Synthesis of novel macrocyclic peroxides by bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols

Article abstract of DOI:10.1016/S0040-4020(02)01556-9

Bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides, prepared by a variety of different methods, afforded the corresponding 10- to 20-membered macrocyclic peroxides having two or three peroxide units located within one ring in moderate yields. By analogy, cyclization of unsaturated alcohols having one or two peroxide bond in the chain afforded the corresponding cyclic ethers. The efficiency of the latter reactions were found to be a function of the structure of the alcohols.

Full text of DOI:10.1016/S0040-4020(02)01556-9

Tetrahedron 59 (2003) 525–536
Synthesis of novel macrocyclic peroxides by
bis(sym-collidine)iodine (I) hexafluorophosphate-mediated
cyclization of unsaturated hydroperoxides and unsaturated alcohols
Toyonari Ito,a Takahiro Tokuyasu,a Araki Masuyama,a Masatomo Nojimaa
,
*
and Kevin J. McCulloughb
,
*
aDepartment of Materials Chemistry and Frontier Research Center, Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
bDepartment of Chemistry, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK
Received 21 October 2002; accepted 22 November 2002
Abstract—Bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides, prepared by a variety of
different methods, afforded the corresponding 10- to 20-membered macrocyclic peroxides having two or three peroxide units located within
one ring in moderate yields. By analogy, cyclization of unsaturated alcohols having one or two peroxide bond in the chain afforded the
corresponding cyclic ethers. The efficiency of the latter reactions were found to be a function of the structure of the alcohols. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
and often possess desirable pharmacological properties.1
Thus, considerable effort has gone into developing
short, efficient synthetic routes to 6- to 9-membered
cyclic peroxides and identifying the key structure–
activity relationships for the antimalarial activity against
During the last decade, the chemistry of cyclic peroxides has
enjoyed a resurgence of interest with the increasing
appreciation that such compounds occur widely in nature
Scheme 1.
Keywords: macrocyclic peroxide; iodonium ion-mediated cyclization; unsaturated hydroperoxide; unsaturated alcohol.
*
Corresponding authors. Tel./fax: þ81-6-6879-7928; e-mail: nojima@ap.chem.eng.osaka-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01556-9

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T. Ito et al. / Tetrahedron 59 (2003) 525–536
drug-resistant forms of malarial such as P. falciparum.2 In
contrast, examples of macrocyclic peroxides are compara-
tively scarce.3–5 Moreover, they are usually derived from
unexpected oligomerization of key intermediates such as
diradicals. In this respect, we recently reported that bis(sym-
collidine)iodine(I) hexafluorophosphate (BCIH)-promoted
cyclization6,7 of some unsaturated hydroperoxides provides
novel macrocyclic peroxides.8 We report herein the scope
and limitation of these cyclization reactions including new
methods of preparation for a variety of unsaturated
hydroperoxides and extension of this cyclization method-
ology to the synthesis of macrocyclic ethers from unsaturated
alcohols having one or more peroxide bond in the chain.
hydroperoxides was based on the mono-ozonolysis of the
symmetrical bis(alkenylperoxy)cyclododecane 3,9 which
was prepared by alkylation of the bishydroperoxide 1 with
2 equiv. of 4-iodo-2-methylbutene in the presence of Ag2O
(Scheme 1).7 Reaction of diene 3 with 1.3 equiv. of ozone in
MeOH–CH2Cl2 gave the unsaturated hydroperoxide 4
(20%) accompanied by di-ozonolysis product (31%) and
unreacted diene 2 (23%) (see Experimental). This suggests
that ozone reacts with diene 3 and the mono-ozonolysis
product 4 at similar rates. In a second method for the
synthesis of unsaturated hydroperoxides, the cobalt(II)-
catalyzed triethylsilylperoxidation of diene 3 with
molecular oxygen and triethylsilane was investigated.10
Thus, treatment of a solution of diene 3 and a catalytic
amount of cobalt(II) acetylacetonate in dry ethanol with
triethylsilane at room temperature for 16 h under an oxygen
atmosphere at slightly positive pressure followed by
removal of triethylsilyl group afforded the hydroperoxide
5 in 17% yield, together with cyclododecanone (23%) and
unreacted diene 3 (36%). Subsequent reaction of 4 with
2. Results and discussion
2.1. Macrocyclization of unsaturated hydroperoxides
A first approach to the synthesis of the required unsaturated
Scheme 2.

T. Ito et al. / Tetrahedron 59 (2003) 525–536
527
1.5 equiv. of BCIH in CH2Cl2 at room temperature for 4 h
gave the expected 13-membered macrocyclic triperoxide 6
in 54% yield (a 3:1 mixture of two inseparable stereo-
isomers). Under similar reaction conditions, the unsaturated
hydroperoxide 5 was converted into the cyclic peroxide 7 in
47% yield (Scheme 1). The structure of the 13-membered
triperoxide 7 has been unambiguously determined by the
X-ray crystallographic analysis.8
Thus, BCIH-promoted cyclization of unsaturated hydro-
peroxides has been proved to be a good procedure for the
preparation of macrocyclic peroxides having three peroxide
bonds in one ring. The major drawback is the poor
selectivity obtained in the mono-peroxidation of diene 3.
Due to the methodology for the preparation of dienes such
as 3, the variation in structure of the derived unsaturated
hydroperoxide substrates is also limited. To overcome these
limitations, we developed a third method for the preparation
of unsaturated hydroperoxide precursors as outlined in
Scheme 2. This approach involved the Ag2O-catalysed
alkylation of the hydroperoxide 10a with the iodoalkyl
hemiperketals 911,12 to provide the peroxides 11 in moderate
yield (however, as a mixture with ca. 20% of cyclodo-
decanone) (Scheme 2). Subsequent deprotection of the
peroxides 11 afforded hydroperoxides 12, which on
BCIH-promoted cyclization gave the corresponding cyclic
peroxides 13a–d. It is noteworthy that the 20-membered
cyclic peroxide 13d, the largest cyclic peroxide hitherto
known, could be obtained in an acceptable yield of 50%.
The crystal structure of the novel 16-membered triperoxide
13b has also been unambiguously determined by the X-ray
analysis.8 In the case of the sterically congested 12e,
however, dehydration competed with the intramolecular
cyclization process, thereby providing aldehyde 14e (38%)
together with the expected macrocyclic peroxide 13e (33%).
Since the product yields in each step are acceptable
and, moreover, the length of the longer tether is readily
variable, the procedure outlined in Scheme 2 should offer a
convenient synthetic entry to a variety of novel macrocyclic
peroxide systems.
Scheme 3.
Unfortunately, the subsequent Ag2O-promoted alkylation
of 23 afforded the peroxides 24 in poor yield. The desired
unsaturated hydroperoxides 25 were then obtained by
removal of the triethylsilyl group. The outcome of the
BCIH-promoted cyclization of 25 was significantly influ-
enced by the substrate structure: 25a gave the expected
12-membered cyclic peroxide 26a whereas 25b, having the
longer chain, underwent cleavage with concomitant elimi-
nation of 3-iodomethyl-3-methyl-1,2-dioxolane (27a). This
implies that formation of the 14-membered cyclic peroxide
from 25b (path a in Scheme 5) is entropically less favorable
than the alternative pathway b involving attack on the
iodonium ion intermediate by the distal oxygen atom of the
inner peroxide bond. In addition to dioxolane 27a, cleavage
path b would result in the formation of a relatively stable
oxonium ion intermediate 28.
The above method was extended to the preparation of
unsaturated hydroperoxides 17. Nucleophilic substitution of
the iodide 9 with the hydroperoxide 15a, followed by
deprotection, gave 17a,b in moderate yields (Scheme 3).
Subsequent BCIH-promoted cyclization gave the 11- and
13-membered 1,2,4,5-tetraoxacycloalkane derivatives
18a,b in acceptable yields.
We have previously reported that the tetroxocane derivative
19a is produced in essentially quantitative yield from an
unsaturated hydroperoxide 10a.7 Under similar reaction
conditions, the larger tetraoxacycloalkane derivatives 19b,c
were successfully prepared in around 50% yields from the
unsaturated hydroperoxide 10b,c having a longer tether than
10a (Scheme 4).
In a further approach to the synthesis of unsaturated
hydroperoxide precursors 25, the carbonyl oxide, cyclo-
hexanone O-oxide, generated in situ by ozonolysis of the
vinyl ether 22, was captured by (triethylsilyl)dioxy-
substituted alcohols 21 to give the corresponding hydro-
peroxide adducts 23 in moderate yield (Scheme 5).9
Scheme 4.

