Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes in dichloromethane- methanol

Article abstract of DOI:10.1016/j.tet.2011.07.055

Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes 3a-d at -78 °C in dichloromethane-methanol gave the hydroperoxides 6a-d in 70-80% yields. Ozonolysis of bis-endo-diacetylbicyclo[2.2.2]octene 15 and bis-endo-diacetyl-7- oxabicyclo-[2.2.1]heptene 16 under the same reaction conditions gave the hydroperoxides 17 and 18, respectively. The intramolecular sequential nucleophilic addition of the carbonyl groups to the carbonyl oxide group was observed for the first time and was found to be faster than the intermolecular nucleophilic addition of a methanol molecule to the carbonyl oxide group. Ozonolysis of compound 23 in CH₂Cl₂-MeOH at -78 °C followed by reduction with Me₂S gave compounds 24 and 25, in which the stereochemistry of the methoxyl groups was determined by X-ray analysis.

Full text of DOI:10.1016/j.tet.2011.07.055

Tetrahedron 67 (2011) 7236e7243
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes in
dichloromethaneemethanol
,
,
,d,
Hui-Chang Lin a b, Chu-Chung Lin a c, Hsien-Jen Wu a
*
a Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan, ROC
b Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan, ROC
c Department of Medicinal Chemistry, TaiGen Biotechnology Co. Ltd., Taipei, Taiwan, ROC
d Department of Environmental Engineering and Health, Yuanpei University, Hsinchu, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Ozonolysis of bis-endo-diacylbicyclo[2.2.1]heptenes 3aed at ꢀ78 ꢁC in dichloromethaneemethanol gave
the hydroperoxides 6aed in 70e80% yields. Ozonolysis of bis-endo-diacetylbicyclo[2.2.2]octene 15 and
bis-endo-diacetyl-7-oxabicyclo-[2.2.1]heptene 16 under the same reaction conditions gave the hydro-
peroxides 17 and 18, respectively. The intramolecular sequential nucleophilic addition of the carbonyl
groups to the carbonyl oxide group was observed for the first time and was found to be faster than the
intermolecular nucleophilic addition of a methanol molecule to the carbonyl oxide group. Ozonolysis of
compound 23 in CH2Cl2eMeOH at ꢀ78 ꢁC followed by reduction with Me2S gave compounds 24 and 25,
in which the stereochemistry of the methoxyl groups was determined by X-ray analysis.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 17 June 2011
Received in revised form 20 July 2011
Accepted 20 July 2011
Available online 26 July 2011
Keywords:
Ozonolysis
Bis-endo-diacylbicyclo[2.2.1]heptenes
1. Introduction
the observation of exclusive regioselective fragmentation of PO
controlled by remote different carbonyl groups and stereoselective
Extensive investigation of the mechanism of alkene ozonolysis
has confirmed the essential features of the pathway originally
proposed by Criegee.1 Apart from the long-established utility of
ozonolysis in synthesis and structure determination, much of the
current interest in this process centers on the factors affecting the
direction of cleavage of the primary ozonide (PO) and the nature of
the transient carbonyl oxide intermediate formed along with
a carbonyl group by fragmentation of the PO.2 Substituent effects
on the regioselectivity of the PO fragmentation have been reported
in cases in which the substituents are directly placed on the
ozonation alkene bond.3 The cleavage of the PO tends to occur
along the path, which results in the placement of electron-donating
substituents on the carbonyl oxide fragment, while electron-
withdrawing substituents are incorporated in the carbonyl product.
An intermolecular nucleophilic addition of a hydroxyl group to
a carbonyl oxide, for instance, ozonolysis of an olefin in an alcohol,
formation of final ozonides on ozonolysis of norbornene de-
rivatives.6 We also demonstrated that reaction of final ozonides
with triethylamine could act as a method for determining the
regiochemistry of carbonyl oxide formation from PO fragmentation.
Later on, we reported the synthesis of new diacetal trioxa-cage
compounds via an intramolecular nucleophilic addition of the hy-
droxyl group to the carbonyl oxide, which was generated by ozo-
nolysis of the alkene bond.7 In this paper we wish to report the
observation for the first time of intramolecular sequential nucleo-
philic addition of carbonyl groups to the carbonyl oxide on ozo-
nolysis
of
bis-endo
diacylnorbornene
derivatives
in
methanoledichloromethane solution.
2. Result and discussion
Oxidation of 2,5-dialkylfurans 1aec with m-chloroperox-
ybenzoic acid (m-CPBA)8 in dichloromethane at 0 ꢁC gave the cis-
enediones 2aec. DielseAlder reaction of 2aec with cyclo-
pentadiene at room temperature gave the endo products 3aec as
the major products in 80e85% yields, respectively.9 Photo-
isomerization of compound 4 (commercially available) via the cis
isomer 5 followed by DielseAlder reaction with cyclopentadiene
gave compound 3d in 70% yield (Scheme 1).10 Ozonolysis of the
endo adducts 3aed in the cosolvents of methanol and dichloro-
methane (1:1) at ꢀ78 ꢁC gave the hydroperoxides 6aed in 70e80%
yields, respectively. No detectable amount of compound 7 was
affords an a
-alkoxy hydroperoxide and a carbonyl compound.2 This
reaction is usually used for the determination of the regiochemistry
of carbonyl oxide formation from PO fragmentation because the
product composition reflects the regioselectivity in the PO cleav-
age.4 This reaction has also been utilized for the synthesis of ter-
minally differentiated compounds.5 Several years ago, we reported
* Corresponding author. Tel.: þ886 3 5720 645; fax: þ886 4 2207 8083; e-mail
address: wuhj47@yahoo.com.tw (H.-J. Wu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.055

H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
7237
m-CPBA
O
O
R
2
R
CH2Cl2
O
1
R R
2
a R = CH
b R = iso-C3H7
c R = n-C4H9
3
3
O
R
+
O
R
O
hv
O
Ph
O
O
Ph
Ph
Ph
Ph
O
O
Ph
4
5
3d
5
O3
MeO
O
6
7
3a-d
HOO
MeO
10
9
3
MeOH-CH2Cl2
-78 oC
4
8
O
R
11
HOO
R
O
O
1
O
2
O12
R
R
6
7
a R = CH3
b R = iso-C3H7
c R = n-C4H9
d R = Ph
Scheme 1.
obtained in each case. Thus, the intramolecular sequential nucle-
ophilic addition of the carbonyl groups to the carbonyl oxide group
is faster than the intermolecular nucleophilic addition of a metha-
nol molecule to the carbonyl oxide group.
