Dibromomethane as one-carbon source in organic synthesis: A versatile methodology to prepare the cyclic and acyclic α-methylene or α-keto acid derivatives from the corresponding terminal alkenes

Article abstract of DOI:10.1016/j.tet.2004.04.013

Ozonolysis of mono-substituted alkenes A-1 followed by reacting with a preheated mixture of CH₂Br₂-Et₂NH affords α-substituted acroleins A-2 in good yields. Under very mild reaction conditions, these α-substituted acroleins A-2 can be easily converted to α-methylene esters A-4, which could be further converted to the corresponding α-keto esters A-5. This methodology can be also applied to the preparation of α-methylene lactones B-4, α-methylene lactams, and α-keto lactones B-5 with various ring sizes.

Full text of DOI:10.1016/j.tet.2004.04.013

Tetrahedron 60 (2004) 4837–4860
Dibromomethane as one-carbon source in organic synthesis:
a versatile methodology to prepare the cyclic and acyclic
a-methylene or a-keto acid derivatives from the corresponding
terminal alkenes
a
a
Yung-Son Hon,a,b Yu-Wei Liu and Cheng-Han Hsieh
,
*
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 11 November 2003; revised 26 March 2004; accepted 1 April 2004
Dedicated to Professor Teh-Chang Chou of National Chung Cheng University on the occasion of his 60th birthday
Abstract—Ozonolysis of mono-substituted alkenes A-1 followed by reacting with a preheated mixture of CH2Br2–Et2NH affords
a-substituted acroleins A-2 in good yields. Under very mild reaction conditions, these a-substituted acroleins A-2 can be easily converted to
a-methylene esters A-4, which could be further converted to the corresponding a-keto esters A-5. This methodology can be also applied to
the preparation of a-methylene lactones B-4, a-methylene lactams, and a-keto lactones B-5 with various ring sizes.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ð2Þ
In the previous studies, the ozonide 2 or aldehyde 3 was
treated with a preheated mixture of CH2Br2 and Et2NH to
give the acrolein 4 in modest to good yields (Eqs. 1 and 2)1
whilst the aryl alkyl ketone 5 reacted with a mixture of
CH2Br2 and Et2NH under microwave condition to give the
ð3Þ
corresponding a-methylene ketone 6 (Eq. 3).2 The b-carbon
of the conjugated carbonyl compound was derived from
CH2Br2. In comparison with similar transformation reported
a-Methylene-g-butyrolactone is an important moiety in
several biological active compounds. Therefore, the
in the literature,3–5 the characteristic features of our
development of their preparative methodologies has been
methodology are described as follows. Both CH2Br2 and
attractive to many synthetic organic chemists.6–19 How-
Et2NH are cheap. Their salts can be easily prepared in situ
ever, there are only few reports to describe the preparation
of a-methylene-b-propiolactones20,21 and a-methylene-d-
and used in the same flask to carry out the a-methylenation.
The reaction was carried out in nonaqueous media under
valerolactones.22,23 To the best of our knowledge, there is
mild reaction condition. In addition, both ozonide and
no general strategy which can be useful to prepare 4- to
7-memebred ring a-methylene lactones.24 a-Keto acid
derivatives play important roles not only in organic
synthesis but also in biologically active natural products.25,26
aldehyde can be converted to the desired product. Therefore,
a preheated mixture of CH2Br2 and Et2NH is a convenient
and economic reagent as one-carbon synthetic equivalent in
organic synthesis.
The preparation of the a-keto acid was categorized as the
following. Oxidation of a-hydroxy esters or their
equivalents,27a–c oxidative cleavage of the double bond of
ð1Þ
a,b-unsaturated carbonyl compounds,27d,e a-oxidation of
carbonyl groups,27f and metal-catalyzed double carbonyl-
ation27g are typical methods to prepare a-keto acid
derivatives.27 Likewise, a-keto amides are mostly obtained
Keywords: Ozonides; a-Methylenation; a-Substituted acroleins;
a-Methylene esters; a-Methylene lactones; a-Methylene lactams; a-Keto
from amidation of a-hydroxy esters or acids, followed by
oxidation. Of the above methods, most lack generality or
suffer from lengthy procedures. The use of toxic KCN and
drastic hydrolytic conditions limit the application of some
esters; a-Keto lactones.
*
Corresponding author. Tel.: þ886-5-2720411x66412; fax: þ886-5-
2721040; e-mail address: cheysh@ccu.edu.tw
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.013

4838
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
Figure 1. Retrosynthesis of the acyclic and cyclic a-methylene or a-keto carboxylates.
methods for the preparation of a-keto acid derivatives with
labile functional groups.27a–c
acrylates by MnO2 in the presence of KCN in methanol has
been reported in high yield.29 In order to avoid using toxic
KCN, we tried to use other reagents. The oxidation of
a-substituted acrolein 4a by Jones reagent gave an
inseparable mixture of the acrylic acid 7a in addition to
an over-oxidized product. We found that a modified
procedure using sodium chlorite in the presence of a
chlorine scavenger (i.e, 2-methyl-2-butene) resulted in the
acrylic acid 7a formation in 98% yield.30 The acrylic acid
7a was treated with 1 equiv. of diazomethane to give the
methyl acrylate 8a in excellent yield. The presence of
excess diazomethane might result in the further 1,3-dipolar
cycloaddition to give D1-pyrazoline.31 In general, the
isolation of the acrylic acid 7a is not necessary before its
reaction with diazomethane. The ozonolysis of methyl
acrylate 8a followed by the reduction with Ph3P afforded
a-keto ester 9a in 69% yield (Scheme 1).
In our previous report, we described a methodology to
prepare the a-methylene acid or a-keto acid derivatives
from the corresponding terminal alkenes. The a-methylene
group is a masked form of carbonyl group. The a-sub-
stituted acroleins were proved to be the suitable precursors
to the formation of a-keto acid derivatives.28 Its retro-
synthetic analysis was described in Figure 1. The a,b-
unsaturated carboxylic acid A-3 would be prepared from the
mild oxidation of the a,b-unsaturated aldehyde A-2, which
would be derived easily from terminal alkene A-1 by our
reaction condition as shown in Eq. 1. The methyl acrylate
A-4 would be a reasonable precursor to the a-keto acid
ester A-5. By using similar methodology, the hydroxy-
alkene B-1 would be a reasonable starting material for
the preparation of a-methylene lactone B-4 and a-keto
lactone B-5. The ring size of the lactone is dependent on the
chain length of the spacer between the hydroxy and alkene
moieties of compound B (Fig. 1). In this report, we shall
describe our effort in the synthesis of acyclic and cyclic
a-methylene acid derivatives and theira-keto acid derivatives
in detail.
As the reaction conditions involved in Scheme 1 were very
mild, it was likely that the sequence might tolerate the
presence of the labile groups. Both the keto-olefins 1b32 and
1c32 can be converted to the a-substituted acroleins 4b and
4c, respectively, in good yields where the keto groups
remain intact. Moreover, the acrolein 4c, with the
quaternary center adjacent to the a-methylene group, was
formed in 61% yield. These acroleins could be converted to
a-keto esters 9b and 9c in good yields. Hydroxy-olefin 1d,
acetoxy-olefin 1e, and iodo-olefin 1f were also transformed
into the corresponding a-keto ester derivatives in good
yields via similar sequences (Scheme 1). The only exception
was that the reducing agent in the ozonolysis of hydroxy-
acrylate 8d was Me2S rather than Ph3P. It is because the
polarity of a-keto ester 9d is close to Ph3PO on silica gel
thin layer chromatography. When a-keto ester 9d was
exposed to the silica gel for a long period of time while
2. Results and discussion
2.1. Preparation of acyclic a-methylene acids and their
a-keto acid derivatives from the corresponding terminal
alkenes
The ozonolysis of 1-decene (1a) followed by addition of a
preheated mixture of CH2Br2 and Et2NH afforded acrolein
4a in 62% yield. The oxidation of acroleins to methyl
Scheme 1. Reagents and conditions: (i) (a) O3, CH2Cl2, 278 8C; (b) preheated mixture of Et2NH and CH2Br2 (mol equiv.¼5:15); (ii) 2.3 mol equiv. NaClO2, t-
BuOH, 2 mol equiv. NaH2PO4·2H2O, 3 mol equiv. MeCHvCMe2; (iii) CH2N2; (iv) (a) O3, CH2Cl2, 278 8C; (b) 0.7 mol equiv. Ph3P; (v) (a) O3, CH2Cl2,
278 8C; (b) 1.1 mol equiv. Me2S.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4839
Scheme 2. Reagents and conditions: (i) 5 mol equiv. SOCl2; (ii) NH4OH; (iii) pyrrolidine; (iv) 1.1 mol equiv. L-valine methyl ester, 2 mol equiv. Et3N; (v) O3,
CH2Cl2, 278 8C; 0.7 mol equiv. Ph3P.
eluting with the lower polarity solvent system, it would
result in the dimerization of the a-keto ester 9d. This
obstacle can be overcome by using Me2S as reducing agent,
where the DMSO byproduct is easily removed by
extraction.
carbaldehyde (12), were treated with acetic anhydride to
give the acetates 14a-14d in excellent yields (Scheme 3).
The ozonolysis of acetoxy-alkene 14a followed by treat-
ment with a preheated mixture of CH2Br2 and Et2NH in the
same flask gave 3-cyclohexylacrolein instead of the desired
a-substituted acrolein. Presumably, the elimination of the
acetic acid from b-acetoxy aldehyde intermediate is a
preferred process. We tried to change the protecting group
with less leaving tendency in order to avoid this elimination
problem. Under the catalysis of acetonyltriphenyl-
phosphonium bromide (ATPB),33 the secondary alcohol
13a reacted with 3,4-dihydro-2H-pyran (DHP) to give
tetrahydropyranyl ether (OTHP) 18a in excellent yield.
Fortunately, we were able to obtain the acrolein product 19a
in 58% yield by using our standard a-methylenation
protocol. The a-substituted acrolein 19a was oxidized by
sodium chlorite to give the corresponding acrylic acid,
which was subsequently deprotected with ATPB in MeOH33
to give the corresponding hydroxy-acid 21a. Compound 21a
was treated with o-nitrophenylsulfonyl chloride34 in the
presence of Na2CO3 to give b-cyclohexyl-a-methylene-b-
propiolactone (17a) in excellent yield.
Acrylic acid 7a was converted to the acryloyl chloride 8a0
with thionyl chloride in excellent yield. There is no double
bond isomerization problem under this acidic condition. The
crude acid chloride 8a0 reacted with ammonium hydroxide
to give an excellent yield of acrylamide 10g, which was
subjected to the ozonolysis to yield the corresponding a-keto
amide 11g in 90% yield. The acryloyl chloride 8a0 also reacted
with pyrrolidine or (^)-valine methyl ester to afford the
correspondingacryloylamides10h and10i inexcellent yields.
Under similar conditions, these a-substituted acryloyl amides
were also converted to the corresponding a-keto amide 11g-
11h in excellent yields. The ozonolysis of acrylic acid 7a
followed by reduction with Ph3P afforded the a-keto acid 9a0
in 73% yield (Scheme 2). In general, the yield for the
formation of a-keto amides is better than that of a-keto
esters. Our methodology is suitable to prepare the acyclic
a-methylene acid derivatives and their a-keto acid derivatives
with labile functional groups.
The ozonolysis of acetoxy-alkene 14b followed by our
standard a-methylenation protocol afforded the desired
a-methylene aldehyde 15b, which was subsequently treated
with NaClO2 followed by reaction with CH2N2 to give
methyl acrylate 16b in excellent yield. The lactonization of
the acetoxy-ester 16b was achieved by treatment with
hydrogen chloride, which was generated in situ from the
2.2. Preparation of mono-substituted a-methylene
lactones with different ring sizes
The secondary alcohols 13a-13d, prepared from the
addition of alkenylmagnesium bromides with cyclohexane-
Scheme 3. Reagents and conditions: (i) CH2vCH(CH2)nMgBr, THF, 278 8C; (ii) cat. DMAP, pyridine, Ac2O, CH2Cl2; (iii) (a) O3, CH2Cl2, 278 8C;
(b) preheated mixture of Et2NH and CH2Br2 (mol ratio 5:15); (iv) 2.3 mol equiv. NaClO2, t-BuOH, 2 mol equiv. NaH2PO4-2H2O, 3 mol equiv.
MeCHvCMe2; (v) CH2N2; (vi) cat. AcCl, MeOH; (vii) DHP, cat. ATPB, CH2Cl2; (viii) cat. ATPB, MeOH; (ix) o-NO2PhSO2Cl, Na2CO3, CH2Cl2.

4840
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
reaction of a catalytic amount of acetyl chloride in the
presence of methanol, to give the g-cyclohexyl-a-methyl-
ene-g-butyrolactone (17b) in 86% yield. Following the
same reaction sequences, the acetoxy-alkene 14c was also
converted to the d-cyclohexyl-a-methylene-d-valerolactone
(17c) in good yield (Scheme 3).
2.3. Preparation of geminal di-substituted a-methylene
lactones with different ring size
The tertiary alcohols 24a-24d, prepared from the addition of
alkenylmagnesium bromides to acetophenone (22) and
cyclohexanone (23) respectively, were treated with acetic
anhydride to give the acetates 25a-25d in excellent yield
(Scheme 4). The ozonolysis of alkene 25a followed by our
standard a-methylenation protocol gave the desired a-
methylene aldehyde 26a. The a-substituted acrolein 26a
was oxidized by sodium chlorite to give the corresponding
acrylic acid, which was subsequently treated with CH2N2 to
give methyl acrylate 27a in excellent yield. The lactoniza-
tion of the acetoxy-ester 27a was achieved by treatment
with a trace amount of HCl in methanol to give a-
methylene-g-butyrolactone 28a in 75% yield. The a-
methylene-g-butyrolactone 28c was also prepared in the
similar manner from the corresponding alkene 24c. The
chemical yields in each step are good to excellent (Scheme
4). Mechanistically, the acetoxy group of compound 27a
will undergo methanolysis to give the corresponding
hydroxy compound as an intermediate, which then under-
goes 5-membered ring formation.
The acetoxy-acrylate 16d was prepared in a similar manner
in good yield from the acetoxy-alkene 14d in order to
synthesize 7-membered ring a-methylene lactone.
Unfortunately, the acetoxy-acrylate 16d cannot undergo
lactonization by treatment with acid methanol (Scheme 3).
We isolated the corresponding acyclic hydroxy-ester from
the methanolysis of the acetoxy group. However, we did not
obtain the lactonization product 17d when compound 16d
was treated with NaOMe in methanol. The disappearance of
the double bond indicates that the 1,4-addition of the methyl
acrylate 16d may occur under this condition. In order to
solve this problem, we tried to use different coupling reagent
to achieve the lactonization. Under the catalysis of ATPB,
the secondary alcohol 13d was protected as OTHP 18d in
excellent yield. The ozonolysis of alkene 18d followed by
our standard a-methylenation protocol afforded the desired
a-methylene aldehyde 19d, which was subsequently treated
with NaClO2 to give the corresponding acrylic acid 20d.
The lactonization of the hydroxy-acid 20d was achieved by
treatment with o-nitrophenylsulfonyl chloride in the
presence of Na2CO3 to give the 1-cyclohexyl-a-methyl-
ene-1-caprolactone (17d) in 86% yield (Scheme 3).
Herein, o-nitrophenylsulfonyl chloride was demonstrated
to be an excellent reagent to promote the 4- and
7-membered ring a-methylene lactones formation from
their hydroxy-acid precursors. The hydrogen chloride in
methanol is suitable to accomplish the 5- and 6-membered
ring a-methylenelactones formation from their acetoxy-
ester precursors.
Since the 5-membered ring a-methylene lactones (28a and
28c) were successfully formed under acidic condition, we
tried to prepare their 6-membered ring analogues (28b and
28d) from their acyclic precursors (27b and 27d) under
similar conditions. However, we obtained the elimination
products rather than the ring formation products in each
case. It is well known that 6-membered ring formation is
slower than that of the 5-membered ring. Before the
lactonization, the tertiary hydroxy compounds derived
from 27b and 27d prefer to form the relatively stable
tertiary carbocation intermediates, which may further
undergo a-proton elimination. In order to solve this
Scheme 4. Reagents and conditions: (i) CH2vCH(CH2)nMgBr, THF, 278 8C; (ii) Ac2O, cat. DMAP, CH2Cl2; (iii) (a) O3, CH2Cl2, 278 8C; (b) preheated
mixture of Et2NH and CH2Br2 (mol equiv.¼5:15); (iv) 2.3 mol equiv. NaClO2, t-BuOH, 2 mol equiv. NaH2PO4–2H2O, 3 mol equiv. MeCHvCMe2; (v)
CH2N2; (vi) cat. AcCl, MeOH; (vii) K2CO3, MeOH; (viii) o-NO2PhSO2Cl, Na2CO3, CH2Cl2.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4841
problem, we considered to use o-nitrophenylsulfonyl
chloride as the promoter. The acetoxy-acrolein 26b was
oxidized by sodium chlorite to give the acetoxy-acrylic acid
29b, in which the acetoxy group was converted to give the
hydroxy-acrylic acid 30b in good yield. The lactonization of
the hydoxy-acid 30b was successfully achieved by treat-
ment with o-nitrophenylsulfonyl chloride in the presence of
Na2CO3 to give a-methylene-d-valerolactone 28b in 71%
yield. The 6-membered ring a-methylenespirolactone 28d
was also prepared under similar condition from the
hydroxy-acid 30d (Scheme 4).
starting material. The phenolic group of compound 37 was
protected as OTHP 38 in good yield. The ozonolysis of
alkene 38 followed by our standard a-methylenation
protocol in the same flask gave the desired a-methylene
aldehyde 39. The a-substituted acrolein 39 was oxidized by
sodium chlorite, followed by treatment with CH2N2 to give
methyl acrylate 40 in excellent yield. When compound 40
was treated with a catalytic amount of acetyl chloride in the
presence of methanol, the reaction was quite messy and we
did not obtain the desired lactone 42. a-Methylene lactone
42 is known to be unstable and it is sensitive to the
nucleophilic solvent.36 Therefore, the OTHP group of
compound 40 was deprotected to give the corresponding
hydroxy-acrylate 41. Compound 41 was treated with
trifluoroacetic acid in toluene at 90 8C for 2 h37 to give the
desired product 42. The crude product was confirmed by the
1H NMR. Since it is too unstable to be purified by silica gel
column chromatography, the crude product 42 was then
treated with cyclopentadiene to give the Diels–Alder
adduct 43 as a mixture of two diastereomers in a ratio of
4 to 1 in 51% overall yield from compound 41. We found
that the major adduct was a less polar isomer.
2.4. Preparation of bicyclic a-methylene lactones with
different ring size
The cyclic trans-alcohols 32a-32b, prepared from the
addition of alkenylmagnesium bromides with 1,2-epoxy-
cyclohexane (31) in the presence of CuI, were treated with
acetic anhydride to give the acetates 33a-33b in excellent
yields (Scheme 5). The ozonolysis of alkene 33a followed
by our standard a-methylenation protocol gave the desired
a-methylene aldehyde 34a. The a-substituted acrolein 34a
was oxidized by sodium chlorite followed by treatment with
CH2N2 to give the methyl acrylate 35a in excellent yield.
The lactonization of the acetoxy-ester 35a was achieved by
treatment with a catalytic amount of HCl in methanol to
give the trans-fused bicyclic a-methylenelactone 36a in
89% yield. The 6-membered ring analogues 36b were also
prepared in a similar manner from the corresponding
terminal alkene precursor 33b. The chemical yields in
each step are good to excellent (Scheme 5).
For the purpose to prepare the 6-membered ring benzo-
fused bicyclic a-methylene lactone from compound 38,
elongation of the side chain is required. The hydroboration
of the alkene 38 followed by treatment with hydrogen
peroxide gave the corresponding primary alcohol 44 in 65%
yield. The alcohol 44 was oxidized by PCC to give the
corresponding aldehyde 45. By using our standard
a-methylenation protocol, the aldehyde 45 was converted
to the desired a-methylene aldehyde 46 in 62% yield. The
a-substituted acrolein 46 was oxidized by sodium chlorite
followed by treatment with CH2N2 to give methyl acrylate
47 in excellent yield. The OTHP-acrylate 47 was treated
with a catalytic amount of acetyl chloride in the presence of
methanol to give benzo-fused a-methylene-g-valerolactone
48 in good yield (Scheme 6). No double bond isomerization
occurred during this acid-catalyzed lactonization.
In order to prepare the cis-fused bicyclic lactones, the
inversion of the hydroxy stereogenic centers of compounds
32a and 32b was achieved by Mitsunobu reaction35 to give
the corresponding cis-benzoxy-alkene 33c and 33d in good
yields. Since the benzoate group of compound 35c is more
reluctant to methanolysis under acidic condition, we tried to
use the basic condition to achieve the lactonization. When
compound 35c was treated with NaOMe in MeOH, we
obtained the cis-fused bicyclic a-methylene-g-lactone 36c
in 76% yield. The 6-membered ring cis-fused bicyclic
analogue 36d was also prepared in a similar manner
(Scheme 5).
2.5. Preparation of mono-substituted a-methylene
lactams with different ring size
In order to demonstrate the applicability of our methodology
to prepare the a-methylene lactams with different ring size,
the secondary alcohol 12c and 12d were converted to the
corresponding azides 49c and 49d by Mitsunobu reaction
condition38 in good yields. We found that these azides were
In order to demonstrate the applicability of our methodology
to prepare the benzo-fused bicyclic a-methylene lactones
with different ring size, 2-allylphenol (37) was used as the
Scheme 5. Reagents and conditions: (i) cat. CuI, CH2vCH(CH2)nMgBr, THF, 278 8C; (ii) cat. DMAP, pyridine, Ac2O, CH2Cl2; (iii) (a) O3, CH2Cl2, 278 8C;
(b) preheated mixture of Et2NH and CH2Br2 (mol equiv.¼5:15); (iv) 2.3 mol equiv. NaClO2, t-BuOH, 2 mol equiv. NaH2PO4·2H2O, 3 mol equiv.
MeCHvCMe2; (v) CH2N2; (vi) cat. AcCl, MeOH; (vii) PhCO2H, DEAD, Ph3P; (viii) NaOMe, MeOH.