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T. Ito et al. / Tetrahedron 59 (2003) 525–536
Scheme 5.
2.2. Macrocyclization of unsaturated alcohols
proceeded very slowly (46% of 20e was recovered after 17 h
reaction) and only the 18-membered cyclic dimer 30e was
obtained in a low yield of 16% (Table 1). These results are at
variance with the observation that the BCIH-promoted
cyclization reactions of unsaturated carboxylic acids gave
the corresponding 7–20-membered lactones in good to
moderate yield.6b Consequently, we tested the efficiency of
the BCIH-promoted cyclization of the relevant unsaturated
hydroperoxides 15b,c (Table 1). After 4 h, the reaction of
the unsaturated hydroperoxide 15b with BCIH gave the
1,2-dioxocane 27b in 63% yield, suggesting that, as
compared to alcohol 20d, the reaction of 15b is significantly
Brunel and Rousseau have reported that the BCIH-promoted
cyclization of unsaturated alcohols provides an excellent
method for the production of the corresponding oxepanes,
whereas the efficiency of formation of the corresponding
oxocanes is very poor.13 Thus, the reaction of an unsaturated
alcohol 20c for 1 h gave the oxepane 29c in 71% yield.
Under similar reaction conditions, the desired oxocane 29d
(9%) and the 16-membered dimer 30d (14%) were obtained
from 20d. In accordance with this, we also found that the
reaction of unsaturated alcohol 20e at room temperature
Table 1. Reaction of unsaturated alcohol 20 and unsaturated hydroperoxide 15 with BCIH
Substrate
X
Reaction time (h)
Products
20c; n¼1
20d; n¼2
20e; n¼3
15b; n¼2
15c; n¼4
CH2
CH2
CH2
O
1
1
17
4
4
29c; n¼l (71%)a
29d; n¼2 (9%)
30d; n¼2 (14%)a
30e; n¼3 (16%)b
27b; n¼2 (63%)c
O
27c; n¼4 (28%)
31c; n¼4 (12%)
a
Taken from the data in Ref. 6c.
The unreacted alcohol 20e was recovered in 46%.
2-Iodomethyl-2-methyloxepane (29c) was also obtained in 14% yield.
b
c

T. Ito et al. / Tetrahedron 59 (2003) 525–536
529
Scheme 6.
faster and the intramolecular cyclization is more efficient.
In the case of the unsaturated hydroperoxide 15c, however,
the 20-membered cyclic dimer 31c (12%) was obtained
together with the expected 1,2-dioxecane 27c (28%). This is
in marked contrast to the fact that only the corresponding
1,2,4,6-tetroxecane derivative 19b is obtained from 10b in
moderate yield (Scheme 4). It is apparent that the number of
oxygen atoms must play an important role in determining
the extent of Pitzer and transannular strain in the ring
formation.6a,14
macrocyclic peroxides 13b,d were obtained in moderate
yields of ca. 50%.
To see if this procedure is applicable to the synthesis of
monocyclic ethers containing one peroxide bond, cycliza-
tion reactions of the unsaturated alcohols 38a–c (for the
method of preparation, see Experimental) were carried out.
Treatment of 38a with BCIH for 17 h led to the formation of
a 1,2,6-trioxecane derivative 39a in low yield (11%). Under
analogous conditions, 38b gave the 1,2,6-trioxacyclodo-
decane derivative 39b in 14% yield and 38c gave the
isomeric 1,2,7-trioxacyclododecane derivative 39c in 19%
yield. In all cases, significant quantities of unchanged
starting material were recovered (Table 2).
These results clearly demonstrate that, for the steric reasons,
the nucleophilicity of the hydroxy group towards the
iodonium ion intermediate is substantially lower than that
of the hydroperoxy group.15 Nevertheless, we expected that
even in the case of unsaturated alcohols, the presence of
oxygen atoms in the chain would make intramolecular
cyclization leading to macrocyclic ethers more probable.
Thus, we investigated the cyclization reactions of the
unsaturated alcohols 32, prepared by treatment of the
corresponding hydroperoxides 12 with 1 equiv. of PPh3
(Scheme 6). On reaction of 32 with BCIH, the expected
cyclic ethers 34 were isolated albeit in poor yield (29% for
34b and 14% for 34d) accompanied by significant amounts
of 1,2-dioxolane 27a and cyclododecanone (35). This is in
marked contrast to the fact that in the case of the
corresponding unsaturated hydroperoxides 12b,d only the
3. Conclusion
We designed several methods for the preparation of
unsaturated hydroperoxide and alcohol precursors. By the
subsequent BCIH-promoted cylization a variety of 10–20-
membered macrocyclic peroxides could be prepared,
demonstrating that this is a new, reliable synthetic method
of a variety of macrocyclic peroxides.
4. Experimental
4.1. General procedure
1H (270 MHz) and 13C NMR (67.5 MHz) spectra were
obtained in CDCl3 with SiMe4 as standard. The precursors
10a,7 15a–d,16 20b,17 20e,18 2-(6-iodohexyloxy)tetrahydro-
pyran19 and 2-(4-iodobutyloxy)tetrahydropyran19 were
prepared by the reported methods.
Table 2. BCIH-promoted cyclization of unsaturated alcohols
4.2. Caution
Substrate
Yield of 39 (%)
Recovered 38 (%)
Since organic peroxides are potentially hazardous com-
pounds, they must be handled with due care; avoid exposure
to strong heat or light, or mechanical shock, or oxidizable
organic materials, or transition metal ions.
38a; m¼l, n¼l
38b; m¼1, n¼3
38c; m¼3, n¼l
11
14
19
45
55
49

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T. Ito et al. / Tetrahedron 59 (2003) 525–536
4.3. Preparation of 1,10-cyclododecylidenebis[(3-methyl-
3-butenyl) peroxide] (3)
4.4.1. 1-Methoxy-1-methyl-3-[[1-[(3-methyl-3-butenyl)-
dioxy]cyclododecyl]dioxy] propyl hydroperoxide (4).
An oil; H NMR d 1.2–1.7 (m, 25H), 1.76 (s, 3H), 1.9–
1
A
mixture of cyclododecylidenebishydroperoxide
2.0 (m, 1H), 2.1–2.2 (m, 1H), 2.35 (t, J¼6.9 Hz, 2H), 3.33
(s, 3H), 4.1–4.2 (m, 4H), 4.75 (s, 1H), 4.78 (s, 1H), 8.72 (s,
1H); 13C NMR d 18.98, 19.18, 21.73, 22.10, 22.64, 25.90,
25.93, 26.78, 33.68, 35.69, 48.65, 70.86, 73.23, 105.55,
111.57, 113.21, 141.99.
(1392 mg, 6 mmol), 4-iodo-2-methylbutene (2352 mg,
12 mmol) and Ag2O (2784 mg, 12 mmol) in CH2Cl2
(20 mL) was stirred at room temperature for 16 h. After
removal of the solid material by filtration over celite, ether
(100 mL) was added to the filtrate and the mixture was
washed with aqueous sodium thiosulfate. After drying the
organic layer over anhydrous MgSO4, the solvent was
removed from it under reduced pressure and the resulting
residue subjected to column chromatography on silica gel.
Elution with ether–hexane (2:98) gave peroxide 3
(1271 mg, 58%). Subsequent elution with ether–hexane
(2:98) gave cyclododecanone (380 mg, 35%).
4.4.2. 20-(Iodomethyl)-17-methoxy-17,20-dimethyl-13,
A
14,18,19,23,24-hexaoxaspiro[11,12]tetracosane (6).
3:1 mixture of two isomers: mp 115–1168C (from
hexane–ether); 1H NMR d 1.1–1.7 (m, 22H), 1.30 (s,
major)þ1.41 (s, major)þ1.42 (s, minor)þ1.47 (s, minor)
(6H), 1.9–2.1 (m, 2H), 2.3–2.4 (m, 2H), 3.35 (s, minor)þ
3.36 (s, major) (3H), 3.40–3.45 (m, 0.7H), 3.54–3.65 (m,
1.3H), 4.0–4.1 (m, 2H), 4.2–4.3 (m, 2H); 13C NMR d
14.09, 14.14, 15.26, 19.61, 20.79, 21.80, 22.14, 26.87,
22.77, 23.63, 25.91, 26.02, 26.06, 26.81, 26.87, 27.10,
31.52, 33.26, 34.88, 35.42, 35.56, 49.00, 49.18, 70.64,
70.71, 71.29, 71.36, 79.77, 80.43, 104.53, 104.58, 113.32,
113.44. Anal. Calcd for C22H41IO7: C, 48.53; H, 7.59.
Found: C, 48.23; H, 7.28.
