Yingzhaosu A analogues: Synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity

Article abstract of DOI:10.1016/S0040-4020(01)00557-9

Ozone-mediated cyclization of a series of unsaturated hydroperoxides 7, prepared from dienes 2, afforded the corresponding yingzhaosu A analogues 9 in moderate to high yield. X-Ray crystallographic analysis of two yingzhaosu A analogues, endo-9f and 13, showed that the 2,3-dioxabicyclo[3.3.1]nonane system adopts a chair-boat arrangement. Subsequent treatment of endoperoxides 9 with Ag₂O/MeI afforded the expected methyldioxy-substituted cyclic peroxides 14, several of which showed notable anti-malarial activity against P. falciparum in vitro.

Full text of DOI:10.1016/S0040-4020(01)00557-9

TETRAHEDRON
Pergamon
Tetrahedron 57 A2001) 5979±5989
Yingzhaosu A analogues: synthesis by the ozonolysis of
unsaturated hydroperoxides, structural analysis and
determination of anti-malarial activity
Takahiro Tokuyasu,a Araki Masuyama,a Masatomo Nojima,a,p Kevin J. McCullough,b,p
c,p
Hye-Sook Kimc andYusuke Wataya
aDepartment of Materials Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
bDepartment of Chemistry, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK
cFaculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Received10 April 2001; accepted16 May 2001
AbstractÐOzone-mediated cyclization of a series of unsaturated hydroperoxides 7, preparedfrom dienes 2, afforded the corresponding
yingzhaosu A analogues 9 in moderate to high yield. X-Ray crystallographic analysis of two yingzhaosu A analogues, endo-9f and 13,
showed that the 2,3-dioxabicyclo[3.3.1]nonane system adopts a chair±boat arrangement. Subsequent treatment of endoperoxides 9 with
Ag2O/MeI afforded the expected methyldioxy-substituted cyclic peroxides 14, several of which showednotable anti-malarial activity against
P. falciparum in vitro. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since malaria parasites are rapidly developing resistance to
the most commonly usedchemo-therapeutic alkaloiadl
drugs, the anti-malarial properties of nonalkaloidal
compounds such as artemisinin, yingzhaosu A and other
related endoperoxides have attracted considerable atten-
tion.1 In this respect, new methods for the synthesis of
1,2,4-trioxanes2,3 and1,2-dioxanes 4±6 have been developed.
Among these endoperoxides, yingzhaosu A, possessing the
unusual 2,3-dioxabicyclo[3.3.1]nonane framework, was an
attractive target. The total synthesis of this endoperoxide
has been independently achieved by Xu and Bachi,7 and
several derivatives have been also synthesized.8,9 We
previously reportedthat ozonolysis of unsaturatedhydro-
peroxy acetals in protic solvent provided a useful synthetic
route to hydroperoxy-substituted 1,2-dioxanes and 1,2-diox-
epanes.5 In this paper, we report further application of this
2. Results and discussion
methodology to the synthesis of 2,3-dioxabicyclo[3.3.1]-
nonane derivatives.9
2.1. Preparation of unsaturated hydroperoxides 7
Ole®nation of ketones 1a,b by the Horner±Emmons reac-
tion AScheme 1) gave the requireddienes 2a,b and 4 which
were subsequently transformedinto the corresponidng
a-methoxy-substituted hydroperoxides 7a,b,f by regio-
selective mono-ozonolysis in methanol as outlinedin
Scheme 2.
Keywords: yingzhaosu A analogues; unsaturated hydroperoxides; ozone-
mediated cyclization; anti-malarial activity.
Corresponding authors. Tel./fax: 181-6-6879-7928;
e-mail: nojima@ap.chem.eng.osaka-u.ac.jp
p
Since ozone is a highly electrophilic reagent, it was
expectedto react selectively at the more electron-rich
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020A01)00557-9

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T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
Scheme 1.
CvC double bond in diene substrates 2a,b and 4.3,4g In
accordance with this notion, the reaction of diene 2a with
1 equiv. of ozone in MeOH±CH2Cl2 at 2708C, followedby
column chromatography on silica gel, gave the unsaturated
hydroperoxide 7a as an inseparable 1:1 mixture of two
stereoisomers in 67% yield. Also, mono-ozonolysis of
diene 4, in which electron-withdrawing ester group was
introduced into the alkene moiety, afforded a ca. 3:3:3:1
mixture of four unsaturated hydroperoxides 7f A94%).
From the reaction of diene 2b Apreparedfrom the commer-
cially available dihydrocarvone as a 1:4 mixture of cis- and
trans-isomers), however, only two isomeric hydroperoxides
trans-7b A49%) and cis-7b A11%), separable by column
chromatography on silica gel, were obtainedAScheme 2).
To prepare unsaturated tert-hydroperoxides cis-7c and 7e,
the CoAII)-catalyzed procedure for the autoxidation of
alkenes developed by Mukaiyama10 was investigated
because the resulting triethylsilyl peroxides can be readily
desilylated on treatment with hydrochloric acid in MeOH.
Certainly, the two-step reaction of diene 3 afforded a
mixture of the unsaturated hydroperoxides cis- and trans-
7c, 7g and the dihydroperoxide 7h, demonstrating that two
ole®nic double bonds could not be differentiated during the
autoxidation process AScheme 4). Although hydroperoxides
cis-7c and 7g couldbe separatedby column chroma-
tography on silica gel, hydroperoxide trans-7c was obtained
as an admixture with 7g. In case of the diene 4, however, the
more electron-rich CvC double bond was selectively
peroxidized, thereby yielding the desired mono-hydro-
peroxide 7e in 74% yieldas a ca. 2:1 mixture of geometrical
isomers.