4842
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
Scheme 6. Reagents and conditions: (i) cat. ATPB, dihydropyran; (ii) (a) O3, CH2Cl2, 278 8C; (b) preheated mixture of Et2NH and CH2Br2
(mol equiv.¼5:15); (iii) 2.3 mol equiv. NaClO2, t-BuOH, 2 mol equiv. NaH2PO4–2H2O, 3 mol equiv. MeCHvCMe2; (iv) CH2N2; (v) cat. ATPB, MeOH; (vi)
(a) CF3CO2H, toluene, 90 8C; (b) cyclopentadiene; (vii) (a) 9-BBN; (b) H2O2, NaOH; ; (viii) PCC, CH2Cl2. (ix) (a) O3, CH2Cl2, 278 8C; (b) preheated mixture
of Et2NH and CH2Br2 (mol equiv.¼4:15); (x) cat. AcCl, MeOH.
decomposed slowly by the silica gel. However, they can still
be purified by flash silica gel column chromatograpy. It is
worthy to mention that both of these compounds are
photosensitive and decomposed rapidly at room temperature
in the pure state. Therefore, they must be freshly prepared
and used directly for further reaction. The ozonolysis of
azido-alkene 49c followed by our standard a-methylenation
protocol gave the desired a-methylene aldehyde 50c. The
azido group is compatible with the ozone treatment. The
freshly prepared azido-acrolein 50c was oxidized by sodium
chlorite to give the corresponding acrylic acid, which was
subsequently treated with CH2N2 to give azido-acrylate 51c
in good yield. Compound 51c was treated with triphenyl-
phosphine followed by the addition of water to give the
a-methylene-g-butyrolactam 52c in 80% yield (Scheme 7).
the desired a-methylene aldehyde 54d. According to the
above-mentioned reaction sequences, the carbamato-
acrolein 55d was converted to the carbamato-acrylate 55d
in excellent yield. The lactamization of compound 55d was
achieved by the treatment of trimethylaluminium in toluene
to give a-methylene-d-valerolactam 56d in 72% yield
(Scheme 7).39
2.6. Preparation of a-keto lactones with different ring
size from the corresponding a-methylene lactones
We have been successful employing our methodology to
prepare 4- to 7-membered ring a-methylenelactones. We
tried to cleave their a-methylene groups by ozone in order
to prepare the corresponding a-keto lactones. The ozo-
nolysis of 5-membered ring a-methylene-g-lactone 17b in
CH2Cl2 at 278 8C followed by the reduction with Ph3P gave
the corresponding a-keto-g-butyrolactone 17b0 as an
intermediate which tautomerized completely to its enol
form 17b00. In CDCl3, no keto form isomer 17b0 was
detected by 1H and 13C NMR spectroscopy. The character-
istic peaks of the 13C NMR spectrum for compound 17b00 are
the ones at d 170.3 ppm for the carbonyl carbon, d
142.2 ppm for the a-carbon, and d 117.6 ppm for the
b-carbon. No absorption appears above d 170.3 ppm in the
13C NMR spectrum as well as none appears between d
2–4 ppm in the 1H NMR spectrum indicate that there is no
keto isomer present in the solution (Eq. 4).
Although the azido compounds 49c, 50c and 51c are not
quite stable, they are still applicable to further functional
group transformations. To our surprise, the azido-acrolein
50d is more unstable than 50c. It was decomposed quickly
by silica gel during the separation and too unstable to the
further transformations. In order to solve this problem, the
azido group of compound 49d was reduced with Ph3P
followed by treatment with water to give the corresponding
amino compound, which was then treated with methyl
chloroformate to give carbamate 53d in high yield. The
ozonolysis of carbamato-alkene 53d followed by our
standard a-methylenation protocol in the same flask gave
Scheme 7. Reagents and conditions: (i) DEAD, Ph3P, (PhO)2PON3; (ii) (a) O3, CH2Cl2, 278 8C; (b) preheated mixture of Et2NH and CH2Br2
(mol equiv.¼5:15); (iii) 2.3 mol equiv. NaClO2, t-BuOH, 2mol equiv. NaH2PO4–2H2O, 3 mol equiv. MeCHvCMe2; (iv) CH2N2; (v) Ph3P; H2O; (vi)
ClCO2Me, K2CO3; (vii) Me3Al, toluene.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4843
the carbonyl carbon, d 135.0 ppm for the a-carbon and d
134.0 ppm for the b-carbon. No absorption appears above d
170.9 ppm in 13C NMR spectrum indicates that there is no
keto isomer present in the solution (Eq. 5).
ð4Þ
ð6Þ
The ozonolysis of the g,g-disubstituted-a-methylene-g-
lactone 28a followed by reduction with Ph3P gave the
a-keto-g-butyrolactone 28a0 as an intermediate which
equilibrated with its enol form 28a00. The b-olefinic proton
absorption of compound 28a00 appears at d 6.52 ppm as a
singlet in CDCl3. The methylene group adjacent to the keto
group of compound 28a0 appears as AB-type splitting
pattern at d 3.18–3.20 ppm. The ratio of the enol form
(28a00) and keto form (28a0) is 100:19 as estimated by
integrations (Eq. 4). Under similar reaction condition, the
g,g-disubstituted-a-methylenespirolactone 28c was con-
verted to the a-keto-g-butyrolactone 28c0 as an intermediate
which equilibrated with its enol form 28c00. The b-olefinic
proton absorption of compound 28c00 appears at d 6.31 ppm
as a singlet in CDCl3. The methylene group adjacent to the
keto group of compound 28c0 appears as a singlet at d
2.75 ppm. The isomeric ratio of the enol form (28c00) and
keto form (28c0) is 100:20 as estimated by integrations
(Eq. 4).
According to the above-mentioned ozonolysis condition,
the 6-membered ring a-methylene lactones (17c and 28b)
gave complicated mixtures. The ozonolysis of the
a-methylene-d-valerolactones (17c and 28b) in dichloro-
methane at 278 8C followed by treatment with Et3N40 also
gave a complicated mixture. Interestingly, when compound
17c was treated with ozone in the presence of methanol, we
isolated the 5-membered ring lactol (17c00) as a mixture of
two diastereomers, which were derived from the skeletal
rearrangement of the corresponding a-keto-d-caprolactones
(17c0) intermediate. The characteristic peaks of the 13C
NMR spectrum for compound 17c00 are the absorptions at d
171.8 ppm for the carbonyl carbon and d 102.0 and
101.5 ppm for quarternary carbon bearing the hydroxy
group. No absorption appears above d 171.8 ppm in 13C
NMR spectrum indicates that there is no keto group present
ð5Þ
The ozonolysis of both the cis- and trans-bicyclic
a-methylene-g-lactones (36a and 36c) followed by
reduction with Ph3P gave the enol product 36c00 only
(Eq. 5). The characteristic peaks of the 13C NMR spectrum
for compound 36c00 are the absorptions at d 170.9 ppm for
in product 17c00 (Eq. 7). A broad and strong OH absorption
at 3447 cm21 in the infrared spectrum also supports the
structure of compound 17c00. Similar result was obtained
from the ozonolysis of compound 28b in the presence of
methanol (Eq. 6).

4844
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
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) or VG-11-250J (Academia Sinica)
Mass Spectrometer. a-Substituted acroleins 4a-4f were
prepared from terminal alkenes 1a-1f according to our
report.1b
ð7Þ
4.1. General procedure to prepare the secondary alcohol
from Grignard reagent with carbonyl compound
Allyl bromide (1/10 of 5.81 g, 48 mmol) is added, without
stirring, to a mixture of magnesium turings (1.21 g,
50 mmol) in 10 mL of anhydrous THF. After the reaction
started, the remaining allyl bromide in 10 mL of THF is
added dropwise with stirring so that the THF barely
refluxes. The mixture is then refluxed for 2 h, cooled to
room temperature, and added 20 mL of THF to dilute the
Grignard reagent. To a solution of cyclohexanecarbalde-
hyde (12) (4.71 g, 42 mmol) in 40 mL of THF was added the
Grignard reagent dropwise at 278 8C and stirred at this
temperature for 1 h. The reaction is quenched with aqueous
ammonium chloride solution and extracted with ethyl
acetate. The organic layer was dried over MgSO4,
concentrated, and chromatographed on silica gel column
to give the secondary alcohol 13a (5.95 g, 38.6 mmol) in
92% yield.
The ozonolysis of 7-membered ring a-methylene lactone
17d in CH2Cl2 at 278 8C followed by the reduction with
Ph3P gave the corresponding a-keto-g-lactone 17d0, which
does not equilibrate to its enol form 17d00 in CDCl3 as
judged from its 13C NMR spectrum (Eq. 7). The
characteristic peaks of the 13C NMR spectrum for
compound 17d0 are the absorptions at d 200.1 ppm for the
keto carbonyl carbon and at d 166.2 ppm for the lactone
carbonyl carbon. No absorption appeares between
100–160 ppm in 13C NMR spectrum indicates that there
is no enol isomer present in the solution (Eq. 7).
3. Conclusions
1
4.1.1. 1-Cyclohexylbut-3-en-1-ol (13a).41 92% Yield; H
In summary, we have developed a general methodology to
prepare the acyclic a-substituted acrylic acids and their
derivatives from the corresponding terminal alkenes. The
further cleavage of their a-methylene groups by the
ozonolysis gave the corresponding a-keto acid derivatives
in good yields. The reaction conditions in each step are quite
mild that substrates with labile functional groups can be
used. This methodology can also be applied to prepare 4- to
7-membered ring a-methylene lactones in good yields. For
the 5- and 7-membered ring a-methylenelactones, the
further cleavage of their a-methylene groups by the
ozonolysis in CH2Cl2 gave the corresponding a-keto
lactones in good yields. Their tautomeric ratio is ring-size
and substituent-dependent. For the 6-membered ring
a-methylene lactones, the further cleavage of their
a-methylene groups by the ozonolysis in the presence of
methanol gave the skeletal rearranged 5-membered ring
lactols in good yields.
NMR (CDCl3, 400 MHz)
d
5.79–5.87 (m, 1H,
–CHvCH2), 5.11–5.16 (m, 2H, –CHvCH2), 3.37–3.41
(m, 1H, CH–OH), 2.30–2.40 (m, 1H, –CH2–CHvCH2),
2.05–2.15 (m, 1H, –CH2–CHvCH2), 1.01–1.77 (m,
11H); 13C NMR (CDCl3, 100 MHz) d 135.4, 117.7, 74.7,
43.0, 38.8, 29.1, 28.0, 26.5, 26.2, 26.1; IR (CH2Cl2, cm21):
3390 (OH), 3074, 2976, 2924, 2852, 1639, 1449, 985, 911;
MS m/z (rel intensity): 144 (Mþ218, 4), 113 (Mþ241, 2),
95 (100), 67 (18); HRMS Calcd for C10H18O–CH2-
CHvCH2 113.0967, found:113.0961.
4.1.2. 1-Cyclohexylpent-4-en-1-ol (13b).42 82% Yield,
TLC Rf¼0.32 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.80–5.87 (m, 1H, –CHvCH2), 4.94–5.06
(m, 2H, –CHvCH2), 3.34–3.38 (m, 1H, CH–OH), 2.25–
2.32 (m, 1H, –CH2–CHvCH2), 2.11–2.18 (m, 1H,
–CH2–CHvCH2), 1.01–1.77 (m, 13H); 13C NMR
(CDCl3, 100 MHz) d 138.8, 114.6, 75.7, 43.7, 33.3, 30.3,
29.2, 27.8, 26.5, 26.3, 26.2; IR (CH2Cl2, cm21): 3398 (OH),
3077, 1450, 1085, 985, 910; MS m/z (rel intensity): 168
(Mþ, 2), 111 (52), 109 (32), 83 (100), 55 (82); HRMS Calcd
for C11H20O 168.1514, found: 168.1516.
4. Experimental
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 ACP 300 and Bruker
Avance DPX400 spectrometer, and chemical shifts were
given in ppm downfield from tetramethylsilane (TMS). IR
spectra were taken with a Perkin–Elmer 682 spectro-
photometer and only noteworthy absorptions were listed.
Mass spectra were measured on a Micromass Trio-2000
4.1.3. 1-Cyclohexylhex-5-en-1-ol (13c).42 85% Yield, TLC
Rf¼0.34 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.76–5.83 (m, 1H, –CHvCH2), 4.91–5.01
(m, 2H, –CHvCH2), 3.32–3.34 (m, 1H, CH–O), 2.05–
2.07 (m, 2H, –CH2–CHvCH2), 1.06–1.76 (m, 15H); 13C
NMR (CDCl3, 100 MHz) d 138.8, 114.5, 76.0, 43.6, 33.7,
33.5, 29.2, 27.7, 26.5, 26.3, 26.2, 25.2; IR (CH2Cl2, cm21):
3323 (OH), 3076, 2978, 2924, 1450, 1086, 909; MS m/z (rel
intensity): 182 (Mþ, 7), 95 (33), 81 (36), 55 (39), 41 (52);
HRMS Calcd for C12H22O 182.1671, found: 182.1665.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4845
4.1.4. 1-Cyclohexylhept-6-en-1-ol (13d). 80% Yield, TLC
Rf¼0.35 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.76–5.82 (m, 1H, –CHvCH2), 4.89–5.00
(m, 2H, –CHvCH2), 3.31 (br, 1H, CH–OH), 2.03–2.05
(m, 2H, –CH2–CHvCH2), 0.86–1.76 (m, 17H); 13C NMR
(CDCl3, 100 MHz) d 138.9, 114.2, 76.0, 43.5, 33.9, 33.7,
29.2, 29.0, 27.7, 26.5, 26.3, 26.2, 25.4; IR (CH2Cl2, cm21):
3420 (OH), 3076, 2926, 1451, 1086; MS m/z (rel intensity):
196 (Mþ, 2), 113 (23), 95 (100), 69 (16), 55 (13); HRMS
Calcd for C13H24O 196.1827, found: 196.1835.
well-stirred suspension of copper(I) iodide (171 mg,
0.9 mmol) in 10 mL of THF at 25 8C. After the copper
iodide dissolved (ca. 30 min) the solution is cooled to
220 8C, and cyclohexene oxide (588 mg, 6 mmol) is added
dropwise. The reaction is warmed slowly to room
temperature and stirred at room temperature for 10 h. The
reaction mixture is poured into 10 mL of iced cold, saturated
NH4Cl solution. The aqueous phase is extracted with
saturated NaCl solution, dried over MgSO4, concentrated
and chromatographed on silica gel column to give the
alcohol 32a as colorless oil (789 mg, 5.64 mmol) in 94%
yield.
4.1.5. 2-Phenylhex-5-en-2-ol (24a).43 90% Yield, TLC
Rf¼0.35 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 7.24–7.46 (m, 5H), 5.76–5.85 (m, 1H,
–CHvCH2), 4.93–5.01 (m, 2H, –CHvCH2), 1.89–2.11
(m, 4H), 1.58 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 147.6,
138.7, 128.1, 126.5, 124.7, 114.5, 74.6, 43.0, 30.2, 28.4; IR
(CH2Cl2, cm21): 3420 (OH), 3025, 2926, 1638, 1456, 997,
912; MS m/z (rel intensity): 176 (Mþ, 7), 121 (100), 105
(22), 77 (12), 43 (43); HRMS Calcd for C12H16O 176.1201,
found: 176.1200.
4.2.1. trans-2-Allylcyclohexanol (32a).46 94% Yield, TLC
Rf¼0.30 (hexane/EtOAc¼3:1); 1H NMR (CDCl3,
400 MHz) d 5.78–5.84 (m, 1H, –CHvCH2), 4.96–5.04
(m, 2H, –CHvCH2), 3.19–3.23 (m, 1H, CH–OH), 2.41–
2.44 (m, 1H, –CH2–CHvCH2), 2.05–2.08 (m, 1H,
–CH2–CHvCH2), 0.91–1.94 (m, 9H); 13C NMR
(CDCl3, 100 MHz) d 137.4, 115.8, 74.4, 44.8, 37.2, 35.5,
30.2, 25.4, 24.8; IR (CH2Cl2, cm21): 3445 (OH), 3025,
2925, 1637, 1495, 1027; MS m/z (rel intensity): 122
(Mþ218, 62), 98 (59), 93 (56), 81 (100), 79 (58); HRMS
Calcd for C9H16O–H2O 122.1096, found: 122.1086.
4.1.6. 2-Phenylhept-6-en-2-ol (24b).44 81% Yield, TLC
Rf¼0.38 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 7.41–7.43 (m, 2H), 7.30–7.34 (m, 2H),
7.20–7.24 (m, 1H), 5.69–5.76 (m, 1H, –CHvCH2),
4.89–4.97 (m, 2H, –CHvCH2), 1.96–2.02 (m, 2H,
–CH2–CHvCH2), 1.77–1.82 (m, 2H), 1.54 (s, 3H),
1.35–1.38 (m, 1H), 1.23–1.35 (m, 1H); 13C NMR
(CDCl3, 100 MHz) d 147.9, 138.6, 128.1, 126.5, 124.7,
114.6, 74.6, 43.6, 33.9, 30.1, 23.2; IR (CH2Cl2, cm21): 3407
(OH), 3063, 2929, 1753, 1678, 1493, 997, 911; MS m/z (rel
intensity): 190 (Mþ, 3), 175 (8), 121 (100), 105 (13), 43
(37); HRMS Calcd for C13H18O 190.1358, found: 190.1351.
4.2.2. trans-2-But-3-enylcyclohexanol (32b). 90% Yield,
TLC Rf¼0.33 (hexane/EtOAc¼3:1); 1H NMR (CDCl3,
400 MHz) d 5.79–5.86 (m, 1H, –CHvCH2), 4.92–5.04
(m, 2H, –CHvCH2), 3.36–3.41 (m, 1H, CH–OH), 2.18–
2.22 (m, 1H, –CH2–CHvCH2), 2.11–2.15 (m, 1H,
–CH2–CHvCH2), 1.18–1.85 (m, 11H); 13C NMR
(CDCl3, 100 MHz) d 138.7, 114.5, 75.3, 46.3, 35.2, 30.1,
29.1, 28.5, 25.6, 25.5; IR (CH2Cl2, cm21): 3398 (OH), 3014,
1455, 1055; MS m/z (rel intensity): 136 (Mþ218, 30), 97
(Mþ257, 30), 81 (100), 67 (48), 43 (40), 41 (63); HRMS
Calcd for C10H18O 154.1358, found: 154.1361.
4.1.7. 1-But-3-enylcyclohexanol (24c).45 86% Yield, TLC
Rf¼0.4 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.80–5.90 (m, 1H, –CHvCH2), 4.93–5.05
(m, 2H, CHvCH2), 2.13–2.15 (m, 2H, CH2–CHvCH2),
1.27–1.70 (m, 12H); 13C NMR (CDCl3, 100 MHz) d 139.3,
114.2, 71.3, 41.4, 37.4, 27.4, 25.8, 22.2; IR (CH2Cl2, cm21):
3375 (OH), 3077, 2923, 2852, 1640, 1450, 985, 912; MS
m/z (rel intensity): 136 (Mþ218), 99 (65), 98 (100), 81 (50),
55 (63); HRMS Calcd for C10H18O–H2O 136.1252, found:
136.1249.
4.3. General procedure to prepare the acetate from the
corresponding alcohol
To a solution of secondary alcohol 13a (1.0 g, 6.5 mmol),
pyridine (0.63 mL, 7.8 mmol) and a catalytic amount of
DMAP (N,N-dimethylaminopyridine, 9.52 mg, 0.78 mmol)
in 25 mL of CH2Cl2 was added acetic anhydride (0.74 mL,
7.8 mmol). The reaction mixture was stirred at room
temperature for 10 h. The reaction mixture was concen-
trated, chromatographed on silica gel column to give the
corresponding acetate 14a (1.27 g, 6.5 mmol) in 95% yield.
4.1.8. 1-Pent-4-enylcyclohexanol (24d).45 80% Yield, TLC
Rf¼0.42 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.78–5.85 (m, 1H, –CHvCH2), 4.93–5.03
(m, 2H, CHvCH2), 2.05–2.06 (m, 2H, CH2–CHvCH2),
1.43–1.58 (m, 14H); 13C NMR (CDCl3, 100 MHz) d 138.8,
114.4, 71.3, 41.8, 37.3, 34.2, 25.8, 22.2, 22.1; IR (CH2Cl2,
cm21): 3330 (OH), 3077, 2928, 2856, 1640, 1449, 997, 910;
MS m/z (rel intensity): 150 (Mþ218, 33), 99 (62), 98 (100),
81 (41), 55 (36); HRMS Calcd for C11H20O–H2O 150.1409,
found: 150.1402.
4.3.1. 1-Cyclohexylbut-3-enyl acetate (14a).47 95% Yield;
1H NMR (CDCl3, 400 MHz) d 5.71–5.77 (m, 1H,
–CHvCH2), 5.02–5.08 (m, 2H, –CHvCH2), 4.76–4.80
(m, 1H, CH–OAc), 2.20–2.40 (m, 2H, –CH2–CHvCH2),
2.03 (s, 3H, –COCH3), 0.99–1.75 (m, 11H); 13C NMR
(CDCl3, 100 MHz) d 170.7, 134.2, 117.2, 76.7, 40.7, 35.9,
29.0, 28.1, 26.3, 26.0, 25.9, 21.0; IR (CH2Cl2, cm21): 3077,
2928, 2854, 1738, 1644, 1540, 1449, 1371, 914, 834; MS
m/z (rel intensity): 155 (Mþ241, 15), 136 (Mþ260, 8), 95
(100), 83 (34), 69 (26), 55 (40); HRMS Calcd for
C12H20O2–CH2CHvCH2 155.1072, found:. 155.1070.
4.2. General procedure to prepare the secondary alcohol
from Grignard reagent with epoxide
Allylmagnesium bromide obtained from allyl bromide
(847 mg, 7.0 mmol) and magnesium powder (243 mg,
10.0 mmol) in THF. The Grignard reagent was added to a
4.3.2. 1-Cyclohexylpent-4-enyl acetate (14b). 93% Yield,
TLC Rf¼0.7 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,