4.3.1. 1,10-Cyclododecylidenebis[(3-methyl-3-butenyl)
peroxide] (3). An oil; H NMR d 1.3–1.7 (m, 22H), 1.73
(s, 6H), 2.35 (t, J¼6.9 Hz, 4H), 4.18 (t, J¼6.9 Hz, 4H), 4.75
(s, 2H), 4.77 (s, 2H); 13C NMR d 19.23, 21.80, 22.18, 22.70,
25.97, 26.88, 35.80, 73.35, 111.50, 113.14, 142.08. Anal.
Calcd for C22H40O4: C, 71.70; H, 10.94. Found: C, 71.66; H,
10.99.
1
4.5. Co(II)-catalyzed triethylsilylperoxidation of diene 3,
followed by deprotection of the triethylsilyl group and
the subsequent BCIH-promoted cyclization
4.4. Preparation and reaction of unsaturated
hydroperoxide 4 with bis(sym-collidine)-iodine(I)
hexafluorophosphate (BCIH)
In an oven-dried 50 mL two-necked flask were charged
diene 3 (1,960 mg, 5.3 mmol), cobalt(II) acetylacetonate
(70 mg, 0.27 mmol) and dry ethanol (5 mL), and then
triethylsilane (1230 mg, 10.6 mmol) was added via 1.0 mL
gas-tight syringe. The resulting solution was stirred at room
temperature for 8 h under slightly positive oxygen atmos-
phere. After the reaction was complete, the solvent was
carefully rotary-evaporated for flash column chroma-
tography on silica gel. Elution with ether–hexane (2:98)
gave a 2:1 mixture of the unreacted 3 (711 mg) and 1-[(3-
methyl-3-butenyl)dioxy]-1-[[3-methyl-3-[(triethylsilyl)-
dioxy]butyl]dioxy]cyclododecane (689 mg, 1.3 mmol,
25%). Subsequent elution with ether–hexane (5:95) gave
cyclododecanone (210 mg, 23%). Then, the mixture of 3
and the peroxide obtained above was dissolved in methanol
(8 mL) and two drops of conc. HCl was added. After stirring
for 15 min, ether (70 mL) was added and the organic layer
was separated, washed by saturated brine, and dried over
anhydrous MgSO4. After concentration under reduced
pressure, the components of the crude product mixture
were separated by column chromatography on silica gel.
Elution with ether–hexane (2:98) gave diene 3 (550 mg).
Subsequent elution with ether–hexane (8:92) gave 5
(361 mg, 17% based on 3). To a solution of the hydro-
peroxide 5 (122 mg, 0.30 mmol) in CH2Cl2 (10 mL) was
added BCIH (231 mg, 0.45 mmol) and the mixture was
stirred at room temperature for 4 h. After work-up as
described above, the components of the crude product
mixture were separated by column chromatography on
silica gel. Elution with ether–hexane (2:98) gave the
macrocyclic peroxide 7 (72 mg, 47% yield).
A solution of 1,10-cyclododecylidenebis[(3-methyl-3-butenyl)
peroxide] (3) (288 mg, 3.5 mmol) in MeOH (10 mL)–
CH2Cl2 (20 mL) was cooled to 2788C, and a stream of
ozone (1.3 equiv.) was bubbled through it at this tempera-
ture. Aqueous NaHCO3 was added, and the mixture
extracted with ether (70 mL), washed with saturated brine,
and dried over anhydrous MgSO4. After evaporation of the
solvent, the components of the crude product mixture were
separated by column chromatography on silica gel. Elution
with ether–hexane (2:98) gave the unreacted 3 (297 mg,
23%). Second fraction (elution with ether–hexane; 20:80)
gave 1-methoxy-1-methyl-3-[[1-[(3-methyl-3-butenyl)-
dioxy]cyclododecyl]dixoy]propyl hydroperoxide (4)
(292 mg, 20%). 0 Subsequent elution with ether–hexane
(45:55) gave 1,1 -cyclododecylidenebis[(3-hydroperoxy-3-
methoxy)butyl peroxide] derived from the reaction of both
of the double bonds in 3 with two ozone molecules (501 mg,
1
31%); an oil; H NMR d 1.2–1.8 (m, 22H), 1.81 (s, 6H),
4.50 (s, 4H), 4.95 (s, 2H). 5.00 (s, 2H); 13C NMR d 19.34,
19.91, 21.87, 22.25, 26.04, 26.96, 79.12, 113.41, 114.09,
140.81. Anal. Calcd for C20H36O4: C, 70.55; H, 10.66.
Found: C, 70.67; H, 10.56. To a solution of the hydro-
peroxide 4 (200 mg, 0.48 mmol) in CH2Cl2 (10 mL) was
added BCIH (370 mg, 0.72 mmol) and the mixture was
stirred at room temperature for 4 h (the flask was covered by
aluminum foil). Ether (70 mL) was added and the organic
layer was separated, washed with aqueous Na2S2O3
followed by saturated brine, and dried over anhydrous
MgSO4. After concentration under reduced pressure, the
components of the crude product mixture were separated by
column chromatography on silica gel. Elution with diethyl
ether–hexane (6:94) gave the iodomethyl-substituted spiro-
[11,12]tetracosane 6 (140 mg, 54% yield, a 3:1 mixture of
two isomers).
4.5.1. 1,1-Dimethyl-3-[[1-[(3-methyl-3-butenyl)dixoy]-
cyclododecyl]dioxy]propyl hydroperoxide (5). An oil;
1H NMR d 1.1–1.8 (m, 22H), 1.24 (s, 6H), 1.76 (s, 3H), 1.97

T. Ito et al. / Tetrahedron 59 (2003) 525–536
531
(t, J¼5.9 Hz, 2H), 2.35 (t, J¼6.9 Hz, 2H), 4.17 (t, J¼6.9 Hz,
2H), 4.23 (t, J¼5.9 Hz, 2H), 4.75 (s, 1H), 4.78 (s, 1H), 8.39
(s, 1H, OOH); 13C NMR d 19.3 (2C), 21.9 (2C), 22.2 (2C),
22.8, 24.5 (2C), 26.0 (2C), 26.1, 26.9 (2C), 35.5, 35.8, 71.2,
73.3, 81.2, 111.6, 113.4, 142.1. Anal. Calcd for C22H42O6:
C, 65.64; H, 10.52. Found: C, 65.42; H, 10.79.
4.6.3. 4-[[1-[(3-Methyl-3-butenyl)dioxy]cyclododecyl]-
dioxy]butyl hydroperoxide (12a). An oil; 1H NMR d
1.1–1.8 (m, 26H), 1.73 (s, 3H), 2.32 (t, J¼6.9 Hz, 2H), 3.9–
4.1 (m, 4H), 4.15 (t, J¼6.9 Hz, 2H), 4.72 (s, 1H), 4.75 (s,
1H), 8.62 (br s, 1H); 13C NMR d 19.2 (2C), 21.8 (2C), 22.1,
22.2 (2C), 22.8, 24.1, 24.4, 26.0 (2C), 26.9 (2C), 35.7, 73.4,
74.5, 76.5, 111.6, 113.1, 142.2. Anal. Calcd for C21H40O6:
C, 64.92; H, 10.38. Found: C, 64.85; H, 10.50.
4.5.2. 17-(Iodomethyl)-17,20,20-trimethyl-13,14,18,19,23,-
24-hexaoxaspiro[11,12]tetracosane (7). Mp 93–948C
1
(from ether–hexane); H NMR d 1.0–1.7 (m, 22H), 1.17
4.6.4. 6-[[1-[(3-Methyl-3-butenyl)dioxy]cyclododecyl]-
dioxy]hexyl hydroperoxide (12b). An oil; 1H NMR d
1.1–1.8 (m, 30H), 1.73 (s, 3H), 2.33 (t, J¼6.9 Hz, 2H), 3.9–
4.1 (m, 4H), 4.17 (t, J¼6.9 Hz, 2H), 4.72 (s, 1H), 4.75 (s,
1H), 8.36 (br s, 1H); 13C NMR d 19.3 (2C), 21.8 (2C), 22.2
(2C), 22.7, 25.6, 25.9, 26.0 (2C), 26.9 (2C), 27.4, 27.6, 35.8,
73.4, 74.8, 76.8, 111.5, 113.2, 142.2. Anal. Calcd for
C23H44O6: C, 66.31; H, 10.65. Found: C, 66.18; H, 10.54.
