corresponding a-methylenelactone-acetate
(YZMe, Fig. 3) intermediate undergoes the transesterifica-
tion to give the desired (K)-27 in excellent yield. Finally,
compound (K)-27 was treated with Jones reagent to give
the optical active (K)-methylenolactocin ((K)-8a) in 84%
Scheme 3. Reagents and conditions: (i) p-O2N–PhCO2H, DEAD, Ph3P; (ii) Dibal-H, 0 8C to rt, CH2Cl2, 2 h; (iii) TBSCl, cat. DMAP, imidazole, CH2Cl2, 3 h;
(iv) DEAD, Ph3P, p-O2N–PhCO2H, CH2Cl2, 8 h; (v) (a) O3, CH2Cl2, K78 8C, (b) preheated mixture of Et2NH and CH2Br2 (mol equivZ5:15), 2 h;
(vi) NaClO2, t-BuOH, NaH2PO4$2H2O, MeOH]CMe2, 8 h; (vii) CH2N2; (viii) cat. MeCOCl, MeOH, 30 min; (ix) NH4OH (28–30%), MeOH, 0 8C, 2 h;
(x) K2CO3, MeOH/H2O (2:1), rt, 20 min; (xi) DBU, PhH, reflux, 5 h; (xii) Jones reagents, 40 8C, acetone, 5 min.

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Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
Scheme 4. Reagents and conditions: (i) Bu2BOTf, Et3N, n-C5H11CHO (10), K78 to 0 8C, CH2Cl2, 2 h; (ii) NaBH4, THF/H2O (4:1), 2 h; (iii) TBSCl, cat.
DMAP, imidazole, CH2Cl2, 3 h; (iv) Ac2O, cat. DMAP, Et3N, CH2Cl2, 1.5 h; (v) (a) O3, CH2Cl2, K78 8C, (b) preheated miture of Et2NH and CH2Br2
(mol equivZ5:15), 2 h; (vi) NaClO2, t-BuOH, NaH2PO4$2H2O, MeCH]CMe2, 8 h; (vii) CH2N2; (viii) cat. MeCOCl, MeOH, 30 min; (ix) Jones reagent,
40 8C, acetone, 5 min.
yield (Scheme 4). We have accomplished the total synthesis
of (K)-methylenolactocin in eight operation steps in 29%
overall yield from N-acyl oxazolidinone (K)-28.
Perkin–Elmer 682 spectrophotometer and only noteworthy
absorption was listed. Mass spectra were measured on a
VG-Trio-2000GC/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 95XL
(National Chung Hsing University) and FAB mass spectra
were recorded with 3-nitrobenzyl alcohol matrix using
argon or xenon as the target gas.
3. Conclusions
We have developed an efficient methodology for the
synthesis of methylenolactocin in racemic and optically
active forms. The characteristics of this synthetic design are
to introduce the a-methylene group at the early stage of the
synthesis by the ozonolysis of mono-substituted alkene
followed by reacting with a preheated mixture of CH2Br2–
Et2NH. For the racemic synthesis, the relative stereo-
chemistry of b- and g-substituents was established by the
stereoselective allylation of the dianion of b-hydroxy ester
11. As for the overall yield and the number of the
transformations are concerned, method I should be the
most efficient design. However, we cannot solve
the problem of the side product 8a0 formation during the
hydrolysis. Therefore, the epimerization needed to be
operated at the early stage of the synthesis. Guided by this
concept, we finished the total synthesis of (G)-methyleno-
lactocin in nine operation steps in 9.6% overall yield from
b-hydroxy ester 11. Based on the success of this approach,
we tried to complete the total synthesis of (K)-methyleno-
lactocin ((K)-8a). N-Acyl oxazolidinone (K)-28 was used
as chiral auxiliary to induce the asymmetric aldol reaction to
give syn-aldol (K)-29 in excellent diastereoselectivity.
Starting with this chiral alcohol, we have accomplished the
total synthesis of (K)-methylenolactocin in eight operation
steps in 29% overall yield from (K)-28.
4.1.1. 3-Hydroxyoctanoic acid methyl ester (11).14b
A
suspension of the activated zinc dust18 (392 mg, 6 mmol) in
2 mL of anhydrous benzene was heated up to reflux for
10 min. To the refluxing suspension solution was slowly
added a mixture of the n-hexanal (10) (0.55 g, 5.5 mmol)
and methyl bromoacetate (9) (0.57 mL, 6 mmol) in 10 mL
of benzene in a period of 1 h. After 2 h, the reaction mixture
was cooled to 0 8C and then added 1 N HCl to work up the
reaction and extracted with ether (20 mL!3). The com-
bined organic extract was dried (MgSO4), concentrated, and
chromatographed on silica gel column to give the desired
b-hydroxy ester 11 (746 mg, 4.3 mmol) in 78% yield as a
colorless oil. TLC RfZ0.48 (hexane/EtOAcZ3:1); 1H
NMR (CDCl3, 400 MHz) d 3.94–3.98 (m, 1H, CHOH),
3.66 (s, 3H, OMe), 2.95 (br, 1H, OH), 2.36–2.49 (m, 2H,
CH2CO), 1.21–1.42 (m, 8H), 0.85 (t, JZ6.7 Hz, 3H,
CH2CH3); 13C NMR (CDCl3, 100 MHz) d 173.1 (48), 67.8
(38), 51.4 (18), 41.1 (28), 36.4 (28), 31.5 (28), 24.9 (28), 22.3
(28), 13.7 (18); IR (CH2Cl2): 2931, 2859, 1738, 1438,
1168 cmK1; EI mass (m/z): 173 (MCK1, 10), 157 (100),
125 (70), 55 (48), 43 (35); HRMS m/z calcd for C9H18O3
174.1256, found: 174.1259.
4.1.2. (2R*,3R*)-2-Allyl-3-hydroxyoctanoic acid methyl
ester (12). n-Butyllithium (3.95 mL, 6.33 mmol, 1.6 M in
hexane) was added to a stirring solution of diisopropylamine
(0.89 mL, 6.33 mmol) in THF (10 mL) at K78 8C. To the
LDA solution, b-hydroxy ester 11 (0.50 g, 2.87 mmol) in
5 mL of THF was added at K78 8C and stirred at this
temperature for 1 h. At K78 8C, a mixture of allyl bromide
(0.30 mL, 3.44 mmol) and HMPA (1 mL) in THF (4 mL)
was added to the reaction mixture. After stirring at K78 8C
for 1 h, the reaction mixture was partitioned between 40%
ethyl acetate/petroleum ether and saturated aqueous NH4Cl.
The combined organic phase was dried (MgSO4), concen-
trated, and chromatographed on silica gel column to afford
4. Experimental
4.1. General
All reactions were carried out under nitrogen. Unless
otherwise noted, materials were obtained from commercial
suppliers and used without further purification. Melting
points were determined by using a Thomas–Hoover melting
point apparatus and were uncorrected. The 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX-400 and
chemical shifts were given in ppm downfield from
tetramethylsilane (TMS). IR spectra were taken with a

Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
2717
product 12 (522 mg, 2.44 mmol) in 85% yield as a colorless
oil. TLC RfZ0.55 (hexane/EtOAcZ3:1); 1H NMR (CDCl3,
400 MHz) d 5.66–5.73 (m, 1H, CH]CH2), 4.97–5.06 (m,
2H, CH]CH2), 3.65 (s, 3H, OMe), 3.64–3.67 (m, 1H,
CHOH), 2.68–2.75 (br, 1H, OH), 2.47–2.50 (m, CHCO),
2.36–2.39 (m, 2H, CH2CH]CH2), 1.23–1.42 (m, 8H), 0.84
(t, JZ6.9 Hz, 3H, CH3CH2); 13C NMR (CDCl3, 100 MHz)
d 175.1 (48), 134.8 (48), 116.9 (28), 71.6 (38), 51.4 (18), 50.5
(38), 35.3 (28), 33.6 (28), 31.5 (28), 25.2 (28), 22.4 (28), 13.8
(18); IR (CH2Cl2): 3374, 2932, 2859, 1735, 1643, 1438,
1169, 1047 cmK1; EI mass (m/z): 125 (MCK89, 100), 113
(21), 55 (82), 43 (70), 41 (91); HRMS m/z calcd for
C12H22O3–OCH3 183.1385, found: 183.1384.