4846
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
400 MHz) d 5.75–5.82 (m, 1H, –CHvCH2), 4.93–5.01
(m, 2H, –CHvCH2), 4.73–4.78 (m, 1H, CH–OAc), 2.00–
2.04 (m, 2H, –CH2–CHvCH2), 2.01 (s, 3H, –COCH3),
0.98–1.74 (m, 13H); 13C NMR (CDCl3, 100 MHz) d 170.4,
138.1, 114.7, 77.4, 41.3, 30.5, 29.8, 28.9, 28.1, 26.4, 26.1,
26.0, 21.1; IR (CH2Cl2, cm21): 3077, 2927, 2854, 1737,
1449, 1371, 940, 912; MS m/z (rel intensity): 210 (Mþ, 3),
95 (12), 43 (100), 41 (24), 32 (42); HRMS Calcd for
C13H22O2 210.1620, found: 210.1621.
2.02 (s, 3H, –COCH3), 1.94–2.01 (m, 2H), 1.24–1.51 (m,
10H); 13C NMR (CDCl3, 100 MHz) d 170.3, 138.6, 114.3,
83.6, 36.6, 34.5, 27.5, 25.5, 22.2, 21.8; IR (CH2Cl2, cm21):
3077, 2933, 2860, 1731, 1450, 1367, 963, 910; MS m/z (rel
intensity): 141 (Mþ255, 10), 136 (Mþ260, 60), 98 (80), 80
(62), 55 (91), 43 (100); HRMS Calcd for C12H20O2
196.1463, found: 196.1472.
4.3.8. 1-Pent-4-enylcyclohexyl acetate (25d). 92% Yield,
TLC Rf¼0.60 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.69–5.77 (m, 1H, –CHvCH2), 4.88–4.96
(m, 2H, –CHvCH2), 2.11–2.14 (m, 2H, –CH2–
CHvCH2), 1.95 (s, 3H, –COCH3), 1.96–1.99 (m, 2H),
1.80–1.84 (m, 2H), 1.18–1.47 (m, 10H); 13C NMR (CDCl3,
100 MHz) d170.2, 138.5, 114.4, 83.7, 36.9, 34.4, 33.8, 25.5,
22.3, 22.0, 21.7; IR (CH2Cl2, cm21): 3077, 2932, 2861,
1732, 1449, 1366, 966, 910; MS m/z (rel intensity): 150
(Mþ260, 18), 109 (40), 99 (100), 81 (48), 67 (43); HRMS
Calcd for C13H22O2 210.1620, found: 210.1622.
4.3.3. 1-Cyclohexylhex-5-enyl acetate (14c). 90% Yield,
TLC Rf¼0.7 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.70–5.76 (m, 1H, –CHvCH2), 4.89–4.97
(m, 2H, –CHvCH2), 4.70–4.71 (m, 1H, CH–OAc), 1.98–
2.02 (m, 2H, –CH2–CHvCH2), 2.00 (s, 3H, –COCH3),
0.97–1.67 (m, 15H); 13C NMR (CDCl3, 100 MHz) d 170.7,
138.3, 114.6, 77.6, 41.2, 33.5, 30.5, 28.9, 28.0, 26.3, 26.04,
26.00, 24.6, 20.9; IR (CH2Cl2, cm21): 3075, 2928, 2854,
1736, 1449, 1371, 965, 909; MS m/z (rel intensity): 181
(Mþ243, 3), 95 (18), 81 (21), 43 (100), 32 (51); HRMS
Calcd for C14H24O2 224.1776, found: 224.1767.
4.3.9. trans-2-Allylcyclohexyl acetate (33a). 96% Yield,
TLC Rf¼0.7 (hexane/EtOAc¼3:1); 1H NMR (CDCl3,
400 MHz) d 5.66–5.70 (m, 1H, –CHvCH2), 4.90–4.95
(m, 2H, –CHvCH2), 4.44–4.48 (m, 1H, CHOAc), 2.17–
2.20 (m, 2H), 0.98–1.98 (m, 9H), 1.97 (s, 3H, –COCH3);
13C NMR (CDCl3, 100 MHz) d 170.4, 136.3, 115.9, 76.3,
41.6, 36.8, 31.7, 30.1, 25.0, 24.4, 21.1; IR (CH2Cl2, cm21):
3014, 2953, 2868, 1736, 1371, 944, 913; MS m/z (rel
intensity): 140 (Mþ242, 20), 122 (100), 107 (33), 93 (52).
4.3.4. 1-Cyclohexylhept-6-enyl acetate (14d). 91% Yield;
1H NMR (CDCl3, 400 MHz) d 5.76–5.82 (m, 1H,
–CHvCH2), 4.92–5.01 (m, 2H, –CHvCH2), 4.72–4.75
(m, 1H, CH–OAc), 2.03–2.05 (m, 2H, –CH2–CHvCH2),
2.04 (s, 3H, –COCH3), 0.98–1.67 (m, 17H); 13C NMR
(CDCl3, 100 MHz) d 170.9, 138.8, 114.3, 77.9, 41.2, 33.6,
31.0, 29.0, 28.8, 28.1, 26.4, 26.12, 26.05, 24.9, 21.1; IR
(CH2Cl2, cm21): 3076, 2928, 2854, 1735, 1639, 1540, 1450,
1370, 1242, 1019, 993, 970; MS m/z (rel intensity): 238
(Mþ, 4), 167 (Mþ260, 8), 149 (24), 111 (54), 95 (68), 83
(100), 71 (48), 69 (51), 57 (76), 55 (98); HRMS Calcd for
C15H26O2 238.1933, found:.238.1937.
4.3.10. trans-2-But-3-enylcyclohexyl acetate (33b). 97%
Yield, TLC Rf¼0.7 (hexane/EtOAc¼3:1); 1H NMR
(CDCl3, 400 MHz) d 5.74–5.97 (m, 1H, –CHvCH2),
4.92–5.00 (m, 2H, –CHvCH2), 4.81–4.86 (m, 1H,
CHOAc), 2.02–2.05 (m, 3H), 1.28–1.65 (m, 10H), 2.03
(s, 3H, –COCH3); 13C NMR (CDCl3, 100 MHz) d 170.9,
138.0, 114.7, 76.7, 43.8, 32.7, 29.7, 28.9, 28.5, 25.4, 25.2,
21.1; IR (CH2Cl2, cm21): 3071, 2950, 1738, 1450, 1373,
944, 912; MS m/z (rel intensity): 154 (Mþ242, 2), 95 (31),
81 (23), 43 (100), 41 (28).
4.3.5. 2-Phenylhex-5-enyl acetate (25a). 93% Yield, TLC
Rf¼0.50 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 7.22–7.35 (m, 5H), 5.70–5.79 (m, 1H,
–CHvCH2), 4.91–5.00 (m, 2H, –CHvCH2), 1.94–2.16
(m, 4H), 2.05 (s, 3H, –COCH3), 1.86 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 169.5, 144.7, 138.0, 128.1, 127.0,
124.4, 114.5, 83.7, 41.5, 28.1, 24.9, 22.1; IR (CH2Cl2,
cm21): 3024, 2934, 1736, 1639, 1496, 1367, 1014, 734; MS
m/z (rel intensity): 158 (Mþ260, 18), 143 (19), 121 (100),
105 (21), 43 (20); HRMS Calcd for C14H18O2 218.1307,
found: 218.1311.
4.4. General procedure to prepare the benzoate from the
corresponding alcohol by Mitsunobu reaction
To a stirred suspension of Ph3P (2.24 g, 8.57 mmol) and
benzoic acid (1.05 g, 8.57 mmol) in toluene (25 mL) cooled
to 230 8C was added a solution of secondary alcohol 32a
(1000 mg, 7.14 mmol) in toluene (5 mL). A solution of
DEAD (diethyl azodicarboxylate, 1.492 g, 8.57 mmol) in
toluene (10 mL) was added dropwise over 15 min to the
vigorously stirred mixture while the temperature was
maintained at 230 8C. When the addition was complete
the mixture was allowed to warm gradually to 0 8C over 1 h
where upon saturated aqueous sodium bicarbonate 30 (mL)
was added. The aqueous phase was separated and extracted
with ethyl acetate. The organic extracts were combined,
dried, concentrated and chromatographed on silica gel
column to give the benzoate 33c (1.39 g, 5.71 mmol) in 80%
yield.
4.3.6. 2-Phenylhept-6-enyl acetate (25b). 91% Yield, TLC
Rf¼0.51 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 7.20–7.33 (m, 5H), 5.68–5.75 (m, 1H,
–CHvCH2), 4.90–4.98 (m, 2H, –CHvCH2), 1.95–2.05
(m, 4H), 2.04 (s, 3H, –COCH3), 1.82 (s, 3H), 1.27–1.31 (m,
2H); 13C NMR (CDCl3, 100 MHz) d 169.5, 144.9, 138.3,
128.1, 126.7, 124.4, 114.6, 83.9, 41.9, 33.6, 24.8, 22.9, 22.1;
IR (CH2Cl2, cm21): 3027, 2937, 1734, 1640, 1496, 1364,
1016, 735; MS m/z (rel intensity): 232 (Mþ, 2), 163 (23),
131 (13), 121 (100), 43 (27); HRMS Calcd for C15H20O2
232.1463, found: 232.1470.
4.3.7. 1-But-3-enylcyclohexyl acetate (25c).48 94% Yield,
TLC Rf¼0.60 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.75–5.82 (m, 1H, –CHvCH2), 4.91–5.02
(m, 2H, –CHvCH2), 2.17–2.21 (m, 2H, CH2–CHvCH2),
4.4.1. cis-2-Allylcyclohexyl benzoate (33c).49 80% Yield;
1H NMR (CDCl3, 400 MHz) d 8.07–8.09 (m, 2H), 7.41–
7.55 (m, 3H), 5.73–5.80 (m, 1H, –CHvCH2), 5.27 (br s,

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4847
1H, CHOCOPh), 4.92–4.98 (m, 2H, –CHvCH2), 1.26–
2.15 (m, 11H); 13C NMR (CDCl3, 100 MHz) d 165.7, 136.5,
132.6, 130.9, 129.4, 128.2, 116.1, 72.4, 40.4, 36.9, 30.1,
27.4, 25.1, 20.9; IR (CH2Cl2, cm21): 3031, 2930, 2857,
1715, 1490, 1358, 1069; MS m/z (rel intensity): 244 (Mþ,
3), 202 (8), 122 (53), 105 (100), 77 (27); HRMS Calcd for
C16H20O2 244.1463, found: 244.1469.
4.5.3. 2-(2-Allylphenoxy)tetrahydropyran (38). 92%
Yield, TLC Rf¼0.83 (hexane/EtOAc 10¼1); 1H NMR
(CDCl3, 400 MHz) d 7.09–7.25 (m, 3H, Ph), 6.92–6.95 (m,
1H, Ph), 5.95–6.05 (m, 1H), 5.42 (br t, J¼3.2 Hz, 1H),
5.02–5.10 (m, 2H), 3.87–3.90 (m, 1H), 3.59–3.62 (m, 1H),
3.42–3.44 (m, 2H), 1.61–1.89 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 154.7, 137.2, 129.8, 129.1, 127.3, 121.3, 115.2,
114.2, 96.1, 61.8, 34.7, 30.5, 25.3, 18.8; IR (CH2Cl2, cm21):
2942, 2875, 1490, 1455, 1355, 1236, 1201, 1125, 1037, 970;
MS m/z (rel intensity): 218 (Mþ, 5), 134 (80), 133 (12), 119
(15), 115 (12), 91 (16), 85 (100), 57 (28); HRMS Calcd for
C14H18O2 218.1307, found: 218.1302.
4.4.2. cis-2-But-3-enylcyclohexyl benzoate (33d). 68%
Yield, TLC Rf¼0.78 (hexane/EtOAc¼3:1); 1H NMR
(CDCl3, 400 MHz) d 8.05–8.07 (m, 2H), 7.42–7.57 (m,
3H), 5.79–5.85 (m, 1H, –CHvCH2), 5.13–5.18 (m, 1H,
CHOCOPh), 4.94–5.04 (m, 2H, –CHvCH2), 2.13–2.15
(m, 2H), 1.27–1.28 (m, 11H); 13C NMR (CDCl3, 100 MHz)
d 166.3, 138.0, 132.6, 130.7, 129.5, 128.3, 114.8, 77.5, 43.9,
32.9, 29.7, 29.0, 28.5, 25.5, 25.3; IR (CH2Cl2, cm21): 3032,
2949, 2867, 1715, 1451, 1069; MS m/z (rel intensity): 258
(Mþ, 1), 121 (41), 105 (100), 77 (62), 67 (28); HRMS Calcd
for C17H22O2 258.1620, found: 258.1629.
4.5.4. 3-[2-(Tetrahydropyran-2-yloxy)phenyl]propan-1-
ol (44). To a solution of 9-BBN in hexane (0.4 M in hexane,
2.6 mL, 1.04 mmol) was added a solution of alkene 38
(200 mg, 0.92 mmol) in anhydrous benzene (2 mL) drop-
wise over 20 min while the temperature was maintained
under refluxing condition. After stirring under refluxing
condition for 2 h, the resulting solution was cooled to 50 8C.
To the resulting solution was added a mixture of 6N NaOH
(1 mL) and hydrogen peroxide (30 wt% solution in water,
2 mL) dropwise over 5 min and stirred at 50 8C for 1 h. The
reaction mixture was cooled to room temperature and
saturated aqueous K2CO3 (10 mL) was added. The aqueous
phase was separated and extracted with ether. The organic
extracts were combined, dried, concentrated and chromato-
graphed on silica gel column to give the alcohol 44 (141 mg,
0.60 mmol) in 65% yield. TLC Rf¼0.23 (hexane/
4.5. General procedure to prepare the tetrahydro-
pyranyl ether from the corresponding alcohol
To a solution of alcohol 13a (1.00 g, 6.5 mmol) and 3,4-
dihydro-2H-pyran (0.65 mL, 7.2 mmol) in 20 mL of
dichloromethane was added ATPB (0.26 g, 0.65 mmol)
and the solution was stirred at room temperature. The
reaction was complete in 30 min. The solution was
concentrated and chromatographed on silica gel column to
give the desired 18a (1.47 g, 6.17 mmol) in 95% yield as a
mixture of two diastereomers.
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 7.09–7.17
(m, 3H, Ph), 6.92–6.94 (m, 1H, Ph), 5.41–5.43 (m, 1H),
3.80–3.90 (m, 1H), 3.60–3.64 (m, 3H), 2.74–2.78 (m, 2H),
1.63–1.92 (m, 9H); 13C NMR (CDCl3, 100 MHz) d 154.8,
130.6, 130.0, 127.0, 121.5, 114.3, 96.4, 62.1, 61.9, 33.0,
30.5, 26.2, 25.1, 19.0; IR (CH2Cl2, cm21): 3366, 2923,
2851, 1594, 1455, 1355, 1235, 1118, 1053, 978, 751; MS
m/z (rel intensity): 236 (Mþ, 2), 152 (60), 134 (58), 107 (38),
85 (100), 67 (28), 57 (30); HRMS Calcd for C14H20O3
236.1412, found: 236.1410.
4.5.1. 2-(1-Cyclohexylbut-3-enyloxy)tetrahydropyran
(18a). 95% Yield, a mixture of two diastereomers; 1H
NMR (CDCl3, 400 MHz)
d
5.74–5.88 (m, 1H,
–CHvCH2), 4.97–5.04 (m, 2H, –CHvCH2), 4.66 and
4.64 (br, 1H, O–CH–O), 3.80–3.97 (m, 1H, CH–OTHP),
3.41–3.45 (m, 2H, CH2–O–CH), 2.31–2.33 (m, 2H,
–CH2–CHvCH2), 1.01–1.69 (m, 17H); 13C NMR
(CDCl3, 100 MHz) d 135.8, 135.1, 116.4, 115.9, 99.4,
96.8, 81.9, 79.3, 62.5, 62.4, 41.3, 40.6, 36.7, 34.6,
30.92, 30.91, 29.0, 28.8, 28.7, 26.6, 26.3, 26.27, 26.25,
26.22, 25.5, 19.8; IR (CH2Cl2, cm21): 3076, 2926, 2861,
1439, 1132, 1024; MS m/z (rel intensity): 136
(Mþ2HOTHP, 37), 111 (38), 83 (72), 55 (63), 41 (100);
HRMS Calcd for C15H26O2–C5H10O2 136.1252, found:
136.1247.
4.5.5. 3-[2-(Tetrahydropyran-2-yloxy)phenyl]propional-
dehyde (45). To a mixture of alcohol 44 (200 mg,
˚
0.85 mmol), 4 A molecular sieve (200 mg), and sodium
acetate (83.7 mg, 1.02 mmol) in 5 mL of CH2Cl2 was added
PCC (pyridinium chloroformate, 220 mg, 1.02 mmol) at
room temperature. After stirring at room temperature for
2 h, the reaction mixture was concentrated. The crude
residue was added 10 mL of ether. The solution was filtered
and the chromium salt was washed three times with 5 mL of
ether. The combined filtrates were evaporated and the
residue was chromatograped on silica gel column to give the
aldehyde 45 (141 mg, 0.60 mmol) in 71% yield. TLC
Rf¼0.55 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 9.82 (s, 1H, CHO), 7.09–7.19 (m, 3H, Ph),
6.89–6.93 (m, 1H, Ph), 5.42–5.44 (m, 1H), 4.81–4.92 (m,
1H), 4.55–4.65 (m, 1H), 2.96–3.00 (m, 2H), 2.75–2.78 (m,
2H), 1.26–1.88 (m, 6H); 13C NMR (CDCl3, 100 MHz) d
202.0, 154.7, 129.8, 129.0, 127.5, 121.3, 114.1, 96.1, 62.0,
44.0, 30.4, 25.1, 23.5, 18.9; IR (CH2Cl2, cm21): 3030, 2942,
2875, 1719, 1490, 1237, 1123, 1036, 966, 754; MS m/z (rel
intensity): 234 (Mþ, 4), 166 (12), 152 (18), 150 (24), 134
(24), 85 (100), 67 (16), 57 (16); HRMS Calcd for C14H18O3
234.1256, found: 234.1248.
4.5.2. 2-(1-Cyclohexylhep-6-enyloxy)tetrahydropyran
(18d). 89% Yield, TLC Rf¼0.82 (hexane/EtOAc¼10:1), a
mixture of two diastereomers; 1H NMR (CDCl3, 400 MHz)
d 5.77–5.82 (m, 1H, CHvCH2), 4.90–5.00 (m, 2H,
CHvCH2), 4.63 and 4.59 (br, 1H, O–CH–O), 3.89–3.90
(m, 1H, CH–OTHP), 3.35–3.47 (m, 2H, CH2–O–CH),
2.03–2.05 (m, 2H, CH2–CHvCH2), 1.01–1.81 (m, 23H);
13C NMR (CDCl3, 100 MHz) d 139.1, 138.9, 114.2, 114.1,
98.9, 97.5, 82.0, 80.6, 62.8, 62.6, 41.4, 40.7, 33.8, 33.7,
31.6, 31.2, 31.1, 29.6, 29.2, 28.9, 28.5, 26.7, 26.5, 26.48,
26.42, 25.6, 25.5, 24.5, 20.1, 19.9; IR (CH2Cl2, cm21):
3076, 2925, 1453, 1114, 1077; MS m/z (rel intensity):
281 (Mþþ1, 4), 197 (Mþ283, 8), 97 (18), 85 (100), 55 (10),
41 (8); HRMS Calcd for C18H32O2 280.2402, found:
280.2401.

4848
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4.6. General procedure to prepare the azide from the
corresponding alcohol by modified Mitsunobu reaction
CaCl2 drying tube and a magnetic stirring bar is charged
with terminal alkene 14b (400 mg, 1.9 mmol) in CH2Cl2
(10 mL). The flask is cooled to 278 8C and ozone is bubbled
through the solution. When the solution turns blue, ozone
addition is stopped. Nitrogen is passed through the solution
until the blue color is discharged. A mixture of Et2NH
(2.94 mL, 28.5 mmol) and CH2Br2 (0.67 mL, 9.5 mmol)
was heated to 55 8C for 1.5 h to give a yellow solution and
then cooled to room temperature. To a solution of ozonide in
CH2Cl2 generated above was added a preheated mixture of
Et2NH and CH2Br2 at 278 8C. After the addition, the
cooling bath was removed and the reaction mixture was
stirred at room temperature. 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 product 15b (297.9 mg, 1.33 mmol) in 70%
yield.
To a mixture of alcohol 12c (1.0 g, 5.90 mmol) and Ph3P
(1.87 g, 7.14 mmol) in18 mLof THF was subsequentlyadded
DEAD (1.24 g, 7.14 mmol) and diphenylphosphonic azide
(1.96 g, 7.14 mmol) in the dark at room temperature. After
stirring at room temperature for 6 h, the reaction mixture was
concentrated and chromatographed on silica gel column to
give azido compound 49c (0.97 g, 5.01 mmol) in 85% yield.
4.6.1. (1-Azidopent-4-enyl)cyclohexane (49c). 85% Yield,
TLC Rf¼0.86 (hexane/EtOAc¼5:1); 1H NMR (CDCl3,
400 MHz) d 5.74–5.85 (m, 1H, –CHvCH2), 4.99–5.09 (m,
2H, –CHvCH2), 3.08–3.11 (m, 1H, CHN3), 2.13–2.24 (m,
2H, –CH2–CvCH2), 1.07–1.78 (m, 13H); 13C NMR
(CDCl3, 100 MHz) d 137.6, 115.3, 68.0, 42.4, 30.8, 30.6,
29.9, 28.6, 26.3, 26.2, 26.1; IR (CH2Cl2, cm21): 2996, 2094,
1640, 1448, 1088, 910; MS m/z (rel intensity): 193 (Mþ, 3),
192 (20), 138 (30), 95 (25), 83 (47), 67 (31), 55 (100), 41 (67);
HRMS Calcd for C11H19N3 193.1579, found: 193.1577.
4.7.1. 1-Cyclohexyl-3-formylbut-3-enyl acetate (15b).
1
70% Yield, TLC Rf¼0.6 (hexane/EtOAc¼10:1); H NMR
4.6.2. (1-Azidohex-5-enyl)cyclohexane (49d). 78% Yield,
TLC Rf¼0.97 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 5.77–5.84 (m, 1H, –CHvCH2), 4.96–5.05
(m, 2H, –CHvCH2), 3.00–3.10 (m, 1H), 2.08–2.10 (m,
2H), 1.12–1.79 (m, 15H); 13C NMR (CDCl3, 100 MHz) d
138.3, 114.9, 68.6, 42.3, 33.5, 30.8, 30.0, 28.6, 26.3, 26.2,
26.1, 25.7; IR (CH2Cl2, cm21): 3076, 2928, 2854, 2095,
1640, 1449, 1259, 991, 911, 741; MS m/z (rel intensity): 207
(Mþ, 4), 179 (20), 136 (28), 124 (22), 97 (100), 96 (84), 82
(52), 69 (46), 57 (24), 55 (84); HRMS Calcd for C12H21N3
207.1735, found: 207.1742.
(CDCl3, 400 MHz) d 9.43 (s, 1H, CHO), 6.22 (s, 1H,
–CvCH2), 5.97 (s, 1H, –CvCH2), 4.77–4.81 (m, 1H,
CHOAc), 2.55–2.59 (m, 1H, –CH2–CvCH2), 2.27–2.30
(m, 1H, –CH2–CvCH2), 1.90 (s, 3H, –COCH3), 0.98–
1.69 (m, 11H); 13C NMR (CDCl3, 100 MHz) d 193.7, 170.4,
146.6, 135.2, 75.5, 41.5, 29.8, 28.8, 27.9, 26.1, 25.8, 25.8,
20.8; IR (CH2Cl2, cm21): 3089, 2853, 1732, 1695, 1452,
988; MS m/z (rel intensity): 164 (Mþ260, 3), 95 (26), 88
(30), 55 (38), 43 (100); HRMS Calcd for C13H20O3–
CH3CO2H 164.1201, found: 164.1205.
4.7.2. 1-Cyclohexyl-4-formylhex-4-enyl acetate (15c).
65% Yield, TLC Rf¼0.62 (hexane/EtOAc¼10:1); 1H
NMR (CDCl3, 400 MHz) d 9.46 (br s, 1H, CHO), 6.22 (s,
1H, –CvCH2), 5.95 (s, 1H, –CvCH2), 4.67–4.69 (m, 1H,
CHOAc), 2.00–2.15 (m, 2H, –CH2–CvCH2), 1.99 (s, 3H,
–COCH3), 0.91–1.68 (m, 13H); 13C NMR (CDCl3,
100 MHz) d 194.3, 170.8, 149.5, 134.2, 77.0, 41.0, 29.1,
28.8, 28.0, 26.2, 25.9, 25.8, 23.9, 20.9; IR (CH2Cl2, cm21):
3088, 2853, 1731, 1696, 1450, 1085; MS m/z (rel intensity):
195 (Mþ243, 10), 178 (25), 113 (73), 95 (50), 55 (37);
HRMS Calcd for C14H22O3–CH3CO 195.1385, found:
195.1384.
4.6.3. (1-Cyclohexylhex-5-enyl)carbamic acid methyl
ester (53d). To a solution of the azide 49d (4.0 g,
19.33 mmol) in THF (18 mL) was added a solution of
Ph3P (5.57 g, 21.3 mmol) in 2 mL of THF (2 mL) at 40 8C
for 30 min. The resulted solution was added H2O (0.4 mL,
22 mmol) and stirred at room temperature for 10 h. The
resulted solution was treated with K2CO3 (3.3 g,
24.4 mmol) in 20 mL of water and stirred for 20 min
whereupon methyl chloroformate (2.5 g, 24.4 mmol) was
added. After stirring for 1 h, the aqueous phase was
separated and extracted with ethyl acetate. The organic
extracts were combined, dried, concentrated and chromato-
graphed on silica gel column to give the benzoate 53d
(2.31 g, 9.67 mmol) in 50% yield. TLC Rf¼0.73 (hexane/
EtOAc¼1:1); 1H NMR (CDCl3, 400 MHz) d 5.75–5.81 (m,
1H), 4.93–5.03 (m, 2H), 4.38–4.41 (m, 1H), 3.65 (s, 3H),
3.46–3.49 (m, 1H), 2.03–2.07 (m, 2H), 1.50–1.76 (m, 4H),
0.96–1.23 (m, 11H); 13C NMR (CDCl3, 100 MHz) d 157.0,
138.6, 114.6, 55.6, 51.9, 42.3, 33.6, 31.7, 29.6, 28.1, 26.4,
26.24, 26.22, 25.4; IR (CH2Cl2, cm21): 3321, 2925, 2851,
1698, 1540, 1456, 1255, 649; MS m/z (rel intensity): 239
(Mþ, 5), 170 (31), 156 (100), 114 (28), 88 (45), 81 (49), 76
(56), 55 (15); HRMS Calcd for C14H25NO2 239.1885,
found: 239.1875.
4.7.3. 1-Cyclohexyl-5-formylhex-5-enyl acetate (15d).
1
73% Yield; H NMR (CDCl3, 400 MHz) d 9.53 (s, 1H),
6.24 (s, 1H, CvCH2), 5.99 (s, 1H, CvCH2), 4.72–4.77 (m,
1H, CHOCO), 2.23–2.25 (m, 2H), 2.04 (s, 3H, –COCH3),
1.47–1.75 (m, 9H), 1.00–1.18 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 194.4, 170.9, 149.9, 134.0, 77.5, 41.2, 30.7,
28.9, 28.1, 27.6, 26.3, 26.04, 25.97, 23.7, 21.0; IR (CH2Cl2,
cm21): 2929, 2854, 1731, 1696, 1507, 1449, 1371, 1243,
1020, 963, 733; MS m/z (rel intensity): 192 (Mþ260, 24),
109 (44), 95 (40), 81 (100), 67 (36), 55 (56); HRMS Calcd
for C15H24O3–HOAc 192.1514, found: 192.1516.
4.7.4. 2-[Cyclohexyl(tetrahydropyran-2-yloxy)methyl]-
propenal (19a). 58% Yield, TLC Rf¼0.65 (hexane/
4.7. General procedure to prepare the a-substituted
acrolein from terminal alkene
1
EtOAc¼10:1); A mixture of two diastereomers; H NMR
(CDCl3, 400 MHz) d 9.55 (s, 0.6H, CHO), 9.50 (s, 0.4H,
CHO), 6.44 (s, 0.4H, –CvCH2), 6.27 (s, 0.6H, –CvCH2),
A two-necked flask fitted with a glass tube to admit ozone, a