The structure of compounds 6aed was identified by their
spectral data. The infrared (IR) spectra of 6aed showed strong
absorptions at 3500e3200 cmꢀ1 for the hydroperoxide hydroxyl
group and at 1050 cmꢀ1 for the ether CeO bonds and lacked any
carbonyl absorption. The 1H NMR spectrum of 6a revealed a singlet
A reaction mechanism was proposed for the formation of
compounds 6aed by ozonolysis of 3aed in MeOHeCH2Cl2 cosol-
vents (Scheme 2). 1,3-Dipolar cycloaddition of an ozone molecule
with the alkene bond of 3 via the exo face gave the 1,2,3-trioxolane
8. A least-motion fragmentation11 of the 1,2,3-trioxolane ring of the
primary ozonide 8 leads to the syn-oriented carbonyl oxide 9, fol-
lowed by free rotation2,4 of the carbonyl oxide group of 9 to give the
intermediate 10, which is stabilized by hydrogen bonding with
methanol molecule. Sequential intramolecular nucleophilic addi-
tion of the endo acyl groups and the newly-formed formyl group to
the carbonyl oxide group gave the intermediate 11. Intermolecular
nucleophilic addition of a methanol molecule to the oxonium ion of
11 from the stereochemically less hindered convex face gave the
observed products 6aed. Since products 6aed, instead of com-
pounds 7aed, were obtained, the intramolecular sequential nu-
cleophilic addition of the carbonyl groups to the carbonyl oxide
group of 10 is faster than the intermolecular nucleophilic addition
of a methanol molecule to the carbonyl oxide group of 10. On the
other hand, ozonolysis of 3 in dichloromethane in the absence of
methanol gave the final ozonide 9A via the intermediates 8 and 9,
which was converted to the tetraoxa-cages by reduction with di-
methyl sulfide.9a
at
hemiacetal proton on C3, a doublet at
C7, and a singlet at 3.35 for the methoxyl protons. The absorption
at 2.08 (a singlet) for the methyl ketone protons of 3a shifted to
1.63 and 1.58 for the angular methyl protons of 6a. The 13C NMR
spectrum of 6a lacked any carbonyl absorption and displayed two
peaks at 113.63 and 110.97 for the two acetal carbons C3 and C7,
two peaks at 119.80 and
C1 and C9, and one peak at
d
8.70 for the hydroperoxide proton, a doublet at
d 5.46 for the
d
4.91 for the acetal proton on
d
d
d
d
d
d
d
119.66 for the two quaternary carbons
54.94 for the methoxyl carbon. The IR
d
spectra and 1H and 13C NMR spectra of 6b, 6c, and 6d revealed that
these compounds possess the same skeleton as 6a. The coupling
constants for the hemiacetal proton on C3 (J¼2.4 Hz) and for the
acetal proton on C7 (J¼1.2 Hz) may imply that the protons on C3 and
C7 are trans to the protons on C4 and C6, respectively. The stereo-
chemistry of the hydroperoxide group and the methoxyl group of
6aed was also determined on the basis of NOE experiments of 6a.
Reduction of 6aed with dimethyl sulfide in dichloromethane at
room temperature gave compounds 12aed in 85e90% yields
(Scheme 3). Treatment of 6aed with triethylamine in dichloro-
methane at room temperature gave the same products 12aed in
80e85% yields. No detectable amount of compounds 13aed was
obtained. Thus, in reaction with compounds 6aed, triethylamine,
like dimethyl sulfide, acts as a reducing reagent rather than as
a base. On the other hand, in reaction with final ozonides,
Irradiating the hemiacetal proton on C3 of 6a (d 5.46) gives 7.5%
enhancement for the C7 proton absorptions and 2.4% enhancement
for the C4 proton absorptions. Irradiating the acetal proton on C7 of
6a (d 4.91) gives 7.3% enhancement for the C3 proton absorptions
and 2.0% enhancement for the C6 proton absorptions.

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H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
O
O
O
O
O
O
O3
3
O
R
O
R
MeOH-CH2Cl2
-78 oC
O
8
O
9
R
R
O
O
O
MeO H
O
R
6
R
O
O
O
O
O
10
R
O
R
11
O
O3
3
9
8
O
O
R
CH2Cl2
-78 oC
O
O
R
9A
Scheme 2.
in 70e80% yields, respectively. No detectable amount of com-
pounds 19 and 20 was obtained (Scheme 4). Again, the intra-
molecular sequential nucleophilic addition of the carbonyl groups
to the carbonyl oxide group is faster than the intermolecular nu-
cleophilic addition of a methanol molecule to the carbonyl oxide
group. Reduction of 17 and 18 with dimethyl sulfide or triethyl-
amine at room temperature gave compounds 21 and 22,
respectively.