CHO), 6.69 (s, 1H, C]CH2), 6.29 (s, 1H, C]CH2), 5.27
(ddd, JZ3.8, 7.6, 8.4 Hz, 1H, CHOAc), 4.04 (d, JZ7.5 Hz,
1H CHCO2CH3), 3.68 (s, 3H, CO2CH3), 2.02 (s, 3H,
COCH3), 1.40–1.55 (m, 2H), 1.17–1.30 (m, 6H), 0.86 (t, JZ
6.8 Hz, 3H, –CH2CH3); 13C NMR (CDCl3, 100 MHz) d
192.2 (48), 170.7 (48), 170.1 (48), 144.2 (48), 137.6 (28), 73.2
(38), 52.0 (18), 45.4 (38), 31.4 (2!28), 24.6 (28), 22.3 (28),
20.8 (28), 13.8 (18); IR (CH2Cl2): 2955, 2860, 1744, 1696,
1435, 1236, 1024, 734 cmK1; EI mass (m/z): 271 (MCC1,
1), 211 (40), 170 (42), 128 (100), 96 (52), 86 (38), 55 (13);
HRMS m/z calcd for C14H22O5 270.1467, found: 270.1468.
4.3. General procedure to prepare the methyl acrylate
from the corresponding acrolein
4.1.3. (2R*,3R*)-3-Acetoxy-2-allyloctanoic acid methyl
ester (13). To a solution of b-hydroxy ester 12 (500 mg,
2.34 mmol), DMAP (57 mg, 0.47 mmol) and Et3N
(0.49 mL, 3.5 mmol) in CH2Cl2 (4.7 mL) was added acetic
anhydride (0.33 mL, 3.5 mmol) at rt and stirred it for 2 h.
The reaction mixture was concentrated and chromato-
graphed on silica gel column to afford the acetate 13
(574 mg, 2.24 mmol) in 96% yield as a pale yellow oil. TLC
RfZ0.75 (hexane/EtOAcZ3:1); 1H NMR (CDCl3,
400 MHz) d 5.70–5.77 (m, 1H, –CH]CH2), 5.01–5.12
(m, 3H, –CH]CH2 and CHOAc), 3.68 (s, 3H, –OCH3),
2.70–2.75 (m, 1H, CHCO), 2.42–2.24 (m, 2H, –CH2-
CH]CH2), 2.04 (s, 3H, COCH3), 1.55–1.60 (m, 2H), 1.26–
1.30 (m, 6H), 0.88 (t, JZ6.8 Hz, 3H, –CH2CH3); 13C NMR
(CDCl3, 100 MHz) d 172.7 (48), 170.2 (48), 134.8 (38), 117.0
(28), 73.5 (38), 51.5 (18), 49.1 (38), 32.3 (28), 31.6 (28), 31.5
(28), 24.7 (28), 22.4 (28), 20.9 (18), 13.9 (18); IR (CH2Cl2):
2955, 2933, 2861, 1743, 1437, 1238 cmK1; EI mass (m/z):
241 (MCK15, 35), 227 (32), 181 (100), 149 (47), 55 (48);
HRMS m/z calcd for C13H21O4 241.1440 (MCK15), found:
241.1442.
To a solution of acrolein 14 (700 mg, 2.71 mmol), t-butyl
alcohol (14 mL) and 2-methyl-2-butene (0.9 mL, 570 mg,
8.13 mmol) was added dropwise a solution of sodium
chlorite (565 mg, 6.23 mmol) and sodium dihydrogenphos-
phate dihydrate (835 mg, 5.42 mmol) in 4 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 8 mL of water and this extracted with 30 mL
of hexane. The aqueous layer was acidified to pH 3 with 2 N
HCl and extracted with two 25 mL portions of ether. The
combined ether layers were washed with 30 mL of water,
dried with Na2SO4, concentrated to give the crude
carboxylic acid. To a solution of a-substituted acrylic acid
was dissolved in 9.5 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 the further 1,3-dipolar cycloaddition on the
double bond. The reaction mixture was concentrated and the
residue was chromatographed on silica gel column to give
methyl acrylate 15 (642 mg, 2.14 mmol) as a colorless oil in
79% yield.
4.2. General procedure to prepare the a-substituted
acrolein from terminal alkene
4.3.1. (10R*,2R*)-2-(10-Acetoxyhexyl)-3-methylenesuc-
cinic acid dimethyl ester (15). TLC RfZ0.68 (hexane/
EtOAcZ2:1); H NMR (CDCl3, 400 MHz) d 6.46 (s, 1H,
1
A two-necked flask fitted with a glass tube to admit ozone, a
CaCl2 drying tube and a magnetic stirring bar was charged
with terminal alkene 13 (650 mg, 2.54 mmol) in CH2Cl2
(50 mL). The flask was cooled to K78 8C 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 (1.4 mL, 12.7 mmol) and CH2Br2
(2.7 mL, 38.0 mmol) was heated to 55 8C for 1.5 h to give
a yellow solution and then cooled to rt. To a solution of
ozonide in CH2Cl2 generated above was added a preheated
mixture of Et2NH and CH2Br2 at K78 8C. After the
addition, the cooling bath was removed and the reaction
mixture was stirred at rt. The reaction was complete in 1.5 h
and the reaction mixture was concentrated. To the crude
mixture, ether was added and most of the ammonium salts
were precipitated out. After filtration, the filtrate was
concentrated, chromatographed on the silica gel column to
give the desired acrolein 14 (510 mg, 1.97 mmol) in 78%
yield.
C]CH2), 5.96 (s, 1H, C]CH2), 5.32 (ddd, JZ3.7, 8.1,
8.1 Hz, 1H, CHOAc), 3.99 (d, JZ7.9 Hz, 1H, CHCO2Me)
3.79 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.02 (s, 3H,
COCH3), 1.41–1.57 (m, 2H), 1.23–1.30 (m, 6H), 0.86 (t, JZ
6.8 Hz, 3H, –CH2CH3); 13C NMR (CDCl3, 100 MHz) d
170.9 (48), 170.1 (48), 166.2 (48), 135.0 (48), 129.0 (28), 73.4
(38), 52.2 (18), 52.0 (18), 49.1 (38), 31.5 (28), 31.4 (28), 24.6
(28), 22.3 (28), 20.8 (18), 13.8 (18); IR (CH2Cl2): 2955, 2860,
1746, 1437, 1237, 1023, 733 cmK1; EI mass (m/z): 269
(MCK31, 1), 227 (12), 158 (100), 126 (60), 55 (6); HRMS
m/z calcd for C14H21O6 285.1338 (MCK15), found:
285.1344.
4.4. General procedure to prepare the g-butyrolactone
from the corresponding acyloxy-acrylate under acidic
condition
To a mixture of acetoxy-acrylate 15 (100 mg, 0.29 mmol) in
6 mL of MeOH was added a catalytic amount of acetyl
chloride (2 mL, 29 mmol) and stirred at rt for 24 h. The
reaction mixture was concentrated and chromatographed on
silica gel column to give the a-methylenelactone 16 (62 mg,
0.24 mmol) in 82% yield as a pale yellow oil.