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4849
6.13 (s, 0.6H, –CvCH2), 6.08 (s, 0.4H, –CvCH2), 4.21–
4.43 (m, 2H, O–CH–O), 3.82–3.87 (m, 1H), 3.41–3.44 (m,
1H, CH2–O–CH), 1.44–1.83 (m, 17H), 0.87–1.21 (m,
7H); 13C NMR (CDCl3, 100 MHz) d 193.5, 193.2, 150.6,
149.2, 134.9, 100.9, 95.3, 78.1, 74.9, 63.0, 62.1, 42.2, 42.0,
30.6, 30.5, 29.6, 29.5, 29.2, 28.1, 27.7, 26.34, 26.32, 26.14,
26.07, 25.97, 25.92, 25.35, 25.24, 19.8, 19.3; IR (CH2Cl2,
cm21): 2997, 2853, 1689, 1450, 1024, 971; MS m/z (rel
intensity): 151 (Mþ2OTHP, 6), 84 (46), 67 (20), 55 (58), 41
(100); HRMS Calcd for C15H24O3–C5H9O2 151.1123,
found: 151.1114.
4.7.9. 1-(3-Formylbut-3-enyl)cyclohexyl acetate (26d).
1
85% Yield, TLC Rf¼0.5 (hexane/EtOAc¼10:1); H NMR
(CDCl3, 400 MHz) d 9.45 (s, 1H, CHO), 6.19 (s, 1H,
–CvCH2), 5.92 (s, 1H, –CvCH2), 2.12–2.16 (m, 4H),
1.94 (s, 3H, –COCH3), 1.92–1.96 (m, 2H), 1.18–1.46 (m,
8H); 13C NMR (CDCl3, 100 MHz) d 194.3, 170.1, 149.9,
133.7, 83.2, 35.2, 34.3, 25.4, 22.0, 21.6, 21.2; IR (CH2Cl2,
cm21): 3086, 2934, 2860, 1731, 1690, 1450, 1367, 1041;
MS m/z (rel intensity): 165 (Mþ259, 44), 164 (100), 146
(50), 99 (76), 43 (88); HRMS Calcd for C13H20O3 224.1412,
found: 224.1405.
4.7.5. 2-[4-Cyclohexyl-4-(tetrahydropyran-2-yloxy)-
butyl]propenal (19d). 76% Yield, TLC Rf¼0.69 (hexane/
EtOAc¼10:1); A mixture of the diastereomers, ratio¼1:1;
1H NMR (CDCl3, 400 MHz) d 9.50 (s, 1H, CHO), 6.23 (s,
0.5H, CvCH2), 6.21 (s, 0.5H, CvCH2), 5.96 (s, 1H,
CvCH2), 4.57–4.58 (m, 1H, O–CH–O), 4.52–4.59 (m,
1H, O–CH–O), 3.84–3.86 (m, 1H, CH2–O–CH), 3.34–
3.44 (m, 2H, CH–OTHP), 2.19–2.20 (m, 2H, CH2–
CvCH2), 1.43–1.71 (m, 16H), 0.94–1.21 (m, 5H); 13C
NMR (CDCl3, 100 MHz) d 194.6, 194.5, 150.3, 150.2,
133.83, 133.81, 99.1, 97.6, 81.7, 80.4, 62.9, 62.6, 41.4, 40.8,
31.2, 31.1, 29.0, 28.7, 28.5, 28.4, 27.9, 27.7, 26.6, 26.39,
26.37, 26.35, 26.32, 25.5, 25.4, 23.6, 20.2, 19.8; IR
(CH2Cl2, cm21): 3085, 2923, 1693, 1451, 1029; MS m/z
(rel intensity): 276 (Mþ218, 8), 211 (10), 175 (21), 85
(100), 41 (22); HRMS Calcd for C18H30O3 294.2195, found:
294.2196.
4.7.10. trans-2-(1-Formylvinyl)cyclohexyl acetate (34a).
76% Yield, TLC Rf¼0.45 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 9.44 (s, 1H, CHO), 6.21 (s, 1H,
–CvCH2), 5.95 (s, 1H, –CvCH2), 4.79–4.84 (m, 1H,
CHOAc), 2.67–2.72 (m, 1H, –CH–CvCH2), 1.19–2.00
(m, 8H), 1.87 (s, 3H, –COCH3); 13C NMR (CDCl3,
100 MHz) d 193.9, 170.3, 151.3, 133.7, 74.3, 40.5, 31.93,
31.86, 25.3, 24.4, 20.9; IR (CH2Cl2, cm21): 3090, 2996,
1733, 1633, 1455, 1373, 1024; MS m/z(rel intensity): 196
(Mþ, 3), 169 (41), 136 (38), 124 (56), 109 (100), 81 (78), 67
(54); HRMS Calcd for C11H16O3 196.1099, found:
196.1094.
4.7.11. trans-2-(2-Formylallyl)cyclohexyl acetate (34b).
69% Yield, TLC Rf¼0.47 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 9.44 (s, 1H, CHO), 6.23 (s, 1H,
–CvCH2), 5.97 (s, 1H, –CvCH2), 4.84–4.90 (m, 1H,
CHOAc), 2.58–2.61 (m, 1H, –CH2–CvCH2), 2.17–2.31
(m, 1H, –CH2–CvCH2), 1.95–2.05 (m, 1H), 1.91 (s, 3H,
–COCH3), 1.23–1.96 (m, 8H); 13C NMR (CDCl3,
100 MHz) d 193.7, 170.5, 146.3, 135.3, 75.3, 43.7, 31.9,
28.9, 28.5, 25.4, 25.2, 20.9; IR (CH2Cl2, cm21): 3091, 2952,
1732, 1692, 1452, 1372, 946; MS m/z (rel intensity): 167
(Mþ243, 32), 166 (29), 81 (28), 43 (100), 41 (27); HRMS
Calcd for C12H18O3–CH3CO 167.1072, found: 167.1081.
4.7.6. 3-Formyl-1-methyl-1-phenylbut-3-enyl acetate
(26a). 73% Yield, TLC Rf¼0.45 (hexane/EtOAc¼10:1);
1H NMR (CDCl3, 400 MHz) d 9.39 (s, 1H, CHO), 7.21–
7.32 (m, 5H, Ph–H), 6.06 (s, 1H, –CvCH2), 6.04 (s, 1H,
CvCH2), 2.95 (s, 2H, –CH2–CvCH2), 2.03 (s, 3H,
–COCH3), 1.79 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d 193.5, 169.1, 144.8, 143.7, 137.7, 128.0, 127.0,
124.5, 82.8, 39.0, 24.3, 22.9; IR (CH2Cl2, cm21): 3026, 2937,
1736, 1687, 1496, 1016, 735; MS m/z (rel intensity): 173
(Mþ259, 8), 172 (40), 143 (81), 128 (72), 121 (100).
4.7.12. cis-2-(1-Formylvinyl)cyclohexyl benzoate (34c).
1
71% Yield, TLC Rf¼0.6 (hexane/EtOAc¼3:1); H NMR
(CDCl3, 400 MHz) d 9.47 (s, 1H, CHO), 8.00–8.02 (m, 2H,
Ph–H), 7.54–7.57 (m, 1H), 7.27–7.46 (m, 2H), 6.22 (s, 1H,
–CvCH2), 5.94 (s, 1H, –CvCH2), 5.38 (br s, 1H,
CHOCOPh), 2.90–2.94 (br d, J¼12.8 Hz, 1H, –CH–
CvCH2), 1.56–2.05 (m, 8H); 13C NMR (CDCl3,
100 MHz) d 194.4, 165.9, 151.4, 135.0, 133.2, 131.1,
129.8, 128.8, 70.9, 38.6, 30.9, 26.0, 25.2, 20.8; IR (CH2Cl2,
cm21): 3032, 2859, 1715, 1707, 1450, 1069; MS m/z (rel
intensity): 258 (Mþ, 12), 240 (18), 136 (10), 105 (100), 77
(16); HRMS Calcd for C16H18O3 258.1256, found:
258.1259.
4.7.7. 4-Formyl-1-methyl-1-phenylpent-4-enyl acetate
(26b). 81% Yield, TLC Rf¼0.47 (hexane/EtOAc¼10:1);
1H NMR (CDCl3, 400 MHz) d 9.44 (s, 1H, CHO), 7.20–
7.31 (m, 5H), 6.14 (s, 1H, –CvCH2), 5.90 (s, 1H,
–CvCH2), 2.12–2.17 (m, 4H), 2.05 (s, 3H, –COCH3),
1.86 (s, 3H, –CH3); 13C NMR (CDCl3, 100 MHz) d 194.0,
169.2, 149.3, 144.2, 133.6, 128.0, 126.7, 124.2, 83.1, 39.9,
24.6, 22.0, 21.8; IR (CH2Cl2, cm21): 3027, 2845, 1731,
1629, 1496, 1016, 735; MS m/z (rel intensity): 246 (Mþ, 4),
186 (18), 163 (22), 121 (71), 43 (100).
4.7.8. 1-(2-Formylallyl)cyclohexyl acetate (26c). 62%
Yield, TLC Rf¼0.45 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 9.50 (s, 1H, CHO), 6.25 (s, 1H,
–CvCH2), 6.10 (s, 1H, –CvCH2), 2.87 (s, 2H, –CH2–
CvCH2), 2.06–2.09 (m, 2H), 1.97 (s, 3H, –COCH3),
1.19–1.51 (m, 8H); 13C NMR (CDCl3, 100 MHz) d 194.4,
170.6, 145.8, 137.6, 82.9, 34.5, 34.2, 25.2, 22.3, 21.6; IR
(CH2Cl2, cm21): 2997, 2933, 2860, 1730, 1696, 1449, 1368,
964, 920; MS m/z (rel intensity): 164 (Mþ246, 24), 99
(100), 94 (38), 84 (42), 43 (83); HRMS Calcd for C12H18O3
210.1256, found: 210.1253.
4.7.13. cis-2-(2-Formylallyl)cyclohexyl benzoate (34d).
1
64% Yield, TLC Rf¼0.63 (hexane/EtOAc¼3:1); H NMR
(CDCl3, 400 MHz) d 9.51 (s, 1H, CHO), 7.99–8.02 (m,
2H), 7.53–7.56 (m, 1H), 7.41–7.45 (m, 2H), 6.29 (s, 1H,
–CvCH2), 5.98 (s, 1H, –CvCH2), 5.22–5.26 (m, 1H,
CHOCOPh), 2.55–2.76 (m, 2H, –CH2–CvCH2), 1.27–
2.20 (m, 8H); 13C NMR (CDCl3, 100 MHz) d 194.3, 166.5,
146.7, 136.1, 133.2, 130.9, 129.9, 128.7, 76.5, 44.6, 32.5,
29.5, 28.9, 26.0, 25.8; IR (CH2Cl2, cm21): 3033, 2869,
1714, 1629, 1451, 1070; MS m/z (rel intensity): 273
(Mþþ1, 12), 243 (Mþ229, 12), 203 (5), 150 (7), 105

4850
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
(100), 77 (21); HRMS Calcd for C17H20O3 272.1412, found:
272.1406.
10 min period. The pale yellow reaction mixture was stirred
at room temperature for 2.5 h. The reaction mixture was
concentrated, the residue then dissolved in 30 mL of water
and this extracted with 100 mL of hexane. The aqueous
layer was acidified to pH 3 with 2 N HCl and extracted with
two 50 mL portions of ether. The combined ether layers
were washed with 50 mL of water, dried with Na2SO4,
concentrated and chromatographed on silica gel column to
give product 7a (2.77 g, 16.31 mmol) in 98% yield.
4.7.14. 2-[2-(Tetrahydropyran-2-yloxy)phenyl]propenal
1
(39). 52% Yield, TLC Rf¼0.5 (hexane/EtOAc¼5:1); H
NMR (CDCl3, 400 MHz) d 9.76 (s, 1H), 7.18–7.34 (m, 3H),
6.99–7.03 (m, 1H), 6.34 (s, 1H, CvCH2), 6.28 (s, 1H,
CvCH2), 5.42 (br t, 1H), 3.83–3.89 (m, 1H), 3.59–3.63
(m, 1H), 1.56–1.82 (m, 6H); 13C NMR (CDCl3, 100 MHz)
d 192.2, 154.4, 147.4, 132.9, 130.3, 130.1, 124.8, 121.5,
114.7, 96.5, 61.8, 30.2, 25.2, 18.4; IR (CH2Cl2, cm21):
2943, 2870, 1701, 1597, 1488, 1454, 1236, 1201, 1111,
1036, 961, 919; MS m/z (rel intensity): 232 (Mþ, 1), 148
(55), 147 (8), 85 (100), 91 (15), 77 (4), 57 (16); HRMS
Calcd for C14H16O3 232.1099, found: 232.1102.
4.8.1. 2-Heptylacrylic acid (7a). 98% Yield; colorless oil;
1H NMR (CDCl3, 300 MHz) d 10.11 (br, 1H, CO2H), 6.27
(s, 1H, CvCH2), 5.63 (s, 1H, CvCH2), 2.29 (t, J¼7.3 Hz,
2H, –CH2(CvCH2)–), 1.37–1.51 (m, 2H), 1.17–1.37 (m,
8H), 0.88 (t, J¼7.1 Hz, 3H, –CH3); 13C NMR (CDCl3,
75 MHz) d 173.0, 140.4, 126.7, 31.8, 31.5, 29.2, 29.1, 28.4,
22.6, 14.0; IR (CH2Cl2, cm21): 2500–3250 (OH), 1690
(CvO), 1625, 1437, 1160, 948; MS m/z (rel intensity): 170
(Mþ, 6), 152 (10), 113 (13), 97 (42), 87 (100), 69 (35);
HRMS Calcd for C10H18O2 (Mþ) 170.1307, found
170.1313.
4.7.15. 2-[2-(Tetrahydropyran-2-yloxy)benzyl]propenal
1
(46). 62% Yield, TLC Rf¼0.69 (hexane/EtOAc¼5:1); H
NMR (CDCl3, 400 MHz) d 9.65 (s, 1H, CHO), 7.14–7.21
(m, 3H, Ph), 6.95–6.97 (m, 1H, Ph), 6.04 (br s, 2H), 5.42 (br
s, 1H), 3.82–3.85 (m, 1H), 3.62 (s, 3H), 1.29–1.86 (m, 6H);
13C NMR (CDCl3, 100 MHz) d 194.0, 154.9, 149.3, 134.5,
130.9, 127.9, 127.0, 121.3, 114.3, 96.2, 61.9, 30.4, 28.5,
25.2, 18.7; IR (CH2Cl2, cm21): 2942, 2869, 2851, 1693,
1490, 1455, 1238, 1202, 1121, 1036, 967, 922, 872, 754;
MS m/z (rel intensity): 246 (Mþ, 1), 162 (56), 85 (100);
HRMS Calcd for C15H18O3 246.1256, found:. 246.1262.
4.8.2. 2-(3-Oxocyclohexyl)acrylic acid (7b). 83% Yield;
1
white solid, mp 80–81 8C; H NMR (CDCl3, 300 MHz) d
6.42 (s, 1H, CvCH2), 5.70 (s, 1H, CvCH2), 2.97 (t,
J¼10.9 Hz, 1H), 2.20–2.60 (m, 4H), 1.98–2.15 (m, 2H),
1.55–1.85 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 210.8,
171.4, 142.5, 126.5, 46.4, 41.1, 39.4, 30.4, 24.8; IR
(CH2Cl2, cm21): 2500–3550 (OH), 1689 (CvO), 1622,
1416, 1284, 1152; MS m/z (rel intensity): 168 (Mþ, 8), 150
(10), 125 (8), 109 (4), 95 (4), 62 (46), 45 (100).
4.7.16. 2-(2-Azido-2-cyclohexylethyl)propenal (50c). 62%
Yield, TLC Rf¼0.7 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 9.55 (s, 1H, CHO), 6.42 (s, 1H,
–CvCH2), 6.15 (s, 1H, –CvCH2), 3.26–3.29 (m, 1H,
CHN3), 2.59–2.64 (m, 1H, –CH2–CvCH2), 2.24–2.30
(m, 1H, –CH2–CvCH2), 1.09–1.78 (m, 11H); 13C NMR
(CDCl3, 100 MHz) d 194.1, 146.7, 136.8, 66.2, 42.7, 30.6,
29.8, 28.4, 26.2, 26.1, 25.9; IR (CH2Cl2, cm21): 2928, 2853,
2095, 1698, 1449, 1089; MS m/z (rel intensity): 207 (Mþ,
5), 178 (21), 162 (18), 110 (22), 86 (37), 84 (54), 55 (43), 49
(100); HRMS Calcd for C11H17N3O 207.1372, found:
207.1374.
4.8.3. 2-(1,1-Dimethyl-3-oxobutyl)acrylic acid (7c). 72%
Yield; red brown oil; 1H NMR (CDCl3, 300 MHz) d 6.31 (s,
1H, CvCH2), 5.73 (s, 1H, CvCH2), 2.91 (s, 2H,
–CH2CvO), 2.08 (s, 3H, CH3CO), 1.27 (s, 6H,
C(CH3)2); 13C NMR (CDCl3, 75 MHz) d 208.3, 172.3,
146.2, 125.9, 53.0, 36.7, 31.6, 28.2; IR (CH2Cl2, cm21):
2500–3550 (OH), 1714 (CvO), 1611, 1358, 1305, 1258,
1138, 1104; MS m/z (rel intensity): 170 (Mþ, 6), 152 (18),
137 (22), 124 (16), 109 (22), 95 (40), 81 (20), 67 (38), 43
(100); HRMS Calcd for C9H14O3 170.0943, found
170.0949.
4.7.17. (1-Cyclohexyl-4-formylpent-4-enyl)carbamic
acid methyl ester (54d). 65% Yield, TLC Rf¼0.77
1
(hexane/EtOAc¼1:1); H NMR (CDCl3, 400 MHz) d 9.50
(s, 1H, CHO), 6.28 (br s, 1H, –CHvCH2), 5.99 (br s, 1H,
–CvCH2), 4.51–4.55 (m, 1H, NH), 3.64 (s, 3H, OCH3),
3.43–3.46 (m, 1H, NCH), 2.18–2.52 (m, 3H), 1.01–1.72
(m, 12H); 13C NMR (CDCl3, 100 MHz) d 194.5, 157.0,
149.6, 134.6, 55.2, 51.9, 42.2, 30.4, 29.5, 28.1, 26.3, 26.1,
25.9; IR (CH2Cl2, cm21): 3323 (NH), 2925, 1698, 1540,
1456; MS m/z (rel intensity): 253 (Mþ, 1), 252 (Mþ21, 2),
170 (40), 116 (100), 109 (38); HRMS Calcd for C14H23NO3
253.1678, found: 253.1676.
4.8.4. 2-(8-Hydroxyoctyl)acrylic acid (7d). 85% Yield;
1
white solid, mp 32 8C; H NMR (CDCl3, 300 MHz) d 6.25
(s, 1H, CvCH2), 5.61 (s, 1H, CvCH2), 3.63 (t, J¼6.6 Hz,
2H, –CH2OH), 2.29 (t, J¼7.4 Hz, 2H, –CH2(CvCH2)–),
1.25–1.55 (m, 12H); 13C NMR (CDCl3, 75 MHz) d 171.8,
140.4, 126.2, 62.7, 32.4, 31.4, 29.2, 29.0, 28.3, 25.6; IR
(CH2Cl2, cm21): 3418 (OH), 1717 (CvO), 1629, 1436,
1195, 1162, 1052, 943; MS m/z (rel intensity): 183
(Mþ2OH, 4), 137 (15), 108 (10), 92 (72), 91 (100), 81
(9), 69 (10), 55 (12).
4.8. General procedure to prepare the a-substituted
acrylic acid from the corresponding a-substituted
acrolein
4.8.5. 2-(8-Acetoxyoctyl)acrylic acid (7e). 98% Yield; pale
1
yellow oil; H NMR (CDCl3, 300 MHz) d 6.27 (s, 1H,
CvCH2), 5.63 (s, 1H, CvCH2), 4.06 (t, J¼6.8 Hz, 2H,
–CH2(CvCH2)–), 2.29 (t, J¼7.3 Hz, 2H), 2.04 (s, 3H,
OCOCH3), 1.30–1.65 (m, 12H); 13C NMR (CDCl3,
75 MHz) d 172.5, 171.3, 126.7, 64.6, 31.4, 29.2, 29.1,
28.6, 28.3, 25.9, 21.0; IR (CH2Cl2, cm21): 1690 (CvO),
1625, 1437, 1160, 1160, 948; MS m/z (rel intensity): 242
To a solution of aldehyde 4a (2.57 g, 16.64 mmol) in 60 mL
of t-butyl alcohol and 5.3 mL of 2-methyl-2-butene (3.50 g,
49.93 mmol) was added a solution of sodium chlorite
(3.46 g, 38.28 mmol) and sodium dihydrogenphosphate
(5.19 g, 33.29 mmol) in 22 mL of water dropwise over a