To determine the structure of the isomeric hydroperoxide
trans-7b, a series of DEPT, COSY, HMQC andNOE
experiments were conducted on the corresponding benzyl
derivative 8, obtainedby the Ag 2O-mediated alkylation with
benzyl bromide AScheme 3). In the NOE experiment on 8,
irradiation at the methoxy group signal Ad 3.46, s) resulted
in the enhancement of the C-6 hydrogen signals: H-6eq Ad
2.57, ddd) A3.2%) and H-6ax Ad 1.19, t) A1.2%). Also, irra-
diation at the C-2 methyl group signal Ad 1.00, d) induced
the enhancement of the signals of the hydrogen atoms at
C-3: H-3eq Ad 1.5±1.6, m) A2.7%) andH-3ax A d 1.37, qd)
A2.4%). In addition, irradiation of the hydrogen H-3ax signal
resultedin enhancement of the H-5ax A d 2.11, tt) A3.0%)
signal. No NOE was observedbetween H-2ax andH-3ax
AFig. 1). These results are consistent with a trans-relation-
ship between the methoxy andthe methyl groups in hydro-
peroxide trans-7b. Thus, the corresponding intermediate
carbonyl oxide must have been selectively captured by
methanol from the less hindered face anti to the methyl
group as observedpreviously AScheme 2). 6 A similar stereo-
chemical relationship is likely to be developed in the
isomeric hydroperoxide cis-7b.
Finally, the sec-hydroperoxide cis-7d was preparedby the
methodreportedby Bloowd orth.
11
N-Tosylhydrazone 5,
preparedfrom the corresponding ketone 1a, was reduced
to the hydrazine 6 by NaBH3CN/p-TsOH. Subsequent treat-
ment of the crude hydrazine 6 with 30% H2O2 andNa O2
2
afforded a mixture of the desired hydroperoxides cis-7d
A26%) and trans-7d A19%), which couldbe separatedby
column chromatography on silica gel AScheme 5). Replace-
ment of the aqueous solution of H2O2 by a dried solution of
H2O2 in THF afforded the hydroperoxides cis-7d and trans-
7d in improvedyields of 38 and25%, respectively.
2.2. Ozonolysis of unsaturated hydroperoxides 7 in 2,2,2-
tri¯uoroethanol +TFE)
With a series of the unsaturated hydroperoxides 7 in hand,
ozone-mediated cyclizations in 2,2,2-tri¯uoroethanol ATFE)
were conducted. Ozonolysis of the unsaturated hydro-
peroxide 7a Aa 1:1 mixture of two stereoisomers) afforded

T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
5981
Figure 1. NOE enhancement of 8.
ketone 10b A68%) was obtainedfrom trans-7b as the sole
identi®ed product AScheme 7).
To realize intramolecular cyclization of the carbonyl oxide
intermediate 11, it is clear that the hydroperoxy group and
the carbonyl oxide moiety are required to be 1,3-synaxial.
Since the yieldof the bicyclic peroxide 9b A45% from cis-
7b) was signi®cantly higher than that of 9a A34% from cis-
7a), the presence of the methyl group at C-2 in cis-7b must
make the population of the corresponding 1,3-synaxial
conformation more favorable. In respect of the nucleo-
philicity of the hydroperoxy group, the sec-hydroperoxide
cis-7d wouldbe expectedto capture the carbonyl oxide
moiety highly ef®ciently, thereby producing the bicyclic
peroxide 9d in higher yields than the other cases. In reality,
the yieldof 9d A24%) is lower than those of 9a±c, suggest-
ing that the presence of a substituent at the a-position of
7a,c also facilitates the adoption of the corresponding
1,3-synaxial conformation. Thus, it may be concluded
that, in the cyclization process, the ease of population of
the appropriate 1,3-synaxial conformation is a signi®cantly
more important factor than the nucleophilicity of the hydro-
peroxy group.
The cyclic peroxides 9a,b,d were obtainedin each case as a
single isomer. Although compound 9b was crystalline, the
crystals obtained diffracted weakly and decayed substan-
tially during X-ray data collection at 160 K. From the
X-ray data obtained, a structural solution was obtained but
attempts to re®ne the structure were unsatisfactory. The
structure, as depicted in structural formula 9b, consists of
the chair-like cyclohexane ring andthe boat-like 1,2-diox-
ane ring Acf. X-ray crystal structure of endo-9f below) with a
1,2-trans-diequatorial relationship between the methoxy
group and the adjacent methyl group. The hydroperoxy
group occupies the endo-position, suggesting that
compound 9b couldbe stabilizedby an anomeric effect
Scheme 2.
the expectedhydroperoxy-substitutedyingzhaosu A ana-
logue 9a in 17% yieldA34% basedon cis-7a, having a
con®guration favorable for cyclization), together with
the corresponding ketone 10a AScheme 6). Also, from the
ozonolysis reactions of the cis-7b, cis-7c and cis-7d, the
corresponding bicyclic peroxides 9b±d were obtainedin
45, 48 and24% yiel,d respectively ATable 1). The by-
product from the reaction of cis-7b and cis-7c was a
complex mixture of unidenti®ed, highly polar products in
each case. Consistent with the unfavorable con®guration of
the unsaturated hydroperoxide trans-7b, the corresponding
between the peroxide oxygen non-bonded electron pairs
andthe exocyclic C±O bon.d
12
From its structure,
compound 9b must be selectively formedby path a rather
than path b AScheme 8) which differ only by the orientation
of the carbonyl oxide moiety. From the reaction of cis-7c,
however, bicyclic peroxide 9c was obtainedas a 1:1 mixture
of stereoisomers. The reason for the notable difference in
stereoselectivity between 9b and 9c is obscure.
We have previously reportedthat ozonolysis of unsaturated
hydroperoxides in aprotic solvents such as ether resulted in
the formation of a complex mixture of products9 with the
Scheme 3.