(s, 3H), 1.23 (s, 3H), 1.34 (s, 3H), 1.8–2.4 (m, 4H), 3.34 (d,
J¼10.2 Hz, 1H), 3.56 (d, J¼10.2 Hz, 1H), 4.1–4.4 (m, 4H);
13C NMR d 15.4, 19.2 (2C), 21.9 (2C), 22.2 (2C), 23.0
(CH3), 25.1 (CH3), 25.8 (CH3), 26.0 (2C), 26.1, 27.0, 27.1,
32.9, 35.9, 71.4, 71.5, 78.9 (C), 79.9 (C), 113.3 (C). Anal.
Calcd for C22H41IO6: C, 50.00; H, 7.82; I, 24.01. Found: C,
49.99; H, 7.90; I, 23.91.
4.6. Preparation of unsaturated hydroperoxide 12 via
iodoalkyl hydroperoxide protected by 2-methoxy-
propene
4.6.5. 8-[[1-[(3-Methyl-3-butenyl)dioxy]cyclododecyl]-
dioxy]octyl hydroperoxide (12c). An oil; 1H NMR d
1.2–1.7 (m, 34H), 1.72 (s, 3H), 2.31 (t, J¼6.9 Hz, 2H), 3.9–
4.1 (m, 4H), 4.14 (t, J¼6.9 Hz, 2H), 4.71 (s, 1H), 4.74 (s,
1H), 8.93 (br s, 1H); 13C NMR d 19.32, 21.8, 22.2, 22.7,
25.7, 25.8, 26.0, 26.9, 27.4, 27.7, 29.2, 29.3, 35.8, 73.4,
74.8, 76.8, 111.5, 113.1, 142.2.
Preparation of 12a via 11a is representative. To a solution
of Ag2O (1160 mg, 5.0 mmol) in CH2Cl2, was added
2-methoxy-2-propyl hydroperoxide15a (5.0 mmol) (pre-
pared by the ozonolysis of 420 mg of tetramethylethylene
in methanol) in methanol–CH2Cl2 (30 mL, 1:5) at 2788C,
followed by careful evaporation of the solvent under
vacuum and 1,4-diiodobutane (3100 mg, 10 mmol), and
the mixture was stirred at room temperature for 17 h. After
work-up as described before, the resulting residue subjected
to column chromatography on silica gel. Elution with
ether–hexane (5:95) gave peroxide 9a (857 mg, 3.0 mmol,
60%). Subsequently, a mixture of hydroperoxide 10a
(553 mg, 1.8 mmol), the iodide 9a (720 mg, 2.5 mmol)
and Ag2O (418 mg, 1.8 mmol) in CH2Cl2 (20 mL) was
stirred at room temperature for 17 h. The mixture of
products was subjected to column chromatography on silica
gel. Elution with ether–hexane (5:95) gave a mixture of
cyclododecanone (35) (71 mg, 22%) and 1-[[4-[(1-meth-
oxy-1-methylethyl)dioxy]butyl]dioxy]-1-[(3-methyl-3-
butenyl)dioxy]cyclododecane (11a) (576 mg, 72%). Then
the mixture was dissolved into aqueous acetic acid (AcOH–
H2O¼9:1, 5 mL) and the reaction was continued with
stirring at room temperature for 50 min. The mixture of the
products was subjected to column chromatography on silica
gel. Elution with ether–hexane (10:90) gave hydroperoxide
12a (249 mg, 49%).
4.6.6. 10-[[1-[(3-Methyl-3-butenyl)dioxy]cyclododecyl]-
dioxy]decyl hydroperoxide (12d). 1H NMR d 1.2–1.7
(m, 38H), 1.74 (s, 3H), 2.34 (t, J¼6.9 Hz, 2H), 3.99 (t, J¼
6.6 Hz, 2H), 4.04 (t, J¼6.6 Hz, 2H), 4.17 (t, J¼6.9 Hz, 2H),
4.73 (s, 1H), 4.76 (s, 1H), 8.15 (br s, 1H); 13C NMR d 19.3,
21.9, 22.2, 22.8, 25.8, 26.0, 26.1, 27.0, 27.5, 27.8, 29.4,
29.5, 35.9, 73.5, 74.9, 76.5, 111.5, 113.2, 142.3. Anal. Calcd
for C27H52O6: C, 68.60; H, 11.09. Found: C, 68.62; H,
10.64.
4.6.7. 6-[[1-[(2-Methyl-propenyl)dioxy]cyclododecyl]-
dioxy]hexyl hydroperoxide (12e). An oil; 1H NMR d
1.1–2.0 (m, 30H), 1.78 (s, 3H), 3.9–4.1 (m, 4H), 4.46 (s,
2H), 4.91 (s, 1H), 4.97 (s, 1H), 8.62 (br s, 1H); 13C NMR d
19.3 (2C), 19.9, 21.8 (2C), 22.2 (2C), 25.6, 25.7, 25.9, 26.0
(2C), 26.9 (2C), 27.4, 27.6, 74.7, 76.7, 79.1, 113.2, 114.1,
140.7. Anal. Calcd for C22H42O6: C, 65.64; H, 10.52.
Found: C, 65.64; H, 10.49.
4.7. BCIH-promoted cyclization of unsaturated
hydroperoxide 12
The synthesis of macrocyclic peroxide 13a is representative.
To a solution of BCIH (391 mg, 0.76 mmol) in CH2Cl2
(20 mL) was slowly added the hydroperoxide 12a (147 mg,
0.38 mmol) in CH2Cl2 (20 mL) during 2 h using a syringe
and the mixture was stirred at room temperature for
additional 0.5 h. After concentration under reduced pres-
sure, the components of the crude product mixture were
separated by column chromatography on silica gel. Elution
with ether–hexane (2:98) gave the macrocyclic peroxide
13a (133 mg, 68% yield).
4.6.1. 4-Iodobutyl 1-methoxy-1-methylethyl peroxide
1
(9a). An oil; H NMR d 1.38 (s, 6H), 1.7–2.0 (m, 4H),
3.22 (t, J¼6.9 Hz, 2H), 3.30 (s, 3H), 4.03 (t, J¼6.3 Hz,
2H); 13C NMR d 6.33, 22.7 (2C), 28.9, 30.1, 49.2, 73.7,
104.7.
4.6.2. 1-[[4-[(1-Methoxy-1-methylethyl)dioxy]butyl]-
dioxy]-1-[(3-methyl-3-butenyl)dioxy]cyclododecane
(11a). An oil; 1H NMR (admixture with 21% of 35) d 1.0–
1.8 (m, 26H), 1.35 (s, 6H), 1.76 (s, 3H), 2.35 (t, J¼7.3 Hz,
2H), 3.31 (s, 3H), 3.9–4.0 (m, 4H), 4.07 (t, J¼7.3 Hz, 2H),
4.78 (s, 1H), 4.81 (s, 1H); 13C NMR d 19.2 (2C), 21.7 (2C),
22.2 (2C), 22.4, 22.6 (2C), 24.4, 24.6, 25.9, 26.0 (2C), 26.3,
26.9, 35.8, 49.0, 73.4, 74.4, 74.5, 104.4, 111.5, 113.1, 142.1.
4.7.1. 17-(Iodomethyl)-17-methyl-13,14,18,19,24,25-hexa-
oxaspiro[11,13]pentacosane (13a). An oil; 1H NMR d
1.1–2.0 (m, 27H), 1.28 (s, 3H), 2.1–2.2 (m, 1H), 3.36 (d,
J¼10.6 Hz, 1H), 3.56 (d, J¼10.6 Hz, 1H), 3.8–4.2 (m, 5H),

532
T. Ito et al. / Tetrahedron 59 (2003) 525–536
4.3–4.4 (m 1H); 13C NMR d 15.2, 19.1, 19.2, 21.8 (2C),
22.0 (2C), 22.1 (2C), 25.0, 25.4, 26.0, 26.1, 26.7, 26.9, 32.7,
71.5, 74.0, 76.5, 79.6, 113.0. Anal. Calcd for C21H39IO6: C,
49.03; H, 7.64. Found: C, 49.40; H, 7.54.
