New approaches to the synthesis of spiro-peroxylactones

Article abstract of DOI:10.1039/b300342f

Ozonolysis of (alkenyldioxy)cyclododecyl hydroperoxides in trifluoroethanol gave a separable mixture of the corresponding a-hydroperoxy- and a-hydroxy-substituted spiro-tetraoxacycloalkanes with ring sizes in the range 7-12. Dehydration of the hydroperoxides or oxidation of the hydroxy-compounds afforded the corresponding peroxylactones. The solid-state structure of 1,2,6,7-tetraoxaspiro[7.11]nonadecan-3-one was determined by X-ray crystallographic analysis.

Full text of DOI:10.1039/b300342f

View Article Online / Journal Homepage / Table of Contents for this issue
New approaches to the synthesis of spiro-peroxylactones
Kevin J. McCullough,*a Hidekazu Tokuhara,b Araki Masuyamab and Masatomo Nojimab
a Department of Chemistry, School of Engineering and Physical Sciences,
Heriot-Watt University, Edinburgh, UK EH14 4AS
b Department of Materials Chemistry & Frontier Research Center,
Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 14th January 2003, Accepted 10th March 2003
First published as an Advance Article on the web 27th March 2003
Ozonolysis of (alkenyldioxy)cyclododecyl hydroperoxides in trifluoroethanol gave a separable mixture of the
corresponding α-hydroperoxy- and α-hydroxy-substituted spiro-tetraoxacycloalkanes with ring sizes in the range
7–12. Dehydration of the hydroperoxides or oxidation of the hydroxy-compounds afforded the corresponding
peroxylactones. The solid-state structure of 1,2,6,7-tetraoxaspiro[7.11]nonadecan-3-one was determined by X-ray
crystallographic analysis.
Introduction
The discovery of antimalarial activity of naturally occurring
organic peroxides such as artemisinin (1) has stimulated recent
interest in the development of methods for synthesis of new
cyclic peroxide systems.1 In this respect, we recently developed a
convenient synthetic route to the spiro-peroxide, 1,2,6,7-tetra-
oxaspiro[7.11]nonadecane (2) which was found to exhibit anti-
malarial activities in vitro and in vivo comparable with those
reported for artemisinin (1).2 Although a number of natural
products containing cyclic peroxide substructural units of vari-
ous types have been reported to date,1a there are relatively few
examples of molecules containing the peroxylactone moiety;
noteworthy examples include the diterpenoid 3 isolated from
the marine alga Taonia atomaria,3 and arteannuin H (4) isolated
from Artemisia annua L.4 In the search for novel biologically
active compounds, it was of interest to prepare a series of
peroxylactones structurally related to the spiro-peroxide 2.
Results and discussion
Scheme 1 Strategy for the synthesis of spiro-peroxylactones 11.
A new strategy for the synthesis of a series of spiro-peroxyl-
actones is outlined in Scheme 1. Ozonolysis of unsaturated
hydroperoxides 5, prepared in moderate yield (37–54%) by the
Ag-catalysed mono-alkenylation of 1,1-bis(hydroperoxy)cyclo-
dodecane,5 in protic solvent would be expected to give a mixture
of the corresponding α-hydroperoxy- and α-hydroxy-substi-
tuted tetraoxaspiroalkanes 9 and 10. The ozonolysis product
composition will depend on the cleavage mechanisms favoured
by the respective transient primary ozonides 6.6 Subsequent
chemical transformation of the hydroperoxyl or hydroxyl
functional groups in compounds 9 and 10 should provide the
desired peroxylactones 11. In addition, since there are relatively
few reliable procedures for the syntheses of macrocyclic
peroxides,7 it was of interest to investigate the scope of this
particular cyclization reaction.
Ozonolysis of unsaturated hydroperoxides in trifluoroethanol
The results for the ozonolyses of alkenyldioxy-substituted
cyclododecyl hydroperoxides 5a–e in trifluoroethanol (TFE) are
summarized in Table 1. Ozonolysis of 5a (n = 1) afforded a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
1522

View Article Online
Table
1
Yields of α-hydroperoxy- and α-hydroxy-substituted
tetraoxacycloalkanes from 5a–e
Table 2 Dehydration of α-methoxy hydroperoxides
Methoda
(% yield)
Hydroperoxide
Ester
A (84%)
B (84%)
CH3(CH2)7CH(OMe)OOH
12b
CH3(CH2)7C(O)OMe
13b
A (86%)
B (71%)
a; n = 1
b; n = 2
c; n = 3
d; n = 4
e; n = 6
20%
57%
47%a
18%a
9%a
69%
24%
A (91%)
B (95%)
a Significant quantities of polar oligomeric products were also
obtained.
a Method A; dehydration by Ac2O, Et3N. Method B; dehydration by
PhNCO, pyridine.
mixture of the spiro-tetroxepane derivatives 9a and 10a in
yields of 20% and 69% respectively. Under similar conditions,
the reaction of 5b (n = 2) with ozone gave a mixture of 9b
and 10b in yields of 57% and 24%, respectively. These results
demonstrate that there are two modes operating competitively
in the cleavage of the primary ozonides 6a,b: viz. the scission
path a leading to the formation of the carbonyl oxide inter-
mediate 7a,b and formaldehyde, and the alternative path b
providing a mixture of the aldehyde 8a,b and formaldehyde
O-oxide (Scheme 1). Subsequent intramolecular cyclisations
of intermediates 7a,b and 8a,b proceed efficiently, thereby
providing 9a,b and 10a,b in acceptable yields.