5982
T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
Scheme 4.
Scheme 5.
Scheme 6.
concomitant decrease in the yield of the desired cyclic
peroxide.5 In protic solvent such as TFE, however, the
analogous reactions proceeded smoothly to afford the bi-
cyclic peroxides in good yield. As indicated in Scheme 8,
TFE assist the cyclization of the carbonyl oxide inter-
mediate because solvation enhances the electrophilicity of
the carbonyl oxide moiety thereby suppressing the [312]
cycloaddition with the co-produced formaldehyde and facili-
tating the intramolecular capture by the hydroperoxy group.3
Given that the carbonyl oxide intermediates derived from
7a±d require 1,3-synaxial arrangements to produce the
corresponding bicyclic endoperoxides 9a±d, it was
expected that the unsaturated hydroperoxides 7e,f should
undergo cyclization more readily because the resulting car-
bonyl oxide intermediates Ae.g. 12 from 7e) shouldcyclize
through less sterically hindered conformations with only
one axial group. Consistent with this expectation, ozonoly-
sis of the unsaturatedhyrdoperoxieds
7e,f proceeded
Table 1. Ozonolysis of cis-7b, cis-7c and cis-7d in TFE
Substrate
R1
R2
Products Ayield)
cis-7b
cis-7c
cis-7d
Me
H
H
OMe
Me
H
9b A45%)
9c A48%; 1:1)
9d A24%), 10d A33%)
Scheme 7.

T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
5983
be more thermally labile than endo-9f andunderwent exten-
sive decomposition in less than a week on storage at
temperatures below 58C.
The crystal structure of a relatedbicyclo[3.3.1] endo-
peroxide 13, whose synthesis was reportedpreviously,
9
was also determined by X-ray crystallographic analysis
AFig. 3). The molecular skeleton of 13 has the chair±boat
conformational arrangement as observedfor 9b and endo-
9f. It is interesting to note that in the crystal structures of
yingzhaosu A derivative7a andan analogue, 8a both prepared
by intramolecular Michael-type cyclization of hydroperoxy-
cyclohexenone derivatives, the [3.3.1] bicyclic skeleton
adopts the alternative chair±chair arrangement.
Since the presence of the hydroperoxy group was expected
to render the bicyclic endoperoxides 9 highly cytotoxic,
they were convertedinto the corresponidng methylated
compounds 14 on treatment with a mixture of Ag2O and
methyl iodide AScheme 10).
Scheme 8.
smoothly to afford the corresponding bicyclic peroxides 9e,
and endo- and exo-9f, respectively, in high yieldAScheme
9). The isomeric compounds, endo- and exo-9f, couldbe
separatedby column chromatography on silica gel andthe
structure of the highly crystalline endo-9f was determined
by X-ray crystallographic analysis. The crystal structure of
endo-9f consists of the dioxabicyclo[3.3.1]nonane skeleton
with the cyclohexane and1,2-idoxane rings being in a
chair±boat arrangement AFig. 2). The 1,2-dioxane ring
exhibits signi®cant distortion from an ideal boat confor-
mation. The methoxy substituent was locatedat the endo-
position which wouldfavor an anomeric interaction
analogous to that in endoperoxide 9b.12 The other isomer
exo-9f, lacking any stabilizing anomeric effect, was foundto
With the yingzhaosu A analogues 14 in hand, their anti-
malarial activities andcytotoxicities were testedagainst P.
1j
falciparum andFM3A cells,
respectively ATable 2).
Compound 14b was foundto give the best result, providing
an EC50 value of 1.0£1027 M against P. falciparum
[approximately a tenth of the anti-malarial potency of
artemisinin AEC50ˆ7.8£1029 M)]. Moreover, the selectivity
determined by the comparison with the 50% inhibitory
concentration against FM3A cells A3.3£1025 M) was as
high as 330. The other compounds in the series showed
only moderate anti-malarial activities, suggesting that
signi®cant modi®cation of the structure would be required
in order to develop promising candidates as anti-malarial
drugs.
Scheme 9.

5984
T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
Figure 2. The X-ray crystal structure of the bicyclic endoperoxide endo-9f AORTEP17).
3. Conclusion
stereoselective fashion. The ef®ciency of cyclization
process depends more on the ease of population of a confor-
mation favorable for cyclization than the nucleophilicity of
the hydroperoxy group. Consistent with this, structure of
unsaturated hydroperoxides signi®cantly affected the yields
A series of yingzhaosu A analogues were preparedby
ozonolysis of the appropriate unsaturated hydroperoxides
in TFE. In several cases, the reaction proceeded in a highly
Figure 3. The X-ray crystal structure of the bicyclic endoperoxide 13 AORTEP17).

T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
5985
A5 mL) was passeda slow stream of ozone A1 equiv.) at
2708C. Reaction mixture was pouredinto aqueous sodium
bicarbonate, andextractedwith ether A30 mL £2). The
combinedorganic extracts were washedwith saturated
brine, and dried over anhydrous MgSO4. After evaporation
of the solvent under reduced pressure, the products were
isolatedby column chromatography on silica gel. Elution
with diethyl ether±hexane A8:92) gave the unsaturated
hydroperoxide trans-7b A920 mg, 49%). Subsequent elution
with A15:85) gave the unsaturatedhydroperoxy acetal cis-7b
A240 mg, 11%).
4.2.1. +1S,2R,5R)-1-Methoxy-2-methyl-5-+1-methylethenyl)-
cyclohexyl hydroperoxide +trans-7b). An oil; H NMR d
1
0.98 Ad, Jˆ6.9 Hz, 3H), 1.2±1.8 Am, 6H), 1.74 As, 3H), 2.2±
2.6 Am, 2H), 3.44 As, 3H), 4.72 As, 2H), 8.99 As, 1H); 13C
NMR d 13.87 ACH3), 21.10 ACH3), 31.05 ACH2), 31.37
ACH2), 34.34 ACH2), 38.80 ACH), 41.37 ACH), 51.09 ACH3),
106.92 AC), 108.93 AC), 149.38 AC). Anal. Calcdfor
C11H20O3: C, 65.94: H, 10.07. Found: C, 65.91: H, 10.09.