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4851
(Mþ, 2), 224 (2), 209 (5), 137 (15), 91 (100), 81 (15), 69
(11), 55 (13), 43 (20); HRMS Calcd for C13H20O3 224.1412,
found 224.1398.
4.9.1. Methyl 2-heptylacrylate (8a). 98% Yield; colorless
1
oil; H NMR (CDCl3, 300 MHz) d 6.12 (s, 1H, CvCH2),
5.51 (s, 1H, CvCH2), 3.75 (s, 3H, OCH3), 2.29 (t,
J¼7.3 Hz, 2H, –CH2(CvCH2)–), 1.40–1.68 (m, 2H),
1.21–1.40 (m, 8H), 0.88 (t, J¼6.9 Hz, 3H, –CH3); 13C
NMR (CDCl3, 75 MHz) d 167.8, 140.9, 124.3, 51.6, 31.9,
31.8, 29.1, 29.0, 28.4, 22.6, 14.0; IR (CH2Cl2, cm21): 1718
(CvO), 1629, 1435, 1192, 1148, 940; MS m/z (rel
intensity): 184 (Mþ, 8), 153 (12), 127 (20), 101 (100), 88
(58), 81 (18), 69 (30); HRMS Calcd for C11H20O2 184.1463,
found 184.1461.
4.8.6. 2-(8-Iodooctyl)acrylic acid (7f). 98% Yield; yellow
solid, mp 32 8C; 1H NMR (CDCl3, 300 MHz) d 6.29 (s, 1H,
CvCH2), 5.64 (s, 1H, CvCH2), 3.18 (t, J¼7.1 Hz, 2H,
–CH2I), 2.29 (t, J¼7.3 Hz, 2H, –CH2(CvCH2)–), 1.82
(quin, J¼6.9 Hz, 2H), 1.32–1.51 (m, 10H); 13C NMR
(CDCl3, 75 MHz) d 172.8, 140.2, 126.9, 33.5, 31.4, 30.5,
29.1, 29.0, 28.4, 28.3, 7.1; IR (CH2Cl2, cm21): 2500–3450
(OH), 1687 (CvO), 1624; MS m/z (rel intensity): 310 (Mþ,
3), 283 (6), 183 (15), 137 (48), 91 (100), 81 (48), 69 (25), 55
(45), 41 (38); HRMS Calcd for C11H19IO2 (Mþ) 310.0430,
found 310.0414.
4.9.2. Methyl 2-(3-oxocyclohexyl)acrylate (8b). 96%
Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d
6.24 (s, 1H, CvCH2), 5.57 (s, 1H, CvCH2), 3.77 (s, 3H,
OCH3), 2.88–3.05 (m, 1H), 2.25–2.50 (m, 4H), 2.00–2.15
(m, 2H), 1.53–1.80 (m, 2H); 13C NMR (CDCl3, 75 MHz) d
210.5, 166.9, 143.2, 124.0, 51.9, 46.5, 41.1, 39.7, 30.4, 24.8;
IR (CH2Cl2, cm21): 1705 (CvO), 1626, 1436, 1285, 1144;
MS m/z (rel intensity): 182 (Mþ, 42), 150 (100), 139 (32),
122 (52), 108 (22), 95 (36), 79 (44), 67 (34), 53 (38), 41
(50); HRMS Calcd for C10H14O3 182.0943, found
182.0933.
4.8.7. 3-Cyclohexyl-2-methylene-3-(tetrahydropyran-2-
yloxy)propionic acid (20a). 93% Yield, TLC Rf¼0.4
1
(hexane/EtOAc¼1:1); A mixture of the diastereomers; H
NMR (CDCl3, 400 MHz) d 6.46 (s, 0.6H, CvCH2), 6.42 (s,
0.4H, CvCH2), 5.91 (s, 0.4H, CvCH2), 5.79 (s, 0.6H,
CvCH2), 4.63–4.64 (m, 0.4H, O–CH–O), 4.55–4.56 (m,
0.6H, O–CH–O), 4.37–4.39 (m, 0.6H, CH–OTHP), 4.17–
4.19 (m, 0.4H, CH–OTHP), 3.80–3.95 (m, 0.6H, CH2–O–
CH), 3.65–3.75 (m, 0.4H, CH2–O–CH), 3.50–3.53 (m,
0.6H, CH2–O–CH), 3.45–3.55 (m, 0.4H, CH2–O–CH),
0.95–2.00 (m, 17H); 13C NMR (CDCl3, 100 MHz) d
170.96, 170.92, 140.7, 139.4, 128.6, 127.9, 100.7, 94.9,
80.8, 77.1, 62.7, 62.0, 42.5, 42.2, 30.6, 30.4, 29.7, 29.4,
28.3, 27.9, 26.4, 26.4, 26.2, 26.1, 26.0, 25.9, 25.4, 25.3,
19.5, 19.1; IR (CH2Cl2, cm21): 2500–3500 (OH), 1715,
1450, 1028, 734; MS m/z (rel intensity): 268 (Mþ, 3), 185
(66), 167 (90), 85 (100), 55 (14); HRMS Calcd for
C15H24O4 268.1675, found: 268.1685.
4.9.3. Methyl 2-(1,1-dimethyl-3-oxobutyl)acrylate (8c).
86% Yield; yellow oil; 1H NMR (CDCl3, 300 MHz) d 6.10
(s, 1H, CvCH2), 5.62 (s, 1H, CvCH2), 3.73 (s, 3H, OCH3),
2.89 (s, 2H, –CH2CvO), 2.05 (s, 3H, CH3CO), 1.25 (s, 6H,
C(CH3)2); 13C NMR (CDCl3, 75 MHz) d 207.9, 167.8,
147.0, 123.4, 53.1, 51.5, 36.9, 31.6, 28.1; IR (CH2Cl2,
cm21): 1709 (CvO), 1614, 1434, 1357, 1316, 1258, 945;
MS m/z (rel intensity): 184 (Mþ, 2), 152 (4), 127 (5), 95 (4),
81 (3), 67 (3), 62 (48), 45 (100); HRMS Calcd for C10H16O3
184.1099, found 184.1100.
4.8.8. 6-Cyclohexyl-2-methylene-6-(tetrahydropyran-2-
yloxy)hexanoic acid (20d). 91% Yield, TLC Rf¼0.40
(hexane/EtOAc¼1:1). A mixture of the diastereomers,
ratio¼1:1; 1H NMR (CDCl3, 400 MHz) d 6.28 (s, 1H,
CvCH2), 5.64–5.65 (m, 1H, CvCH2), 4.59–4.65 (m, 1H,
O–CH–O), 3.90–3.91 (m, 1H, CH2–O–CH), 3.39–3.50
(m, 2H, CH2–O–CH), 2.29–2.31 (m, 2H, CH2–CvCH2),
1.48–1.75 (m, 16H), 0.88–1.25 (m, 5H); 13C NMR (CDCl3,
100 MHz) d 172.3, 172.2, 140.2, 140.1, 126.8, 126.7, 99.0,
97.7, 81.7, 80.6, 62.9, 62.7, 41.5, 40.87, 40.86, 31.7, 31.5,
31.2, 31.1, 29.4, 29.1, 28.7, 28.6, 28.4, 26.7, 26.4, 25.5,
24.2, 23.8, 20.1, 19.9; IR (CH2Cl2, cm21): 2500–3500
(OH), 2853, 1697, 1626, 1453, 1132, 952; MS m/z (rel
intensity): 209 (Mþ2101, 7), 163 (8), 143 (11), 85 (100), 67
(8); HRMS Calcd for C18H30O4 310.2144, found: 310.2150.
4.9.4. Methyl 2-(8-hydroxyoctyl)acrylate (8d). 91%
Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d
6.12 (s, 1H, CvCH2), 5.51 (s, 1H, CvCH2), 4.03 (s, 3H,
OCH3), 3.63 (t, J¼6.6 Hz, 2H, –CH2OH), 2.29 (t,
J¼7.3 Hz, 2H, –CH2(CvCH2)–), 1.20–1.60 (m, 13H);
13C NMR (CDCl3, 75 MHz) d 167.9, 140.8, 124.4, 63.0,
51.7, 32.7, 31.8, 29.3, 29.1, 28.3, 25.7; IR (CH2Cl2, cm21):
3418 (OH), 1717 (CvO), 1436, 1262, 1195, 1162, 1052,
943; MS m/z (rel intensity): 214 (Mþ, 1), 182 (18), 154 (14),
125 (10), 101 (100), 81 (55), 67 (55), 55 (88), 41 (53).
4.9.5. Methyl 2-(8-acetoxyoctyl)acrylate (8e). 87% Yield;
1
pale yellow oil; H NMR (CDCl3, 300 MHz) d 6.12 (br s,
2H, OH and vCH2), 5.51 (s, 1H, CvCH2), 4.05 (t,
J¼4.7 Hz, 2H, AcOCH2), 3.75 (s, 3H, CO2CH3), 2.29 (t,
J¼7.0 Hz, –CH2(CvCH2)–), 2.03 (s, 3H, OCOCH3),
1.25–1.65 (m, 12H); 13C NMR (CDCl3, 75 MHz) d 171.1,
167.8, 140.8, 124.4, 64.5, 51.6, 31.8, 29.2, 29.1, 29.0, 28.5,
28.3, 25.8, 20.9; IR (CH2Cl2, cm21): 1721 (CvO), 1628,
1437, 1234, 1037, 940, 815; MS m/z (rel intensity): 256
(Mþ, 1), 224 (38), 182 (35), 164 (28), 136 (28), 125 (18),
101 (52), 95 (32), 81 (55), 67 (56), 55 (80), 43 (100); HRMS
Calcd for C14H24O4 256.1674, found 256.1659.
4.9. General procedure to prepare the methyl acrylate
from the corresponding acrylic acid
To a solution of a-substituted acrylic acid 7a (287.2 mg,
1.69 mmol) in 3 mL of CH2Cl2 was added a solution of
CH2N2 in ethyl ether at room temperature. The progress of
the reaction should be monitored carefully by TLC. Excess
of the CH2N2 will cause the further 1,3-dipolar cyclo-
addition on the double bond. When the reaction was
complete, the reaction mixture was concentrated and the
residue was chromatographed on silica gel column to give
methyl acrylate 8a (304 mg, 1.66 mmol) in 98% yield.
4.9.6. Methyl 2-(8-iodooctyl)acrylate (8f). 87% Yield;
pale yellow oil; 1H NMR (CDCl3, 300 MHz) d 6.12 (s, 1H,
CvCH2), 5.52 (s, 1H, CvCH2), 3.75 (s, 3H, OCH3), 3.18
(t, J¼7.1 Hz, 2H, –CH2I), 2.29 (t, J¼7.2 Hz, 2H,