The chain length of the alkenyldioxy group in the unsatur-
ated hydroperoxides 5 dramatically affects the efficiency of the
intramolecular cyclization of the ozonolysis intermediates 7
and 8. Thus, from 5c was obtained the corresponding hydro-
peroxy-substituted tetraoxacycloalkane 9c in 47% yield. Simi-
larly, the hydroperoxides 9d,e, albeit in low yield (18% for 9d
and 9% for 9e), were the only readily identifiable products iso-
lated from the ozonolysis of the unsaturated hydroperoxides
5d,e. In each case, although the corresponding hydroxy com-
pounds 10c–e were not observed, significant quantities of
unidentified polar oligomeric products were obtained instead.
These limited results tend to suggest that (i) a carbonyl oxide,
being a reactive 1,3-dipole, would be captured by a hydro-
peroxyl group more readily than the aldehyde group in a
similar position, and (ii) in the case of particularly 7d,e
and/or 8d,e leading to bigger rings, entropically more favoured
intermolecular reactions occur predominantly.
Table 3 Dehydration of α-hydroperoxy-substituted tetraoxacyclo-
alkanesa
a; n = 1
a; n = 1
b; n = 2
b; n = 2
c; n = 3
d; n = 4
e; n = 6
A
B
A
B
A
A
A
0%b
47%b
81%
77%
95%
80%
83%
a Method A; dehydration by Ac2O, Et3N. Method B; dehydration by
PhNCO, pyridine. b A significant amount of cyclododecanone was
produced.
gel, and (b) applicability to the preparation of base-sensitive
products since only a catalytic amount of pyridine was
required.
In the light of the results above, the dehydration of α-hydro-
peroxy-substituted tetraoxacycloalkanes 9a–e was attempted
using both methods (Table 3). It is interesting to note that under
the conditions of method A, the hydroperoxide 9a was trans-
formed into cyclododecanone (86% yield), whereas using
method B, the desired peroxylactone 11a was obtained in
47% yield. Since the hydrogen atoms of the methylene group
attached to both the peroxy and carbonyl groups are likely to be
relatively acidic, it seems reasonable that the peroxylactone 11a,
if formed, would be susceptible to Et3N-catalysed decom-
position. In the case of 9b, however, both methods A and B
were used successfully, affording the corresponding per-
oxylactone 11b in the acceptable yields of around 80%.
Dehydration of the other hydroperoxides 9c–e using method A
produced the corresponding peroxylactones 11c–e in yields of
around 85%.
Although the product yields were relatively low, the 10- and
12-membered cyclic peroxides 9d,e were certainly obtained by
the ozonolysis of the unsaturated hydroperoxides 5d,e in TFE,
suggesting that this methodology offers a synthetic route to
novel macrocyclic peroxides.
Dehydration of ꢀ-methoxyalkyl hydroperoxides and ꢀ-hydro-
peroxy-substituted tetraoxacycloalkane
Before attempting the dehydration of α-hydroperoxy-substi-
tuted tetraoxacycloalkanes 9a–e, the readily prepared α-alkoxy-
alkyl hydroperoxides 12a–c were used as model substrates for
two different dehydration procedures: method A utilising a
mixture of Ac2O–Et3N as developed by Schreiber et al.,8 and
method B using PhNCO in the presence of a catalytic amount
of pyridine.9 The results, summarised in Table 2, demonstrate
that the yields of esters 13a–c obtained from the two procedures
are fairly comparable. The major advantage of method A is the
fact that the reactions generally proceeded rapidly and were
complete after about 2 h. Although the reactions using method
B were significantly slower, requiring about 16 h for completion,
there were some advantages with this latter procedure: (a) ease
of work-up: after concentration of the reaction mixture, the
ester 13 was easily isolated by column chromatography on silica
Synthesis of peroxylactones 11 by the oxidation of ꢀ-hydroxy-
substituted tetraoxacycloalkanes 10
As described above, the α-hydroxy-substituted tetraoxacyclo-
alkanes 10a,b were obtained in significant quantities, in addi-
tion to the α-hydroperoxy-compounds 9a,b, by the ozonolysis
of the unsaturated hydroperoxides 5a,b. Oxidation of 10a by
treatment with Jones reagent, followed by column chromato-
graphy on silica gel, resulted in the isolation of cyclododecan-
one (57%) together with the unchanged alcohol 10a (14%)
(Scheme 2). Under similar reaction conditions, oxidation of 10b
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
1523

View Article Online
is a distinct flattening of the ring in the vicinity of the carbonyl
group. In contrast to 2 and 11b, the 8-membered peroxylactone
ring in natural product 3 adopts a tub-shaped conformation
presumably as a consequence of forming part of a poly-fused
ring system.3
The relative orientations of the peroxide groups in 11b
are similar to those observed in the crystal structure of 1,1-
bis(hydroperoxy)cyclododecane.11 Such an arrangement would
not only reduce steric interactions between the adjacent per-
oxide groups, but would also, if reproduced in carbonyl oxide
intermediates 7a–c, facilitate the formation of the medium-ring
hydroperoxyl compounds 9a–c.