4.2.1. (10R*,2R*)-2-(10-Acetoxyhexyl)-3-formylbut-3-
enoic acid methyl ester (14). TLC RfZ0.38 (hexane/
1
EtOAcZ3:1); H NMR (CDCl3, 400 MHz) d 9.51 (s, 1H,

2718
Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
4.4.1. (2R*,3R*)-4-Methylene-5-oxo-2-pentyltetrahydro-
furan-3-carboxylic acid methyl ester (16).9u TLC RfZ
0.57 (hexane/EtOAcZ3:1); H NMR (CDCl3, 400 MHz) d
layer was dried over MgSO4, concentrated, and chromato-
graphed on silica gel column to give diol 20 (1.23 g,
6.61 mmol) in 79% yield as a colorless oil. TLC RfZ0.29
(hexane/EtOAcZ5:1); 1H NMR (CDCl3, 400 MHz) d 5.76–
5.87 (m, 1H, –CH]CH2), 5.03–5.12 (m, 2H, –CH]CH2),
3.91–3.94 (m, 1H, CHOH), 3.66–3.70 (m, 2H, –CH2OH),
2.45 (br s, 1H, OH), 2.20–2.28 (m, 3H, –CH2CH]CH2
and CHCH2OH), 1.31–1.61 (m, 8H), 0.90 (t, JZ6.6 Hz, 3H,
–CH2CH3); 13C NMR (CDCl3, 100 MHz) d 136.6 (38),
116.4 (28), 75.0 (38), 63.6 (28), 44.0 (38), 35.4 (28), 33.3 (28),
31.8 (28), 25.3 (28), 22.6 (28), 13.9 (18); IR (CH2Cl2): 3349,
2955, 2859, 1443, 1128, 1026, 733 cmK1; FAB mass (m/z):
187 (MCC1, 27), 178 (34), 169 (49), 151 (62), 136 (58),
109 (56), 95 (93), 81 (88), 55 (100); HRMS m/z calcd for
C11H22O2 186.1620, found: 186.1624.
1
6.40 (d, JZ2.4 Hz, 1H, C]CH2), 5.82 (d, JZ2.4 Hz, 1H,
C]CH2), 4.59–4.64 (m, 1H, CHOCO), 4.00 (dt, JZ2.2,
7.6 Hz, 1H, CHC]CH2), 3.75 (s, 3H, OMe), 1.29–1.64 (m,
8H), 0.88–0.90 (t, JZ6.9 Hz, 3H, CH3CH2); 13C NMR
(CDCl3, 100 MHz) d 169.3 (48), 168.8 (48), 133.7 (48), 124.8
(28), 78.2 (38), 52.3 (18), 49.1 (38), 31.4 (28), 31.3 (28), 25.1
(28), 22.3 (28), 13.8 (18); IR (CH2Cl2): 2931, 2861, 1768,
1666, 1437, 1170, 714 cmK1; EI mass (m/z): 166 (MCK60,
29), 155 (78), 127 (38), 126 (100), 67 (42); HRMS m/z calcd
for C12H18O4 226.1205, found: 226.1213.
4.4.2. (2S*,3R*)-4-Methylene-5-oxo-2-pentyltetrahydro-
furan-3-carboxylic acid methyl ester (17)9u and
4-methyl-5-oxo-2-pentyl-2,5-dihydrofuran-3-carboxylic
acid methyl ester (18)9j A solution of methyl ester 16
(113 mg, 0.5 mmol) in butanone (3 mL) containing HCl
(6 N, 3 drops) was heated under reflux for 2 h. H2O (5 mL)
was added and the organic solvent was removed. The
aqueous layer was extracted with CH2Cl2 (3!15 mL) and
solvents were evaporated to give an inseparable mixture of
methylenolactocin (8a) and butenolide 8a0 (mol ratio is
about 4:1). To the crude mixtures in 5 mL of CH2Cl2 were
added a solution of CH2N2 in ether. After stirring at rt for
20 min, the reaction mixture was concentrated, chromato-
graphed on silica gel column to give the methyl ester of the
methylenolactocin 17 (72 mg, 0.32 mmol, 64% yield) and
its isomer 18 (18 mg, 0.08 mmol, 16%).
4.4.4. (4R*,5S*)-4-(tert-Butyldimethylsilyloxymethyl)-
dec-1-en-5-ol (21). To a solution of the diol 20 (1.9 g,
10.21 mmol), DMAP (250 mg, 2.04 mmol) and imidazole
(765 mg, 11.23 mmol) in 21 mL of CH2Cl2 was added
t-butyldimethylsilyl chloride (1.7 g, 11.2 mmol) at rt and
stirred it for 3 h. The reaction is quenched with water and
extracted with ethyl acetate. The organic layer was dried
over MgSO4, concentrated, and chromatographed on silica
gel column to give the secondary alcohol 21 (2.81 g,
9.87 mmol) in 97% yield as a pale yellow oil. TLC RfZ0.60
(hexane/EtOAcZ10:1); 1H NMR (CDCl3, 400 MHz) d
5.73–5.84 (m, 1H, –CH]CH2), 5.02–5.09 (m, 2H,
–CH]CH2), 3.91 (dd, JZ3.5, 10.2 Hz, 1H, –CH2OTBS),
3.66 (dd, JZ5.0, 10.2 Hz, 1H, –CH2OTBS), 3.59–3.64 (m,
1H, –CHOH), 3.29 (d, JZ6.2 Hz, 1H, OH), 2.14–2.30 (m,
2H, –CH2CH]CH2), 1.38–1.51 (m, 3H, CHCH2OTBS),
1.20–1.35 (m, 6H), 0.88–0.91 (m, 12H, CH2CH3 and
(CH3)3CSiMe2), 0.08 (s, 3H, t-BuSi(CH3)2), 0.07 (s, 3H,
t-BuSi(CH3)2); 13C NMR (CDCl3, 100 MHz) d 136.9 (38),
116.3 (28), 74.6 (38), 64.1 (28), 43.8 (38), 35.7 (28), 33.3 (28),
32.0 (28), 25.8 (3!18), 25.6 (28), 22.7 (28), 18.1 (48), 14.0
(18), K5.7 (2!18); IR (CH2Cl2): 3464, 2955, 2857, 1470,
1255, 1087, 777 cmK1; FAB mass (m/z): 301 (MCC1, 61),
283 (23), 154 (100), 136 (99), 95 (62), 81 (58), 73 (90), 55
(65); HRMS m/z calcd for C17H36O2Si 300.2485, found:
300.2481.
1
Compound 17. H NMR (CDCl3, 400 MHz) d 6.40 (d, JZ
2.4 Hz, 1H, C]CH2), 5.91 (d, JZ2.4 Hz, 1H, C]CH2),
4.79 (q, JZ6.0 Hz, 1H, CHOCO), 3.80 (s, 3H, OMe), 3.56–
3.59 (m, 1H, CHC]CH2), 1.25–1.73 (m, 8H), 0.88–0.91
(m, 3H, CH3CH2); 13C NMR (CDCl3, 100 MHz) d 169.7
(48), 168.2 (48), 133.2 (48), 125.0 (28), 79.0 (38), 52.8 (18),
49.9 (38), 35.7 (28), 29.6 (28), 24.4 (28), 22.4 (28), 13.8 (18);
IR (CH2Cl2):2927, 2857, 1770, 1740, 1437, 1115, 738 cmK1
;
EI mass (m/z): 226 (MC, 6), 156 (68), 155 (100), 127 (90),
99 (62); HRMS m/z calcd for C12H18O4 226.1205, found:
226.1207.