0.77 mmol) was dissolved into a mixed solvent of acetic
acid–THF–H2O (7.7 mL, 4:2:1.7) and the mixture was
stirred at room temperature for 10 h. Column chroma-
tography on silica gel (elution with ether–hexane, 10:90)
gave 4-[(3-methyl-3-butenyl)dioxy]butyl hydroperoxide
(17a) (114 mg, 70%). To a solution of BCIH (447 mg,
0.87 mmol) in CH2Cl2 (20 mL) was slowly added the
hydroperoxide 17a (110 mg, 0.58 mmol) in CH2Cl2
(20 mL) during 2 h using a syringe and the mixture was
stirred at room temperature for additional 0.5 h. After
concentration under reduced pressure, the components of
the crude product mixture were separated by column chroma-
tography on silica gel. Elution with ether–hexane (2:98)
gave the macrocyclic peroxide 18a (82 mg, 45% yield).
4.7.2. 17-(Iodomethyl)-17-methyl-13,14,18,19,26,27-hexa-
oxaspiro[11,15]heptacosane (13b). Mp 98–998C (from
ether–hexane); 1H NMR d 1.1–1.8 (m, 30H), 1.28 (s, 3H),
1.9–2.0 (m, 1H), 2.2–2.3 (m, 1H), 3.32 (d, J¼10.2 Hz, 1H),
3.58 (d, J¼10.2 Hz, 1H), 3.9–4.4 (m, 6H); 13C NMR d 14.9,
19.2 (2C), 21.8 (2C), 22.1 (2C), 22.8, 25.3, 25.5, 26.0 (2C),
26.1, 26.8 (2C), 27.1, 27.7, 33.2, 71.4, 73.8, 73.9, 79.8,
112.8. Anal. Calcd for C23H43IO6: C, 50.92; H, 7.99. Found:
C, 50.95; H, 7.81.
4.7.3. 17-(Iodomethyl)-17-methyl-13,14,18,19,28,29-hexa-
oxaspiro[11,17]nonacosane (13c). An oil; 1H NMR d 1.2–
1.7 (m, 37H), 1.8–1.9 (m, 1H), 2.1–2.2 (m, 1H), 3.32 (d,
J¼10.2 Hz, 1H), 3.53 (d, J¼10.2 Hz, 1H), 3.9–4.1 (m, 4H),
4.2–4.3 (m, 2H); 13C NMR d 14.7, 19.3, 21.9, 22.2, 22.6,
24.8, 25.1, 26.0, 26.1, 26.9, 27.0, 27.1, 27.4, 27.6, 31.6,
74.5, 76.5, 80.2, 113.2. Anal. Calcd for C25H47IO6: C,
52.63: H, 8.30; I, 22.24. Found: C, 52.85; H, 8.16; I, 22.31.
4.8.1. 4-[(1-Methoxy-1-methylethyl)dioxy]butyl
1
3-methyl-3-butenyl peroxide (16a). An oil; H NMR d
1.35 (s, 6H), 1.6–1.7 (m, 4H), 1.72 (s, 3H), 2.29 (t, J¼
6.9 Hz, 2H), 3.27 (s, 3H), 3.9–4.1 (m, 4H), 4.04 (t, J¼
6.9 Hz, 2H), 4.70 (s, 1H), 4.75 (s, 1H); 13C NMR d 22.6,
22.7, 24.5, 35.9, 49.1, 72.6, 73.7, 104.5, 111.7, 142.0.
4.8.2. 4-[(3-Methyl-3-butenyl)dioxy]butyl hydroperoxide
(17a). An oil; 1H NMR d 1.6–1.7 (m, 4H), 1.72 (s, 3H), 2.31
(t, J¼6.9 Hz, 2H), 3.9–4.0 (m, 4H), 4.01 (t, J¼6.9 Hz, 2H),
4.71 (s, 1H), 4.72 (s, 1H), 8.60 (br s, 1H); 13C NMR d 22.5,
24.1, 24.2, 35.8, 72.4, 73.7, 76.5, 11.8, 141.9. Anal. Calcd
for C9H18O4: C, 56.82; H, 9.54. Found: C, 56.95; H, 9.44.
4.7.4. 17-(Iodomethyl)-17-methyl-13,14,18,19,30,31-hexa-
1
oxaspiro[11,19]hentriacontane (13d). An oil; H NMR d
1.2–1.7 (m, 41H), 1.9–2.3 (m, 2H), 3.34 (d, J¼10.2 Hz,
1H), 3.52 (d, J¼10.2 Hz, 1H), 4.0–4.2 (m, 6H); 13C NMR d
14.7, 19.3, 21.8, 22.2, 22.7, 25.3, 25.6, 26.0, 26.1, 26.9,
27.0, 27.3, 27.5, 27.6, 27.8, 27.9, 34.1, 71.0, 74.5, 74.7,
80.3, 113.1. Anal. Calcd for C27H51IO6: C, 54.18; H, 8.59; I,
21.20. Found: C, 54.29; H, 8.31; I, 21.26.
4.8.3. 3-(Iodomethyl)-3-methyl-1,2,6,7-tetraoxacyclo-
1
undecane (18a). An oil; H NMR d 1.20 (s, 3H), 1.5–2.0
(m, 4H), 2.3–2.5 (m, 2H), 3.28 (d, J¼10.2 Hz, 1H), 3.53 (d,
J¼10.2 Hz, 1H), 3.9–4.1 (m, 6H); 13C NMR d14.7, 23.1,
25.2, 25.9, 34.3, 70.5, 73.6, 74.0, 80.1. Anal. Calcd for
C9H17IO4: C, 34.19; H, 5.42. Found: C, 34.31; H, 5.13.
4.7.5. 16-(Iodomethyl)-16-methyl-13,14,17,18,25,26-hexa-
oxaspiro[11,14]hexacosane (13e). Mp 88–898C: 1H NMR
d 1.1–1.8 (m, 30H), 1.28 (s, 3H), 3.37 (d, J¼10.9 Hz, 1H),
3.61 (d, J¼10.9 Hz, 1H), 3.9–4.1 (m, 4H), 4.37 (d,
J¼9.6 Hz, 1H), 4.61 (d, J¼9.6 Hz, 1H); 13C NMR d 12.2,
19.1 (2C), 21.6, 21.7 (2C), 22.0 (2C), 23.9, 24.4, 25.9 (2C),
26.0, 26.5, 26.6, 26.7, 26.8, 72.5, 73.5, 77.3, 80.3, 113.6.
Anal. Calcd for C22H41IO6: C, 50.00; H, 7.82; I, 24.01.
Found: C, 49.93; H, 7.76; I, 23.97.
4.8.4. 3-(Iodomethyl)-3-methyl-1,2,6,7-tetraoxacyclotri-
1
decane (18b). An oil; H NMR d1.18 (s, 3H), 1.1–1.6 (m,
8H), 1.9–2.0 (m, 1H), 2.5–2.6 (m, 1H), 3.27 (d, J¼10.2 Hz,
1H), 3.56 (d, J¼10.2 Hz, 1H), 3.9–4.2 (m, 6H); 13C NMR
d15.3, 22.6, 24.9, 25.1, 26.5, 26.6, 32.6, 70.4, 73.3, 73.7,
79.8; HRMS (EI) m/z calcd for C11H21IO4 (Mþ) 344.0485,
found 344.0485. Anal. Calcd for C11H21IO4: C, 38.39; H,
6.15. Found: C, 38.91; H, 5.77.
4.7.6. 6-[[1-(2-Methylpropenyl)cyclododecyl]dioxy]hex-
1
anal (14e). H NMR d 1.1–1.9 (m, 28H), 1.75 (s, 3H),
2.37 (t, J¼5.9 Hz, 2H), 4.03 (t, J¼6.6 Hz, 2H), 4.43 (s, 2H),
4.89 (s, 1H), 4.94 (s, 1H), 9.71 (br s, 1H); 13C NMR d 19.5
(2C), 20.1, 21.9, 22.0 (2C), 22.4 (2C), 25.9, 26.2 (2C), 27.1
(2C), 27.8, 43.9, 74.7, 79.3, 113.4, 114.3, 140.9, 202.5.
4.9. Preparation of tetraoxacycloalkane 19 from
unsaturated hydroperoxide 10
The preparation of 19c is representative. A mixture of
bishydroperoxide 1 (1044 mg, 4.5 mmol), 9-iodo-2-methyl-
1-nonene (798 mg, 3 mmol) and Ag2O (696 mg, 3 mmol) in
CH2Cl2 (40 mL) was stirred at room temperature for 17 h.