4.2.2. +1R,2S,5R)-1-Methoxy-2-methyl-5-+1-methylethenyl)-
cyclohexyl hydroperoxide +cis-7b). An oil; H NMR d
1
Scheme 10.
1.03 Ad, Jˆ7.3 Hz, 3H), 1.2±2.4 Am, 8H), 1.73 As, 3H),
3.30 As, 3H), 4.71 As, 2H), 7.81 As, 1H); 13C NMR d 14.29
ACH3), 20.81 ACH3), 25.10 ACH2), 28.84 ACH2), 28.95 ACH2),
32.96 ACH), 41.40 ACH), 48.09 ACH3), 108.43 AC), 109.00
AC), 148.96 AC). Anal. Calcdfor C 11H20O3: C, 65.94: H,
10.07. Found: C, 65.34: H, 10.00.
Table 2. In vitro anti-malarial activities of yingzhaosu A analogues 14
against P. falciparum andcytotoxicities against FM3A cells
Ec50 values AM)
Selecta
P. falciparum
FM3A
4.2.3. 1-Methoxy-3-+1-methylethenyl)cyclohexyl hydro-
peroxide +7a). An oil Aa 1:1 mixture of two stereoisomers);
1H NMR d 1.0±1.6 Am, 4H), 1.6±1.9 Am, 2H), 1.72 As, 3H),
2.0±2.3 Am, 3H), 3.30 As)13.35 As) A3H), 4.70 As, 2H), 8.49
As, 1H); 13C NMR d 20.70 A2C), 22.12, 22.28, 30.30, 30.69,
30.82, 30.86, 35.55, 35.99, 41.10, 41.15, 48.12, 48.25,
105.79, 105.93, 108.75, 108.82, 148.95, 149.04. Anal.
Calcdfor C 10H18O3: C, 64.49: H, 9.74. Found: C, 64.06:
H, 9.62.
14a
14b
14c
14e
endo-14f
exo-14f
Artemisinin
4.6£1026
1.0£1027
2.9£1025
7.0£1025
1.7£1025
1.8£1026
7.8£1029
1.4£1024
3.3£1025
4.6£1024
6.8£1025
4.7£1025
9.8£1025
1.0£1026
30
330
16
,1
3
54
1280
a
SelectˆAEC50 value for FM3A cells)/AEC50 value for P. falciparum).
4.2.4. Ethyl 3-+1-hydroperoxy-1-methoxyethyl)cyclohexyl-
ideneacetate +7f). An oil Aa 1:1:1 mixture of three major
of the bicyclic endoperoxides. Some of the obtained bicyclic
endoperoxides, prepared in this study, showed notable anti-
malarial activity in vitro.
1
isomers); H NMR d 1.2±2.6 Am, 14H), 3.30 As)13.31
As)13.47 As) A3H), 3.8±4.0 Am, 1H), 4.1±4.3 Am, 2H),
5.6±5.7 Am, 1H), 8.58 As)18.69 As)18.70 As) A1H); 13C
NMR d 13.95 ACH3), 14.09 ACH3), 15.06 ACH3), 15.47
ACH3), 22.48 ACH2), 26.36 ACH2), 26.52 ACH2), 27.08
ACH2), 27.17 ACH2), 29.29 ACH2), 30.66 ACH2), 31.41
ACH2), 37.45 ACH2), 38.58 ACH2), 38.67 ACH2), 42.86
ACH), 43.63 ACH), 48.56 ACH3), 48.59 ACH3), 59.50 ACH2),
59.55 ACH2), 107.76 AC), 107.84 AC), 108.00 AC), 113.71
ACH), 113.87 ACH), 114.02 ACH), 161.58 AC), 161.83 AC),
161.90, AC) 166.68 AC), 166.85 AC); the additional following
signals were assignedto the minor isomer. 1H NMR d 3.38
As, 3H), 9.24 As, 1H); 13C NMR d 27.76 ACH2), 28.66 ACH2),
32.45 ACH2), 37.83 ACH2), 44.96 ACH), 49.00 ACH3), 60.16
ACH2), 107.85 AC), 112.47 ACH), 163.72 AC). Anal. Calcdfor
C13H22O5: C, 60.45: H, 8.58. Found: C, 60.33: H, 8.71.
4. Experimental
4.1. General procedures
1H A270 MHz; 400 MHz for COSY, HMQC andNOE
measurements) and 13C A67.5 MHz) NMR spectra were
obtainedin CDCl solution with SiMe4 as the standard.
Unsaturatedketone 1b was commercial available, andthe
other unsaturatedketone 1a13 andthe derivatives 214, 315
and 416 were prepared by literature procedures. The detailed
procedures for the determination of antimalarial activities
of peroxides in vitro and in vivo have been previously
described.1j
3
4.2. Mono-ozonolysis of dienes 2,4 in MeOH±CH2Cl2
4.3. Mono-peroxygenation of dienes 3,4 with Co+II)-
catalyst
Ozonolysis of the diene 2b is representative. Into a solution
of 2b A1.7 g, 9.4 mmol) in CH2Cl2 A25 mL) andmethanol
Mono-peroxygenation of the diene 4 is representative. Into a

5986
T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
two-neck 50 mL ¯ask, charged with dioxygen, the diene
4 A200 mg, 0.96 mmol), bisA1-morpholinocarbamoly-4,4-
dimethyl-1,3-pentanedionato)-cobaltAII) ACoAmodp)2) A26 mg,
0.048 mmol) and 1,2-dichloroethane A10 mL) were added,
andthen the ¯ask was again chargedwith idoxygen.