In summary, a series of novel peroxylactone derivatives
11a–e, with ring sizes ranging from 7–12, have been prepared
from the corresponding unsaturated hydroperoxides 5a–e by an
ozonolysis–cyclisation–dehydration sequence. The dehydration
of the cyclic hydroperoxy compounds 9a–e has been accom-
plished using either a mixture of Ac2O and Et3N or PhNCO
in the presence of catalytic quantities of pyridine; the latter
procedure is particularly useful for the preparation of base-
sensitive peroxylactones such as 11a.
Experimental section
General
1H (270 MHz) and 13C (67.5 MHz) NMR spectra were obtained
in CDCl3 solution with SiMe4 as standard. The α-alkoxyalkyl
hydroperoxides, 12a,b12 and 12c,13 and hemiperacetals, 14a and
14b,9 were prepared by literature procedures.
Scheme 2
proceeded smoothly to provide the peroxylactone 11b in 57%
yield. To investigate the scope of this procedure, the oxidation
of hemiperacetals 14a,b using Jones reagent was undertaken.
The ring-opened carboxylic acids 15a,b were isolated in yields
of 55% and 71%, respectively.
Ag2O-mediated synthesis of 1-(alkenyldioxy)cyclododecyl
hydroperoxides 5a–e5
Swern oxidation of 10b using DMSO–oxalyl chloride also
gave the peroxylactone 11b but in a very low yield (2%) together
with cyclododecanone (34%).
In general, direct oxidation of the hydroxy-substituted tetra-
oxacycloalkanes 10 does not provide such a convenient syn-
thetic route to the corresponding peroxylactones 11 as does
the dehydration of the analogous hydroperoxy-substituted
compounds 9.
The preparation of the hydroperoxide 5b is representative. To
a solution of Ag2O (698 mg, 3.01 mmol) and 1,1-bis(hydro-
peroxy)cyclododecane (1000 mg, 4.31 mmol) in CH2Cl2 (10
mL) was added a solution of 4-iodobutene (783 mg, 4.31 mmol)
in CH2Cl2 (5 mL) via syringe over 5 min. The reaction was
stirred at room temperature for a further 15 h. After removal
of the solid material by filtration through Celite, diethyl ether
(100 mL) was added to the filtrate and the organic layer was
washed in turn with 3% aqueous sodium thiosulfate (50 mL),
aqueous NaHCO3, saturated brine, and dried over anhydrous
MgSO4. After evaporation of the solvent under reduced pres-
sure, the components of the residue were separated by column
chromatography on silica gel. The first fraction (eluting with
diethyl ether–hexane, 5 : 95) gave cyclododecanone (336 mg,
43%). From the second fraction (eluting with diethyl ether–
hexane, 6 : 94) was obtained the monoalkylated hydroperoxide
5b (664 mg, 54%).
X-ray crystallographic analysis of peroxylactone 11b
Of the various peroxylactones 11a–e prepared in this study,
only compound 11b gave single crystals suitable for X-ray
crystallographic analysis. The solid state structure is depicted in
Fig. 1. The O–O and C–O distances around the 1,2,4,5-tetra-
oxocane ring lie within normal ranges, suggesting that this ring
is relatively strain-free. The 1,2,4,5-tetraoxocane ring in 11b
adopts a distorted twist-boat–chair conformation similar to
that observed for compound 210 though, not surprisingly, there
1-[(2-Propenyl)dioxy]cyclododecyl hydroperoxide (5a). (52%
yield). Mp 40–42 ЊC (from hexane–ethyl acetate); 1H NMR
δ 1.2–1.8 (m, 22 H), 4.55 (d, J = 6.3 Hz, 2 H), 5.2–5.4 (m, 2 H),
6.08 (ddt, J = 17.2, 10.3 and 6.3 Hz, 1 H), 8.18 (s, 1 H); 13C
NMR δ 19.23 (2 C), 21.76 (2 C), 22.19 (2 C), 25.90 (2 C), 26.04,
26.35 (2 C), 76.16, 114.20, 119.89, 133.80. Anal. Calcd for
C15H28O4: C, 66.14; H, 10.11. Found: C, 66.23; H, 10.36%.
1-[(3-Butenyl)dioxy]cyclododecyl hydroperoxide (5b). An oil;
1H NMR δ 1.2–1.8 (m, 22 H), 2.43 (qt, J = 6.6 and 1.3 Hz, 2 H),
4.12 (t, J = 6.6 Hz, 2 H), 5.0–5.2 (m, 2 H), 5.85 (ddt, J = 17.2,
10.2 and 6.6 Hz, 1 H), 7.85 (s, 1 H); 13C NMR δ 19.21 (2 C),
21.80 (2 C), 22.14 (2 C), 25.91 (2 C), 26.02 (2 C), 26.38, 32.38,
74.09, 113.91, 116.86, 134.61. Anal. Calcd for C16H30O4: C,
67.10; H, 10.56. Found: C, 66.97; H, 10.62%.