To understand the feasibility of a thioester group on the se-
quential nucleophilic addition, compound 23 was prepared.14
Ozonolysis of 23 in CH2Cl2eMeOH (1:1) at ꢀ78 ꢁC followed by re-
duction with dimethyl sulfide gave compound 24 as the major
product and compound 25 as the minor product (Scheme 5). The
stereochemistry of the methoxyl groups of 24 and 25 was difficultly
determined on the basis of H,H-COSY and NOESY experiments. The
structures of 24 and 25 were finally determined by X-ray analysis,
Figs. 1 and 2. Ozonolysis of 23 in CH2Cl2eMeOH (1:1) at ꢀ78 ꢁC
without reduction gave compound 26 as the major product (65%)
with unidentified minor products. In this ozonolysis reaction, the
thioester group of 23 did not participate the intramolecular se-
quential nucleophilic addition. Reduction of compound 26 with
dimethyl sulfide in CH2Cl2 gave the hemiacetal 27. While the
thioester group of compound 23 was replaced with an ester group,
a similar result for the ozonolysis reaction was observed that the
ester group did not participate the intramolecular sequential nu-
cleophilic addition.15
MeO
HO
Me2S
6a-d
6a-d
3a-d
CH2Cl2
r.t.
R
O
O
O
R
12a-d
MeO
O
Et3N
R
12a-d
O
CH2Cl2
r.t.
O
O
R
13
MeO
MeO
O3
Me2S
R
O
MeOH-CH2Cl2
O
O
R
14a-d
Scheme 3.
3. Conclusion
triethylamine acted as a base, different from dimethyl sulfide, to
give different products.5,9a Ozonolysis of 3aed in the cosolvents of
dichloromethane and methanol (1:1) at ꢀ78 ꢁC followed by re-
duction with dimethyl sulfide gave compounds 14aed in 70e75%
yields.
To extend the intramolecular sequential nucleophilic addition of
the carbonyl groups to the carbonyl oxide group, bis-endo-diac-
etylbicyclo[2.2.2]octane 1512 and bis-endo-diacetyl-7-oxabicyclo
[2.2.1]heptane 1613 were prepared. Ozonolysis of 15 and 16 in
CH2Cl2eMeOH (1:1) at ꢀ78 ꢁC gave the hydroperoxides 17 and 18
Ozonolysis of compounds 3aed, 15, 16, and 23 at ꢀ78 ꢁC in
dichloromethaneemethanol solutions gave the hydroperoxides
6aed, 17, 18, and 26 in high yields, respectively. The intramolecular
sequential nucleophilic addition of the carbonyl groups to the
carbonyl oxide group was observed for the first time and was found
to be faster than the intermolecular nucleophilic addition of
a methanol molecule to the carbonyl oxide group. In the ozonolysis
of compound 23, the thioester group was found not to participate
the sequential nucleophilic addition reaction. The structures and

H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
7239
MeO
O
O3
HOO
MeO
O
CH3
HOO
O
CH3
MeOH-CH2Cl2
-78 oC
O
O
CH3
O
O
CH3
O
CH3
H3C
17
15
19
O
O
O
MeO
HOO
O
O3
HOO
MeO
O
CH3
O
CH3
CH3
MeOH-CH2Cl2
-78 oC
O
O
O
CH3
O
O
CH3
H3C
16
18
20
O
MeO
MeO
HO
Me2S
Me2S
or Et3N
CH2Cl2
or Et3N
CH2Cl2
HO
CH3
17
CH3
18
O
O
O
O
O
O
H3C
21
H3C
22
Scheme 4.
MeO
MeO
O3
Me2S
MeO
MeO
O
O
O
SCH3
+
MeOH-CH2Cl2
-78 oC
O
O
SCH3
CH3
SCH3
CH3
O
O
O
CH3
23
24
25
O3
MeO
HOO
O
23
minor products
+
MeOH-CH2Cl2
-78 oC
O
SCH3
CH3
O
26
Me2S
MeO
HO
26
O
CH2Cl2
O
SCH3
CH3
O
27
Scheme 5.
stereochemistry of the methoxyl groups of compounds 24 and 25
were determined by X-ray analysis.
and 13C NMR spectra were determined at 75 MHz on Fourier
transform spectrometers. Chemical shifts are reported in parts per
million relative to TMS in the solvents specified. The multiplicities
of 13C signals were determined by DEPT techniques. High resolution
mass values were obtained with a high resolution mass spec-
trometer at the Department of Chemistry, National Tsing Hua
University. Elemental analyses were performed at the microanal-
ysis laboratory of this department. X-ray analyses were carried out
on a diffractometer at the Department of Chemistry, National
Chung Hsing University. For thin-layer chromatography (TLC)
analysis, precoated TLC plates (Kieselgel 60 F254) were used, and
4. Experimental section
4.1. General
Melting points were determined in capillary tubes with a Labo-
ratory Devices melting point apparatus and uncorrected. Infrared
spectra were recorded in CHCl3 solutions or on neat thin films
between NaCl disks. 1H NMR spectra were determined at 300 MHz,

7240
H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
(Mþ, 5), 153 (100); HRMS (EI) calcd for C12H18O6 258.1103, found
258.1108.
4.2.2. 1,9-Diisopropyl-3b-hydroperoxy-7a-methoxy-2,8,12-
trioxatetracyclo[7.2.1.0.4,11 0.6,10]dodecane 6b. White ꢀs1olid; mp
65e66 ꢁC; yield 80%; IR (CHCl3) 3550e3300, 1100 cm
;
1H NMR
(300 MHz, CDCl3)
d
8.67 (s, 1H), 5.54 (d, J¼2.7 Hz, 1H), 4.97 (d,
J¼1.5 Hz, 1H), 3.39 (s, 3H), 3.29e3.25 (m, 2H), 2.70e2.58 (m, 2H),
2.31e2.27 (m, 2H), 2.05e1.95 (m, 2H), 1.08e0.91 (m, 12H); 13C NMR
(75 MHz, CDCl3, DEPT)
d 123.85 (C), 123.82 (C), 113.58 (CH), 111.42
(CH), 56.64 (CH), 56.49 (CH), 55.53 (OCH3), 52.09 (CH), 48.49 (CH),
37.35 (CH2), 35.88 (CH), 35.73 (CH), 17.59 (CH3), 17.51 (CH3), 17.32
(CH3), 17.10 (CH3); LRMS m/z (rel int) 314 (Mþ, 6), 209 (100); HRMS
(EI) calcd for C16H26O6 314.1729, found 314.1726.