4852
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
–CH2(CvCH2)–), 1.82 (quin, J¼6.9 Hz, 2H), 1.31–1.48
(m, 10H); 13C NMR (CDCl3, 75 MHz) d 167.8, 140.8,
124.4, 51.7, 33.5, 31.8, 30.4, 29.1, 29.0, 28.4, 28.3, 7.1; IR
(CH2Cl2, cm21): 1716 (CvO), 1628, 1435, 1194, 1155,
945; MS m/z (rel intensity): 324 (Mþ, 8), 293 (12), 197 (43),
165 (32), 137 (100), 109 (18), 95 (65), 81 (82), 67 (48), 55
(65), 41 (45); HRMS Calcd for C12H21IO2 324.0586, found
324.0584.
4.11. General procedure to prepare the methyl acrylate
from the corresponding acrolein in one flask
To a mixture of aldehyde 15b (324 mg, 1.0 mmol), t-butyl
alcohol (3.6 mL) and 2-methyl-2-butene (210 mg,
3.0 mmol) was added a solution of sodium chlorite
(208 mg, 2.30 mmol) and sodium dihydrogenphosphate
(312 mg, 2.0 mmol) in 1.3 mL of water dropwise over a
10 min period. The pale yellow reaction mixture was stirred
at room temperature for 2.5 h. The reaction mixture was
concentrated, redissolved in 3 mL of water and extracted
with 10 mL of hexane. The aqueous layer was acidified to
pH 3 with 2 N HCl and extracted with two 15 mL portions
of ether. The combined ether layers were washed with
10 mL of water, dried with Na2SO4 and concentrated to give
the crude product of the acrylic acid. To a solution of the
crude acrylic acid in 3 mL of CH2Cl2 was added a solution
of CH2N2 in ethyl ether at room temperature. When the
reaction was complete, the reaction mixture was concen-
trated and the residue was chromatographed on silica gel
column to give methyl acrylate 16b (241 mg, 0.95 mmol) in
95% yield.
4.10. General procedure to prepare the acrylic amide
from the corresponding acrylic acid
To a solution of a-substituted acrylic acid 7a (522.9 mg,
3.07 mmol) in 10 mL of CH2Cl2 was added thionyl chloride
(1.10 g, 9.21 mmol). The reaction mixture was refluxed for
3 h and then concentrated in vacuo. The residue was
redissolved in 10 mL of CH2Cl2 and the resulted solution
was treated with 28% aqueous NH3 solution at 0 8C and
stirred for 30 min. The reaction mixture was added 20 mL of
water and extracted with CH2Cl2. The combined organic
layer was washed with 50 mL of water, dried with Na2SO4
and concentrated. The crude mixture was chromatographed
on silica gel column to give acrylic amide 10g (462 mg,
2.73 mmol) in 89% yield.
4.11.1. 4-Acetoxy-4-cyclohexyl-2-methylenebutyric acid
methyl ester (16b). 95% Yield, 1H NMR (CDCl3,
400 MHz) d 6.11 (br s, 1H, CvCH2), 5.51 (br s, 1H,
CvCH2), 4.85–4.90 (m, 1H, CHOCO), 3.71 (s, 3H, OCH3),
2.65–2.69 (m, 1H, CH2–CvCH2), 2.27–2.33 (m, 1H,
CH2–CvCH2), 1.93 (s, 3H, –COCH3), 1.00–1.71 (m,
11H); 13C NMR (CDCl3, 100 MHz) d 170.5, 167.1, 137.2,
126.7, 75.8, 51.8, 41.5, 34.4, 28.9, 28.0, 26.3, 25.91, 25.87,
20.8; IR (CH2Cl2, cm21): 2928, 2857, 1730, 1650, 1237;
MS m/z (rel intensity): 223 (Mþ231, 4), 141 (43), 95 (100),
83 (41), 58 (43); HRMS Calcd for C14H22O4–OCH3
223.1334, found: 223.1324.
4.10.1. 2-Heptylacrylamide (10g). 89% Yield; white solid,
mp 70–71 8C; 1H NMR (CDCl3, 300 MHz) d 5.82 (br, 1H,
NH2), 5.68 (s, 1H, CvCH2), 5.33 (s, 1H, CvCH2), 2.30 (t,
J¼9.5 Hz, 2H, –CH2(CvCH2)–), 1.40–1.51 (m, 2H),
1.20–1.34 (m, 8H), 0.88 (t, J¼6.5 Hz, 3H, –CH3); 13C
NMR (CDCl3, 75 MHz) d 170.9, 144.7, 118.5, 32.2, 31.8,
29.2, 29.1, 28.1, 22.6, 14.0; IR (CH2Cl2, cm21): 3528 (N–
H), 3409 (N–H), 1673 (CvO), 1623, 1580, 1375; MS m/z
(rel intensity): 169 (Mþ, 3), 112 (12), 98 (6), 86 (10), 62
(46), 45 (100).
4.10.2. 2-Heptyl-1-(pyrrolidin-1-yl)prop-2-en-1-one
(10h). 83% Yield; pale yellow oil; 1H NMR (CDCl3,
300 MHz) d 5.19 (s, 1H, CvCH2), 5.11 (s, 1H, CvCH2),
2.30 (t, J¼7.3 Hz, 2H, –CH2(CvCH2)–), 1.85–1.93 (m,
4H, 2x–NCH2), 1.40–1.50 (m, 2H), 1.21–1.35 (m, 8H),
0.88 (t, J¼6.8 Hz, 3H, –CH3); 13C NMR (CDCl3, 75 MHz)
d 170.6, 146.6, 114.2, 48.6, 45.3, 33.7, 31.7, 29.2, 29.0,
27.6, 26.1, 24.3, 22.5, 13.9; IR (CH2Cl2, cm21): 1614
(CvO), 1438, 912; MS m/z (rel intensity): 223 (Mþ, 42),
208 (12), 194 (10), 180 (13), 166 (50), 152 (42), 138 (100),
126 (36), 98 (28), 70 (42); HRMS Calcd for C14H25NO
223.1936, found 223.1932.
4.11.2. 5-Acetoxy-5-cyclohexyl-2-methylenepentanoic
acid methyl ester (16c). 93% Yield, TLC Rf¼0.65
(hexane/EtOAc¼10:1); 1H NMR (CDCl3, 400 MHz) d
6.09 (s, 1H, CvCH2), 5.49 (s, 1H, CvCH2), 4.68–4.73
(m, 1H, CHOCO), 3.70 (s, 3H, OCH3), 2.24–2.27 (m, 2H,
CH2–CvCH2), 2.00 (s, 3H, –COCH3), 1.60–1.71 (m, 9H),
0.93–1.17 (m, 4H); 13C NMR (CDCl3, 100 MHz) d 170.8,
167.3, 139.9, 124.9, 77.2, 51.6, 41.1, 29.9, 28.8, 28.1, 28.0,
26.3, 26.0, 25.9, 21.0; IR (CH2Cl2, cm21): 2919, 2850,
1735, 1636, 1264; MS m/z (rel intensity): 225 (Mþ243),
208 (10), 177 (6), 149 (Mþ2119, 25), 143 (28), 111 (32), 43
(100), 32 (95); HRMS Calcd for C15H24O4 268.1675, found:
268.1682.
4.10.3. N-(2-n-Heptylacryloyl))valine methyl ester (10i).
1
89% Yield; pale yellow oil; H NMR (CDCl3, 300 MHz)
4.11.3. 2-(4-Acetoxy-4-cyclohexylbutyl)acrylic acid
methyl ester (16d). 96% Yield, 1H NMR (CDCl3,
400 MHz) d 6.14 (s, 1H, CvCH2), 5.52 (s, 1H, CvCH2),
4.73–4.77 (m, 1H, CHOCO), 3.75 (s, 3H), 2.25–2.30
(m, 2H), 2.05 (s, 3H, –COCH3), 1.44–1.75 (m, 10H),
0.97–1.16 (m, 5H); 13C NMR (CDCl3, 100 MHz) d
170.8, 167.5, 140.3, 124.8, 77.5, 51.6, 41.2, 31.6, 30.6,
28.9, 28.1, 26.3, 26.04, 25.98, 24.2, 21.0; IR (CH2Cl2,
cm21): 2929, 2854, 1730, 1632, 1447, 1371, 1243, 1020,
966, 751; MS m/z (rel intensity): 222 (Mþ260, 24), 157
(84), 140 (72), 125 (100), 95 (48), 81 (56), 67 (42), 55 (68);
HRMS Calcd for C16H26O4–HOAc 222.1620, found:
222.1623.
d 6.27 (br d, J¼8.6 Hz, 1H, NH), 5.66 (s, 1H, CvCH2),
5.31 (s, 1H, CvCH2), 4.64 (d, J¼11.7 Hz, 0.5H), 4.62
(d, J¼11.7 Hz, 0.5 H), 3.76 (s, 3H, OCH3), 2.18–2.40
(m, 3H), 1.40–1.51 (m, 2 H), 1.20–1.40 (m, 8H),
0.85–0.98 (m, 9H, 3xCH3); 13C NMR (CDCl3, 75 MHz)
d 172.6, 168.7, 145.5, 117.7, 56.9, 52.1, 32.3, 31.7,
31.4, 29.1, 29.0, 28.0, 22.6, 19.0, 17.8, 14.0; IR (CH2Cl2,
cm21): 3332 (N–H), 1744 (CvO), 1659 (CvO),
1620, 1509, 1203; MS m/z (rel intensity): 283 (Mþ, 10),
252 (6), 224 (100), 170 (46), 153 (65), 69 (18), 55 (39), 41
(40); HRMS Calcd for C16H29NO3 283.2147, found
283.2134.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4853
4.11.4. 4-Acetoxy-2-methylene-4-phenylpentanoic acid
methyl ester (27a). 95% Yield, TLC Rf¼0.48 (hexane/
4.11.9. trans-3-(2-Acetoxy-1-cyclohexyl)-2-methylene-
propionic acid methyl ester (35b). 91% Yield, TLC
Rf¼0.53 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 6.12 (s, 1H, CvCH2), 5.53 (s, 1H, CvCH2),
4.95–4.96 (m, 1H, CHOCO), 3.73 (s, 3H, OCH3), 2.68–
2.69 (m, 1H, CH2–CvCH2), 2.31–2.34 (m, 1H, CH2–
CvCH2), 1.94–2.01 (m, 1H), 1.94 (s, 3H, –COCH3),
1.63–1.68 (m, 8H); 13C NMR (CDCl3, 100 MHz) d 170.6,
167.1, 136.9, 126.8, 75.6, 51.8, 43.8, 36.5, 28.9, 28.5, 25.5,
25.3, 20.9; IR (CH2Cl2, cm21): 2952, 2869, 1731, 1632,
1439, 945; MS m/z (rel intensity): 240 (Mþ, 33), 141 (12),
82 (15), 43 (100), 41 (25).
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 7.21–7.30
(m, 5H), 6.16 (s, 1H, CvCH2), 5.39 (s, 1H, CvCH2), 3.57
(s, 3H, OCH3), 3.00 (s, 2H, CH2–CvCH2), 2.02 (s, 3H,
–COCH3), 1.85 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
169.2, 167.7, 143.6, 135.9, 128.6, 127.9, 126.9, 124.7, 83.0,
51.6, 43.7, 24.0, 22.0; IR (CH2Cl2, cm21): 2949, 2845,
1735, 1631, 1496, 1017, 768; MS m/z (rel intensity): 261
(Mþ21, 2), 220 (14), 163 (22), 121 (100), 43 (20); HRMS
Calcd for C15H18O4 262.1205, found: 262.1198.
4.11.5. 5-Acetoxy-2-methylene-5-phenylhexanoic acid
methyl ester (27b). 96% Yield, TLC Rf¼0.52 (hexane/
4.11.10. cis-2-(1-Methoxycarbonylvinyl)cyclohexyl ben-
zoate (35c). 94% Yield, TLC Rf¼0.62 (hexane/
EtOAc¼3:1); 1H NMR (CDCl3, 400 MHz) d 7.99–8.02
(m, 2H), 7.51–7.55 (m, 1H), 7.40–7.44 (m, 1H), 6.17 (s,
1H, CvCH2), 5.54 (s, 1H, CvCH2), 5.47 (br s, 1H,
CHOCO), 3.75 (s, 3H, OCH3), 2.88–2.91 (m, 1H, CH–
CvCH2), 1.59–2.07 (m, 8H); 13C NMR (CDCl3, 100 MHz)
d 167.2, 165.6, 141.4, 132.7, 130.9, 129.4, 128.3, 125.2,
70.8, 51.9, 41.5, 30.5, 25.8, 25.3, 20.4; IR (CH2Cl2, cm21):
2936, 2860, 1715, 1629, 1025, 735; MS m/z (rel intensity):
288 (Mþ, 11), 256 (20), 166 (13), 105 (100), 77 (16); HRMS
Calcd for C17H20O4 288.1362, found: 288.1368.
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 7.21–7.32
(m, 5H), 6.09 (s, 1H, CvCH2), 5.47 (s, 1H, CvCH2), 3.69
(s, 3H, OCH3), 2.14–2.21 (m, 4H), 2.06 (s, 3H, –COCH3),
1.87 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 169.3, 167.2,
144.4, 139.9, 128.0, 126.7, 124.6, 124.3, 83.4, 51.5, 40.8,
26.3, 24.8, 21.9; IR (CH2Cl2, cm21): 2949, 2845, 1731,
1629, 1063, 735; MS m/z (rel intensity): 276 (Mþ, 5), 187
(13), 121 (100), 77 (12), 43 (62); HRMS Calcd for
C16H20O4 276.1362, found: 276.1362.
4.11.6. 3-(1-Acetoxy-1-cyclohexyl)-2-methylene-
propionic acid methyl ester (27c). 96% Yield, TLC
Rf¼0.47 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 6.19 (s, 1H, –CvCH2), 5.50 (s, 1H,
–CvCH2), 3.70 (s, 3H, OCH3), 2.93 (s, 2H, –CH2–
CvCH2), 2.11–2.14 (m, 2H), 1.95 (s, 3H, –COCH3),
1.22–1.47 (m, 8H); 13C NMR (CDCl3, 100 MHz) d
170.4, 168.0, 136.3, 128.2, 83.1, 51.8, 38.4, 34.3, 31.5,
25.2, 22.5, 22.2, 21.6; IR (CH2Cl2, cm21): 2999, 2933,
2861, 1726, 1627, 1451, 1100; MS m/z (rel intensity): 181
(Mþ259, 33), 141 (Mþ299, 33), 99 (64), 98 (75), 81 (25),
43 (100); HRMS Calcd for C13H20O4 240.1362, found:
240.1367.
4.11.11. cis-2-(2-Methoxycarbonylallyl)cyclohexyl ben-
zoate (35d). 95% Yield, TLC Rf¼0.65 (hexane/
EtOAc¼3:1); 1H NMR (CDCl3, 400 MHz) d 7.98–8.01
(m, 2H), 7.50–7.52 (m, 1H), 7.39–7.43 (m, 2H), 6.10 (s,
1H, CvCH2), 5.56 (s, 1H, CvCH2), 5.26–5.27 (m, 1H,
CHOCO), 3.69 (s, 3H, OCH3), 2.82–2.86 (m, 1H, CH2–
CvCH2), 2.51–2.57 (m, 1H, CH2–CvCH2), 2.18–2.20
(m, 1H), 1.53–1.79 (m, 7H); 13C NMR (CDCl3, 100 MHz)
d 167.2, 166.0, 136.7, 132.6, 130.5, 129.4, 128.2, 127.2,
76.3, 51.8, 43.8, 36.4, 29.0, 28.5, 25.6, 25.4; IR (CH2Cl2,
cm21): 2952, 2869, 1714, 1632, 1025; MS m/z (rel
intensity): 303 (Mþþ1, 3), 202 (Mþ2100, 3), 180 (12),
120 (3), 105 (100), 77 (13); HRMS Calcd for C18H22O4
302.1518, found: 302.1521.
4.11.7. 4-(1-Acetoxy-1-cyclohexyl)-2-methylenebutyric
acid methyl ester (27d). 90% Yield, TLC Rf¼0.47
(hexane/EtOAc¼10:1); 1H NMR (CDCl3, 400 MHz) d
6.08 (s, 1H, CvCH2), 5.50 (s, 1H, CvCH2), 3.70 (s, 3H,
OMe), 2.01–2.25 (m, 4H), 1.97–2.01 (m, 2H), 1.96 (s, 3H,
–COCH3), 1.34–1.47 (m, 8H); 13C NMR (CDCl3,
100 MHz) d 170.2, 167.5, 140.2, 124.7, 83.4, 51.7, 36.0,
34.4, 25.5, 22.1, 21.7; IR (CH2Cl2, cm21): 2935, 2861,
1730, 1632, 1450, 1367, 1107; MS m/z (rel intensity): 194
(Mþ260, 20), 135 (40), 134 (51), 99 (100), 95 (47); HRMS
Calcd for C13H20O4–CH3CO2H 194.1307, found:
194.1301.
4.11.12. 2-[2-(Tetrahydropyran-2-yloxy)phenyl]acrylic
acid methyl ester (40). 88% Yield, TLC Rf¼0.44
(hexane/EtOAc¼10:1); 1H NMR (CDCl3, 400 MHz) d
7.22–7.30 (m, 2H), 7.14–7.16 (m, 1H), 6.99–7.01 (m,
1H), 6.26 (s, 1H, CvCH2), 5.73 (s, 1H, CvCH2), 5.43 (br t,
1H), 3.81–3.85 (m, 1H), 3.76 (s, 3H, OCH3), 3.58–3.61 (m,
1H), 1.55–1.80 (m, 6H); 13C NMR (CDCl3, 100 MHz) d
167.9, 154.3, 140.2, 129.9, 129.7, 127.5, 126.1, 121.4,
114.3, 96.2, 61.4, 51.9, 30.2, 25.1, 18.1; IR (CH2Cl2, cm21):
2947, 2874, 1726, 1487, 1455, 1323, 1274, 1233, 1202,
1123, 1035, 962, 920; MS m/z (rel intensity): 262 (Mþ, 1),
178 (56), 146 (50), 118 (16), 85 (100), 67 (13), 57 (16);
HRMS Calcd for C15H18O4 262.1205, found: 262.1206.
4.11.8. trans-2-(2-Acetoxy-1-cyclohexyl)acrylic acid
methyl ester (35a). 98% Yield, TLC Rf¼0.48 (hexane/
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 6.06 (s, 1H,
CvCH2), 5.45 (s, 1H, CvCH2), 4.72–4.78 (m, 1H,
CHOCO), 3.65 (s, 3H, OCH3), 2.59–2.65 (m, 1H, CH–
CvCH2), 1.59–2.02 (m, 4H), 1.83 (s, 3H, –COCH3),
1.17–1.32 (m, 4H); 13C NMR (CDCl3, 100 MHz) d 170.2,
167.3, 141.8, 123.9, 74.7, 51.5, 44.2, 32.1, 31.9, 25.3, 24.4,
20.8; IR (CH2Cl2, cm21): 2938, 2860, 1731, 1629, 1438,
925; MS m/z (rel intensity): 166 (Mþ260, 73), 151 (47),
134 (45), 79 (48), 43 (100); HRMS Calcd for C12H18O4
226.1205, found: 226.1196.
4.11.13. 2-[2-(Tetrahydropyran-2-yloxy)benzyl]acrylic
acid methyl ester (47). 82% Yield, TLC Rf¼0.71
(hexane/EtOAc¼5:1); 1H NMR (CDCl3, 400 MHz) d
7.13–7.18 (m, 3H), 6.92–6.94 (m, 1H), 6.19 (br s, 1H,
CvCH2), 5.43 (br t, J¼3.0 Hz, 1H), 5.35 (br s, 1H,
CvCH2), 3.60–3.84 (m, 2H), 3.76 (s, 3H, OCH3), 1.60–
1.84 (m, 6H); 13C NMR (CDCl3, 100 MHz) d 167.6, 155.0,
139.5, 130.6, 127.7, 127.5, 125.6, 121.2, 114.2, 96.1, 61.8,

4854
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
51.7, 32.2, 30.4, 25.2, 18.7; IR (CH2Cl2, cm21): 2946, 2875,
2844, 1717, 1490, 1455, 1238, 1137, 1037, 968, 754; MS
m/z (rel intensity): 276 (Mþ, 4), 192 (64), 160 (52), 131 (30),
85 (100), 67 (16), 57 (18); HRMS Calcd for C16H20O4
276.1362, found: 276.1358.
165 (100), 139 (3), 105 (13), 77 (11); HRMS Calcd for
C13H22O3 226.1569, found: 226.1575.
4.12.3. 2-(2-Hydroxyphenyl)acrylic acid methyl ester
(41).50 77% Yield, TLC Rf¼0.26 (hexane/EtOAc¼5:1); 1H
NMR (CDCl3, 400 MHz) d 7.40 (br s, 1H, OH), 7.12–7.26
(m, 2H), 6.91–6.95 (m, 1H), 6.44 (br s, 1H, CvCH2), 5.90
(br s, 1H, CvCH2), 3.86 (s, 3H, OCH3); 13C NMR (CDCl3,
100 MHz) d 169.5, 153.5, 139.4, 130.6, 130.2, 129.8, 124.7,
120.6, 117.3, 52.8; IR (CH2Cl2, cm21): 3393, 2952, 1698,
1622, 1455, 1437, 1326, 1287, 1222, 1112; MS m/z (rel
intensity): 179 (Mþþ1, 4), 178 (Mþ, 44), 146 (100), 119
(26), 91 (40), 90 (38), 89 (20), 65 (16); HRMS Calcd for
C10H10O3 178.0630, found: 178.0632.
4.11.14. 4-Azido-4-cyclohexyl-2-methylenebutyric acid
methyl ester (51c). 62% Yield, TLC Rf¼0.73 (hexane/
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 6.25 (s, 1H,
–CvCH2), 5.68 (s, 1H, –CvCH2), 3.74 (s, 3H, OCH3),
3.30 (m, 1H, CHN3), 2.61–2.63 (m, 1H, –CH2–CvCH2),
2.30–2.33 (m, 1H, –CH2–CvCH2), 1.65–1.76 (m, 6H),
1.11–1.20 (m, 5H); 13C NMR (CDCl3, 100 MHz) d 167.0,
137.0, 128.0, 66.7, 51.8, 42.4, 34.6, 29.7, 28.2, 26.2, 26.0,
25.9; IR (CH2Cl2, cm21): 2999, 2853, 2103, 1731, 1631,
1450; MS m/z (rel intensity): 206 (Mþ231, 33), 100 (31),
83 (42), 55 (100), 41 (98), 39 (43); HRMS Calcd for
C12H19N3O2–OCH3 206.1293, found: 206.1294.
4.13. General procedure to prepare the hydroxy-acid
from the corresponding acetoxy-aldehyde
According to general procedure described above, acrolein
26b (246 mg, 1.0 mmol) was converted to the correspond-
ing acrylic acid 29b. The crude product of compound 29b
was mixed with K2CO3 (207 mg, 1.5 mmol) in 5 mL of
MeOH and stirred at room temperature for 6 h. The reaction
mixture was concentrated and the crude mixtures were
dissolved in ethyl acetate. The organic phase was extracted
with water, 1 N HCl and brine, respectively. The organic
phase was dried over MgSO4, concentrated and chromato-
graphed on silica gel column to give hydroxy-acid 30b
(172 mg, 0.78 mmol) in 78% yield.
4.11.15. 2-(3-Cyclohexyl-3-methoxycarbonylamino-
propyl)acrylic acid methyl ester (55d). 82% Yield, TLC
Rf¼0.82 (hexane/EtOAc¼1:1); 1H NMR (CDCl3,
400 MHz) d 6.14 (s, 1H, CvCH2), 5.58 (s, 1H, CvCH2),
4.47 (br d, J¼9.6 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.49–
3.66 (m, 1H), 2.20–2.45 (m, 2H), 1.13–1.75 (m, 13H); 13C
NMR (CDCl3, 100 MHz) d 167.9, 157.4, 140.5, 125.7, 55.8,
52.4, 52.2, 42.7, 31.8, 29.9, 29.3, 28.6, 26.8, 26.62, 26.60;
IR (CH2Cl2, cm21): 3326 (N–H), 2926, 2852, 1717, 1634,
1539, 1448, 1244, 1158, 1081, 948; MS m/z (rel intensity):
283 (Mþ, 4), 200 (100), 170 (16), 168 (48), 136 (12), 124
(30), 88 (16), 55 (12); HRMS Calcd for C15H25NO4
283.1784, found: 283.1778.
4.13.1. 5-Hydroxy-2-methylene-5-phenylhexanoic acid
1
(30b). 78% Yield, H NMR (CDCl3, 400 MHz) d 7.21–
7.45 (m, 5H), 6.22 (s, 1H, CvCH2), 5.58 (s, 1H, CvCH2),
2.29–2.32 (m, 1H), 2.15–2.18 (m, 1H), 1.96–2.04 (m, 2H),
1.58 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 172.2, 147.3,
140.1, 128.2, 127.0, 126.7, 124.8, 74.6, 42.8, 30.3, 26.4; IR
(CH2Cl2, cm21): 2500–3500 (OH), 2923, 1702, 1625,
1446, 1151; MS m/z (rel intensity): 220 (Mþ, 1), 187 (16),
121 (100), 105 (14), 77 (10); HRMS Calcd for C13H16O3
220.1099, found: 220.1092.
4.12. General procedure of the deprotection of OTHP to
the corresponding alcohol catalyzed by ATPB
To a solution of OTHP-protected compound 20a (143 mg,
0.5 mmol) in a mixture of CH2Cl2/MeOH (5 mL, 1:1 by
volume) was added ATPB (20 mg, 0.05 mmol) and the
solution was stirred at room temperature for 1 h. The
solution was concentrated and chromatographed on silica
gel column to give the desired 21a (85 mg, 0.47 mmol) in
93% yield.
4.13.2. 4-(1-Hydroxy-1-cyclohexyl)-2-methylenebutyric
acid (30d). 82% Yield, 1H NMR (CDCl3, 400 MHz) d
6.24 (s, 1H, CvCH2), 5.65 (s, 1H, CvCH2), 2.37–2.41 (m,
2H, CH2–CvCH2), 1.10–1.65 (m, 12H); 13C NMR
(CDCl3, 100 MHz) d 171.9, 140.7, 126.6, 71.6, 40.9, 37.3,
25.8, 25.3, 22.2; IR (CH2Cl2, cm21): 2500–3500 (OH),
2925, 1715, 1627, 1438, 1154; MS m/z (rel intensity): 198
(Mþ, 2), 137 (70), 99 (100), 81 (38), 55 (22); HRMS Calcd
for C11H18O3 198.1256, found: 198.1259.
4.12.1. 3-Cyclohexyl-3-hydroxy-2-methylenepropionic
acid (21a). 93% Yield; 1H NMR (CDCl3, 400 MHz) d
6.41 (s, 1H, CvCH2), 5.83 (s, 1H, CvCH2), 4.11 (d,
J¼7.1 Hz, 1H, CH–OH), 1.93–1.97 (m, 1H), 1.56–1.75
(m, 6H), 0.96–1.24 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d 171.2, 140.3, 128.6, 77.2, 42.3, 29.9, 28.2, 26.3, 26.0,
25.9; IR (CH2Cl2, cm21): 2500–3500 (OH), 2927, 1695,
1627, 1450, 1132, 949; MS m/z (rel intensity): 166
(Mþ218, 3), 102 (100), 83 (43), 55 (52), 41 (52); HRMS
Calcd for C10H16O3–H2O 166.0994, found: 166.0996.
4.14. General procedure to prepare the lactone from the
acetoxy-acrylate under acidic condition
To a mixture of acetoxy-acrylate 16b (150 mg, 0.59 mmol)
in 3 mL of MeOH was added catalytic amount of acetyl
chloride and stirred at room temperature for 7 h. The
reaction mixture was concentrated and chromatographed on
silica gel column to give the lactone 17b (91 mg,
0.51 mmol) in 86% yield.
4.12.2. 6-Cyclohexyl-6-hydroxy-2-methylenehexanoic
acid (21d). 95% Yield; 1H NMR (CDCl3, 400 MHz) d
6.25 (s, 1H, CvCH2), 5.62 (s, 1H, CvCH2), 3.36–3.39 (m,
1H, CH–OH), 2.29–2.33 (m, 2H, CH2–CvCH2), 0.99–
1.76 (m, 15H); 13C NMR (CDCl3, 100 MHz) d 171.8, 140.2,
126.5, 76.0, 43.6, 33.4, 31.4, 29.2, 27.8, 26.5, 26.3, 26.2,
24.7; IR (CH2Cl2, cm21): 2500–3500 (OH), 2925, 1714,
1627, 1438, 1154, 944; MS m/z (rel intensity): 226 (Mþ, 8),
4.14.1. 5-Cyclohexyl-3-methylenedihydrofuran-2-one
1
(17b).51 86% Yield; H NMR (CDCl3, 400 MHz) d 6.18