1-[(4-Pentenyl)dioxy]cyclododecyl hydroperoxide (5c). (37%
yield). Mp 42–43 ЊC (from diethyl ether–hexane); H NMR
δ 1.0–1.8 (m, 24 H), 1.9–2.2 (m, 2 H), 4.01 (t, J = 6.6 Hz, 2 H),
1
Fig. 1 Solid-state structure of peroxylactone 11b (ORTEP,17 50%
probability ellipsoids).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
1524

View Article Online
4.8–5.0 (m, 2 H), 5.72 (ddt, J = 17.0, 10.3 and 6.6 Hz, 1 H), 8.53
(s, 1 H); 13C NMR δ 19.17, 21.77, 22.13, 22.43, 24.06, 24.43,
24.59, 25.90, 25.97, 26.39, 26.88, 30.05, 40.17, 74.28, 113.60,
114.74, 137.5. Anal. Calcd for C17H32O4: C, 67.96; H, 10.74.
Found: C, 68.17; H, 10.62%.
3-Hydroxy-1,2,6,7-tetraoxaspiro[7.11]nonadecane (10b). An
oil (a 3 : 1 mixture of two diastereoisomers); H NMR (major
1
isomer) δ 1.2–1.8 (m, 22 H), 2.00 (dt, J = 17.0 and 4.8 Hz, 1 H),
2.53 (dddd, J = 17.0, 11.4, 8.9 and 1.7 Hz, 1 H), 3.75 (br s, 1 H),
4.03 (ddd, J = 15.2, 4.8 and 1.7 Hz, 1 H), 4.19 (dd, J = 15.2 and
11.4 Hz, 1 H), 5.29 (dd, J = 8.9 and 4.8 Hz, 1 H); 13C NMR
δ 19.09, 19.53, 21.90 (2 C), 22.16 (2 C), 25.86 (2 C), 26.00, 26.04,
26.24, 36.25, 71.44, 99.65, 111.98. The following additional
1-[(5-Hexenyl)dioxy]cyclododecyl hydroperoxide (5d). (53%
1
yield). Mp 38–40 ЊC (from diethyl ether–hexane); H NMR
1
δ 1.1–1.7 (m, 26 H), 2.01 (q, J = 6.8 Hz, 2 H), 4.02 (t, J = 6.4 Hz,
2 H), 4.8–5.0 (m, 2 H), 5.72 (ddt, J = 16.8, 13.4 and 6.8 Hz, 1 H),
8.43 (br s, 1 H); 13C NMR δ 19.25, 21.83, 22.20, 25.30, 25.96,
26.04, 26.47, 27.20, 33.42, 74.91, 113.73, 114.51, 138.08. Anal.
Calcd for C18H34O4: C, 68.75; H, 10.90. Found: C, 68.94; H,
10.93%.
signals were assigned to the minor isomer: H NMR δ 2.1–2.2
(m, 1 H), 2.8–3.0 (m, 1 H), 3.91 (td, J = 12.7 and 3.1 Hz, 1 H);
13C NMR δ 19.37, 19.46, 21.70, 21.84, 22.16 (2 C), 25.86 (2 C),
26.00, 26.04, 26.24, 36.25, 71.44, 99.65, 111.98; HRMS (CI)
[M ϩ H]ϩ m/z Calcd for C15H94O5 289.2015, Found 289.2006.
1,2,7,8-Tetraoxaspiro[8.11]icosan-3-yl hydroperoxide (9c).
Mp 66–67 ЊC (from hexane–diethyl ether); H NMR δ 1.1–1.8
1
1-[(7-Octenyl)dioxy]cyclododecyl hydroperoxide (5e). (45%
yield). An oil; 1H NMR δ 1.1–1.8 (m, 30 H), 1.9–2.1 (m, 2 H),
4.03 (t, J = 6.6 Hz, 2 H), 4.8–5.0 (m, 2 H), 5.75 (ddt, J = 17.0,
10.2 and 6.8 Hz, 1 H), 8.14 (s, 1 H); 13C NMR δ 19.32 (2 C),
21.89, 22.45 (2 C), 25.96, 26.02 (2 C), 26.10, 26.51 (2 C), 27.78,
28.78, 28.91, 33.70, 40.35, 75.19, 113.84, 114.14, 138.76. Anal.
Calcd for C20H38O4: C, 70.13; H, 11.18. Found: C, 70.08; H,
11.02%.
(m, 24 H), 2.0–2.3 (m, 2 H), 3.59 (td, J = 12.6 and 4.0 Hz, 1 H),
4.22 (dd, J = 12.8 and 4.6 Hz, 1 H), 5.07 (dd, J = 10.3 and
5.0 Hz, 1 H), 9.11 (br s, 1 H); 13C NMR δ 19.37, 19.42, 20.26,
20.82, 21.88, 22.18, 25.91, 26.13, 26.30, 26.49, 72.78, 109.68,
112.21. Anal. Calcd for C16H30O6: C, 60.35; H, 9.50. Found: C,
60.51; H, 9.47%.
1,2,8,9-Tetraoxaspiro[9.11]henicosan-3-yl hydroperoxide (9d).