Compound 18. 1H NMR (CDCl3, 400 MHz) d 5.09 (m, 1H,
CHOCO), 3.88 (s, 3H, OMe), 2.18 (d, JZ2.0 Hz, 3H,
CH3C]C), 2.04–2.07 (m, 2H), 1.25–1.58 (m, 6H), 0.88 (t,
JZ6.8 Hz, 3H, CH3CH2); 13C NMR (CDCl3, 100 MHz) d
172.8 (48), 162.6 (48), 147.6 (48), 137.4 (48), 81.3 (38), 52.2
(18), 32.7 (28), 31.6 (28), 24.4 (28), 22.3 (28), 13.8 (18), 10.8
(18); IR (CH2Cl2): 2928, 2859, 1768, 1728, 1438, 1152,
759 cmK1; EI mass (m/z): 226 (MC, 4), 197 (48), 156 (100),
99 (28), 67 (30); HRMS m/z calcd for C12H18O4 226.1205,
found: 226.1206.
4.4.5. 4-Nitrobenzoic acid (1S*,2S*)-2-(tert-butyl-
dimethylsilyloxymethyl)-1-pentylpent-4-enyl ester (22).
To a mixture of the secondary alcohol 21 (1.2 g, 5.90 mmol)
in 18 mL of THF was added a solution of Ph3P (2.21 g,
8.43 mmol) and 4-nitrobenzoic acid (1.41 g, 8.43 mmol) in
20 mL of THF at rt under nitrogen. To the resulted solution
was added DEAD (40% in toluene, 3.83 mL, 8.43 mmol) by
syringe pump dropwise in 1 h at 0 8C. After the addition, the
cooling bath was removed and the reaction mixture was
stirred at rt for 8 h. The reaction mixture was concentrated
and chromatographed on silica gel column to give
4-nitrobenzoate 22 (1.46 g, 3.25 mmol) in 77% yield as a
pale yellow solid. TLC RfZ0.82 (hexane/EtOAcZ10:1);
4.4.3. (2S*,3R*)-2-Allyloctane-1,3-diol (20). To a solution
of b-hydroxy ester 12 (1.8 g, 8.40 mmol) in 42 mL of
CH2Cl2 was added diisobutylaluminium hydride (Dibal-H,
1 M in hexane, 21 mL, 21.0 mmol) at 0 8C. After the
addition, the cooling bath was removed and the reaction
mixture was stirred at ambient temperature for 2 h. To the
reaction mixture was added 10 mL of ethyl acetate in order
to quench the excess of Dibal-H at 0 8C. The reaction
mixture was then washed with 30 mL of water. The organic
1
mp 47.3 8C; H NMR (CDCl3, 400 MHz) d 8.27–8.30 (m,
2H, O2NPh–H), 8.18–8.20 (m, 2H, O2NPh–H), 5.77–5.87
(m, 1H, –CH]CH2), 5.36 (dt, JZ5.0, 7.7 Hz, 1H,
CHOCOAr), 5.02–5.08 (m, 2H, –CH]CH2), 3.65 (dd,
JZ4.8, 10.1 Hz, 1H, –CH2OTBS), 3.57 (dd, JZ6.0,
10.1 Hz, 1H, –CH2OTBS), 2.20–2.27 (m, 2H, –CH2-
CH]CH2), 1.91–1.95 (m, 1H, –CHCH2OTBS), 1.71–1.78

Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
2719
(m, 2H), 1.26–1.30 (m, 6H), 0.85–0.90 (m, 12H, –CH2CH3
and (CH3)3CSiMe2), 0.01 (s, 3H, t-BuSi(CH3)2), K0.01 (s,
3H, t-BuSi(CH3)2); 13C NMR (CDCl3, 100 MHz) d 164.2
(48), 150.5 (48), 136.7 (38), 136.2 (48), 130.6 (2!38), 123.5
(2!38), 116.3 (28), 76.4 (38), 62.1 (28), 43.8 (38), 31.6 (28),
31.5 (28), 31.3 (28), 25.8 (3!18), 25.3 (28), 22.4 (28), 18.1
(48), 13.9 (18), K5.6 (2!18); IR (CH2Cl2): 2955, 2857,
1725, 1530, 1274, 1101, 719 cmK1; EI mass (m/z): 173
(MCC1, 1), 224 (100), 150 (21), 109 (16), 95 (27), 55 (7);
HRMS m/z calcd for C24H39SiNO5 449.2598, found:
449.2598.
4.4.8. 4-Nitrobenzoic acid (2S*,3S*)-4-methylene-5-oxo-
2-pentyltetrahydrofuran-3-ylmethyl ester (25). Follow-
ing the general procedure to prepare the g-butyrolactone
from the corresponding acyloxy-acrylate under acidic
condition, g-butyrolactone 25 (351 mg, 1.01 mmol) was
prepared from acetoxy-acrylate 24 (650 mg, 1.32 mmol) in
77% yield as a pale yellow oil. TLC RfZ0.33 (hexane/
EtOAcZ3:1); 1H NMR (CDCl3, 400 MHz) d 8.29–8.31 (m,
2H, O2NPh–H), 8.14–8.16 (m, 2H, O2NPh–H), 6.45 (d, JZ
2.0 Hz, 1H, C]CH2), 5.78 (d, JZ2.0 Hz, 1H, C]CH2),
5.35 (quint, JZ4.4 Hz, 1H, CHOCO), 4.41 (dd, JZ7.7,
9.6 Hz, 1H, CH2OCOAr), 4.35 (dd, JZ2.9, 9.6 Hz, 1H,
CH2OCOAr), 3.46–3.49 (m, 1H, CHC]CH2), 1.66–1.82
(m, 2H), 1.26–1.39 (m, 6H), 0.87 (t, JZ7.0 Hz, 3H,
CH2CH3); 13C NMR (CDCl3, 100 MHz) d 169.9 (48),
164.2 (48), 150.8 (48), 134.9 (48), 134.1 (48), 130.7 (2!38),
124.9 (28), 123.7 (2!38), 76.7 (38), 67.6 (28), 42.1 (38), 31.3
(28), 30.1 (28), 25.1 (28), 22.4 (28), 13.8 (18); IR (CH2Cl2):
2961, 2859, 1766, 1723, 1527, 1269, 1102, 719 cmK1; EI
mass (m/z): 347 (MC, 1), 150 (100), 104 (22), 92 (8); HRMS
m/z calcd for C18H21NO6 347.1369, found: 347.1379.
4.4.6. 4-Nitrobenzoic acid (1S*,2S*)-2-(tert-butyldi-
methylsilyloxymethyl)-3-formyl-1-pentylbut-3-enyl
ester (23). Following the general procedure to prepare the
a-substituted acrolein from terminal alkene, compound 23
(873 mg, 1.88 mmol) was prepared from alkene 22 (1.25 g,
2.78 mmol) in 68% yield as a white solid. TLC RfZ0.85
(hexane/EtOAcZ3:1); mp 77.1 8C; 1H NMR (CDCl3,
400 MHz) d 9.50 (s, 1H, CHO), 8.26–8.29 (m, 2H,
O2NPh–H), 8.10–8.13 (m, 2H, O2NPh–H), 6.59 (s, 1H,
C]CH2), 6.17 (s, 1H, C]CH2), 5.60 (dt, JZ4.7, 7.3 Hz,
1H, CHOCO), 3.74 (dd, JZ5.1, 10.2 Hz, 1H, CH2OTBS),
3.63 (dd, JZ5.5, 10.2 Hz, 1H, CH2OTBS), 3.26–3.31 (m,
1H, CHC]CH2), 1.62–1.76 (m, 2H), 1.26–1.36 (m, 6H),
0.84–0.87 (m, 12H, CH2CH3 and (CH3)3CSiMe2), 0.01 (s,
3H, t-BuSi(CH3)2), K0.02 (s, 3H, t-BuSi(CH3)2); 13C NMR
(CDCl3, 100 MHz) d 194.0 (48), 164.0 (48), 150.5 (48), 147.9
(48), 137.0 (28), 135.8 (48), 130.6 (2!38), 123.5 (2!38),
75.0 (38), 62.5 (28), 41.8 (38), 32.5 (28), 31.5 (28), 25.7 (3!