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4855
(br t, J¼2.8 Hz, 1H, CvCH2), 5.59 (br t, J¼2.8 Hz, 1H,
CvCH2), 4.21–4.27 (m, 1H, CHOCO), 2.91–2.97 (m, 1H,
CH2–CvCH2), 2.67–2.69 (m, 1H, CH2–CvCH2), 1.01–
1.92 (m, 11H); 13C NMR (CDCl3, 100 MHz) d 170.4, 134.9,
121.5, 81.4, 43.0, 31.2, 28.1, 27.7, 26.2, 25.6, 25.4; IR
(CH2Cl2, cm21): 2927, 2854, 1763, 1450, 1121, 1027; MS
m/z (rel intensity): 180 (Mþ, 10), 151 (44), 134 (72), 97
(100), 69 (80); HRMS Calcd for C11H16O2 180.1150, found:
180.1158.
MS m/z (rel intensity): 166 (Mþ, 7), 97 (100), 96 (43), 40
(70), 39 (92); HRMS Calcd for C10H14O2 166.0994, found:
166.1003.
4.14.7. 3-Methylenechroman-2-one (48).55 67% Yield,
TLC Rf¼0.64 (hexane/EtOAc¼5:1); 1H NMR (CDCl3,
400 MHz) d 7.06–7.28 (m, 4H), 6.43 (s, 1H, –CvCH2),
5.78 (s, 1H, –CvCH2) 3.81 (s, 2H); 13C NMR (CDCl3,
100 MHz) d 163.2, 150.9, 131.8, 128.4, 128.2, 127.7, 124.5,
121.2, 117.0, 32.0; IR (CH2Cl2, cm21): 2927, 2855, 1713,
1456, 1224, 1150; MS m/z (rel intensity): 160 (Mþ, 100),
131 (48), 105 (8), 91 (8), 77 (16), 69 (18); HRMS Calcd for
C10H8O2 160.0524, found: 160.0521.
4.14.2. 6-Cyclohexyl-3-methylenetetrahydropyran-2-one
(17c). 79% Yield, TLC Rf¼0.48 (hexane/EtOAc¼10:1); 1H
NMR (CDCl3, 400 MHz) d 6.39 (s, 1H, CvCH2), 5.53 (s,
1H, CvCH2), 4.07–4.11 (m, 1H, CHOCO), 2.67–2.68 (m,
1H, CH2–CvCH2), 2.52–2.53 (m, 1H, CH2–CvCH2),
1.66–1.93 (m, 9H), 1.13–1.23 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 166.0, 134.2, 127.5, 84.9, 42.2, 28.1, 27.3, 26.3,
26.0, 25.9, 25.2; IR (CH2Cl2, cm21): 2926, 2854, 1714,
1624, 1174, 1087, 974; MS m/z (rel intensity): 194 (Mþ, 5),
112 (75), 110 (100), 83 (76), 41 (84); HRMS Calcd for
C12H18O2 194.1307, found: 194.1304.
4.15. General procedure to prepare the lactone from
benzoxy-acrylates promoted by NaOMe/MeOH
To a mixture of benzoate-acrylate 35c (150 mg, 0.52 mmol)
in 4 mL of MeOH was added NaOMe (31 mg, 0.57 mmol)
and stirred at room temperature for 4 h. The reaction
mixture was concentrated and chromatographed on silica
gel column to give the lactone 36c (60 mg, 0.40 mmol) in
76% yield.
4.14.3. 5-Methyl-3-methylene-5-phenyldihydrofuran-2-
one (28a).52 75% Yield, TLC Rf¼0.43 (hexane/
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 7.26–7.38
4.15.1. cis-3-Methylenehexahydrobenzofuran-2-one
(36c).54 76% Yield, TLC Rf¼0.41 (hexane/EtOAc¼3:1);
1H NMR (CDCl3, 400 MHz) d 6.19 (d, J¼2.4 Hz, 1H,
CvCH2), 5.50 (d, J¼2.4 Hz, 1H, CvCH2), 4.51–4.56 (m,
1H, CHOCO), 3.00–3.03 (m, 1H, CH–CvCH2), 1.25–
1.87 (m, 8H); 13C NMR (CDCl3, 100 MHz) d 170.9, 139.9,
119.7, 76.9, 39.6, 28.9, 26.3, 21.1, 20.5; IR (CH2Cl2, cm21):
2938, 1771, 1224, 1131, 935.
(m, 5H), 6.26 (br s, 1H, CvCH2), 5.63 (br s, 1H, CvCH2),
3.15–3.16 (m, 2H, CH2–CvCH2), 1.73 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 169.6, 144.6, 135.1, 128.6, 127.7,
124.1, 122.5, 83.8, 42.6, 30.0; IR (CH2Cl2, cm21): 2928,
1761, 1667, 1447, 1115, 737; MS m/z (rel intensity): 188
(Mþ, 22), 173 (100), 105 (76), 77 (41), 68 (68); HRMS
Calcd for C12H12O2 188.0837, found: 188.0828.
4.14.4. 3-Methylene-1-oxa-spiro[4.5]decan-2-one (28c).53
79% Yield, TLC Rf¼0.40 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 6.21 (t, J¼2.8 Hz, 1H, CvCH2), 5.59
(t, J¼2.8 Hz, 1H, CvCH2), 2.70 (t, J¼2.8 Hz, 2H, CH2–
CvCH2), 1.39–1.80 (m, 10H); 13C NMR (CDCl3,
100 MHz) d 169.9, 135.6, 122.1, 83.4, 39.5, 37.4, 24.7,
22.4; IR (CH2Cl2, cm21): 2998, 2933, 2859, 1759, 1665,
1448, 1191; MS m/z (rel intensity): 166 (Mþ, 33), 124 (15),
123 (100), 110 (52), 68 (40); HRMS Calcd for C10H14O2
166.0994, found: 166.0993.
4.15.2. cis-3-Methyleneoctahydrochromen-2-one (36d).54
1
70% Yield, TLC Rf¼0.40 (hexane/EtOAc¼3:1); H NMR
(CDCl3, 400 MHz) d 6.21 (t, J¼2.8 Hz, 1H, CvCH2), 5.60
(t, J¼2.8 Hz, 1H, CvCH2), 4.35–4.38 (m, 1H, CHOCO),
2.99–3.05 (m, 1H, CH–CvCH2), 2.64–2.65 (m, 1H, CH–
CvCH2), 1.27–2.08 (m, 9H); 13C NMR (CDCl3, 100 MHz)
d 170.5, 135.0, 121.7, 81.1, 45.1, 32.5, 28.6, 27.9, 25.4,
25.3; IR (CH2Cl2, cm21): 2942, 2868, 1719, 1622, 1186,
944; MS m/z (rel intensity): 166 (Mþ, 6), 137 (10), 98 (12),
97 (100), 69 (24); HRMS Calcd for C10H14O2 166.0994,
found: 166.0986.
4.14.5. trans-3-Methylenehexahydrobenzofuran-2-one
(36a).54 89% Yield, TLC Rf¼0.43 (hexane/EtOAc¼10:1);
1H NMR (CDCl3, 400 MHz) d 6.04 (d, J¼3.2 Hz, 1H,
CvCH2), 5.36 (d, J¼3.2 Hz, 1H, CvCH2), 3.67–3.72 (m,
1H, CHOCO), 1.24–2.39 (m, 9H); 13C NMR (CDCl3,
100 MHz) d 170.5, 139.6, 117.0, 83.0, 48.8, 30.4, 25.7, 24.8,
24.0; IR (CH2Cl2, cm21): 2939, 2864, 1769, 1675, 1456,
1117, 935; MS m/z (rel intensity): 152 (Mþ, 2), 124 (100),
95 (83), 79 (81), 67 (51); HRMS Calcd for C9H12O2
152.0837, found: 152.0843.
4.15.3. General procedure to prepare lactone from the
hydroxy-acid promoted by o-nitrobenzenesulfonyl
chloride. Anhydrous Na2CO3 (456.0 mg, 4.34 mmol) was
added to a solution of 21a (79.2 mg, 0.43 mmol) in CH2Cl2
(2.5 mL). After 15 min, o-nitrobenzenesulfonyl chloride
(144.1 mg, 0.65 mmol) was added and the mixture left to
stir at room temperature for 2 h. The mixture was diluted
with CH2Cl2 (7.5 mL) and water (2.5 mL) and stirred for
15 min. The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3£15 mL). The combined
organic extracts were dried (Na2SO4), filtered and concen-
trated. Purification by silica gel column chromatography
(hexane/EtOAc¼98:2) provided 17a as a colorless oil
(58.3 mg, 81%).
4.14.6. trans-3-Methyleneoctahydrochromen-2-one
(36b).54 87% Yield, TLC Rf¼0.45 (hexane/EtOAc¼10:1);
1H NMR (CDCl3, 400 MHz) d 6.35 (s, 1H, CvCH2), 5.50
(s, 1H, CvCH2), 4.07–4.13 (m, 1H, CHOCO), 2.64–2.65
(m, 1H, CH2–CvCH2), 2.51–2.52 (m, 1H, CH2–CvCH2),
1.25–2.04 (m, 9H); 13C NMR (CDCl3, 100 MHz) d 166.4,
134.6, 127.9, 84.8, 45.1, 29.1, 28.9, 27.7, 25.8, 25.7; IR
(CH2Cl2, cm21): 2951, 2869, 1759, 1666, 1436, 1125, 941;
4.15.4. 4-Cyclohexyl-3-methylene-1-oxetan-2-one (17a).
81% Yield, TLC Rf¼0.42 (hexane/EtOAc¼10:1); 1H NMR
(CDCl3, 400 MHz) d 5.91 (t, J¼1.7 Hz, 1H, CvCH2), 5.42

4856
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
(t, J¼1.7 Hz, 1H, CvCH2), 4.69 (dt, J¼7.1, 1.7 Hz, 1H,
CHOCO), 1.10–1.87 (m, 11H); 13C NMR (CDCl3,
100 MHz) d 163.7, 145.2, 115.1, 83.2, 40.9, 28.0, 27.4,
26.0, 25.4, 25.3; IR (CH2Cl2, cm21): 2928, 2854, 1827,
1452, 1206, 939; MS m/z (rel intensity): 149 (Mþ217, 20),
111 (51), 83 (70), 55 (96), 43 (100); HRMS Calcd for
C10H14O2 166.0994, found: 166.0990.
133.2, 133.1, 128.4, 123.9, 123.1, 110.5, 55.6, 50.9, 48.0,
43.4, 41.8; IR (CH2Cl2, cm21): 3063, 2973, 2877, 1794,
1617, 1475, 1460, 1234, 1125, 1073, 1037; MS m/z (rel
intensity): 212 (Mþ, 56), 146 (88), 118 (68), 90 (58), 66
(100);HRMSCalcdforC14H12O2 212.0837, found:212.0834.
43-major: pale yellow solid, mp 83–84 8C; 44% yield, TLC
Rf¼0.87 (hexane/EtOAc¼5:1); 1H NMR (CDCl3,
400 MHz) d 7.22–7.27 (m, 1H), 7.01–7.09 (m, 3H),
6.61–6.64 (m, 1H), 6.19–6.21 (m, 1H), 3.19 (s, 1H,
bridgehead-H), 3.07 (s, 1H, bridgehead-H), 2.44–2.49 (m,
2H), 1.50–1.56 (m, 2H); 13C NMR (CDCl3, 100 MHz) d
181.2, 153.1, 141.0, 134.0, 132.0, 128.3, 124.6, 123.5,
110.2, 54.4, 50.6, 47.2, 43.6, 42.4; IR (CH2Cl2, cm21):
3053, 2974, 2875, 1795, 1615, 1478, 1461, 1236, 1123,
1075, 1038; MS m/z (rel intensity): 212 (Mþ, 40), 146 (76),
118 (48), 90 (26), 66 (100); HRMS Calcd for C14H12O2
212.0837, found:. 212.0838.
4.15.5. 7-Cyclohexyl-3-methyleneoxepan-2-one (17d).
87% Yield, TLC Rf¼0.47 (hexane/EtOAc¼10:1); 1H
NMR (CDCl3, 400 MHz) d 5.64 (s, 1H, CvCH2), 5.36 (s,
1H, CvCH2), 3.90–3.95 (m, 1H, CHOCO), 2.32–2.44 (m,
2H, CH2–CvCH2), 1.04–1.84 (m, 15H); 13C NMR
(CDCl3, 100 MHz) d 172.6, 143.5, 122.2, 84.1, 42.9, 31.4,
30.6, 28.6, 27.9, 26.3, 26.1, 26.0, 25.9; IR (CH2Cl2, cm21):
2926, 2854, 1729, 1449, 1168, 928, 878; MS m/z (rel
intensity): 208 (Mþ, 2), 180 (20), 125 (73), 97 (100), 83
(57); HRMS Calcd for C13H20O2 208.1463, found:
208.1472.
4.15.9. 5-Cyclohexyl-3-methylenepyrrolidin-2-one
(52c).39 The solution of the azide 51c (30.8 mg,
0.13 mmol) and Ph3P (39.3 mg, 0.15 mmol) in THF
(1 mL) was stirred at room temperature for 30 min. To the
resulting solution was added H2O (0.1 mL) and stirred at
room temperature for 6 h. The reaction mixture was
concentrated, chromatographed on silica gel column to
give the lactam 52c (18.6 mg, 0.10 mmol) in 80% yield.
TLC Rf¼0.5 (hexane/EtOAc¼10:1); 1H NMR (CDCl3,
400 MHz) d 7.03 (br, 1H, NH), 5.94 (t, J¼2.7 Hz, 1H,
CHvCH2), 5.30 (s, 1H, CHvCH2), 3.38–3.40 (m, 1H,
CHNCO), 2.83–2.85 (m, 1H, CH2CHvCH2), 2.51–2.56
(m, 1H, –CH2CHvCH2), 0.90–1.77 (m, 11H); 13C NMR
(CDCl3, 100 MHz) d 170.7, 139.6, 115.4, 56.2, 43.6, 30.9,
28.7, 28.5, 26.3, 25.8, 25.7, 25.8; IR (CH2Cl2, cm21): 3216
(NH), 2928, 2855, 1697, 1661, 1450, 1264, 928; MS m/z (rel
intensity) 178 (Mþ21, 2), 96 (100), 55 (7), 53 (15), 41 (20);
HRMS Calcd for C11H17NO 179.1310, found: 179.1313.
4.15.6. 6-Methyl-3-methylene-6-phenyltetrahydro-
pyran-2-one (28b). 71% Yield, TLC Rf¼0.45 (hexane/
1
EtOAc¼10:1); H NMR (CDCl3, 400 MHz) d 7.26–7.36
(m, 5H), 6.45 (s, 1H, CvCH2), 5.48 (s, 1H, CvCH2), 2.53–
2.57 (m, 1H), 2.32–2.38 (m, 2H), 2.12–2.17 (m, 1H), 1.69
(s, 3H); 13C NMR (CDCl3, 100 MHz) d 165.7, 143.9, 132.9,
128.7, 128.4, 127.3, 124.4, 84.9, 34.2, 30.9, 24.5; IR
(CH2Cl2, cm21): 2979, 2932, 1714, 1622, 1446, 1140, 929;
MS m/z (rel intensity): 202 (Mþ, 9), 187 (9), 121 (100), 105
(11), 43 (64); HRMS Calcd for C13H14O2 202.0994, found:
202.0997.
4.15.7. 2-Methylene-1-oxaspiro[5.5]undecan-2-one
(28d). 80% Yield, TLC Rf¼0.35 (hexane/EtOAc¼10:1);
1H NMR (CDCl3, 400 MHz) d 6.44 (s, 1H, CvCH2), 5.54
(s, 1H, CvCH2), 2.62–2.66 (m, 2H, CH2–CvCH2), 1.73–
1.86 (m, 6H), 1.32–1.58 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 165.6, 133.4, 127.7, 82.2, 36.5, 31.9, 25.2, 23.5,
21.5; IR (CH2Cl2, cm21): 2929, 2861, 1714, 1622, 1447,
1132; MS m/z (rel intensity): 180 (Mþ, 64), 137 (100), 124
(46), 82 (22), 55 (24); HRMS Calcd for C11H16O2 180.1150,
found: 180.1151.
4.15.10. 6-Cyclohexyl-3-methylene-2-oxo-piperidine-1-
carboxylic acid methyl ester (56d). A mixture of the
acrylate 55d (101.9 mg, 0.36 mmol) in toluene (3.2 mL)
was added Me3Al (2.0 M in toluene, 0.35 mL, 0.71 mmol)
at 0 8C dropwise over 5 min and stirred at 0 8C for 2 h. The
reaction mixture was quenched by the addition of brine at
0 8C. The aqueous phase was separated and extracted with
ethyl acetate. The organic extracts were combined, dried,
concentrated and chromatographed on silica gel column to
give compound 56d (65 mg, 0.26 mmol) in 72% yield. TLC
Rf¼0.64 (hexane/EtOAc¼1:1); 1H NMR (CDCl3,
400 MHz) d 5.11 (s, 1H, CvCH2), 4.77 (s, 1H, CvCH2),
3.66 (s, 3H, –OCH3), 3.52–3.55 (m, 1H), 2.13–2.17 (m,
2H), 1.14–1.76 (m, 13H); 13C NMR (CDCl3, 100 MHz) d
176.3, 157.7, 155.9, 107.5, 55.9, 52.4, 42.9, 30.0, 29.7, 29.6,
28.6, 26.8, 26.64, 26.63; IR (CH2Cl2, cm21): 2927, 2852,
1703, 1634, 1539, 1449, 1361, 1258, 1191, 1148, 1081, 962,
893; MS m/z (rel intensity): 252 (Mþþ1, 2), 251 (Mþ, 1),
200 (28), 182 (40), 170 (56), 107 (100), 88 (48), 76 (48);
HRMS Calcd for C14H21NO3 251.1521, found: 251.1531.
4.15.8. 3-Methylene-3H-benzofuran-2-one (42).37 A sol-
ution of hydroxy-ester 41 (49.9 mg, 0.28 mmol) in dry
toluene (1.4 mL) was treated with trifluoroacetic acid (5
drops). The lactone 42 was formed after the mixture was
refluxed for 2 h. The lactone 42 was known to be stable for a
few days in solution. However, it polymerizes quickly on
the silica gel during the separation. Therefore, the reaction
mixture was cooled down to room temperature and then
added cyclopentadiene (0.2 mL, 2.8 mmol) and stirred at
ambient temperature for 1.5 h. The resulting solution was
concentrated under vacuum and two diastereomers (55%
yield) can be separated by column chromatography.
Compound 43-minor: pale yellow solid, mp 51–52 8C; 11%
yield, TLC Rf¼0.82 (hexane/EtOAc¼5:1); 1H NMR
(CDCl3, 400 MHz) d 7.26–7.32 (m, 2H), 7.09–7.15 (m,
2H), 6.50–6.52 (m, 1H), 6.18–6.20 (m, 1H), 3.22 (s, 1H,
bridgehead-H), 2.91 (s, 1H, bridgehead-H), 2.11–2.15 (m,
1H), 2.04–2.06 (m, 1H), 1.82–1.86 (m, 1H), 1.62–1.65 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 179.4, 152.8, 139.6,
4.16. General procedure to prepare the a-keto ester
from the methyl acrylate by ozonolysis
In a 25 mL of two-necked flask, equipped with a magnetic

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4857
stirrer, a drying tube and a gas dispersing tube (with
porous fritted tip), were placed 10 mL of CH2Cl2 and
a-substituted acrylate 8a (250.7 mg, 1.36 mmol). A stream
of ozone was bubbled through the solution at 278 8C.
Ozone treatment was terminated when the mixture assumed
a blue color. A stream of nitrogen removed excess ozone. To
the resulted solution was added Ph3P (356.7 mg,
1.36 mmol) and the reaction was warmed slowly to room
temperature and stirred for 4 h. The reaction mixture was
concentrated and the residue was chromatographed on
silica gel column to give 176 mg of a-keto ester 9a in 69%
yield.
4.16.6. 10-Iodo-2-oxodecanoic acid methyl ester (9f).
67% Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d
3.86 (s, 3H, OCH3), 3.18 (t, J¼6.8 Hz, 2H, –CH2I), 2.83 (t,
J¼7.2 Hz, 2H, –CH2CvO), 1.82 (quin, J¼7.1 Hz, 2H),
1.52–1.65 (m, 2H), 1.31–1.40 (m, 8H); 13C NMR (CDCl3,
75 MHz) d 194.2, 161.6, 52.8, 39.2, 33.4, 30.3, 29.0, 28.8,
28.2, 22.8, 7.03; IR (CH2Cl2, cm21): 1725 (CvO), 1433,
1268, 1061; MS m/z (rel intensity): 326 (Mþ, 2), 267 (100),
197 (8), 181 (10), 169 (11), 155 (13), 139 (16), 91 (30), 69
(58), 55 (60), 41 (39); HRMS Calcd for C11H19IO3
326.0379, found 326.0374.
4.16.7. 2-Oxononanamide (11g). 90% Yield; white solid,
mp 91–92 8C; 1H NMR (CDCl3, 300 MHz) d 6.85 (br s, 1H,
NH2), 5.80 (br s, 1H, NH2), 2.90 (t, J¼9.7 Hz, 2H,
–CH2(CvO)), 1.55–1.65 (m, 2H), 1.15–1.45 (m, 8H),
0.88 (t, J¼6.8 Hz, 3H, –CH3); 13C NMR (CDCl3, 75 MHz)
d 198.8, 162.1, 36.5, 31.6, 29.0, 23.2, 22.6, 14.0; IR
(CH2Cl2, cm21): 3404 (N–H), 3216 (N–H), 1716 (CvO),
1671 (CONH2), 1403, 1103; MS m/z (rel intensity): 171
(Mþ, 3), 149 (8), 127 (31), 109 (5), 62 (46), 57 (50), 45
(100); HRMS Calcd for C9H17NO2 171.1259, found
171.1266.
4.16.1. 2-Oxononanoic acid methyl ester (9a). 69% Yield;
pale yellow oil; 1H NMR (CDCl3, 300 MHz) d 3.86 (s, 3H,
OCH3), 2.83 (t, J¼7.1 Hz, 2H, –CH2(CvO)), 1.61–1.66
(m, 2H), 1.20–1.35 (m, 8H), 0.88 (t, J¼6.8 Hz, 3H, –CH3);
13C NMR (CDCl3, 75 MHz) d 194.3, 161.6, 52.8, 39.3, 31.5,
28.8, 22.9, 22.5, 14.0; IR (CH2Cl2, cm21): 1728 (CvO),
1435, 1273, 1067; MS m/z (rel intensity): 186 (Mþ, 3), 128
(12), 127 (100), 109 (10), 97 (3); HRMS Calcd for
C10H18O3 186.1256, found 186.1255.
4.16.2. 2-Oxo-2-(3-oxocyclohexyl)acetic acid methyl
1
ester (9b). 64% Yield; pale yellow oil; H NMR (CDCl3,
4.16.8. 1-Pyrrolidin-1-yl-nonane-1,2-dione (11h). 85%
Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d
3.60 (t, J¼6.5 Hz, 2H, NCH2), 3.51 (t, J¼6.8 Hz, 2H,
NCH2), 2.83 (t, J¼7.4 Hz, 2H, –CH2CvO), 1.77–1.96 (m,
4H), 1.56–1.63 (m, 2H), 1.25–1.40 (m, 8H), 0.88 (t,
J¼6.8 Hz, 3H, –CH3); 13C NMR (CDCl3, 75 MHz) d 201.1,
163.2, 47.2, 46.2, 39.2, 31.6, 29.1, 29.0, 26.3, 23.6, 23.0,
22.5, 14.0; IR (CH2Cl2, cm21): 1711 (CvO), 1634 (CvO),
1400, 1086; MS m/z (rel intensity): 225 (Mþ, 8), 98 (88), 75
(100).
300 MHz) d 3.89 (s, 3H, OCH3), 2.00–2.60 (m, 6H), 1.50–
1.85 (m, 3H); 13C NMR (CDCl3, 75 MHz) d 208.4, 193.9,
161.1, 53.1, 46.1, 41.2, 40.8, 26.6, 24.5; IR (CH2Cl2, cm21):
1732, 1706 (CvO), 1446, 1251, 1106, 1061, 1033; MS m/z
(rel intensity): 184 (Mþ, 8), 156 (6), 125 (50), 97 (100), 69
(76), 55 (38), 41 (88).
4.16.3. 3,3-Dimethyl-2,5-dioxohexanoic acid (9c). 71%
1
Yield; yellow oil; H NMR (CDCl3, 300 MHz) d 3.81 (s,
3H, OCH3), 3.12 (s, 2H, –CH2CvO), 2.13 (s, 3H, CH3CO),
1.26 (s, 6H, C(CH3)2); 13C NMR (CDCl3, 75 MHz) d 207.4,
196.9, 161.9, 54.0, 52.3, 43.7, 29.9, 24.8; IR (CH2Cl2,
cm21): 2500–3550 (OH), 1689 (CvO), 1622, 1416, 1284,
1152; MS m/z (rel intensity): 187 (Mþþ1, 2), 127 (42), 99
(22), 83 (3), 69 (3), 59 (4), 43 (100).
4.16.9. N-(2-Oxononanoyl)valine methyl ester (11i). 85%
Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d 7.37
(br d, J¼8.6 Hz, 1H, NH), 4.48 (d, J¼9.4 Hz, 0.5H), 4.47 (d,
J¼9.4 Hz, 0.5H), 3.75 (s, 3H, OCH3), 2.90 (t, J¼7.6 Hz,
2H), 2.22 (sext, J¼5.2 Hz, 1H), 1.52–1.65 (m, 3H), 1.20–
1.35 (m, 7H), 0.85–0.97 (m, 9H, 3xCH3); 13C NMR
(CDCl3, 75 MHz) d 198.6, 171.3, 160.0, 57.3, 52.3, 36.8,
31.6, 31.3, 29.0, 23.2, 22.6, 18.9, 17.7, 14.0; IR (CH2Cl2,
cm21): 3400 (N–H), 1741 (CvO), 1681 (CvO), 1510,
1461, 920; MS m/z (rel intensity): 285 (Mþ, 8), 254 (2), 224
(9), 158 (15), 130 (100), 98 (15), 72 (22), 57 (42), 41 (20);
HRMS Calcd for C15H27NO4 285.1940, found 285.1947.
4.16.4. 10-Hydroxy-2-oxodecanoic acid methyl ester
(9d). 62% Yield; pale yellow oil; 1H NMR (CDCl3,
300 MHz) d 3.86 (s, 3H, OCH3), 3.62 (t, J¼6.6 Hz, 2H,
–CH2OH), 2.83 (t, J¼7.3 Hz, 2H, –CH2(CvCH2)–),
1.25–1.70 (m, 13H); 13C NMR (CDCl3, 75 MHz) d 194.3,
161.6, 62.8, 52.8, 39.2, 32.6, 29.1, 28.8, 25.6, 22.8; IR
(CH2Cl2, cm21): 3441 (OH), 1735 (CvO), 1436, 1263,
1067; MS m/z (rel intensity): 216 (Mþ, 2), 157 (32), 139
(35), 121 (17), 97 (23), 81 (13), 69 (100), 55 (82), 41
(39); HRMS Calcd for C11H20O4 216.1362, found
216.1356.
4.17. General procedure to prepare the a-keto lactone
from a-methylene lactone by ozonolysis in CH2Cl2
A two-necked flask fitted with a glass tube to admit ozone, a
CaCl2 drying tube and a magnetic stirring bar is charged
with a-methylene lactone 17b (90.0 mg, 0.50 mmol) in
CH2Cl2 (5 mL). The flask is cooled to 278 8C and ozone is
bubbled through the solution. When the solution turns blue,
ozone addition is stopped. Nitrogen is passed through the
solution until the blue color is discharged. To the resulted
solution was added Ph3P (104.9 mg, 0.40 mmol) and
warmed slowly to room temperature. The reaction mixture
was concentrated and the residue was chromatographed on
silica gel column to give a-keto lactone 17b0 (72.8 mg,
0.40 mmol) in 80% yield.
4.16.5. 10-Acetoxy-2-oxodecanoic acid methyl ester (9e).
69% Yield; pale yellow oil; 1H NMR (CDCl3, 300 MHz) d
4.05 (t, J¼6.9 Hz, 2H, CH2OAc), 3.86 (s, 3H, OCH3), 2.83
(t, J¼7.3 Hz, 2H, CH2(CvCH2)–), 2.04 (s, 3H, OCOCH3),
1.25–1.65 (m, 12H); 13C NMR (CDCl3, 75 MHz) d 194.3,
171.2, 161.6, 64.5, 52.8, 39.2, 29.1, 29.0, 28.8, 28.5, 25.8,
22.9, 21.0; IR (CH2Cl2, cm21): 1731 (CvO), 1437, 1237,
1064; MS m/z (rel intensity): 258 (Mþ, 1), 199 (42), 157
(92), 139 (52), 95 (12), 69 (100), 55 (70), 43 (88); HRMS
Calcd for C13H22O5 258.1467, found 258.1461.