Triethylsilane A220 mg, 1.9 mmol) was added via 1.0 mL
gas-tight syringe, andreaction mixture was stirredvigor-
ously under oxygen atmosphere at room temperature.
After 1.5 h, the solvent was evaporated under reduced
pressure. The components of the residue were separated
by column chromatography on silica gel. Elution with
diethyl ether±hexane A3:97) gave a mixture of the diene 4
and the corresponding triethylsilyl peroxide. After treatment
of the mixture with a drop of conc. HCl in methanol A5 mL),
the reaction mixture was pouredinto aqueous sodium bicar-
bonate, andextractedwith ether A30 mL £2). The combined
organic extracts were washedwith saturatedbrine, anddried
over anhydrous MgSO4. After evaporation of the solvent
under reduced pressure, the products were isolated by
column chromatography on silica gel. The diene 2c
A60 mg) was recoveredby elution with diethyl ether±hexane
A3:97). Subsequent elution with diethyl ether±hexane
A15:85) gave a ca. 2:1 mixture of the unsaturatedhydro-
peroxide 7e A120 mg, 74%). This hydroperoxide 7e was
labile even in refrigerator, anddecomposition was observed
within one week. Therefore satisfactory elemental analysis
data could not be obtained. The reduction of 7e with Ph3P
gave the corresponding alcohol, which gave satisfactory
elemental analysis.
4.3.5. 3-+1-Hydroperoxy-1-methylethyl)methylenecyclo-
hexane +7g). An oil; H NMR d 1.0±1.4 Am, 2H), 1.18 As,
3H), 1.19 As, 3H), 1.6±2.0 Am, 5H), 2.2±2.4 Am, 2H), 4.63 As,
2H), 7.41 As, 1H); 13C NMR d 21.19, 21.58, 27.01, 27.39,
34.90, 36.10, 45.66, 84.78, 107.48, 149.18.
1
4.3.6. 3-+1-Hydroperoxy-1-methylethyl)-1-methylcyclo-
hexyl hydroperoxide +7h). An oil Aa 1:1 mixture of two
stereoisomers); 1H NMR d 0.8±2.2 Am, 9H), 1.06
As)11.13 As)11.17 As)11.21 As)11.24 As)11.28 As) A9H),
7.99 As)18.13 As)18.25 As)18.26 As) A2H); 13C NMR d
20.15, 20.88, 21.17, 21.66, 21.75, 22.55, 22.99, 25.73,
26.85 A2C), 34.31, 34.34, 34.56, 35.51, 38.19, 41.17,
81.65, 83.94, 84.67, 84.75. Anal. Calcdfor C 10H20O4: C,
58.80: H, 9.87. Found: C, 58.72: H, 9.92.
4.4. Preparation of hydrazone 5
Into a 100 mL ¯ask, p-tosylhydrazine A13.0 g, 69.9 mmol)
and ethanol A20 mL) were added. The ¯ask was warmed to
40±508C, andthen the unsaturatedketone
1a A9.6 g,
70.0 mmol) was added with stirring. After stirring for
0.5 h, the reaction mixture was pouredinto water A50 mL),
andextractedwith diethyl ether A50 mL £2). The combined
organic extracts were washedwith saturatedbrine anddried
over anhydrous MgSO4. After evaporation of the solvent
under reduced pressure, recrystallization of the residue
from ethyl acetate±hexane gave the hydrazone 5 A17.7 g,
83%) as a 1:1 mixture of geometric isomers.
4.4.1. 3-+1-Methylethenyl)cyclohexanone p-tosylhydra-
zone +5). Mp 110±1158C Aethyl acetate±hexane) Aa 1:1
mixture of two stereoisomers); H NMR d 1.2±1.5 Am,
4.3.1. Ethyl 3-+1-hydroperoxy-1-methylethyl)cyclohexyl-
ideneacetate +7e). An oil Aa ca. 2:1 mixture of two stereo-
isomers); 1H NMR d 1.0±2.4 Am, 17H), 3.83 Abr t,
Jˆ12.7 Hz, 1H), 4.0±4.2 Am, 2H), 5.61 As)15.63 As,
major) A1H), 7.95 As, major)18.87 As) A1H); 13C NMR
Amajor isomer) d 14.20, 20.83, 21.91, 26.85, 27.14, 29.42,
38.53, 46.11, 59.55, 84.17, 113.71, 162.77, 166.94; the
following additional signals were assigned to the minor
isomer in 13C NMR spectrum; d 19.77, 22.59, 27.89, 28.92,
31.54, 37.83, 46.29, 59.95, 84.12, 112.09, 164.53, 167.67.
1
2H), 1.6±2.2 Am, 5H), 1.65 As)11.67 As) A3H), 2.3±2.5 Am,
1H), 2.41 As, 3H), 2.6±2.8 Am, 1H), 4.64 As, 1H), 4.68 As,
1H), 7.30 Ad, Jˆ8.1 Hz, 2H), 7.86 Ad, Jˆ8.1 Hz, 2H), 8.20
Abr s, 1H); 13C NMR d 20.52 ACH3), 20.61 ACH3), 21.44
ACH3, 2C), 24.44 ACH2), 25.39 ACH2), 26.33 ACH2), 30.24
ACH2), 30.41 ACH2), 31.59 ACH2), 34.65 ACH2), 39.89 ACH2),
44.05 ACH), 44.94 ACH), 109.27 ACH2), 109.63 ACH2),
127.87 ACH, 4C), 128.12 AC), 129.33 ACH, 4C), 129.72
AC), 135.24 AC), 143.65 AC), 147.66 AC), 148.03 AC),
161.69 AC), 161.83 AC). Anal. Calcdfor C 16H22N2SO2: C,
62.71: H, 7.24: N, 9.14: S, 10.46. Found: C, 62.57: H, 7.16:
N, 9.13: S, 10.44.