Fig. 1. ORTEP diagram of 24.
4.2.3. 1,9-Di-n-butyl-3b-hydroperoxy-7a-methoxy-2,8,12-
trioxatetracyclo[7.2.1.0.4,11 0.6,10]dodecane 6c. White ꢀs1olid; mp
70e71 ꢁC; yield 80%; IR (CHCl3) 3550e3300, 1100 cm
;
1H NMR
(300 MHz, CDCl3)
d
8.53 (s, 1H), 5.49 (d, J¼2.7 Hz, 1H), 4.92 (d,
J¼1.5 Hz, 1H), 3.35 (s, 3H), 3.22e3.19 (m, 2H), 2.71e2.68 (m, 2H),
2.40e2.24 (m, 1H), 2.20e2.10 (m, 1H), 1.85e1.73 (m, 4H), 1.48e1.33
(m, 8H), 0.94e0.89 (m, 6H); 13C NMR (75 MHz, CDCl3, DEPT)
d
121.89 (C), 121.70 (C), 113.54 (CH), 111.12 (CH), 58.20 (CH), 58.06
(CH), 55.29 (OCH3), 52.09 (CH), 48.48 (CH), 39.18 (2CH2), 36.82
(CH2), 26.42 (CH2), 26.24 (CH2), 22.75 (2CH2), 14.01 (2CH3); LRMS
m/z (rel int) 342 (Mþ, 12), 71 (100); HRMS (EI) calcd for C18H30O6
342.2042, found 342.2047.
4.2.4. 1,9-Diphenyl-3b-hydroperoxy-7a-methoxy-2,8,12-
trioxatetracyclo[7.2.1.0.4,110.6,10]-dodecane 6d. White solid; mp
149e150 ꢁC; yield 70%; IR (CHCl3) 3550e3300, 1600, 1100, 750,
690 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 8.63 (s, 1H), 7.63e7.55 (m,
4H), 7.40e7.26 (m, 6H), 5.78 (d, J¼2.7 Hz, 1H), 5.24 (d, J¼1.8 Hz, 1H),
3.80e3.76 (m, 2H), 3.41 (s, 3H), 2.94e2.92 (m, 2H), 2.42e2.38 (m,
2H); 13C NMR (75 MHz, CDCl3, DEPT)
d 141.39 (C), 141.27 (C), 128.26
(2CH), 128.09 (2CH), 127.94 (2CH), 125.79 (2CH), 125.53 (2CH),
120.44 (2C), 114.19 (CH), 112.36 (CH), 62.13 (CH), 61.81 (CH), 55.99
(OCH3), 52.44 (CH), 48.87 (CH), 36.71 (CH2); LRMS m/z (rel int) 382
(Mþ, 5), 277 (100); HRMS (EI) calcd for C22H22O6 382.1416, found
382.1413.
Fig. 2. ORTEP diagram of 25.
column chromatography was done by using Kieselgel 60
(70e230 mesh) as the stationary phase. THF was distilled imme-
diately prior to use from sodium benzophenone ketyl under ni-
trogen. CH2Cl2 was distilled from CaH2 under nitrogen.
4.3. General procedure for the reduction of 6aed with
dimethyl sulfide
To a solution of 6a (0.30 g, 1.16 mmol) in dichloromethane
(20 mL) was added excess dimethyl sulfide (0.50 g) at 0 ꢁC. The
reaction mixture was stirred at room temperature for 1 h. The
solvent and excess dimethyl sulfide were evaporated, and the crude
product was purified by flash column chromatography to give the
hemiacetal product 12a (0.27 g, 85%).
4.2. General procedure for the ozonolysis of 3aed in the
cosolvent of dichloromethaneemethanol. Formation of the
hydroperoxides 6aed
The solution of 3a (0.50 g, 2.8 mmol) in dichloromethane and
methanol (volume 1:1) (40 mL) was cooled to ꢀ78 ꢁC, and ozone
was bubbled through it at ꢀ78 ꢁC until the solution turned light
blue. The reaction mixture was stirred at room temperature for
30 min. The solvent was evaporated, and the crude product was
purified by flash column chromatography to give the hydroperox-
ide 6a (0.45 g, 75%).
4.3.1. 1,9-Dimethyl-3
[7.2.1.0.4,110.6,10]dodecane 12a. White solid; mp 102e103 ꢁC; yield
85%; IR (CHCl3) 3500, 1100 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.39
b-hydroxy-7a-methoxy-2,8,12-trioxatetracyclo
d
(d, J¼3.0 Hz, 1H), 4.88 (s, 1H), 4.01 (d, J¼3.9 Hz, 1H), 3.29 (s, 3H),
3.25e3.14 (m, 2H), 2.74e2.67 (m, 2H), 2.29e2.18 (m, 1H), 2.04e1.90
(m, 1H), 1.55 (s, 3H), 1.50 (s, 3H); 13C NMR (75 MHz, CDCl3, DEPT)
4.2.1. 1,9-Dimethyl-3
trioxatetracyclo[7.2.1.0.4,110.6,10
103e104 ꢁC; yield 75%; IR (CHCl3) 3550e3300, 1100 cmꢀ1; 1H NMR
(300 MHz, CDCl3)
b
-hydroperoxy-7
a
-methoxy-2,8,12-
d 119.54 (C), 118.99 (C), 111.00 (CH), 104.13 (CH), 60.04 (CH), 59.05
]
dodecane 6a. White solid; mp
(CH), 54.59 (OCH3), 53.72 (CH), 52.61 (CH), 35.48 (CH2), 27.64 (CH3),
27.44 (CH3); LRMS m/z (rel int) 242 (Mþ, 3), 153 (100); HRMS (EI)
calcd for C12H18O5 242.1154, found 242.1158. Anal. Calcd for
C12H18O5: C, 59.49; H, 7.49. Found: C, 59.53; H, 7.52.