An oil; 1H NMR δ 1.2–1.8 (m, 26 H), 2.2–2.8 (m, 2 H), 3.7–4.0
(m, 1 H), 4.2–4.4 (m, 1 H), 5.1–5.3 (m, 1 H), 8.75 (s, 1 H); 13C
NMR δ 19.28, 19.47, 21.88, 21.92, 22.22, 25.91, 26.11, 26.42,
26.75, 76.30, 111.75, 111.89. Anal. Calcd for C17H32O6: C,
69.19; H, 10.32. Found: C, 69.17; H, 10.25%.
Ozonolysis of the unsaturated hydroperoxides 5a–e in TFE
The ozonolysis of the unsaturated hydroperoxide 5b is repre-
sentative. Into a solution of 5b (373 mg, 1.3 mmol) in CH2Cl2
(25 mL) and 2,2,2-trifluoroethanol (TFE) (5 mL) was passed a
slow stream of ozone (1.5 equiv.) at 0 ЊC. The reaction mixture
was poured into aqueous sodium bicarbonate, and extracted
with diethyl ether (30 mL × 2). The combined organic layer was
washed with saturated brine, and dried over anhydrous MgSO4.
After evaporation of the solvent under reduced pressure, the
products were isolated by column chromatography on silica gel.
Elution with diethyl ether–hexane (5 : 95) gave cyclododecan-
one (15 mg, 6%). From the second fraction (eluting with diethyl
ether–hexane, 15 : 85) was obtained the hydroperoxide 9b (226
mg, 57%). Further elution with diethyl ether–hexane (20 : 80)
gave the alcohol 10b (91 mg, 24%).
1,2,10,11-Tetraoxaspiro[11.11]tricosan-3-yl
hydroperoxide
(9e). Mp 93–95 ЊC (from hexane–diethyl ether); 1H NMR δ 1.1–
2.2 (m, 32 H), 3.91 (ddd, J = 12.3, 10.2 and 2.0 Hz, 1 H), 4.1–4.3
(m, 1 H), 5.5–5.7 (m, 1 H), 8.54 (s, 1 H); 13C NMR δ 19.37,
19.41, 20.84, 21.89, 21.92, 22.20, 22.22, 23.89, 25.44, 25.97,
26.00, 26.20, 26.44, 26.83, 26.89, 28.85, 75.59, 110.27, 111.75,
112.72. Anal. Calcd for C19H36O6: C, 63.31; H, 10.07. Found: C,
63.47; H, 9.95%.
Dehydration of hydroperoxides 9a–e with Ac2O–Et3N
1,2,5,6-Tetraoxaspiro[6.11]octadecan-3-yl hydroperoxide (9a).
Mp 122–123 ЊC (from hexane–diethyl ether); H NMR δ 1.2–
2.3 (m, 22 H), 4.2–4.6 (m, 2 H), 5.4–5.6 (m, 1 H), 9.20 (br s,
1 H); 13C NMR δ 19.37, 21.79, 22.04, 22.37, 22.39, 25.98, 26.05,
75.09, 107.32, 116.34. Anal. Calcd for C14H26O6: C, 57.91; H,
9.03. Found: C, 59.73; H, 8.64%.
1
The reaction of 6b is representative. To a solution of 6b
(214 mg, 0.7 mmol) in CH2Cl2 (5 mL) was added a mixture of
acetic anhydride (216 mg, 2.1 mmol) and triethylamine (107 mg,
1.06 mmol) in CH2Cl2 (5 mL). The resulting solution was
stirred at room temperature for 2 h. This mixture was treated
with methanol (1 mL) for 15 min and then diluted with diethyl
ether (50 mL). The solution was washed in turn with 5%
NaHCO3 and saturated NaCl, dried over MgSO4, and concen-
trated under reduced pressure. The products were isolated by
column chromatography on silica gel. From the fraction eluted
by diethyl ether–hexane (1.5 : 98.5) was obtained cyclo-
dodecanone (6 mg, 7%). Subsequent elution with diethyl ether–
hexane (5 : 95) gave the peroxylactone 11b (162 mg, 81%).
3-Hydroxy-1,2,5,6-tetraoxaspiro[6.11]octadecane (10a). Mp
103–104 ЊC (from hexane–diethyl ether); 1H NMR δ 1.2–2.0 (m,
22 H), 4.1–4.5 (m, 3 H), 5.2–5.4 (m, 1 H); 13C NMR δ 19.28,
21.81, 21.97, 22.33, 25.87, 25.93, 25.98, 79.20, 97.99, 115.98.
Anal. Calcd for C14H26O6: C, 57.91; H, 9.03. Found: C, 57.73;
H, 8.64%.