18), 24.8 (28), 22.4 (28), 18.1 (48), 13.9 (18), K5.6 (18), K5.7
(18); IR (CH2Cl2): 2955, 2857, 1725, 1696, 1273, 1101,
719 cmK1; IR (CH2Cl2): 2955, 2857, 1725, 1696, 1273,
1101, 719 cmK1; EI mass (m/z): 433 (MCK30, 1), 239
(100), 224 (66), 169 (14), 150 (61), 95 (10), 75 (31), 55 (4);
HRMS m/z calcd for C24H37SiNO6 463.2390, found:
463.2393.
4.4.9.
(3S*,4S*,5S*)-4-Hydroxymethyl-3-methoxy-
methyl-5-pentyldihydrofuran-2-one (26). To a mixture
of 4-nitrobenzoate 25 (120 mg, 0.34 mmol) in 1.2 mL of
MeOH was added a solution of K2CO3 (53 mg, 0.38 mmol)
in 0.6 mL of water and stirred at rt for 20 min. The reaction
mixture was added 1 mL of water and extracted with ethyl
acetate. The organic phase was dried over MgSO4,
concentrated and chromatographed on silica gel column to
give hydroxy-lactone 26 (56 mg, 0.24 mmol) in 71% yield
as a pale yellow oil. TLC RfZ0.35 (hexane/EtOAcZ1:1);
1H NMR (CDCl3, 400 MHz) d 4.10 (ddd, JZ3.5, 8.8,
8.8 Hz, 1H, CHOCO), 3.86 (dd, JZ3.7, 9.5 Hz, 1H), 3.69–
3.76 (br m, 1H), 3.60 (dd, JZ7.6, 11.0 Hz, 1H), .3.51 (dd,
JZ9.0, 9.0 Hz, 1H,), 3.43 (s, 3H, OCH3), 2.79 (ddd, JZ3.7,
8.6, 10.4 Hz, 1H, CHCO), 2.23–2.30 (m, 1H, CHCH2OH),
1.64–1.73 (m, 2H), 1.26–1.33 (m, 6H), 0.90 (t, JZ6.8 Hz,
3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 175.3 (48),
80.4 (38), 71.3 (28), 62.7 (28), 59.2 (18), 49.4 (38), 46.4 (38),
34.6 (28), 31.5 (28), 25.3 (28), 22.4 (28), 13.9 (18); IR
4.4.7. 4-Nitrobenzoic acid (1S*,2S*)-2-(tert-butyldi-
methylsilyloxymethyl)-3-methoxycarbonyl-1-pentyl-
but-3-enyl ester (24). Following the general procedure to
prepare the methyl acrylate from a-substituted acrolein,
methyl acrylate 24 (650 mg, 2.14 mmol) was prepared from
acrolein 23 (873 mg, 1.88 mmol) in 70% yield as a pale
yellow oil. TLC RfZ0.70 (hexane/EtOAcZ10:1); 1H NMR
(CDCl3, 400 MHz) d 8.26–8.29 (m, 2H, O2NPh–H), 8.12–
8.15 (m, 2H, O2NPh–H), 6.34 (s, 1H, C]CH2), 5.84 (s, 1H,
C]CH2), 5.56 (dt, JZ4.2, 7.3 Hz, 1H, CHOCOAr), 3.77
(dd, JZ5.4, 10.2 Hz, 1H, CH2OTBS), 3.72 (s, 3H, OCH3),
3.71 (dd, JZ6.1, 10.2 Hz, 1H, CH2OTBS), 3.25 (q, JZ
6.0 Hz, 1H, CHC]CH2), 1.66–1.80 (m, 2H), 1.24–1.37 (m,
6H), 0.84–0.90 (m, 12H, CH2CH3 and (CH3)3CSiMe2), 0.01
(s, 3H, t-BuSi(CH3)2), K0.01 (s, 3H, t-BuSi(CH3)2); 13C
NMR (CDCl3, 100 MHz) d 167.6 (48), 164.1 (48), 150.5
(48), 138.2 (48), 136.0 (48), 130.6 (2!38), 127.4 (28), 123.5
(2!38), 75.4 (38), 63.0 (28), 52.0 (18), 45.9 (38), 32.5 (28),
31.6 (28), 25.8 (3!18), 24.9 (28), 22.4 (28), 18.1 (48), 13.9
(18), K5.6 (18), K5.7 (18); IR (CH2Cl2): 2954, 2857, 1725,
1530, 1273, 1101, 719 cmK1; EI mass (m/z): 478 (MCK15,
1), 269 (100), 224 (48), 150 (35), 89 (19), 55 (2); HRMS m/z
calcd for C25H39SiNO7 478.2261 (MKCH3), found:
478.2252.
(CH2Cl2): 3462, 2931, 2872, 1757, 1459, 1185, 733 cmK1
;
EI mass (m/z): 230 (MC, 1), 126 (29), 103 (52), 85 (35), 55
(28), 45 (100); HRMS m/z calcd for C12H22O4 230.1518,
found: 230.1523.
4.4.10. (4S*,5S*)-4-Hydroxymethyl-3-methylene-5-pen-
tyldihydrofuran-2-one (27). Method A (from compound
25). To a mixture of 4-nitrobenzoate 25 (50 mg, 0.14 mmol)
in 0.7 mL of MeOH was added a solution of ammonium
water (28–30% in water, 20 mL, 0.16 mmol) at 0 8C and
stirred at this temperature for 2 h. The reaction mixture was
added 0.3 mL of water and extracted with ethyl acetate. The
organic phase was dried over MgSO4, concentrated and
chromatographed on silica gel column to give a-methyl-
enelactone 27 (18 mg, 0.09 mmol) in 63% yield as a pale
yellow oil.
Method B (from compound 26). To a solution of compound
26 (13 mg, 56.4 mmol) and DBU (9.5 mg, 62.1 mmol) in
0.7 mL of benzene. The resulting solution was heated to
reflux for 5 h. The reaction mixture was concentrated
and chromatographed on silica gel column to give the

2720
Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
a-methylenelactone 27 (8.4 mg, 42.3 mmol) in 75% yield as
a pale yellow oil. TLC RfZ0.55 (hexane/EtOAcZ1:1); 1H
NMR (CDCl3, 400 MHz) d 6.33 (d, JZ2.8 Hz, 1H,
C]CH2), 5.72 (d, JZ2.4 Hz, 1H, C]CH2), 4.40 (ddd,
JZ4.4, 6.4, 6.4 Hz, 1H, CHOCO), 3.74–3.79 (m, 2H,
CH2OH), 2.85–2.90 (m, 1H, CHCH2OH), 1.65–1.71 (m,
3H), 1.31–1.51 (m, 6H), 0.89 (t, JZ7.2 Hz, 3H, CH3CH2);
13C NMR (CDCl3, 100 MHz) d 170.3 (48), 136.2 (48), 123.4
(28), 80.9 (38), 63.8 (28), 46.8 (38) 36.0 (28), 31.4 (28), 24.6
(28), 22.4 (28), 13.9 (18); IR (CH2Cl2): 3459, 2932, 2860,
1748, 1465, 1151, 733 cmK1; FAB mass (m/z): 199 (MC
C1, 16), 181 (10), 154 (23), 136 (27), 91 (40), 81 (39), 55
(100); HRMS m/z calcd for C11H18O3 198.1256, found:
198.1248.