By column chromatography on silica gel (elution with
ether–hexane 5:95) was obtained 1-[(8-methyl-8-none-
nyl)dioxy]cyclododecyl hydroperoxide (10c) (600 mg,
53%). Then, to the solution of BCIH (1645 mg, 2.4 mmol)
in CH2Cl2 (20 mL) was slowly added the hydroperoxide 10c
(600 mg, 1.6 mmol) in CH2Cl2 (20 mL) during 2 h using a
syringe. After concentration under reduced pressure, the
components of the crude product mixture were separated by
column chromatography on silica gel. Elution with ether–
hexane (2:98) gave the macrocyclic peroxide 19c (412 mg,
52% yield).
4.8. Preparation of unsaturated hydroperoxides 17 and
their BCIH-promoted cyclization leading to macrocyclic
peroxides 18
The synthesis of 18a via 17a is representative. A mixture of
hydroperoxide 15a (163 mg, 1.6 mmol), iodide 9a (432 mg,
1.5 mmol) and Ag2O (371 mg, 1.6 mmol) in CH2Cl2
(20 mL) was stirred at room temperature for 5 h. After
conventional work-up as described above, the resulting
residue subjected to column chromatography on silica gel.
Elution with ether–hexane (7:93) gave 4-[(1-methoxy-1-
methylethyl)dioxy]buthyl 3-methyl-3-butenyl peroxide
(16a) (118 mg, 30%). Then the peroxide 16a (207 mg,

T. Ito et al. / Tetrahedron 59 (2003) 525–536
533
4.9.1. 1-[(8-Methyl-8-nonenyl)dioxy]cyclododecyl hydro-
1
peroxide (10c). An oil; H NMR d1.1–1.8 (m, 32H), 1.68
1.21 (s, 6H), 1.22 (br s, 1H), 1.69 (t, J¼5.6 Hz, 2H), 3.89
(t, J¼5.6 Hz, 2H); 13C NMR d 4.09 (3C), 6.65 (3C), 29.12
(2C), 42.8, 60.5, 70.9. Anal. Calcd for C11H26O2Si: C,
60.49; H, 12.00. Found: C, 60.22; H, 11.74.
(s, 3H), 1.94 (t, J¼6.9 Hz, 2H), 4.02 (t, J¼6.6 Hz, 2H), 4.60
(s, 1H), 4.62 (s, 1H), 8.28 (br s, 1H); 13C NMR d19.3, 21.9,
22.2, 22.4, 26.0, 26.1, 26.5, 27.5, 27.8, 29.1, 29.3, 37.7,
40.3, 75.2, 109.5, 113.8, 145.8. Anal. Calcd for C22H42O4:
C, 71.31; H, 11.42. Found: C, 71.64; H, 11.50.
4.10.1. 3-Methyl-3-[(triethylsilyl)dioxy]butanol (21a). An
1
oil; H NMR d0.69 (q, J¼7.9 Hz, 6H), 0.97 (t, J¼7.9 Hz,
9H), 1.23 (s, 6H), 1.86 (t, J¼5.9 Hz, 2H), 2.91 (br s, 1H,
OH), 3.73 (t, J¼5.9 Hz, 2H); 13C NMR d3.74 (3C), 6.65
(3C), 24.7 (2C), 41.1, 58.8, 82.6. Anal. Calcd for
C11H26O3Si: C, 56.36; H, 11.18. Found: C, 56.54; H, 10.86.
4.9.2. 15-(Iodomethyl)-15-methyl-13,14,23,24-tetraoxa-
1
spiro[11,12]tetracosane (19c). Mp 71–728C; H NMR d
1.1–1.8 (m, 34H), 1.23 (s, 3H), 3.27 (d, J¼10.2 Hz, 1H),
3.39 (d, J¼10.2 Hz, 1H), 4.0–4.1 (m, 2H); 13C NMR d 15.1,
19.5, 20.9, 22.0, 22.4, 23.3, 24.4, 26.1, 26.2, 26.3, 27.2,
27.3, 27.4, 35.1, 74.3, 81.3, 112.1. Anal. Calcd for
C22H41IO4: C, 53.22; H, 8.32. Found: C, 53.08; H, 8.00.
4.11. Preparation of unsaturated hydroperoxides 25,
followed by BCIH-promoted cyclization
The preparation of 25a and its reaction is representative. To
a solution of methoxymethylenecyclohexane (22) (245 mg,
1.9 mmol) and an unsaturated alcohol 21a (1334 mg,
5.7 mmol) in CH2Cl2 (25 mL) was passed a slow stream
of ozone (1.5 equiv) at 270 8C. After concentration under
reduced pressure, the components of the crude mixture were
separated by column chromatography on silica gel. Elution
with ether–hexane (5:95) gave 1-[[3-methyl-3-(triethyl-
silyl)dioxy]butoxy]cyclohexyl hydroperoxide (23a)
(425 mg, 63%). Then, the mixture of 23a (470 mg,
1.4 mmol), 4-iodo-2-methyl-1-butene (549 mg, 2.8 mmol)
and Ag2O (325 mg, 1.4 mmol) in CH2Cl2 (40 mL) was
stirred at room temperature for 17 h. Column chroma-
tography on silica gel (elution with ether–hexane, 2:98)
gave 1-[[3-methyl-3-(triethylsilyl)dioxy]butoxy]cyclohexyl
3-methyl-3-butenyl peroxide (24a) (99 mg, 17%). Subse-
quently, a mixture of 24a (120 mg, 0.29 mmol), KF (17 mg,
0.29 mmol) and 18-crown-6 (37 mg, 0.14 mmol) in THF
was stirred at room temperature for 17 h. Ether (100 mL)
was added and the organic layer was washed with saturated
brine. Column chromatography on silica gel (elution with
ether–hexane, 7:93) gave 1,1-dimethy1-3-[[1-(2-methyl-1-
butenyl)dioxy]cyclohexyloxy]propyl hydroperoxide (25a)
(56 mg, 66%). Treatment of 25a (56 mg, 0.19 mmol) with
BCIH (129 mg, 0.25 mmol) in CH2Cl2 (10 mL) at room
temperature for 3 h, followed by column chromatography
on silica gel, was obtained 26a (30 mg, 37%).
4.9.3. 3-(Iodomethyl)-3-methyl-1,2,6,7-tetraoxaspiro-
[7.11]nonadecane (19a). A 7:3 mixture of two conformers:
mp 61–638C (from methanol); H NMR d 1.3–1.7 (m,
1
24.4H), 1.81 (d, J¼6.7 Hz, 0.3H), 1.97 (d, J¼6.3 Hz, 0.3H),
2.03 (d, J¼6.3 Hz, 0.3H), 2.1–2.2 (m, 0.7H), 2.4–2.5 (m,
0.7H), 2.7–2.9 (m, 0.3H), 3.4–3.5 (m, 2H), 4.0–4.2 (m,
1H), 4.3–4.4 (m, 1H); 13C NMR d 15.56, 15.65, 19.05,
19.12, 19.30, 19.34, 19.45, 20.07, 21.62, 21.80, 21.85,
21.96, 22.09, 22.30, 25.54, 25.81, 25.90, 25.95, 26.00,
26.06, 26.11, 26.18, 28.14, 28.14, 31.23, 38.30, 38.55,
70.49, 71.86, 80.50, 81.44, 111.75, 113.19. Anal. Calcd for
C17H31IO4: C, 47.89; H, 7.33; I, 29.77. Found: C, 47.76; H,
7.15; I, 29.52.
4.9.4. 3-(Iodomethyl)-3-methyl-1,2,8,9-tetraoxaspiro-
1
[9.11]henicosane (19b). Mp 95–978C; H NMR d 1.1–
1.6 (m, 26H), 1.15 (s, 3H), 2.32 (br s, 1H), 2.58 (br s, 1H),
3.13 (d, J¼10.2 Hz, 1H), 3.54 (d, J¼10.2 Hz, 1H), 3.7–3.8
(m, 1H), 4.0–4.1 (m, 1H); 13C NMR d 19.3, 19.5, 21.9, 22.0,
22.3, 22.4, 26.0, 26.1, 26.2, 26.6, 26.7, 76.6, 81.7, 110.9;
HRMS (EI) m/z Calcd for C19H35IO4 (Mþ) 454.1581.
Found: 454.1581.