1,2,6,7-Tetraoxaspiro[7.11]nonadecan-3-yl
hydroperoxide
1,2,6,7-Tetraoxaspiro[7.11]nonadecan-3-one (11b). Mp 126–
127 ЊC (from diethyl ether–hexane); H NMR δ 1.2–1.8 (m,
(9b). (a 4 : 1 mixture of two diastereoisomers). Mp 108–109 ЊC
(from diethyl ether–hexane); 1H NMR (major isomer) δ 1.2–1.8
(m, 22 H), 1.97 (dt, J = 15.8 and 4.6 Hz, 1 H), 2.42 (dddd,
J = 15.8, 10.9, 9.6 and 2.2 Hz, 1 H), 4.13 (ddd, J = 15.4, 4.6
and 2.2 Hz, 1 H), 4.28 (dd, J = 15.4 and 10.9 Hz, 1 H), 5.40 (dd,
J = 9.6 and 4.6 Hz, 1 H), 9.04 (s, 1 H); 13C NMR δ 19.02, 19.44,
21.84 (2 C), 22.21 (2 C), 25.78, 25.80, 25.83, 25.99, 26.15, 31.20,
71.07, 108.50, 112.20. The following additional signals were
assigned to the minor isomer: 1H NMR δ 2.0–2.2 (m, 1 H), 2.6–
2.9 (m, 1 H), 3.97 (td, J = 12.7 and 3.1 Hz, 2 H), 5.38 (dd,
J = 10.2 and 2.6 Hz, 2 H), 5.38 (dd, J = 10.2 and 2.6 Hz, 1 H),
9.13 (s, 1 H); 13C NMR δ 19.29, 19.37, 21.65, 21.98, 22.34 (2 C),
25.44, 25.66, 25.88, 25.91, 25.94, 27.82, 70.15, 108.69, 113.11.
Anal. Calcd for C15H28O6: C, 59.19; H, 9.27. Found: C, 59.12;
H, 9.25%.
1
22 H), 2.51 (ddd, J = 12.7, 3.8 and 1.0 Hz, 1 H), 3.35 (ddd,
J = 12.7, 11.9 and 3.8 Hz, 1 H), 4.23 (dt, J = 14.2 and 3.8 Hz,
1 H), 4.46 (ddd, J = 14.2, 11.9 and 1.0 Hz, 1 H); 13C NMR
δ 18.98, 19.25, 21.20 (2 C), 21.93 (2 C), 25.39, 25.54, 25.61,
25.64, 26.04, 35.24, 72.26, 117.11, 177.61. Anal. Calcd for
C15H26O5: C, 62.91; H, 9.15. Found: C, 62.79; H, 9.26%.
1,2,7,8-Tetraoxaspiro[8.11]icosan-3-one (11c). Mp 105–
1
106 ЊC (from hexane–diethyl ether); H NMR δ 1.1–1.8 (m,
22 H), 2.0–2.5 (m, 3 H), 3.3–3.7 (m, 1 H), 3.9–4.3 (m, 2 H); 13
C
NMR δ 18.98, 19.40, 21.81, 22.17, 24.32, 24.80, 25.84, 26.08,
26.24, 26.87, 71.96, 116.65, 178.81. Anal. Calcd for C16H28O5:
C, 63.97; H, 9.40. Found: C, 64.04; H, 9.11%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
1525

View Article Online
1,2,8,9-Tetraoxaspiro[9.11]henicosan-3-one (11d). Mp 97–
o-(Methoxycarbonyl)phenylacetic acid (15b).15 Mp 146–
148 ЊC (from hexane–diethyl ether); H NMR δ 3.88 (s, 3 H),
4.03 (s, 2 H), 7.2–7.3 (m, 1 H), 7.37 (td, J = 7.6 and 1.4 Hz, 1 H),
7.50 (td, J = 7.6 and 1.4 Hz, 1 H), 8.02 (dd, J = 7.6 and 1.4 Hz,
1 H), 10.67 (br s, 1 H); 13C NMR δ 40.76, 52.25, 127.58, 129.26,
130.98, 132.26, 132.51, 135.17, 167.60, 176.92.
1
1
98 ЊC (from hexane–diethyl ether); H NMR δ 1.1–2.4 (m, 28
H), 3.7–4.3 (m, 2 H); 13C NMR δ 19.11, 21.81, 22.14, 22.60,
24.09, 24.22, 24.76, 25.82, 26.13, 26.34, 28.03, 40.38, 75.88,
114.80, 179.07. Anal. Calcd for C17H30O5: C, 64.94; H, 9.62.
Found: C, 65.07; H, 9.49%.
Oxidation of alcohols 10 by DMSO–oxalyl chloride16
1,2,10,11-Tetraoxaspiro[11.11]tricosan-3-one (11e). Mp 88–
91 ЊC (from hexane–diethyl ether); 1H NMR δ1.1–1.9 (m, 30 H),
2.3–2.5 (m, 2 H), 4.00 (t, J = 5.0 Hz, 2 H); 13C NMR δ 19.28,
21.88, 22.21, 22.34, 22.42, 25.91, 26.05, 26.78, 73.14, 113.61,
170.89. C19H34O5: C, 66.64; H, 10.01. Found: C, 66.45; H,
9.99%.