13.31 mmol) in 88% yield. TLC RfZ0.44 (hexane/
EtOAcZ3:1); 1H NMR (CDCl3, 400 MHz) d 7.20–7.35
(m, 5H, Ph–H), 5.84–5.94 (m, 1H, CH]CH2), 5.02–5.14
(m, 2H, CH]CH2), 4.68–4.71 (m, 1H, CHNCO), 4.15–4.22
(m, 2H, CH2OCO), 3.30 (dd, JZ13.4, 3.3 Hz, 1H, PhCH2),
2.76 (dd, JZ13.4, 9.6 Hz, 1H, PhCH2), 2.98–3.14 (m, 2H,
CH2CH]CH2), 2.49–2.43 (m, 2H, CH2CO); 13C NMR
(CDCl3, 100 MHz) d 172.4 (48), 153.4 (48), 136.6 (48), 135.2
(38), 129.3 (38), 128.9 (38), 127.3 (38), 115.6 (28), 66.1 (28),
55.0 (38), 37.8 (28), 34.7 (28), 28.1 (28); IR (CH2Cl2): 2980,
2872, 1782, 1703, 1389, 1210, 1101, 703 cmK1
.
4.5.3. (K)-(2R,3S,4R)-4-Benzyl-3-(3-hydroxy-2-allyloc-
tanoyl)oxazolidin-2-one ((K)-29).17 To a solution of
oxazolidinone (K)-28 (2.5 g, 9.65 mmol) in 17 mL of
CH2Cl2 in an ice bath was added Bu2OTf (1 M in CH2Cl2,
11.6 mL, 11.6 mmol) over a 10 min period and then
addition of Et3N (1.75 mL, 12.5 mmol) over a 10 min
period. The resulting light yellow solution was stirred at
0 8C for 10 min. The ice bath was replaced with a dry ice/
acetone bath (78 8C) and freshly distilled n-hexanal
(1.4 mL, 11.6 mmol) was added by syringe over a 5 min
period. The reaction mixture was stirred at K78 8C for 1 h,
warmed to 0 8C for 2 h, and quenched by addition of 2 mL
of pH 7 buffer and 2 mL of MeOH. A solution of 1.2 mL of
MeOH/30% aqueous H2O2 (2:1 by volume) was added
dropwise and the biphasic mixture was stirred vigorously at
rt for 1 h. The mixture was diluted with 100 mL of water and
the layers were separated. The aqueous layer was washed
with CH2Cl2 and the combined organic layers were washed
with saturated aqueous NaHCO3, dried over MgSO4 and
concentrated. The crude product was chromatographed on
silica gel column to give compound (K)-29 (2.52 g,
7.0 mmol) in 73% yield as a pale yellow oil. TLC RfZ
4.5. General procedure to prepare the carboxylic acid
from the corresponding primary alcohol by Jones
reagent
To a solution of primary alcohol 27 (50 mg, 0.25 mmol) in
acetone (1 mL) at 40 8C was added Jones reagent dropwise
until the orange color persisted and the resulting solution
was stirred at this temperature for 5 min. After cooling to
0 8C, the reaction mixture was added isopropanol to quench
the excess of Jones reagent. The mixture was partitioned
between CH2Cl2 and water. The organic phase was dried
(MgSO4) and evaporated in vacuo. The residual oil was
chromatographed on silica gel column to give a white solid
8a (45 mg, 0.21 mmol) in 84% yield.
4.5.1. (2S*,3R*)-4-Methylene-5-oxo-2-pentyltetrahydro-
furan-3-carboxylic acid (8a). TLC RfZ0.20 (hexane/
1
EtOAcZ1:1); H NMR (CDCl3, 400 MHz) d 6.47 (d, JZ
3.1 Hz, 1H, C]CH2), 6.02 (d, JZ2.2 Hz, 1H, C]CH2),
4.78–4.83 (m, 1H, CHOCO), 3.62–3.64 (m, 1H,
CHC]CH2), 1.71–1.78 (m, 2H), 1.26–1.51 (m, 6H), 0.90
(t, JZ7.0 Hz, 3H, CH3CH2); 13C NMR (CDCl3, 100 MHz)
d 173.4 (48), 168.6 (48), 132.5 (48), 125.8 (28), 79.2 (38), 49.4
(38), 35.4 (28), 31.1 (28), 24.2 (28), 22.2 (28), 13.7 (18); IR
(CH2Cl2): 3462, 2954, 2861, 1743, 1660, 1465, 1257, 1186,
737 cmK1; EI mass (m/z): 212 (MC, 2), 183 (24), 141 (100),
123 (21), 113 (61), 81 (9), 55 (24); HRMS m/z calcd for
C11H16O4 212.1049, found: 212.1053.
1
0.38 (hexane/EtOAcZ3:1); H NMR (CDCl3, 400 MHz) d
7.21–7.35 (m, 5H, Ph–H), 5.83–5.93 (m, 1H, CH]CH2),
5.04–5.15 (m, 2H, CH]CH2), 4.68–4.74 (m, 1H, CHNCO),
4.13–4.20 (m, 3H, CH2OCO and OH), 3.91–3.94 (m, 1H,
CHOH), 3.33 (dd, JZ3.2, 13.3 Hz, 1H, PhCH2), 2.64 (dd,
JZ10.1, 13.3 Hz, 1H, PhCH2), 2.57–2.65 (m, 1H, CHCO),
2.46–2.51 (m, 2H, CH2CH]CH2), 1.49–1.58 (m, 2H),
1.31–1.36 (m, 6H), 0.89 (t, JZ6.3 Hz, 3H, CH2CH3); 13C
NMR (CDCl3, 100 MHz) d 175.3 (48), 153.4 (48), 135.4
(48), 135.3 (38), 129.3 (38), 128.9 (38), 127.2 (38), 117.1 (28),
72.0 (38), 65.9 (28), 55.5 (38), 47.1 (38), 37.9 (28), 34.0 (28),
31.6 (28), 31.5 (28), 25.6 (28), 22.5 (28), 13.9 (18); [a]3D0Z
K7.0 (cZ0.55, CHCl3); IR (CH2Cl2): 3524, 2954, 2859,
1779, 1696, 1385, 1208, 1104, 702 cmK1; EI mass (m/z):
359 (MC, 4), 341 (24), 270 (46), 259 (77), 178 (100), 117
(66), 91 (48), 83 (40), 55 (48); HRMS m/z calcd for
C21H29NO4 359.2097, found: 359.2093.
4.5.2. (K)-(4R)-4-Benzyl-3-pent-4-enoyloxazolidin-2-one
((K)-28).16 To a stirred solution of 4-pentenoic acid (1.65 g,
16.52 mmol) and Et3N (2.8 mL, 19.98 mmol) in 48 mL of
dry THF, cooled to K78 8C under nitrogen, was added
pivaloyl chloride (2.08 g, 17.27 mmol). The mixture was
warmed to 0 8C for 60 min, and then recooled to K78 8C. A
solution of (4S)-(phenylmethyl)-2-oxazolidone (2.66 g,
15.0 mmol) in 42 mL of THF, stirred at K30 8C to
K45 8C under nitrogen, was treated dropwise with n-BuLi
(2.50 M in hexane, 6.6 mL, 16.52 mmol). The resulting
solution was cooled to K78 8C and then added, via rapid
cannulation, to the above stirred mixture containing
the mixed anhydride. The resulting mixture was stirred at
K78 8C for 30 min. After warming to 0 8C, the mixture was
partitioned between CH2Cl2 and pH 7 phosphate buffer. The
CH2Cl2 phase washed with 5% aqueous NaHCO3 followed
by saturated aqueous NaCl, dried (MgSO4), and evaporated
in vacuo. The residual oil was chromatographed on silica gel
column to give a colorless, viscous oil (K)-28 (3.45 g,
4.5.4. (K)-(2S,3S)-2-Allyloctane-1,3-diol ((K)-30). To a
0 8C solution of aldol (K)-29 (100 mg, 0.28 mmol) in
2.4 mL of THF was added dropwise a solution of NaBH4
(43 mg, 1.11 mmol) in 0.6 mL of deionized H2O. Once
addition was complete, the ice bath was removed and the
biphasic mixture was stirred vigorously at rt for 2 h. The
mixture was then recooled in an ice bath and 5 mL of 1 N
HCl was added carefully to quench the excess hydride
reagent. The aqueous layer was extracted with 15 mL of
CH2Cl2. The organic layers was washed with brine, dried
over MgSO4, and concentrated. Purification of the crude

Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
2721
product by silica gel column chromatography gave the diol
(K)-30 (48 mg, 0.26 mmol) in 93% yield as a colorless oil.