d
8.70 (s, 1H), 5.46 (d, J¼2.4 Hz, 1H), 4.91 (d,
J¼1.2 Hz, 1H), 3.35 (s, 3H), 3.25e3.22 (m, 2H), 2.79e2.73 (m, 2H),
2.39e2.30 (m, 1H), 2.14e2.08 (m, 1H), 1.63 (s, 3H), 1.58 (s, 3H); 13C
NMR (75 MHz, CDCl3, DEPT)
110.97 (CH), 59.90 (CH), 59.64 (CH), 54.94 (OCH3), 52.26 (CH), 48.74
(CH), 36.50 (CH2), 27.06 (CH3), 26.94 (CH3); LRMS m/z (rel int) 258
d
119.80 (C), 119.66 (C), 113.63 (CH),
4.3.2. 1,9-Diisopropyl-3
[7.2.1.0.4,110.6,10]-dodecane 12b. White solid; mp 70e71 ꢁC; yield 90%;
IR (CHCl3) 3500, 1100 cmꢀ1 1H NMR (300 MHz, CDCl3)
5.46 (d,
b-hydroxy-7a-methoxy-2,8,12-trioxatetracyclo
;
d

H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
7241
J¼3.9 Hz, 1H), 4.96 (s, 1H), 3.33 (s, 3H), 3.28e3.25 (m, 2H), 2.84 (d,
J¼3.9 Hz, 1H), 2.74e2.50 (m, 2H), 2.26e2.22 (m, 2H), 2.04e1.93 (m,
(rel int) 256 (Mþ, 14), 117 (100); HRMS (EI) calcd for C13H20O5
256.1311, found 256.1317. Anal. Calcd for C13H20O5: C, 60.92; H, 7.87.
Found: C, 60.95; H, 7.89.
2H), 1.08e0.88 (m, 12H); 13C NMR (75 MHz, CDCl3, DEPT)
d 123.72
(C), 122.36 (C), 111.76 (CH), 104.14 (CH), 57.48 (CH), 56.18 (CH), 55.28
(OCH3), 53.69 (CH), 52.40 (CH), 36.75 (CH2), 36.12 (CH), 35.80 (CH),
17.70 (CH3), 17.45 (2CH3), 17.08 (CH3); LRMS m/z (rel int) 298 (Mþ, 3),
223 (100); HRMS (EI) calcd for C16H26O5 298.1780, found 298.1786.
Anal. Calcd for C16H26O5: C, 64.41; H, 8.78. Found: C, 64.45; H, 8.83.
4.5.2. 1,9-Diisopropyl-3,7-dimethoxy-2,8,12-trioxatetracyclo
[7.2.1.0.4,110.6,10]dodecane 14b. White solid; mp 80e81 ꢁC; yield
75%; IR (CHCl3) 1100 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 4.93 (d,
J¼2.4 Hz, 2H), 3.34 (s, 6H), 3.24e3.21 (m, 2H), 2.64e2.53 (m, 2H),
2.30e2.19 (m, 2H), 1.95e1.91 (m, 2H), 1.08e0.89 (m, 12H); 13C NMR
4. 3.3. 1,9-Di-n-butyl-3
trioxatetracyclo[7.2.1.0.4,110.6,10]-dodecane 12c. White solid; mp
75e76 ꢁC; yield 90%; IR (CHCl3) 3500, 1100 cmꢀ1 1H NMR
(300 MHz, CDCl3)
b
-hydroxy-7
a
-methoxy-2,8,12-
(75 MHz, CDCl3, DEPT) d 123.70 (2C), 111.60 (2CH), 56.87 (2CH),
55.62 (2OCH3), 52.54 (2CH), 36.03 (CH2), 35.96 (2CH), 17.64 (2CH3),
17.30 (2CH3); LRMS m/z (rel int) 312 (Mþ, 4), 194 (100); HRMS (EI)
calcd for C17H28O5 312.1937, found 312.1931. Anal. Calcd for
C17H28O5: C, 65.36; H, 9.03. Found: C, 65.39; H, 9.07.
;
d
5.44 (d, J¼3.9 Hz, 1H), 4.93 (s, 1H), 3.79 (d,
J¼3.9 Hz, 1H), 3.33 (s, 3H), 3.27e3.17 (m, 2H), 2.78e2.58 (m, 2H),
2.31e2.05 (m, 2H), 1.83e1.62 (m, 4H), 1.45e1.30 (m, 8H), 0.91 (t,
J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3, DEPT)