To a solution of oxalyl chloride (280 mg, 2.2 mmol) in CH2Cl2
(10 mL) was added DMSO (375 mg, 4.8 mmol) in CH2Cl2
(2 mL) at Ϫ70 ЊC during 20 min and then, to this solution was
added a solution of alcohol 10b (288 mg, 1.0 mmol) in CH2Cl2
(3 mL) at Ϫ10 ЊC during 20 min. The mixture was cooled again
to Ϫ70 ЊC and triethylamine (505 mg, 5 mmol) was added
during 5 min. Then, the mixture was poured into water,
extracted with CH2Cl2, washed with saturated brine, and dried
over anhydrous MgSO4. By column chromatography on silica
gel (elution with diethyl ether–hexane, 1.5 : 98.5) was obtained
cyclododecanone (56 mg, 31%). Further elution with diethyl
ether–hexane (1.5 : 98.5) gave peroxylactone 11b (6 mg, 2%).
Further elution with diethyl ether–hexane (20 : 80) gave a
mixture of polar, unidentified products (32 mg).
Reaction of hydroperoxides 9a-e with phenyl isocyanate in the
presence of catalytic quantities of pyridine
The reaction of hydroperoxide 9a is representative. To a solu-
tion of hydroperoxide 9a (76 mg, 0.26 mmol) and phenyl iso-
cyanate (62 mg, 0.52 mmol) in benzene (20 mL), was added one
drop of pyridine and the resulting reaction mixture was stirred
at room temperature for 15 h. After concentration under
reduced pressure, the products were separated by column
chromatography on silica gel. Elution with diethyl ether–
hexane (1 : 99) gave peroxylactone 11a (33 mg, 47%). From the
second fraction (elution with diethyl ether–hexane, 5 : 95) was
obtained cyclododecanone (11 mg, 23%).
Crystal structure determination of peroxylactone 11b†
Single crystals of peroxylactone 11b suitable for X-ray crystallo-
graphic analysis were grown from a diethyl ether–hexane
solution by slow evaporation.
The X-ray diffraction data were collected on a Brucker AXS
P4 diffractometer at 160 K using graphite-monochromated
MoKα λ = 0.71073 Å. The structure was solved by direct
methods and refined using least-squares techniques. All
crystallographic calculations and preparation of structure plots
and tables were carried out using the SHELXTL PC suite of
programs.17
1,2,5,6-Tetraoxaspiro[6.11]octadecan-3-one (11a). Mp 62–
63 ЊC (from hexane–diethyl ether); 1H NMR δ 1.2–1.9 (m,
22 H), 5.0–5.2 (m, 2 H); 13C NMR δ 18.63, 19.45, 21.87, 22.23,
25.49, 25.68, 25.78, 25.95, 26.04, 75.92, 117.74, 171.44. HRMS
(CI) [M ϩ 1]ϩ m/z calcd for C14H24O5 273.1702, found
273.1703.
The reaction of hydroperoxide 12c under similar conditions
gave the lactone 13c.
3-Methoxy-1H,3H-naphtho[1,8-cd]pyran-1-one (13c).14 Mp
105–106 ЊC (from hexane–diethyl ether); 1H NMR δ 3.73
(s, 3 H), 6.50 (s, 1 H), 7.5–8.5 (m, 6 H); 13C NMR δ 56.32,
102.21, 119.35, 125.36, 126.45, 127.21, 128.64, 129.78, 131.61,
133.66, 163.23; IR 2950, 1740, 1250, 1090, 780 cmϪ1. Anal.
Calcd for C13H10O3: C, 72.89; H, 4.70. Found: C, 72.70; H,
4.78%.
Crystal data
C15H26O5, M = 286.36, colorless platelets, monoclinic, space
group P21/c (No. 14), a 18.827 (4), b 5.0970 (10), c 16.083 (3) Å,
β 96.99 (2)Њ, U 1531.9 (5) Å3, Z = 4, Dc 1.242 g cmϪ3, F(000) 624,
µ(MoKα) 0.092 mmϪ1, 3693 reflections measured, 2685 unique
(Rint 0.041) which were used in all calculations. The final
discrepancy factors were: R1 = 0.056 and wR(F 2) = 0.1125
(all data).
Oxidation of alcohols 10a,b by Jones reagent
The reaction of the α-hydroxy-substituted tetroxocane 10b is
representative. To a solution of CrO3 (186 mg, 1.86 mmol) in
water (0.29 mL) was added conc. H2SO4 (0.16 mL) at 0 ЊC and
then, water was added to adjust the total volume to 0.7 mL. The
resulting Jones reagent was added (10 min) to a solution of 10b
(268 mg, 0.93 mmol) in acetone (3 mL) at 0 ЊC. The reaction
mixture was stirred at room temperature for a further 3 h and
then poured into aqueous sodium hydrogen sulfite, extracted
with diethyl ether (5 mL × 3), and dried over anhydrous
MgSO4. By column chromatography on silica gel (eluting with
diethyl ether–hexane, 1.25 : 98.75) was obtained cyclododecan-
one (15 mg, 9%). Further elution with diethyl ether–hexane
(5 : 95) gave peroxylactone 11b (152 mg, 57%).
† CCDC reference number 202065. See http://www.rsc.org/suppdata/
ob/b3/b300342f/ for crystallographic files in .cif or other electronic
format.