4858
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4.17.1. 5-Cyclohexyl-3-hydroxy-5H-furan-2-one (17b0).
80% Yield, TLC Rf¼0.4 (hexane/EtOAc¼10:1); enol form
only; 1H NMR (CDCl3, 400 MHz) d 6.21 (d, J¼2.0 Hz, 1H,
CHvCOH), 5.87 (br s, 1H, OH), 4.74 (dd, J¼5.6 and
2.0 Hz, 1H, CHOCO), 1.64–1.80 (m, 5H), 1.14–1.27 (m,
6H,); 13C NMR (CDCl3, 100 MHz) d 170.3, 142.2, 117.6,
83.7, 41.8, 28.2, 28.1, 26.1, 25.7, 25.6; IR (CH2Cl2, cm21):
3391 (OH), 2928, 1757, 1264, 1037; MS m/z (rel intensity):
182 (Mþ, 2), 137 (12), 100 (100), 83 (18), 55 (33); HRMS
Calcd for C10H14O3 182.0943, found: 182.0940.
4.18. General procedure to prepare the a-keto lactone
from a-methylene lactone by ozonolysis in
methanol/CH2Cl2
A two-necked flask fitted with a glass tube to admit ozone, a
CaCl2 drying tube and a magnetic stirring bar is charged
with a-methylene-lactone 17c (95 mg, 0.49 mmol) in
CH2Cl2 (3 mL) and methanol (2 mL). The flask is cooled
to 278 8C and ozone is bubbled through the solution. When
the solution turns blue, ozone addition is stopped. Nitrogen
is passed through the solution until the blue color is
discharges. To the resulted solution was added Ph3P
(131 mg, 0.50 mmol) and warmed slowly to room tempera-
ture. The reaction mixture was concentrated and the residue
was chromatographed on silica gel column to give a-keto
lactone 17c0 (79.3 mg, 0.35 mmol) in 71% yield.
4.17.2. 7-Cyclohexyl-oxepane-2,3-dione (17d0). 80%
Yield, TLC Rf¼0.43 (hexane/EtOAc¼3:1); keto form
1
only; H NMR (CDCl3, 400 MHz) d 3.95–3.99 (m, 1H,
CH2–CO), 2.60–2.62 (m, 1H), 2.48–2.51 (m, 1H), 1.03–
1.99 (m, 15H,); 13C NMR (CDCl3, 100 MHz) d 200.1,
166.2, 82.8, 42.4, 38.2, 29.8, 28.5, 28.2, 26.1, 25.8, 25.7,
20.1; IR (CH2Cl2, cm21): 2925, 2854, 1747, 1714, 1652,
1451, 1118, 736; MS m/z (rel intensity): 210 (Mþ, 33), 122
(40), 109 (100), 81 (78), 67 (86); HRMS Calcd for
C12H18O3 210.1256, found: 210.1266.
4.18.1. 5-Cyclohexyl-2-hydroxytetrahydrofuran-2-car-
boxylic acid methyl ester (17c00). 71% Yield; a mixture
of two diastereomers; 1H NMR (CDCl3, 400 MHz) d 3.83–
3.88 (m, 1H), 3.82 (s, 3H), 0.99–1.26 (m, 15H); 13C NMR
(CDCl3, 100 MHz) d 171.8, 171.7, 102.0, 101.5, 87.1, 85.1,
52.9, 43.4, 42.2, 35.5, 35.2, 29.9, 29.4, 28.7, 28.5, 27.9,
26.4, 25.9, 25.8, 25.7; IR (CH2Cl2, cm21): 3447 (OH), 2924,
2852, 1747, 1449, 1272, 1198, 1156, 1056, 890; MS m/z (rel
intensity): 227 (Mþ21, 2), 151 (95), 145 (68), 133 (42), 127
(45), 109 (45), 85 (100), 67 (43), 55 (46); HRMS Calcd for
C12H20O4–CO2CH3 169.1229, found: 169.1233.
4.17.3. 5-Methyl-5-phenyldihydrofuran-2,3-dione (28a0)
and00 3-Hydroxy-5-methyl-5-phenyl-5H-furan-2-one
(28a ).56 73% Yield, TLC Rf¼0.37 (hexane/EtOAc¼10:1);
a mixture of keto and enol forms (1: 5). Keto form 28a0: 1H
NMR (CDCl3, 400 MHz) d 7.25–7.40 (m, 5H), 3.19–3.20
(m, 1H, CH2–CO), 1.90 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 193.2, 159.4, 142.7, 129.0, 128.7, 125.1,
83.5, 48.1, 31.9. Enol form (28a00): 1H NMR (CDCl3,
400 MHz) d 7.25–7.40 (m, 5H), 6.52 (s, 1H, CHvCOH),
1.89 (s, 3H), 1.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
169.7, 142.7, 140.3, 128.5, 128.3, 124.8, 123.9, 85.7, 22.7;
IR (CH2Cl2, cm21): 2500–3500 (OH), 2931, 1746, 1264,
915; MS m/z (rel intensity): 190 (30), 189 (52), 144 (100),
134 (83), 104 (41); HRMS Calcd for C11H10O3 190.0630,
found: 190.0627.
4.18.2. 2-Hydroxy-5-methyl-5-phenyltetrahydrofuran-2-
carboxylic acid methyl ester (28b00). 75% Yield; a mixture
of two diastereomers; 1H NMR (CDCl3, 400 MHz) d 7.23–
7.49 (m, 5H), 3.99 (br s, 1H, OH), 3.87 and 3.83 (s, 3H),
2.14–2.58 (m, 4H), 1.72 and 1.70 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 172.5, 172.6, 147.5, 147.0, 128.1,
128.0, 126.7, 126.6, 124.9, 124.6, 102.4, 88.0, 87.8, 53.2,
53.0, 39.2, 38.9, 35.1, 34.9, 30.9, 29.2; IR (CH2Cl2, cm21):
3472 (OH), 2924, 2852, 1744, 1494, 1445, 1265, 1066, 892;
MS m/z (rel intensity): 221 (Mþ215, 60), 177 (100), 161
(60), 131 (64), 117 (44), 105 (42), 91 (28), 77 (25); HRMS
Calcd for C13H16O4–CH3 221.0814, found: 221.0810.
4.17.4. 1-Oxaspiro[4.5]decane-2,3-dione (28c0) and 3-
hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (28c00).57 80%
Yield, TLC Rf¼0.35 (hexane/EtOAc¼10:1), a mixture of
keto and enol forms (2: 5). Keto form 28c0: 1H NMR
(CDCl3, 400 MHz) d 2.75 (s, 2H, CH2–CO), 1.26–1.89 (m,
10H,); 13C NMR (CDCl3, 100 MHz) d 194.1, 159.9, 83.3,
45.7, 29.6, 24.3, 22.0 (28). Enol form 28c00: 1H NMR
(CDCl3, 400 MHz) d 6.31 (s, 1H, CHvCOH), 1.26–1.89
(m, 10H); 13C NMR (CDCl3, 100 MHz) d 169.9, 141.3,
124.1, 85.4, 35.8, 24.7, 22.6; IR (CH2Cl2, cm21): 3433
(OH), 2932, 1742, 1264, 1193, 972; MS m/z (rel intensity):
168 (Mþ, 30), 123 (100), 122 (32), 112 (47), 67 (24); HRMS
Calcd for C9H12O3 168.0786, found: 168.0784.
Acknowledgements
We are grateful to the National Science Council, National
Chung Cheng University, and Academia Sinica, Republic of
China for financial support.
References and notes
4.17.5. 3-Hydroxy-5,6,7,7a-tetrahydro-4H-benzofuran-
2-one (36c00). 81% Yield, TLC Rf¼0.37 (hexane/
EtOAc¼3:1); enol form only; 1H NMR (CDCl3,
400 MHz) d 4.60 (dd, J¼11.2, 6.0 Hz, 1H, CHOCO),
2.93–2.98 (m, 1H), 2.40–2.53 (m, 1H), 1.88–2.03 (m, 3H),
1.21–1.38 (m, 4H); 13C NMR (CDCl3, 100 MHz) d 170.9,
134.9, 134.0, 78.4, 33.9, 25.4, 23.7, 22.7; IR (CH2Cl2,
cm21): 3253 (OH), 2939, 1752, 1218, 1061; MS m/z
(rel intensity): 154 (Mþ, 22), 109 (100), 97 (22), 81 (20),
69 (20); HRMS Calcd for C8H10O3 154.0630, found:
154.0635.
1 (a) Hon, Y. S.; Chang, F. J.; Lu, L. Chem. Commun. 1994,
2041–2042. (b) Hon, Y. S.; Chang, F. J.; Lu, L.; Lin, W. C.
Tetrahedron 1998, 54, 5233–5246.
2. Hon, Y. S.; Hsu, T. R.; Chen, C. Y.; Lin, Y. H.; Chang, F. R.;
Hsieh, C. H.; Szu, P. H. Tetrahedron 2003, 59, 1509–1520.
3. Using Eschenmoser’s salt, please see: (a) Nicolaou, K. C.;
Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y. J. Am. Chem.
Soc. 1992, 114, 7935–7936. (b) Takano, S.; Inomata, K.;
Samizu, K.; Tomita, S.; Yanase, M. Chem. Lett. 1989,
1283–1284.

Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
4859
4. Using methylenedimethylaminoammonium chloride, please
see: (a) Takano, S.; Iwabichi, Y.; Ogasawara, K. Chem.
Commun. 1988, 1204–1206. (b) Herdewijn, P.; Claes, P. J.;
Vanderhaeghe, H. J. Med. Chem. 1986, 29, 661–664.
5. Using dimethylamine hydrogen chloride, formaldehyde,
please see: Nakatsuji, Y.; Nakamura, T.; Yonetani, M.;
Yuya, H.; Okahara, M. J. Am. Chem. Soc. 1988, 110,
531–538.
26. Hon, Y. S. Chemistry (The Chinese Chemical Society, Taipei)
1996, 54, 95–102.
27. For oxidation of a-hydroxy esters or their equivalents, see:
(a) Burkhardt, J. P.; Peet, N. P.; Bey, P. Tetrahedron Lett.
1990, 31, 1385–1388. (b) Peet, N. P.; Burkhart, J. P.;
Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P.; Kolb,
M.; Neises, B.; Schirlin, D. J. Med. Chem. 1990, 33, 394–407.
(c) Wipf, P.; Kim, H. Y. Tetrahedron Lett. 1992, 33,
4275–4278. For oxidative cleavage of the double bond of a,
b-unsaturated carbonyl compounds, see: (d) Angelastro, M. R.;
Peet, N. P.; Bey, P. J. Org. Chem. 1989, 54, 3913–3916.
(e) Wasserman, H. H.; Ho, W. B. J. Org. Chem. 1994, 59,
4364–4366. For a-oxidation of carbonyl groups, see: (f) Sliwa,
H.; Tartar, A. J. Org. Chem. 1976, 41, 160–163. For metal-
catalyzed double carbonylation, see: (g) Sakakura, T.;
Yamashita, H.; Kobayashi, T.; Hayashi, T.; Tanaka, M.
J. Org. Chem. 1987, 52, 5733–5740. Miscellaneous, see:
(h) Melillo, D. G.; Larsen, R. D.; Mathre, D. J.; Shukis, W. F.;
Wood, A. W.; Colleluori, J. R. J. Org. Chem. 1987, 52,
5143–5150. (i) Nimitz, J. S.; Mosher, H. S. J. Org. Chem.
1981, 46, 211–213. (j) Creary, X. J. Org. Chem. 1987, 52,
5026–5030. (k) Takahashi, T.; Okano, T.; Harada, T.;
Imamura, K.; Yamada, H. Synlett 1994, 121–122. See also:
(l) Barton, D.; Ollis, W. D. Comprehensive Organic
Chemistry; Pergamon: Oxford, 1979; Vol. 2. pp 779–781.
28. Hon, Y. S.; Lin, W. C. Tetrahedron Lett. 1995, 36,
7693–7696.
6. Hosomi, A.; Hashimoto, H.; Sakurai, H. Tetrahedron Lett.
1980, 27, 951–954.
7. Baldwin, J. E.; Adlington, R. M.; Sweeney, J. B. Tetrahedron
Lett. 1986, 27, 5423–5424.
8. (a) Zhou, J. Y.; Lu, G. D.; Wu, S. H. Synth. Commun. 1992, 22,
481–487. (b) Drewes, S. E.; Taylor, R. B.; Ramesar, N. S.;
Field, J. S. Synth. Commun. 1995, 25, 321–329. (c) Tanaka,
K.; Yoda, H.; Isobe, Y.; Kaji, A. J. Org. Chem. 1986, 51,
1856–1866. (d) Isaac, M. B.; Paquette, L. A. J. Org. Chem.
1997, 62, 5333–5338.
9. Mattes, H.; Beneza, C. J. Org. Chem. 1988, 53, 2732–2737.
10. Masuyama, Y.; Nimura, Y.; Kurusu, Y. Tetrahedron Lett.
1991, 32, 225–228.
11. Adlington, R. M.; Baldwin, J. E.; Gansauer, A.; McCoull, W.;
Russell, A. T. J. Chem. Soc., Perkin Trans. 1 1994,
1697–1702.
12. (a) Nishiyama, H.; Yokoyama, H.; Narimatsu, S.; Itoh, K.
Tetrahedron Lett. 1982, 23, 1267–1270. (b) Ochiai, M.;
Fujita, E. Tetrahedron Lett. 1983, 24, 777–780.
13. (a) Ballini, R.; Marcantoni, E.; Perella, S. J. Org. Chem. 1999,
64, 2954–2957. (b) Fujiwara, T.; Morita, K.; Takeda, T. Bull.
Chem. Soc. Jpn 1989, 62, 1524–1527.
29. Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616–5617.
30. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091–2096.
14. Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63,
2829–2834.
31. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vol. 1. Chapter 4.
15. (a) Chandrasekharam, M.; Liu, R. S. J. Org. Chem. 1998, 63,
9122–9124. (b) Narkunan, K.; Liu, R. S. Chem. Commun.
1998, 1521–1522. (c) Lin, H. S.; Wang, S. L.; Wu, M. J.; Liu,
R. S. Chem. Commun. 1997, 2055–2056. (d) Chen, C. C.; Fan,
J. S.; Shieh, S. J.; Lee, G. H.; Peng, S. M.; Wang, S. L.; Liu,
R. S. J. Am. Chem. Soc. 1996, 118, 9279–9287.
16. Carlson, R. M.; Yang, Q. Tetrahedron Lett. 1994, 35,
7919–7922.
32. Sakurai, H.; Hosomi, A.; Hayashi, J. Organic Synthesis; 1990;
Collect. Vol. VII. pp 443–446.
33. (a) Hon, Y. S.; Lee, C. F. Tetrahedron Lett. 1999, 40,
2389–2392. (b) Hon, Y. S.; Lee, C. F.; Chen, R. J.; Szu, P. H.
Tetrahedron 2001, 57, 5991–6001. (c) Hon, Y. S.; Lee, C. F.;
Chen, R. J.; Huang, Y. F. Synth. Commun. 2003, 33,
2829–2842.
34. Martinez, I.; Andrews, A. E.; Emch, J. D.; Ndalaka, A. J.;
Wang, J.; Howell, A. R. Org. Lett. 2003, 5, 399–402.
35. Hughes, D. L. Org. React. 1992, 42, 335–656.
36. (a) Bloch, R.; Orvane, P. Tetrahedron Lett. 1981, 22,
3597–3600. (b) Pennanen, S. I. Synth. Commun. 1985, 15,
865–872.
17. (a) Lee, C. W.; Gil, J. M.; Oh, D. Y. Heterocycles 1997, 45,
943–948. (b) Minami, T.; Hirakawa, K.; Koyanagi, S.;
Nakamura, S. J. Chem. Soc., Perkin Trans. 1 1990,
2385–2390.
18. Martin, T.; Rodriguez, C. M.; Martin, V. S. J. Org. Chem.
1996, 61, 6450–6453.
37. Schley, D.; Radspieler, A.; Christoph, G.; Liebscher, J. Eur.
J. Org. Chem. 2002, 369–374.
19. (a) Murta, M. M.; de Azevedo, M. B. M.; Greene, A. E. Synth.
Commun. 1993, 23, 495–503. (b) Murray, A. W.; Reid, R. G.
Chem. Commun. 1984, 132–133.
38. (a) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 18, 1977–1980. (b) Thompson, A. S.;
Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski,
E. J. J. J. Org. Chem. 1993, 58, 5886–5888.
20. Danheiser, R. L.; Choi, Y. M.; Menichincheri, M.; Stoner, E. J.
J. Org. Chem. 1993, 58, 322–327.
21. Adam, W.; Albert, R.; Grau, N. D.; Hasemann, L.; Nestler, B.;
Peters, E. M.; Peters, K.; Prechtl, F.; Schnering, H. G. V.
J. Org. Chem. 1991, 56, 5578–5781.
39. Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67,
4530–4535.
40. (a) Hon, Y. S.; Lin, S. W.; Chen, Y. J. Synth. Commun. 1993,
23, 1543–1553. (b) Hon, Y. S.; Lin, S. W.; Lu, L.; Chen, Y. J.
Tetrahedron 1995, 51, 5019–5034. (c) Hon, Y. S.; Wu, K. C.
Tetrahedron 2003, 59, 493–498.
22. Ghera, E.; Yechezkel, T.; Hassner, A. J. Org. Chem. 1990, 55,
5977–5982.
23. Carlson, R. M.; White, L. L. Synth. Commun. 1983, 13,
237–241.
41. (a) Kakiya, H.; Nishimae, S.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 8807–8816. (b) Bloodworth, A. J.;
Korkodilos, D. Tetrahedron Lett. 1991, 32, 6953–6956.
42. Craig, D. C.; Edwards, G. L.; Muldoon, C. A. Tetrahedron
1997, 53, 6171–6182.
24. Hon, Y. S.; Wong, J. L. Chemistry (The Chinese Chemical
Society, Taipei) 2001, 59, 1–10.
25. Burkhardt, J. P.; Peet, N. P.; Bey, P. Tetrahedron Lett. 1988,
29, 3433–3436, and the references cited therein.

4860
Y.-S. Hon et al. / Tetrahedron 60 (2004) 4837–4860
43. Basu, M. K.; Banik, B. K. Tetrahedron Lett. 2001, 42,
187–190.
52. Okabe, M.; Abe, M.; Tada, M. J. Org. Chem. 1982, 47,
1775–1777.
44. Alfred, V.; Stephen, A. M. Tetrahedron Lett. 1977, 42,
4496–4498.
53. Trost, B. M.; Coppola, B. P. J. Am. Chem. Soc. 1982, 104,
6879–6881.
45. Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. J. Org. Chem. 1989,
54, 4391–4397.
54. Ghera, E.; Yechezkel, T.; Hassner, A. J. Org. Chem. 1990, 55,
5977–5982.
46. Baskaran, S.; Islam, I.; Chandrasekaran, S. J. Org. Chem.
1990, 55, 891–895.
55. (a) Sunitha, K.; Balasubramanian, K. K.; Rajagopalan, K.
Tetrahedron Lett. 1984, 25, 3125–3126. (b) Sunitha, K.;
Balasubramanian, K. K.; Rajagopalan, K. J. Org. Chem. 1985,
50, 1530–1531. (c) Gopalan, B.; Rajagopalan, K.; Sunitha, K.;
Balasubramanian, K. K. Tetrahedron 1985, 41, 3153–3160.
(d) Harmon, A. D.; Hutchinson, C. R. J. Org. Chem. 1975, 40,
3474–3480.
47. Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. C.
J. Org. Chem. 1990, 55, 4109–4117.
48. Dodd, J. H.; Schwender, C. F. Synth. Commun. 1993, 18,
1009–1020.
49. Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118,
1209–1210.
56. Tapia, I.; Alcazar, V.; Moran, J. R.; Caballero, C.; Grande, M.
Chem. Lett. 1990, 697–700.
50. Padwa, A.; Au, A.; Lee, G. A.; Owens, W. J. Am. Chem. Soc.
1976, 98, 3555–3564.
57. Kato, Y.; Asano, Y.; Cooper, A. J. L. Tetrahedron Lett. 1995,
36, 4809–4812.
51. Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989,
111, 5495–5496.