TLC RfZ0.25 (hexane/EtOAcZ3:1); 1H NMR (CDCl3,
400 MHz) d 5.76–5.81 (m, 1H, CH]CH2), 5.02–5.10 (m,
2H, CH]CH2), 3.86–3.90 (m, 1H, CHOH), 3.80 (dd, JZ
6.4, 10.8 Hz, 1H, CH2OH), 3.74 (dd, JZ3.8, 10.8 Hz, 1H,
CH2OH), 2.13 (dd, JZ7.2, 7.2 Hz, 2H, CH2CH]CH2),
1.73–1.78 (m, 1H,), 1.44–1.55 (m, 2H), 1.31–1.32 (br m,
6H), 0.89 (t, JZ6.2 Hz, 3H, CH2CH3); 13C NMR (CDCl3,
100 MHz) d 137.1 (38), 116.2 (28), 74.6 (38), 64.4 (28), 44.0
(38), 33.4 (28), 31.8 (28), 29.9 (28), 25.9 (28), 22.6 (28), 14.0
(18); [a]2D8ZK7.1 (cZ0.52, CHCl3); IR (CH2Cl2): 3419,
2931, 2859, 1416, 1160, 1026, cmK1; FAB mass (m/z): 187
(MCC1, 27), 178 (45), 169 (53), 151 (68), 136 (57), 109
(65), 95 (97), 81 (94), 55 (100); HRMS m/z calcd for
C11H22O2 186.1620, found: 186.1613.
(28), 43.7 (38), 31.7 (28), 31.5 (28), 31.3 (28), 25.8 (3!18),
25.2 (28), 22.5 (28), 21.2 (18), 18.2 (48), 14.0 (18), K5.6 (2!
18); [a]3D4ZK2.9 (cZ0.52, CHCl3); IR (CH2Cl2): 2955,
2857, 1740, 1471, 1242, 1098, 776 cmK1; FAB mass (m/z):
343 (MCC1, 9), 307 (52), 154 (99), 136 (100), 107 (65), 91
(55), 81 (29), 73 (83), 55 (43); HRMS m/z calcd for
C19H38O3Si 342.2590, found: 342.2580.
4.5.7. (C)-(1S,2S)-2-[2-Acetoxy-1-(tert-butyldimethyl-
silyloxymethyl)heptyl]acrolein ((C)-33). Following the
general procedure to prepare the a-substituted acrolein from
terminal alkene, compound (C)-33 (1.07 g, 3.0 mmol) was
prepared from alkene (K)-32 (1.2 g, 3.50 mmol) in 86%
yield as a colorless oil. TLC RfZ0.25 (hexane/EtOAcZ
1
20:1); H NMR (CDCl3, 400 MHz) d 9.50 (s, 1H, CHO),
6.53 (s, 1H, C]CH2), 6.15 (s, 1H, C]CH2), 5.27–5.31 (m,
1H, CHOCO), 3.63 (dd, JZ5.5, 10.1 Hz, 1H, CH2OTBS),
3.56 (dd, JZ5.9, 10.1 Hz, 1H, CH2OTBS), 3.09–3.13 (m,
1H, CH–C]CH2), 1.99 (s, 3H, COCH3), 1.48–1.51 (m,
2H), 1.25–1.27 (m, 6H), 0.84–0.90 (m, 12H), 0.02 (s, 3H,
t-BuSi(CH3)2), K0.02 (s, 3H, t-BuSi(CH3)2); 13C NMR
(CDCl3, 100 MHz) d 194.1 (48), 170.2 (48), 147.8 (48), 137.0
(28), 72.7 (38), 62.6 (28), 41.7 (38), 32.4 (28), 31.6 (28), 25.7
(3!18), 24.8 (28), 22.4 (28), 21.0 (18), 18.1 (48), 13.9 (18),
K5.6 (18), K5.7 (18); [a]3D2ZC1.4 (cZ0.52, CHCl3); IR
(CH2Cl2): 2955, 2858, 1741, 1697, 1471, 1239, 1104, 1022,
777 cmK1; FAB mass (m/z): 357 (MCC1, 16), 297 (42),
239 (71), 117 (84), 91 (22), 81 (31), 73 (100), 55 (44);
HRMS m/z calcd for C19H36O4Si 356.2383, found:
356.2391.
4.5.5. (K)-(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-
dec-1-en-5-ol ((K)-31). To a solution of the diol (K)-30
(160 mg, 0.86 mmol), DMAP (21 mg, 0.17 mmol) and
imidazole (64.4 mg, 0.94 mmol) in 1.8 mL of CH2Cl2 was
added t-butyldimethylsilyl chloride (142.5 mg, 0.94 mmol)
at rt and stirred it for 3 h. The reaction is quenched with
water and extracted with ethyl acetate. The organic layer
was dried over MgSO4, concentrated, and chromatographed
on silica gel column to give the silyl ether (K)-31 (231 mg,
0.81 mmol) in 94% yield as a pale yellow oil. TLC RfZ0.38
(hexane/EtOAcZ20:1); 1H NMR (CDCl3, 400 MHz) d
5.72–5.83 (m, 1H, CH]CH2), 5.01–5.08 (m, 2H,
CH]CH2), 3.81–3.85 (m, 1H, CHOH), 3.78 (dd, JZ5.2,
9.8 Hz, 1H, CH2OTBS), 3.73 (dd, JZ3.5, 9.8 Hz, 1H,
CH2OTBS), 3.27 (br d, JZ3.7 Hz, 1H, OH), 2.14–2.17 (m,
2H, CH2CH]CH2), 1.61–1.68 (m, 1H, CHCH2OTBS),
1.47–1.55 (m, 2H), 1.30–1.43 (m, 6H), 0.88–0.91 (m, 12H,
CH2CH3 and (CH3)3CSiMe2), 0.08 (s, 3H, t-BuSi(CH3)2),
0.07 (s, 3H, t-BuSi(CH3)2); 13C NMR (CDCl3, 100 MHz) d
137.3 (38), 116.1 (28), 74.9 (38), 65.4 (28), 43.8 (38), 33.8
(28), 31.9 (28), 29.3 (28), 25.9 (28), 25.8 (3!18), 22.6 (28),
18.0 (48), 14.0 (18), K5.6 (18), K5.7 (18); [a]3D1ZK8.6 (cZ
0.52, CHCl3); IR (CH2Cl2): 3447, 2955, 2857, 1471, 1255,
1091, 777 cmK1; FAB mass (m/z): 301 (MCC1, 7), 283 (7),
154 (27), 136 (40), 95 (21), 91 (23), 81 (24), 73 (100), 55
(42); HRMS m/z calcd for C17H36O2Si 300.2485, found:
300.2483.
4.5.8. (K)-(1S,2S)-2-[2-Acetoxy-1-(tert-butyldimethylsilyl-
oxymethyl)heptyl]acrylic acid methyl ester ((K)-34).