4.3.2. Ethyl 3-+1-hydroxy-1-methylethyl)cyclohexyl-
ideneacetate. An oil Aa ca. 2:1 mixture of two stereo-
1
isomers); H NMR d 1.2±2.4 Am, 18H), 3.82 Abr t, Jˆ
13.5 Hz, major)13.98 Abr t, Jˆ12.2 Hz) A1H), 4.10 Aq,
Jˆ7.2 Hz, 2H), 5.61 As, 1H); 13C NMR d 14.22 A2C),
26.51, 26.79 A2C), 26.96, 27.05 A2C), 27.30, 27.66, 29.31,
30.84, 37.58, 38.71, 50.28, 50.84, 59.44, 59.50, 72.29,
72.42, 113.28, 113.60, 162.93, 163.13, 166.74, 166.81.
Anal. Calcdfor C 13H22O3: C, 68.99: H, 9.80. Found: C,
68.68: H, 9.90.
4.5. Reduction of the hydrazone 5 to the corresponding
hydrazine 6
Into a four-necked¯ask, equippedwith two rdopping
funnels, the hydrazone 5 A3.6 g, 11.7 mmol) andbromo-
cresol green Aca. 10 mg) were added, and dissolved in
THF A50 mL) under a gentle stream of nitrogen. The exit
gases were passedthrough three Dreschel bottles Athe ®rst
bottle was empty, andthe ®nal two bottles containedan
aqueous solution of sodium hypochlorite). A solution of
sodium cyanoborohydride A3.0 g, 48.1 mmol) in THF
A60 mL) was added in one portion from one dropping
funnel. From another dropping funnel, a solution of
p-TsOH´H2O A4.5 g, 23.9 mmol) in THF A50 mL) was
added in small portions to maintain the solution at pH 3.5
Athe indicator showed a tan color). After the addition of
sodium cyanoborohydride was complete, the reaction
4.3.3. trans-1-Methyl-3-+1-methylethenyl)cyclohexyl hydro-
peroxide +trans-7c). An oil; the following signals were
assigned; H NMR d 1.25 As, 3H), 1.70 As, 3H), 4.67 As,
1
2H); 13C NMR d 20.90, 21.49, 25.66, 30.82, 33.86, 39.32,
39.68, 81.49, 108.34, 150.19.
4.3.4. cis-1-Methyl-3-+1-methylethenyl)cyclohexyl hydro-
peroxide +cis-7c). An oil; 1H NMR d 1.1±2.0 Am, 9H), 1.31
As, 3H), 1.71 As, 3H), 4.69 As, 2H), 7.61 As, 1H); 13C NMR d
20.76, 20.94, 23.13, 31.27, 34.22, 39.62, 42.28, 83.63,
108.72, 149.51.

T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
5987
mixture was stirred for additional 4 h. The white precipitate
was removedby ®ltration over Celite, andthe ®ltrate was
concentrated under reduced pressure. Water A80 mL) was
added to the residue, and extracted with CH2Cl2
A50 mL£3). The combinedorganic extracts were rdied
over anhydrous MgSO4, andevaporation of the solvent
under reduced pressure afforded the crude hydrazine 6
A3.4 g).
silica gel. Elution with diethyl ether±hexane A2:98) gave
the corresponding benzyl peroxide 8 A590 mg, 81%).
4.7.1. +1S,2R,5R)-1-Benzyldioxy-1-methoxy-2-methyl-5-
+1-methylethenyl)cyclohexane +8). An oil; 1H NMR
A400 MHz) d 1.00 Ad, Jˆ6.9 Hz, 3H, H-9), 1.19 At, Jˆ
12.9 Hz, 1H, H-6ax), 1.17 Aqd, Jˆ12.9 and4.1 Hz, 1H, H-
4ax), 1.37 Aqd, Jˆ12.9 and3.5 Hz, 1H, H-3ax), 1.5±1.6 Am,
1H, H-3eq), 1.6±1.8 Am, 2H, H-2ax and4-eq), 1.70 As, 3H,
H-12), 2.11 Att, Jˆ12.9 and 3.3 Hz, 1H, H-5ax), 2.57 Addd,
Jˆ12.9, 3.3 and2.0 Hz, 1H, H-6eq), 3.46 As, 3H, H-8), 4.67
As, 1H, H-11), 4.70 As, 1H, H-11), 5.02 As, 2H, H-7), 7.2-7.4
Am, 5H, Ph); 13C NMR A100 MHz) d 14.27 ACH3, C-9),
21.07 ACH3, C-12), 31.15 ACH2, C-4), 31.71 ACH2, C-3),
35.24 ACH2, C-6), 40.90 ACH, C-2), 41.49 ACH, C-5),
51.22 ACH3, C-8), 77.11 ACH2, C-7), 106.17 AC, C-1),
108.64 ACH2, C-11) 128.33 ACH, Ph), 128.40 ACH, Ph,
2C), 129.31 ACH, Ph, 2C), 136.06 AC, Ph), 149.69 AC,
C-10). Anal. Calcdfor C 18H26O3: C, 74.45: H, 9.02.
Found: C, 74.72: H, 9.07.
4.5.1. N-[3-+1-Methylethenyl)cyclohexyl]-N0-p-tosylhydra-
zine +6). 13C NMR d 20.69, 21.53, 24.32, 30.86, 31.04,
36.16, 43.58, 58.74, 108.46, 128.12 A2C), 129.47 A2C),
135.18, 143.88, 149.58.