4.10. Co(II)-catalyzed peroxidation of unsaturated
alcohols 20
In a 50 mL two-necked flask were charged 3-methyl-3-
butenol 20a (430 mg, 5.0 mmol), bis(1-morpholinocarba-
moyl-4,4-dimethyl-1,3-pentanedionato)-cobalt(II) (135 mg,
0.25 mmol) and dichloroethane (10 mL), and then triethyl-
silane (1160 mg, 10 mmol) was added via 1.0 mL gas-tight
syringe. The resulting solution was stirred at room
temperature for 3 h under slightly positive oxygen atmos-
phere. After the reaction was complete, the products were
separated by column chromatography on silica gel. Elution
with ether–hexane (2:98) gave 1,1-dimethyl-3-(triethyl-
siloxy)propyl triethylsilyl peroxide (452 mg, 26%); an oil;
1H NMR d 0.5–0.7 (m, 12H), 0.8–1.0 (m, 18H), 1.19 (s,
6H), 1.84 (t, J¼7.6 Hz, 2H), 3.72 (t, J¼7.6 Hz, 2H); 13C
NMR d3.87 (3C), 4.41 (3C), 6.63 (3C), 6.78 (3C), 24.7 (2C),
41.6, 59.1, 81.3. Anal. Calcd for C17H40O3Si2: C, 58.56; H,
11.56. Found: C, 58.62; H, 11.63. Subsequent elution with
ether–hexane (10:90) gave 3-methyl-3-[(triethylsilyl)dioxy]-
butanol (21a) (284 mg, 26%). From the final fraction
(elution with ether–hexane, 12:88) was obtained
3-methyl-3-(triethylsiloxy)butanol (287 mg, 24%); an oil;
1H NMR d 0.62 (q, J¼7.9 Hz, 6H), 0.95 (t, J¼7.9 Hz, 9H),
4.11.1. 1-[[3-Methyl-3-(triethylsilyl)dioxy]butoxy]cyclo-
1
hexyl hydroperoxide (23a). An oil; H NMR d0.71 (q,
J¼7.9 Hz, 6H), 0.99 (t, J¼7.9 Hz, 9H), 1.27 (s, 6H), 1.2–
1.8 (m, 10H), 1.91 (t, J¼6.6 Hz, 2H), 3.66 (t, J¼6.6 Hz,
2H), 8.62 (s, 1H); 13C NMR d 3.69 (3C), 6.65 (3C), 22.6
(2C), 25.2 (2C), 25.5, 31.5 (2C), 38.1, 56.0, 82.1 105.1.
Anal. Calcd for C17H36O5Si: C, 58.58; H, 10.41. Found: C,
58.43; H, 10.16.
4.11.2. 1-[[3-Methyl-3-(triethylsilyl)dioxy]butoxy]cyclo-
hexyl 3-methyl-3-butenyl peroxide (24a). An oil; 1H NMR
d0.66 (q, J¼7.9 Hz, 6H), 0.98 (t, J¼7.9 Hz, 9H), 1.22 (s,
6H), 1.1–1.8 (m, 10H), 1.76 (s, 3H), 1.91 (t, J¼7.9 Hz, 2H),
2.34 (t, J¼6.9 Hz, 2H), 3.62 (t, J¼7.9 Hz, 2H), 4.12 (t,
J¼6.9 Hz, 2H), 4.74 (s, 1H), 4.78 (s, 1H); 13C NMR d 3.88
(3C), 6.81 (3C), 22.8 (2C), 24.6, 24.7 (2C), 25.6, 32.1 (2C),
36.0, 38.8, 56.7, 73.5, 81.5, 104.9, 111.7, 142.3.
4.11.3. 1,1-Dimethy1-3-[[1-(2-methyl-1-butenyl)dioxy]-
1
cyclohexyloxy]propyl hydroperoxide (25a). An oil; H

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T. Ito et al. / Tetrahedron 59 (2003) 525–536
NMR d 1.1–1.8 (m, 10H), 1.21 (s, 6H), 1.73 (s, 3H), 1.88 (t,
J¼5.3 Hz, 2H), 2.33 (t, J¼6.9 Hz, 2H), 3.67 (t, J¼5.3 Hz,
2 Hz), 4.11 (t, J¼6.9 Hz, 2H), 4.72 (s, 1H), 4.76 (s,
1H), 9.44 (br s, 1H); 13C NMR d22.6 (2C), 22.8, 24.7 (2C),
25.3, 31.9 (2C), 35.8, 37.8, 56.3, 73.4, 81.1, 105.1, 111.7,
142.1.
3H), 1.21 (s, 3H), 0.9–1.8 (m, 24H), 3.2–3.2 (m, 2H), 3.4–
3.5 (m, 2H), 3.8 (m, 4H); 13C NMR d 15.4, 16.2, 22.4, 22.6,
23.7, 24.1, 26.1, 26.2, 27.9, 29.2, 29.5, 29.9, 30.2, 35.2,
35.4, 73.9, 74.3, 80.9, 81.1; HRMS (EI) m/z calcd for
C20H38I2O4 (Mþ) 596.0860, found 596.0873. Anal. Calcd
for C20H38I2O4: C, 40.28; H, 6.42; I, 42.56. Found: C, 40.35;
H, 6.30; I, 42.62.
4.11.4. 11-(Iodomethyl)-11,14,14-trimethyl-7,8,12,13,17-
pentaoxaspiro[5,11]heptadecane (26a). An oil; 1H NMR d
0.9–2.1 (m, 13H), 0.96 (s, 3H), 1.07 (s, 3H), 1.26 (s, 3H),
2.5–2.7 (m, 1H), 3.21 (d, J¼10.6 Hz, 1H), 3.4–3.6 (m, 1H),
3.54 (d, J¼10.4 Hz, 1H), 3.7–4.1 (m, 2H), 4.4–4.6 (m, 1H);
13C NMR d15.7, 22.7, 22.8, 23.8, 25.4, 26.1, 29.7, 31.3,
31.6, 33.3, 36.6, 56.3, 72.7, 78.7, 80.0, 106.6; MS (EI) m/z
428 (Mþ); HRMS (EI) m/z calcd for C16H29IO5 428.1060,
found 428.1061.
4.13.3. 3-(Iodomethyl)-3-methyl-1,2-dioxocane (27b). An
1
oil; H NMR d 1.13 (s, 3H), 1.1–2.0 (m, 8H), 3.20 (d,
J¼10.4 Hz, 1H), 3.51 (d, J¼10.4 Hz, 1H), 3.6–3.7 (m, 1H),
4.0–4.2 (m, 1H); 13C NMR d16.7, 21.6, 24.6, 25.7, 28.2,
32.2, 74.7, 81.1; HRMS (EI) m/z calcd for C8H15IO2:
270.0117, found 270.0122.
4.14. Preparation of unsaturated alcohols 32 and their
cyclization
4.12. Reaction of unsaturated alcohol 20e with BCIH
The preparation and cyclization of 32b is representative. To
a solution of hydroperoxide 12b (430 mg, 1.0 mmol) in
CH2Cl2 (25 mL) was added PPh3 (262 mg, 1.0 mmol) at 08C
during 30 min. After evaporation of the solvent under
reduced pressure, the crude products were separated by
column chromatography on silica gel. Elution with ether–
hexane (30:70) gave 6-[[1-[(3-methyl-3-butenyl)dioxy]-
cyclododecyl]dioxy]hexanol (32b) (330 mg, 80%). To the
solution of BCIH (216 mg, 0.42 mmol) in CH2Cl2 (20 mL)
was slowly added unsaturated hydroperoxide 32b (85 mg,
0.21 mmol) in CH2Cl2 (20 mL) during 3 h using a syringe
and the mixture was stirred at room temperature for 17 h.
After concentration under reduced pressure, the components
of the crude product mixture were separated by column
chromatography on silica gel. First fraction (elution with
ether–hexane, 1:99) contained the cyclic peroxide 34b
(33 mg, 29%). From the second fraction (elution with
ether–hexane, 3:97) was obtained the dioxolane 27a (7 mg,
14%). The final fraction (elution with ether–hexane, 5:95)
contained cyclododecanone (35) (11 mg, 29%).
Treatment of 8-methyl-8-nonean-1-ol (20e) (312 mg,
2.0 mmol) with BCIH (1542 mg, 3.0 mmol) in CH2Cl2
(40 mL) at room temperature for 4 h, followed by column
chromatography on silica gel (elution with ether–hexane
5:95) was obtained 30e (91 mg, 16%). Further elution with
ether–hexane (30:70) gave the unreacted alcohol 20e
(142 mg, 46%).