Following the general procedure to prepare the methyl
acrylate from a-substituted acrolein, methyl acrylate (K)-
34 (910 mg, 2.35 mmol) was prepared from acrolein (C)-33
(1.07 g, 3.00 mmol) in 78% yield as a colorless oil. TLC
RfZ0.70 (hexane/EtOAcZ10:1); 1H NMR (CDCl3,
400 MHz) d 6.32 (s, 1H, C]CH2), 5.77 (s, 1H, C]CH2),
5.24 (ddd, JZ5.0, 7.2, 7.2 Hz, 1H, CHOCO), 3.76 (s, 3H,
OCH3), 3.68 (dd, JZ5.7, 10.1 Hz, 1H, CH2OTBS), 3.63
(dd, JZ6.2, 10.1 Hz, 1H, CH2OTBS), 3.05–3.09 (m, 1H,
CHC]CH2), 1.98 (s, 3H, COCH3), 1.51–1.62 (m, 2H),
1.22–1.33 (m, 6H), 0.83–0.91 (m, 12H), 0.01 (s, 6H,
t-BuSi(CH3)2); 13C NMR (CDCl3, 100 MHz) d 170.3 (48),
167.7 (48), 138.1 (48), 127.3 (28), 73.1 (38), 63.0 (28), 51.9
(18), 45.7 (38), 32.4 (28), 31.6 (28), 25.8 (3!18), 24.9 (28),
22.5 (28), 21.0 (18), 18.1 (48), 13.9 (18), K5.6 (18), K5.7
(18); [a]3D2ZK2.4 (cZ0.52, CHCl3); IR (CH2Cl2): 2955,
2858, 1739, 1438, 1242, 1104, 777 cmK1; FAB mass (m/z):
387 (MCC1, 15), 329 (34), 269 (52), 154 (12), 117 (40), 91
(11), 73 (100), 55 (9); HRMS m/z calcd for C20H38O5Si
386.2489, found: 386.2493.
4.5.6. (K)-Acetic acid (1S,2S)-2-(tert-butyldimethylsilyl-
oxymethyl)-1-pentylpent-4-enyl ester ((K)-32). To a
solution of the alcohol (K)-31 (231 mg, 0.86 mmol),
DMAP (21 mg, 0.86 mmol) and Et3N (0.18 mL,
1.29 mmol) in 1.8 mL of CH2Cl2 was added acetic
anhydride (0.12 mL, 1.29 mmol) at rt and stirred it for 2 h.
The reaction mixture was concentrated and chromato-
graphed on silica gel column to afford the acetate (K)-32
(260 mg, 0.76 mmol) in 88% yield as a pale yellow oil. TLC
RfZ0.50 (hexane/EtOAcZ20:1); 1H NMR (CDCl3,
400 MHz) d 5.73–5.84 (m, 1H, CH]CH2), 4.99–5.06 (m,
3H, CH]CH2 and CHOCO), 3.56 (dd, JZ5.1, 10.1 Hz, 1H,
CH2OTBS), 3.52 (dd, JZ5.6, 10.1 Hz, 1H, CH2OTBS),
2.12–2.15 (m, 2H, CH2CH]CH2), 2.03 (s, 3H, COCH3),
1.72–1.79 (m, 1H, CHCH2OTBS), 1.55–1.57 (m, 2H), 1.25–
1.35 (br m, 6H), 0.86–0.92 (m, 12H, CH2CH3 and (CH3)3-
CSiMe2), 0.02 (s, 6H, t-BuSi(CH3)2); 13C NMR (CDCl3,
100 MHz) d 170.6 (48), 137.1 (38), 116.0 (28), 74.4 (38), 61.9
4.5.9. (K)-(4R,5S)-4-Hydroxymethyl-3-methylene-5-
pentyldihydrofuran-2-one ((K)-27). To a mixture of
acetoxy-acrylate (K)-34 (50 mg, 0.13 mmol) in 0.3 mL of
MeOH was added catalytic amount of acetyl chloride (1 mL,
13 mmol) and stirred at rt for 24 h. The reaction mixture was
concentrated and chromatographed on silica gel column to
give the a-methylenelactone (K)-27 (23.4 mg, 0.12 mmol)
in 91% yield as a pale yellow oil. TLC RfZ0.55 (hexane/
EtOAcZ1:1); 1H NMR (CDCl3, 400 MHz) d 6.33 (d,

2722
Y.-S. Hon et al. / Tetrahedron 61 (2005) 2713–2723
Agric. Biol. Chem. 1987, 51, 3443. (b) Park, B. K.; Nakagawa,
M.; Hirota, A.; Nakayama, M. J. Antibiot. 1988, 44, 751–758.
(c) Nakayama, M.; Nakagawa, S.; Boku, T.; Hirota, A.; Shima,
S.; Nakanishi, O.; Yamada, Y. Jpn. Kokai Tokkyo Koho 1989,
1(16), 776. Chem. Abstr. 1990, 112, 34404f.
JZ2.8 Hz, 1H, C]CH2), 5.72 (d, JZ2.8 Hz, 1H, C]CH2),
4.40 (ddd, JZ4.4, 6.4, 6.4 Hz, 1H, CHOCO), 3.74–3.79 (m,
2H, CH2–OH), 2.85–2.90 (m, 1H, CHCH2OH), 1.65–1.71
(m, 3H), 1.31–1.51 (m, 6H), 0.89 (t, JZ7.2 Hz, 3H,
CH2CH3); 13C NMR (CDCl3, 100 MHz) d 170.3 (48),
136.2 (48), 123.4 (28), 80.9 (38), 63.8 (28), 46.8 (38) 36.0 (28),
31.4 (28), 24.6 (28), 22.4 (28), 13.9 (18); [a]3D0ZK16.2
(cZ0.52, CHCl3); IR (CH2Cl2): 3459, 2932, 2860, 1748,
1465, 1151, 733 cmK1; FAB mass (m/z): 199 (MCC1, 16),
181 (10), 154 (23), 136 (27), 91 (40), 81 (39), 55
(100); HRMS m/z calcd for C11H18O3 198.1256, found:
198.1248.
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4.5.10. (K)-(4R,5S)-4-Methylene-5-oxo-2-pentyltetra-
hydrofuran-3-carboxylic acid ((K)-8a). Following the
general procedure to prepare the carboxylic acid from the
corresponding primary alcohol by Jones reagent, (K)-
methylenolactocin ((K)-8a) (492 mg, 0.21 mmol) was
prepared from primary alcohol (K)-27 (550 mg,
2.52 mmol) in 84% yield as a white solid. TLC RfZ0.20
(hexane/EtOAcZ1:1); mp 82.5 8C; 1H NMR (CDCl3,
400 MHz) d 6.47 (d, JZ3.1 Hz, 1H, C]CH2), 6.02 (d,
JZ2.2 Hz, 1H, C]CH2), 4.78–4.83 (m, 1H, CHOCO), 3.63
(ddd, JZ2.8, 2.8, 5.6 Hz, 1H, CHC]CH2), 1.71–1.78 (m,
2H), 1.26–1.51 (m, 6H), 0.90 (t, JZ7.0 Hz, 3H, CH2CH3);
13C NMR (CDCl3, 100 MHz) d 173.4 (48), 168.8 (48), 132.5
(48), 125.8 (28), 79.2 (38), 49.4 (38), 35.4 (28), 31.1 (28), 24.2
(28), 22.2 (28), 13.7 (18); [a]3D2ZK18.8 (cZ0.31, CHCl3);
IR (CH2Cl2):3462, 2954, 2861, 1743, 1257, 1186, 737 cmK1
;
EI mass (m/z): 212 (MC, 2), 183 (24), 141 (100), 123 (21),
113 (61), 81 (9), 55 (24); HRMS m/z calcd for C11H16O4
212.1049, found: 212.1053.
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Acknowledgements
We are grateful to the National Science Council, National
Chung Cheng University and Academia Sinica for the
financial support.
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