References
1 (a) D. A. Casteel, Nat. Prod. Rep., 1992, 9, 289; D. A. Casteel,
Nat. Prod. Rep., 1999, 16, 55; (b) K. J. McCullough and M. Nojima,
Curr. Org. Chem., 2001, 5, 601; (c) C. W. Jefford, in Comprehensive
Heterocyclic Chemistry, Ed. A. R. Katritzky, C. W. Rees and
E. F. V. Scriven, Pergamon, Oxford, 1996, Vol. 6, Chap. 20;
(d ) R. K. Haynes and S. C. Vonwiller, Acc. Chem. Res., 1997, 30, 73;
(e) A. K. Bhattacharya and R. P. Sharma, Heterocycles, 1999, 51,
1681; ( f ) Y. Dong, Mini Rev. Med. Chem., 2002, 2, 113. For
the synthesis of 1,2,4-trioxan-5-ones relevant to the present
work, see; (g) C. W. Jefford, J.-C. Rossier and G. D. Richardson,
J. Chem. Soc., Chem. Commun., 1983, 1064; (h) C. W. Jefford, J.
Currie, G. D. Richardson and J.-C. Rossier, Helv. Chim. Acta, 1991,
74, 1239.
2 H.-S. Kim, Y. Nagai, K. Ono, K. Begum, Y. Wataya, Y. Hamada,
K. Tsuchiya, A. Masuyama, M. Nojima and K. J. McCullough,
J. Med. Chem., 2001, 44, 2357.
3 A. Gonzalez, J. Martin, C. Peret, J. Rovirosa, B. Tagle and J. Clardy,
Chem. Lett., 1984, 1469.
4 L. Sy, G. D. Brown and R. K. Haynes, Tetrahedron, 1998, 54, 4345.
5 (a) Y. Nonami, T. Tokuyasu, A. Masuyama, M. Nojima, K. J.
McCullough, H.-S. Kim and Y. Wataya, Tetrahedron Lett., 2000, 41,
Under similar conditions, Jones oxidation of hemiperacetals
14a and 14b afforded the corresponding carboxylic acids, 15a
and 15b.
o-(Methoxycarbonylmethyl)benzoic acid (15a).15 Mp 98–
100 ЊC (from hexane–diethyl ether); 1H NMR δ 3.70 (s,
3 H), 4.05 (s, 2 H), 7.28 (dd, J = 7.6 and 1.3 Hz, 1 H), 7.39 (td,
J = 7.6 and 1.3 Hz, 1 H), 7.54 (td, J = 7.6 and 1.3 Hz, 1 H), 8.14
(dd, J = 7.6 and 1.3 Hz, 1 H), 10.10 (br s, 1 H); 13C NMR
δ 40.63, 52.01, 127.47, 128.36, 131.80, 132.31, 133.20, 136.54,
171.99, 172.23.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
1526

View Article Online
4681; (b) Y. Hamada, H. Tokuhara, A. Masuyama, M. Nojima,
H.-J. Kim, K. Ono, N. Ogura and Y. Wataya, J. Med. Chem., 2002,
45, 1374.
10 K. Tsuchiya, Y. Hamada, A. Masuyama, M. Nojima, K. J.
McCullough, H.-S. Kim, Y. Shibata and Y. Wataya, Tetrahedron
Lett., 1999, 40, 4077.
11 P. Groth, Acta Chem. Scand., Sect. A, 1975, 29, 59.
12 K. Griesbaum, W.-S. Kim, N. Nakamura, M. Mori, M. Nojima and
S. Kusabayashi, J. Org. Chem., 1990, 55, 6153.
13 T. Sugimoto, M. Nojima and S. Kusabayashi, J. Org. Chem., 1990,
55, 3816.
14 D. Timothy, D. D. Deininger, R. Russo, N. A. Senko, A. Katz,
J. M. Kitzen, R. Mitchell, G. Oshiro, A. Russo, R. Stupienski and
R. J. McCaully, J. Med. Chem., 1992, 35, 823.
15 C. Kaneko and T. M. C. Naito, Heterocycles, 1982, 18, 2275.
16 A. Mancuso, S.-L. Huang and D. Swern, J. Org. Chem., 1978, 43,
2480.
6 (a) W. H. Bunnelle and T. A. Isbell, J. Org. Chem., 1992, 57, 729;
(b) S. Kawamura, H. Yamakoshi and M. Nojima, J. Org. Chem.,
1996, 61, 5953; (c) Y. Ushigoe, Y. Torao, A. Masuyama and
M. Nojima, J. Org. Chem., 1997, 62, 4949; (d ) A. Rajca, S. Rajca,
S. R. Dedai and V. W. Day, J. Org. Chem., 1997, 62, 6524.
7 K. J. McCullough, T. Ito, T. Tokuyasu, A. Masuyama and
M. Nojima, Tetrahedron Lett., 2001, 42, 5529 . See also C.-S. Huang,
C.-C. Peng and C.-H. Chou, Tetrahedron Lett., 1994, 35, 4175 and
ref. 6c.
8 S. L. Schreiber, R. E. Claus and J. Reagan, Tetrahedron Lett., 1982,
23, 3867.
9 K. Teshima, S. Kawamura, Y. Ushigoe, M. Nojima and K. J.
McCullough, J. Org. Chem., 1995, 60, 4755.
17 G. M. Sheldrick, SHELXTL PC (vers. 5.1), Brucker AXS: Madison,
WI, USA.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 2 – 1 5 2 7
1527