d
121.45 (C), 120.69
4.5.3. 1,9-Di-n-butyl-3,7-dimethoxy-2,8,12-trioxatetracyclo
(C), 111.22 (CH), 104.01 (CH), 58.56 (CH), 57.55 (CH), 54.89 (OCH3),
53.56 (CH), 52.32 (CH), 39.66 (CH2), 39.44 (CH2), 35.91 (CH2), 26.37
(CH2), 26.17 (CH2), 22.77 (2CH2), 14.01 (CH3), 13.98 (CH3); LRMS m/z
(rel int) 326 (Mþ, 5), 237 (100); HRMS (EI) calcd for C18H30O5
326.2093, found 326.2095. Anal. Calcd for C18H30O5: C, 66.23; H,
9.26. Found: C, 66.27; H, 9.28.
[7.2.1.0.4,110.6,10]dodecane 14c. White solid; mp 75e76 ꢁC; yield 75%;
IR (CHCl3) 1100 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
4.91 (d, J¼2.4 Hz,
2H), 3.35 (s, 6H), 3.20e3.17 (m, 2H), 2.71e2.65 (m, 2H), 2.31e2.26
(m, 1H), 2.07e2.02 (m, 1H), 1.85e1.67 (m, 4H), 1.51e1.26 (m, 8H),
0.91 (t, J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3, DEPT)
d 121.58 (2C),
111.09 (2CH), 58.09 (2CH), 55.18 (2OCH3), 52.41 (2CH), 39.59
(2CH2), 36.50 (CH2), 26.22 (2CH2), 22.78 (2CH2),13.98 (2CH3); LRMS
m/z (rel int) 340 (Mþ, 8), 195 (100); HRMS (EI) calcd for C19H32O5
340.2249, found 340.2245. Anal. Calcd for C19H32O5: C, 67.03; H,
9.47. Found: C, 67.05; H, 9.51.
4.3.4. 1,9-Diphenyl-3
[7.2.1.0.4,110.6,10]dodecane 12d. White solid; mp 155e156 ꢁC; yield
85%; IR (CHCl3) 3500, 1600, 1100, 750, 690 cmꢀ1 1H NMR
(300 MHz, CDCl3) 7.63e7.59 (m, 4H), 7.39e7.28 (m, 6H), 5.80 (d,
b-hydroxy-7a-methoxy-2,8,12-trioxatetracyclo
;
d
J¼3.9 Hz, 1H), 5.23 (s, 1H), 3.89 (d, J¼3.9 Hz, 1H), 3.79e3.74 (m, 2H),
4.5.4. 1,9-Diphenyl-3,7-dimethoxy-2,8,12-trioxatetracyclo
3.34 (s, 3H), 2.93e2.85 (m, 2H), 2.35e2.31 (m, 2H); 13C NMR
[7.2.1.0.4,110.6,10]dodecane 14d. White solid; mp 112e113 ꢁC; yield
(75 MHz, CDCl3, DEPT)
d
142.03 (C), 141.77 (C), 128.12 (2CH), 128.06
75%; IR (CHCl3) 1600, 1100, 750, 690 cmꢀ1 1H NMR (300 MHz,
;
(2CH), 128.03 (2CH), 126.01 (2CH), 125.90 (2CH), 120.62 (C), 119.60
(C), 112.71 (CH), 105.35 (CH), 63.32 (CH), 61.63 (CH), 55.66 (OCH3),
53.79 (CH), 52.79 (CH), 36.43 (CH2); LRMS m/z (rel int) 366 (Mþ, 3),
203 (100); HRMS (EI) calcd for C22H22O5 366.1467, found 366.1463.
Anal. Calcd for C22H22O5: C, 72.12; H, 6.05. Found: C, 72.16; H, 6.09.
CDCl3)
2H), 3.78e3.75 (m, 2H), 3.41 (s, 6H), 2.94e2.89 (m, 2H), 2.39e2.35
(m, 2H); 13C NMR (75 MHz, CDCl3, DEPT)
141.83 (2C), 128.04
(4CH), 127.99 (4CH), 125.91 (2CH), 120.47 (2C), 112.55 (2CH), 62.32
(2CH), 55.93 (2OCH3), 52.79 (2CH), 36.97 (CH2); LRMS m/z (rel int)
380 (Mþ, 3), 198 (100); HRMS (EI) calcd for C23H24O5 380.1623,
found 380.1628. Anal. Calcd for C23H24O5: C, 72.61; H, 6.36. Found:
C, 72.64; H, 6.39.
d
7.61e7.58 (m, 4H), 7.37e7.30 (m, 6H), 5.25 (d, J¼2.4 Hz,
d
4.4. General procedure for the reaction of 6aed with
triethylamine
To a solution of 6a (0.30 g, 1.16 mmol) in dichloromethane
(20 mL) was added excess triethylamine (0.60 g) at 0 ꢁC. The re-
action mixture was stirred at room temperature for 1 h. The solvent
and excess triethylamine were evaporated, and the crude product
was purified by flash column chromatography to give the hemi-
acetal product 12a (0.27 g, 85%). No detectable amount of the lac-
tone 13a was obtained.
4.6. Ozonolysis of compounds 15 and 16 in CH2Cl2eMeOH
The same reaction conditions of ozonolysis of 3aed were ap-
plied for the ozonolysis of compounds 15 and 16 in the cosolvents
of dichloromethaneemethanol to give the hydroperoxides 17 and
18, respectively.
4.6.1. 1,10-Dimethyl-3b-hydroperoxy-8a-methoxy-2,9,13-
4.5. General procedure for the ozonolysis of 3aed. Formation
of the diacetals 14aed
trioxatetracyclo[8.2.1.0.4,12 0.7,11]tridecane 17. White solid; mp
106e107 ꢁC; yield 70%; IR (CHCl3) 3600e3300, 1100 cmꢀ1; 1H NMR
(300 MHz, CDCl3)
d
8.66 (s, 1H), 5.39 (d, J¼2.4 Hz, 1H), 4.81 (d,
The solution of 3a (0.50 g, 2.8 mmol) in dichloromethane and
methanol (volume 1:1) (40 mL) was cooled to ꢀ78 ꢁC, and ozone
was bubbled through it at ꢀ78 ꢁC until the solution turned light
blue. To this solution was added dimethyl sulfide (0.52 g, 8.4 mmol)
at ꢀ78 ꢁC. The reaction mixture was stirred at room temperature
for 4 h. The solvent was evaporated, and the crude product was
purified by column chromatography to give the diacetal 14a (0.46 g,
70%).