4.12.1. 2,11-Di(iodomethyl)-2,11-dimethyl-1,10-dioxa-
1
cyclooctadecane (30e). An oil; H NMR d 1.1–1.7 (m,
24H), 1.22 (s, 6H), 3.1–3.3 (m, 8H); 13C NMR d 17.2, 17.5,
22.6, 22.9, 24.3, 24.5, 25.9, 26.0, 29.1, 29.2, 29.7, 29.8,
30.0, 35.4, 35.8, 60.7, 60.8, 73.8, 73.9; HRMS (EI) m/z
calcd for C20H38I2O2 (Mþ) 564.0962, found 564.0973.
4.13. Reaction of unsaturated hydroperoxide 15 with
BCIH
Reaction of 15c is representative. To the solution of BCIH
(925 mg, 1.8 mmol) in CH2Cl2 (20 mL) was slowly added
8-methyl-8-nonenyl hydroperoxide (15c) (200 mg,
1.2 mmol) in CH2Cl2 (20 mL) during 3 h using a syringe
and the mixture was stirred at room temperature for
additional 1 h. The monitoring by TLC suggested that the
hydroperoxide 15c reacted completely. After concentration
under reduced pressure, the components of the crude
product mixture were separated by column chromatography
on silica gel. First fraction (elution with benzene–hexane,
30:70) gave the monomeric peroxide 27c (98 mg, 28%).
From the second fraction (elution with benzene–hexane,
40:60) was obtained the dimeric peroxide 31c (83 mg,
12%).
4.14.1. 6-[[1-[(3-Methyl-3-butenyl)dioxy]cyclododecyl]-
dioxy]hexanol (32b). An oil; 1H NMR d1.3–1.7 (m,
31H), 1.74 (s, 3H), 2.33 (t, J¼6.9 Hz, 2H), 3.62 (t, J¼
6.3 Hz, 2H), 4.05 (t, J¼6.6 Hz, 2H), 4.17 (t, J¼6.9 Hz, 2H),
4.72 (s, 1H), 4.76 (s, 1H); 13C NMR d19.3, 21.9, 22.2, 22.8,
25.5, 25.9, 26.0, 27.0, 27.8, 32.6, 35.8, 62.8, 73.5, 74.8,
111.5, 113.2, 142.3. Anal. Calcd for C23H44O5: C, 68.96; H,
11.07. Found: C, 68.67; H, 10.92.
4.14.2. 17-(Iodomethyl)-17-methyl-13,14,18,25,26-penta-
oxaspiro[11,14]hexacosane (34b). An oil; 1H NMR d 1.2–
1.7 (m, 30H), 1.33 (s, 3H), 1.7–1.8 (m, 1H), 2.0–2.1 (m,
1H), 3.26 (d, J¼10.6 Hz, 1H), 3.24 (d, J¼10.6 Hz, 1H), 3.39
(t, J¼6.6 Hz, 2H), 4.09 (t, J¼5.6 Hz, 2H), 4.2–4.3 (m, 2H);
13C NMR d16.3, 19.3, 21.8, 22.2, 23.9, 24.5, 25.0, 26.0,
26.1, 26.9, 27.0, 27.4, 28.4, 34.7, 60.5, 71.5, 73.4, 113.0.
Anal. Calcd for C23H43IO5: C, 52.47; H, 8.23. Found: C,
52.76; H, 7.81.
4.13.1. 3-(Iodomethyl)-3-methyl-1,2-dioxecane (27c). An
1
oil; H NMR d1.18 (s, 3H), 1.4–2.2 (m, 12H), 3.24 (d,
J¼10.2 Hz, 1H), 3.52 (d, J¼10.2 Hz, 1H), 3.9–4.0 (m, 1H),
4.1–4.2 (m, 1H); 13C NMR d 16.6, 22.0, 22.4, 22.5, 25.1,
25.6, 27.8, 29.5, 75.5, 81.1; HRMS (EI) m/z calcd for
C10H19IO2 298.0430, found 298.0437. Anal. Calcd for
C10H19IO2: C, 40.28; H, 6.42; I, 42.56. Found: C, 40.03; H,
6.19; I, 42.56.
4.14.3. 3-(Iodomethyl)-3-methyl-1,2-dioxolane (27a). An
1
oil; H NMR d1.55 (s, 3H), 2.3–2.4 (m, 1H), 2.7–2.8 (m,
1H), 3.36 (s, 2H), 4.1–4.2 (m, 2H); 13C NMR d13.8, 23.4,
45.0, 70.9, 83.4; HRMS (EI) m/z calcd for C5H9IO2 (Mþ)
227.9648, found 227.9649.
4.13.2. 3,13-Di(iodomethyl)-3,13-dimethyl-1,2,11,12-
1
tetraoxacycloicosane (31c). An oil; H NMR d 1.12 (s,

T. Ito et al. / Tetrahedron 59 (2003) 525–536
535
4.14.4. 17-(Iodomethyl)-17-methyl-13,14,18,29,30-penta-
oxaspiro[11,18]triacontane (34d). An oil; 1H NMR d1.2–
1.7 (m, 38H), 1.33 (s, 3H), 2.0–2.1 (m, 1H), 2.2–2.3 (m,
1H), 3.26 (d, J10.6 Hz, 1H), 3.33 (d, J¼10.6 Hz, 1H), 3.34
(t, J¼7.3 Hz, 2H), 4.09 (t, J¼6.6 Hz, 2H), 4.1–4.2 (m, 2H);
13C NMR d16.5, 19.3, 21.9, 22.2, 23.4, 25.0, 25.3, 26.0,
26.1, 26.9, 27.0, 27.1, 27.4, 27.5, 27.6, 29.0, 35.3, 60.8,
70.9, 73.3, 74.7, 113.3. Anal. Calcd for C27H51IO5: C,
55.66; H, 8.82. Found: C, 55.80; H, 8.53.
(d, J¼10.6 Hz, 1H), 3.27 (d, J10.6 Hz, 1H), 3.5–3.7 (m,
2H), 3.9–4.1 (m, 4H); 13C NMR d 16.7, 22.6, 25.4, 28.3,
29.7, 59.9, 69.9, 74.0, 75.3; HRMS (EI) m/z calcd for
C9H17IO3 300.0223, found 300.0221.
4.15.5. 8-(Iodomethyl)-8-methyl-1,2,7-trioxacyclodo-
1
decane (39c). An oil; H NMR d 1.23 (s, 3H), 1.2–1.9
(m, 10H), 3.24 (d, J¼10.6 Hz, 1H), 3.37 (d, J¼10.6 Hz,
1H), 3.4–3.5 (m, 2H), 3.8–4.0 (m, 4H); 13C NMR d 17.7,
19.7, 23.4, 24.6, 25.3, 27.5, 33.3, 62.1, 70.7, 74.0, 74.7;
HRMS (CI) m/z calcd for C11H21IO3: 329.0614, found
329.0613.
4.15. Synthesis of macrocyclic peroxides 39 from
unsaturated alcohol 38
The synthesis of 39b is representative. A mixture of
hydroperoxide 15a (612 mg, 6.0 mmol), 2-(6-iodohexyl-
oxy)tetrahydropyran (36b) (2808 mg, 19.0 mmol) and
Ag2O (1392 mg, 6.0 mmol) in CH2Cl2 (40 mL) was stirred
at room temperature for 17 h. By column chromatography
on silica gel (elution with ether-hexane, 8:92) was obtained
2-[6-[(3-methyl-3-butenyl)dioxy]hexyloxy]tetrahydropyran
(37b) (1230 mg, 72%). The peroxide 37b (1230 mg,
4.3 mmol) was dissolved in AcOH (4 mL)–THF (2 mL)–
H2O (1 mL) and the mixture was stirred at room
temperature for 2 days to give 6-[(3-methyl-3-butenyl)-
dioxy]hexanol (38b) (626 mg, 72%) the solution of BCIH
(1542 mg, 3.0 mmol) in CH2Cl2 (20 mL) was slowly added
unsaturated hydroperoxide (38b) (400 mg, 2.0 mmol) in
CH2Cl2 (20 mL) during 3 h using a syringe and the mixture
was stirred at room temperature for 17 h. After concen-
tration under reduced pressure, the components of the crude
product mixture were separated by column chromatography
on silica gel. First fraction (elution with ether–hexane,
1:99) contained the cyclic peroxide 39b (87 mg, 14%).
From the second fraction (elution with ether–hexane,
30:70) was obtained unreacted alcohol 38b (220 mg, 55%).
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research on Priority Areas from the Ministry of
Education, Science, Culture and Sports of Japan (14021066,
13650904).
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1
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