4.6. Preparation of the unsaturated hydroperoxide 7d
An aqueous solution of H2O2 A30%, 250 mL) was extracted
with diethyl ether A100 mL£3) [caution!], andthe combined
organic extracts were dried over anhydrous MgSO4. About
250 mL of diethyl ether was evaporated under reduced
pressure. Then, 80 mL of THF was added, and further
80 mL of solvents was evaporated under reduced pressure.
This operation was repeatedthree times. To the cooledA0 8C)
solution of H2O2 in THF was added in turn an additional
aliquot of THF A120 mL), followed by the crude hydrazine 6
A3.4 g), and®nally an aqueous solution A10 mL) of sodium
peroxide A2.3 g, 29.0 mmol). After stirring for 30 h, the
reaction mixture was pouredinto coldwater A100 mL) and
4.8. Ozonolysis of the unsaturated hydroperoxides 7 in
TFE
The ozonolysis of the unsaturatedhyrdoperoxied
7a is
representative. Into a solution of 7a A380 mg, 2.0 mmol)
in CH2Cl2 A25 mL) and2,2,2-tri¯uoroethanol ATFE)
A5 mL) was passeda slow stream of ozone A1.5 equiv.) at
08C. The reaction mixture was pouredinto aqueous sodium
bicarbonate, andextractedwith ether A30 mL £2). The
combinedorganic layer was washedwith saturatedbrine,
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 A20:80) gave the bicyclic peroxide
9a A71 mg, 17%). Subsequent elution with A50:50) gave
the ketone 10a A160 mg, 42%).
neutralizedwith 2N HCl. After extraction with CH Cl2
2
A70 mL£3), the combinedorganic extracts were driedover
anhydrous MgSO4, andthe solvent was evaporatedunder
reduced pressure. By column chromatography on silica gel,
elution with diethyl ether±hexane A4:96) the unsaturated
hydroperoxide trans-7d was obtained®rst A460 mg, 25%).
Subsequent elution gave the unsaturatedhydroperoxide cis-
7d A700 mg, 38%).
4.6.1. trans-3-+1-Methylethenyl)cyclohexyl hydroperoxide
+trans-7d). An oil; 1H NMR d 1.3±1.8 Am, 6H), 1.70 As, 3H),
2.0±2.3 Am, 3H), 4.30 Aqi, Jˆ3.0 Hz, 1H), 4.6±4.7 Am, 2H),
8.12 As, 1H); 13C NMR d 20.99 ACH2), 21.31 ACH3), 28.54
ACH2), 31.54 ACH2), 33.80 ACH2), 39.10 ACH), 80.54 ACH),
4.8.1. 1-Methoxy-4-methyl-2,3-dioxabicyclo[3.3.1]nonan-
1
4-yl hydroperoxide +9a). An oil; H NMR d 1.2±2.5 Am,
9H), 1.47 As, 3H), 3.40 As, 3H), 8.77 As, 1H); 13C NMR d
20.33 ACH3), 21.35 ACH2), 22.99 ACH2), 31.23 ACH2), 31.95
ACH2), 39.59 ACH), 48.97 ACH3), 104.64 AC), 110.15 AC).
108.99 ACH2), 150.46 AC). Anal. Calcdfor C H16O2: C,
9
69.19: H, 10.32. Found: C, 69.10: H, 10.26.
Anal. Calcdfor C H16O5: C, 52.93: H, 7.90. Found: C,
9
52.58: H, 7.71.
4.6.2. cis-3-+1-Methylethenyl)cyclohexyl hydroperoxide
+cis-7d). An oil; H NMR d 1.0±1.4 Am, 5H), 1.70 As,
1
4.8.2. 1-+3-Hydroperoxy-3-methoxycyclohexyl)ethanone
+10a). An oil Aa 4:3 mixture of two stereoisomers); H
3H), 1.8±2.2 Am, 4H), 3.98 Att, Jˆ11.1 and4.0 Hz, 1H),
4.69 As, 2H), 8.32 As, 1H); 13C NMR d 20.72 ACH3), 23.83
ACH2), 30.01 ACH2), 30.91 ACH2), 35.35 ACH2), 43.38 ACH),
84.01 ACH), 108.81 ACH2), 149.20 AC). Anal. Calcdfor
C9H16O2: C, 69.19: H, 10.32. Found: C, 69.68: H, 10.02.
1
NMR d 1.1±2.7 Am, 9H), 2.10 As, major)12.11 As) A3H),
3.23 As)13.26 As, major) A3H), 8.75 As, major)18.95 As)
A1H); 13C NMR d 21.35, 21.75, 27.50, 28.07, 29.35,
30.46, 32.51, 32.60, 47.62, 47.67, 48.11, 48.36, 104.83,
105.67, 211.46, 211.82. Anal. Calcdfor C 9H16O4: C,
57.43: H, 8.57. Found: C, 57.20: H, 8.47.
4.7. Preparation of the benzyl peroxide 8 from the
hydroperoxide trans-7b
4.8.3. +1R,4S,5R,8S)-1-Methoxy-4,8-dimethyl-2,3-dioxa-
bicyclo[3.3.1]nonan-4-yl hydroperoxide +9b). Mp 161±
1638C Afrom ethyl acetate±hexane); H NMR d 0.81 Ad,
Jˆ4.9 Hz, 3H), 1.2±1.8 Am, 6H), 1.39 As, 3H), 2.2±2.4 Am,
2H), 3.35 As, 3H), 8.50 As, 1H); 13C NMR d 13.71 ACH3),
20.65 ACH3), 23.51 ACH2), 29.18 ACH2), 30.59 ACH2), 39.73
ACH), 40.20 ACH), 49.26 ACH3), 105.34 AC), 110.03 AC).
Into a solution of trans-7b A500 mg, 2.5 mmol) andbenzyl
bromide A430 mg, 2.5 mmol) in CH2Cl2 A10 mL), Ag2O
A580 mg, 2.5 mmol) was added. After stirring for 2.5 h,
the solidmaterial was removedby ®ltration over Celite,
and the ®ltrate was concentrated under reduced pressure.