J¼2.1 Hz, 1H), 3.55e3.48 (m, 2H), 3.35 (s, 3H), 2.80e2.72 (m, 2H),
2.48e2.34 (m, 2H), 1.73e1.67 (m, 2H), 1.63 (s, 3H), 1.59 (s, 3H); 13C
NMR (75 MHz, CDCl3, DEPT)
d 121.29 (C), 121.08 (C), 113.25 (CH),
111.29 (CH), 55.14 (OCH3), 45.84 (CH), 45.09 (CH), 41.38 (CH), 37.99
(CH), 28.16 (CH3), 28.06 (CH3), 21.68 (CH2), 21.07 (CH2); LRMS m/z
(rel int) 272 (Mþ, 3), 91 (100); HRMS (EI) calcd for C13H20O6
272.1259, found 272.1256.
4.6.2. 1,9-Dimethyl-3b-hydroperoxy-7a-methoxy-2,5,8,12-
4.5.1. 1,9-Dimethyl-3,7-dimethoxy-2,8,12-trioxatetracyclo
tetraoxatetracyclo[7.2.1.0.4,110.6,10]dodecane 18. White ꢀs1olid; mp
[7.2.1.0.4,110.6,10]dodecane 14a. White solid; mp 100e101 ꢁC; yield
85e86 ꢁC; yield 80%; IR (CHCl3) 3600e3300, 1100 cm
;
1H NMR
70%; IR (CHCl3) 1100 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
4.90 (d,
(300 MHz, CDCl3)
(m, 1H), 4.59e4.57 (m, 1H), 3.48e3.46 (m, 2H), 3.34 (s, 3H), 1.66 (s,
3H),1.58 (s, 3H); 13C NMR (75 MHz, CDCl3, DEPT)
121.82 (C),121.02
d 9.17 (s, 1H), 5.57 (s, 1H), 5.03 (s, 1H), 4.70e4.67
J¼1.8 Hz, 2H), 3.36 (s, 6H), 3.24e3.21 (m, 2H), 2.74e2.71 (m, 2H),
2.39e2.28 (m, 1H), 2.05e1.95 (m, 1H), 1.57 (s, 6H); 13C NMR
d
(75 MHz, CDCl3, DEPT)
d
119.56 (2C), 111.00 (2CH), 59.61 (2CH),
(C), 111.57 (CH), 108.39 (CH), 90.45 (CH), 88.04 (CH), 59.39 (CH),
54.92 (2OCH3), 52.62 (2CH), 36.10 (CH2), 27.31 (2CH3); LRMS m/z
59.24 (CH), 54.29 (OCH3), 27.40 (CH3), 27.24 (CH3); LRMS m/z (rel

7242
H.-C. Lin et al. / Tetrahedron 67 (2011) 7236e7243
int) 260 (Mþ, 5), 113 (100); HRMS (EI) calcd for C11H16O7 260.0896,
found 260.0894.
int) 288 (Mþ, 11), 241 (49), 153 (100); HRMS (EI) calcd for C13H20O5S
288.1031, found 288.1033.
4.9. Ozonolysis of compounds 23 in
dichloromethaneemethanol
4.7. Reduction of compounds 17 and 18 with dimethyl sulfide
or triethylamine
The same reaction conditions for the ozonolysis of 3aed to form
thehydroperoxides6aedwereapplied fortheozonolysis of23to give
compound26asthemajorproductwithunidentifiedminorproducts.
The same reaction conditions of the reduction of 6aed with
dimethyl sulfide or triethylamine were applied for the reduction of
compounds 17 and 18 to give the hemiacetals 21 and 22,
respectively.
4.9.1. 4-Methyl-2
thiocarboxyl-3,5-dioxatricyclo-[5.2.1.0.4,9]decane 26. White solid;
mp 90e91 ꢁC; IR (CHCl3) 3500e3200, 1680, 1150 cmꢀ1 1H NMR
(300 MHz, CDCl3)
b-hydroperoxy-6b-methoxy-8a-methyl-
4.7.1. 1,10-Dimethyl-3
[8.2.1.0.4,120.7,11]tri-decane 21. White solid; mp 112e113 ꢁC; 80%
yield; IR (CHCl3) 3500, 1100 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.34
b-hydroxy-8a-methoxy-2,9,13-trioxatetracyclo
;
d
8.75 (s, 1H), 5.34 (s, 1H), 5.12 (d, J¼5.4 Hz, 1H),
d
3.41 (s, 3H), 3.16e3.11 (m, 1H), 2.91e2.85 (m, 2H), 2.68e2.63 (m,
1H), 2.35 (s, 3H), 2.22e2.16 (m, 1H), 1.83e1.78 (m, 1H), 1.66 (s, 3H);
(d, J¼2.4 Hz, 1H), 4.81 (s, 1H), 3.32 (s, 3H), 2.78e2.75 (m, 2H),
2.43e2.40 (m, 2H), 1.69e1.49 (m, 10H), 1.26 (s, 1H); 13C NMR
13C NMR (75 MHz, CDCl3, DEPT)
d 196.84 (COS), 111.54 (CH), 110.26
(75 MHz, CDCl3, DEPT)
d 120.30 (C), 120.00 (C), 110.69 (CH), 104.52
(C), 98.88 (CH), 56.07 (CH), 55.23 (OCH3), 48.57 (CH), 43.51 (CH),
39.35 (CH), 28.64 (CH3), 27.23 (CH2), 11.34 (SCH3); LRMS m/z (rel
int) 290 (Mþ, 2), 211 (100); HRMS (EI) calcd for C12H18O6S 290.0824,
found 290.0829.
(CH), 54.91 (OCH3), 45.79 (CH), 45.27 (CH), 42.10 (CH), 41.37 (CH),
28.34 (CH3), 28.08 (CH3), 21.70 (CH2), 20.53 (CH2); LRMS m/z (rel
int) 256 (Mþ, 5), 69 (100); HRMS (EI) calcd for C13H20O5 256.1310,
found 256.1315. Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C,
60.96; H, 7.91.
4.10. Reduction of compound 26 with dimethyl sulfide
4.7.2. 1,9-Dimethyl-3
tetraoxatetracyclo[7.2.1.0.4,110.6,10]-dodecane 22. White solid; mp
141e142 ꢁC; yield 75%; IR (CHCl3) 3500, 1100 cmꢀ1 1H NMR
(300 MHz, CDCl3)
b-hydroxy-7a-methoxy-2,5,8,12-
The same reaction conditions for the reduction of 6aed with
dimethyl sulfide were applied for the reduction of compound 26 to
give compound 27.
;
d
5.52 (d, J¼2.4 Hz, 1H), 5.01 (s, 1H), 4.58 (d,
J¼6.0 Hz, 1H), 4.54 (d, J¼6.0 Hz, 1H), 3.54e3.41 (m, 2H), 3.33 (s, 3H),
4.10.1. 4-Methyl-2b-hydroxy-6b-methoxy-8a-methylthiocarboxyl-
3.10 (s,1H),1.65 (s, 3H),1.58 (s, 3H); 13C NMR (75 MHz, CDCl3, DEPT)
3,5-dioxatricyclo[5.2.1.0.4,9]decane 27. White solid; mp 113e114 ꢁC;
IR (CHCl3) 3500e3200, 1680, 1150 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
121.74 (C), 121.36 (C), 108.27 (CH), 102.23 (CH), 91.12 (CH), 90.48
(CH), 59.35 (CH), 59.15 (CH), 54.29 (OCH3), 28.15 (CH3), 27.74 (CH3);
LRMS m/z (rel int) 244 (Mþ, 10), 231 (100); HRMS (EI) calcd for
C11H16O6 244.0946, found 244.0942. Anal. Calcd for C11H16O6: C,
54.09; H, 6.60. Found: C, 54.12; H, 6.62.
d
5.28 (s, 1H), 5.08 (d, J¼5.7 Hz, 1H), 4.04 (br s, 1H), 3.38 (s, 3H),
3.26e3.23(m,1H), 2.74e2.82 (m, 2H), 2.62e2.54(m,1H), 2.34(s, 3H),
2.13e2.08 (m,1H),1.81e1.69 (m,1H),1.64 (s, 3H); 13C NMR (75 MHz,
CDCl3, DEPT)
d 196.92 (COS), 109.44 (C), 102.06 (CH), 98.94 (CH),
55.97 (CH), 54.99 (OCH3), 48.19 (CH), 46.88 (CH), 39.30 (CH), 29.51
(CH3), 26.36 (CH2),11.20 (SCH3); LRMS m/z (rel int) 274 (Mþ,10), 227
(100); HRMS (EI) calcd for C12H18O5S 274.0875, found 274.0868.
4.8. Ozonolysis of compound 23 in
dichloromethaneemethanol followed by reduction with
dimethyl sulfide
Acknowledgements
The same reaction conditions for the ozonolysis of 3aed to form
the diacetals 14aed were applied for the ozonolysis of 23 to give
the major product 24 (74%) and the minor product 25 (11%).
We thank Dr. C.-C.L. at the Department of Chemistry, National
Chung Hsin University, for carrying out the X-ray crystallographic
analysis.
4.8.1. 4-Methyl-2
dioxatricyclo[5.2.1.0.4,9]-decane 24. White solid; mp 79e80 ꢁC; IR
(CHCl3) 1680, 1125, 1050 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.09 (d,
J¼5.7 Hz, 1H), 4.78 (s, 1H), 3.42 (s, 3H), 3.31 (s, 3H), 3.16e3.13 (m,
1H), 2.93e2.80 (m, 2H), 2.57e2.51 (m, 1H), 2.34 (s, 3H), 2.13e2.04
(m, 1H), 1.80e1.73 (m, 1H), 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3,
b,6b-dimethoxy-8a-methylthiocarboxyl-3,5-
Supplementary data
d
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2011.07.055. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
DEPT)
d 196.93 (COS), 109.37 (C), 108.21 (CH), 99.29 (CH), 55.99
(OCH3), 55.38 (CH), 54.10 (OCH3), 48.33 (CH), 46.17 (CH), 39.39
(CH), 29.27 (CH3), 26.16 (CH2), 11.24 (SCH3); LRMS m/z (rel int) 288
(Mþ, 16), 241 (62), 153 (100); HRMS (EI) calcd for C13H20O5S
288.1031, found 288.1036.
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dioxatricyclo[5.2.1.0.4,9]-decane 25. White solid; mp 85e86 ꢁC; IR
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4.73 (s,
b,6a-dimethoxy-8a-methylthiocarboxyl-3,5-
d
1H), 4.47 (s, 1H), 3.44 (s, 3H), 3.33 (s, 3H), 3.12e3.09 (m, 1H),
2.87e2.84 (m, 1H), 2.71e2.67 (m, 1H), 2.62e2.54 (m, 1H), 2.34 (s,
3H), 2.18e2.02 (m, 1H), 1.72 (s, 3H), 1.52e1.46 (m, 1H); 13C NMR
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(CH), 57.07 (OCH3), 55.91 (CH), 54.13 (OCH3), 47.86 (CH), 46.70 (CH),
42.94 (CH), 32.98 (CH2), 28.40 (CH3), 11.47 (SCH3); LRMS m/z (rel

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