The product was isolated by column chromatography on
1

5988
T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
Anal. Calcdfor C 10H18O5: C, 55.03: H, 8.31. Found: C,
54.95: H, 8.18.
Into a solution of 9e A120 mg, 0.64 mmol) in CH2Cl2
A10 mL), methyl iodide A200 mg, 1.4 mmol) and Ag2O
A150 mg, 0.64 mmol) was added. After stirring for 1.5 h,
the solidmaterial was removedby ®ltration over Celite,
and the ®ltrate was concentrated under reduced pressure.
The product was isolated by column chromatography on
silica gel. Elution with diethyl ether±hexane A6:94) gave
the methylatedcyclic peroxide 14e A110 mg, 85%).
4.8.4. 1-[+1R,3S,4R)-3-Hydroperoxy-3-methoxy-4-methyl-
cyclohexyl]ethanone +10b). An oil; H NMR d 0.98 Ad,
1
Jˆ6.9 Hz, 3H), 1.2±2.0 Am, 6H), 2.20 As, 3H), 2.4±2.6 Am,
1H), 2.7±2.9 Am, 1H), 3.43 As, 3H), 9.27 As, 1H); 13C NMR d
13.76 ACH3), 27.22 ACH2), 28.32 ACH3), 30.40 ACH2), 30.57
ACH2), 37.86 ACH), 47.89 ACH), 50.94 ACH3), 106.20 AC),
211.69 AC). Anal. Calcdfor C 10H18O4: C, 59.39: H, 8.97.
Found: C, 60.03: H, 9.15.
4.9.1.
4,4-Dimethyl-1-methyldioxy-2,3-dioxabicyclo-
1
[3.3.1]nonane +14e). An oil; H NMR d 1.1±2.3 Am, 9H),
1.15 As, 3H), 1.34 As, 3H), 3.91 As, 3H); 13C NMR d 20.78,
21.89, 25.48, 25.63, 29.92, 30.48, 39.10, 64.33, 82.05,
108.32. Anal. Calcdfor C 10H18O4: C, 59.39: H, 8.97.
Found: C, 59.43: H, 9.25.
4.8.5.
1,4-Dimethyl-2,3-dioxabicyclo[3.3.1]nonan-4-yl
hydroperoxide +9c). An oil Aa 1:1 mixture of two stereo-
isomers); 1H NMR d 1.0±2.4 Am, 9H), 1.08 As)11.27
As)11.42 As)11.44 As) A6H), the quite broadsignal, assigned
to the signal of the OOH, was observedat 9.2±9.7 ppm; 13C
NMR d 17.67, 19.68, 19.75, 20.42, 22.93, 26.17, 26.48,
27.03, 31.79, 33.77, 34.74, 35.37, 35.93, 37.41, 77.16,
79.12, 107.69, 109.79.
4.9.2. 1-Methoxy-4-methyl-4-methyldioxy-2,3-dioxabi-
cylo[3.3.1]nonane +14a). An oil; H NMR d 1.1±1.6 Am,
1
4H), 1.42 As, 3H), 1.8±2.0 Am, 3H), 2.0±2.2 Am, 1H), 2.3±
2.5 Am, 1H), 3.37 As, 3H), 3.96 As, 3H); 13C NMR d 20.54,
21.39, 23.09, 30.91, 32.20, 39.91, 48.93, 64.01, 104.48,
109.45. Anal. Calcdfor C 10H18O5: C, 55.03: H, 8.31.
Found: C, 55.53: H, 8.25.
4.8.6. 4-Methyl-2,3-dioxabicyclo[3.3.1]nonan-4-yl hydro-
peroxide +9d). An oil; 1H NMR d 1.2±1.6 Am, 4H), 1.47 As,
3H), 1.8±1.9 Am, 1H), 1.9±2.0 Am, 1H), 2.1±2.3 Am, 3H),
4.62 At, Jˆ4.8 Hz, 1H), 8.45 As, 1H); 13C NMR d 18.45
ACH2), 20.70 ACH3), 23.61 ACH2), 28.82 ACH2), 29.34
ACH2), 35.60 ACH), 74.64 ACH), 110.56 AC).
4.9.3. +1R,4S,5R,8S)-1-Methoxy-4,8-dimethyl-4-methyl-
dioxy-2,3-dioxabicylo[3.3.1]nonane +14b). An oil; 1H
NMR d 0.84 Ad, Jˆ6.3 Hz, 3H), 1.1±1.3 Am, 3H), 1.37 As,
3H), 1.6±1.8 Am, 3H), 2.2±2.4 Am, 2H), 3.36 As, 3H), 3.92 As,
3H); 13C NMR d 13.75, 20.87, 23.60, 28.92, 30.62, 40.02,
40.27, 49.18, 63.99, 105.12, 109.26. Anal. Calcdfor
C11H20O5: C, 56.88: H, 8.68. Found: C, 56.88: H, 8.60.
4.8.7. 1-+3-Hydroperoxycyclohexyl)ethanone +10d). An
oil; H NMR d 1.2±1.5 Am, 4H), 1.8±2.0 Am, 2H), 2.0±
1
2.1 Am, 1H), 2.20 As, 3H), 2.2±2.3 Am, 1H), 2.4±2.5 Am,
1H), 3.98 Att, Jˆ10.2 and4.0 Hz, 1H), 9.52 As, 1H); 13C
NMR d 22.75 ACH2), 27.48 ACH2), 27.85 ACH3), 29.36
ACH2), 31.39 ACH2), 49.02 ACH), 82.25 ACH), 221.89 AC).
Anal. Calcdfor C H14O3: C, 60.74: H, 8.92. Found: C,
8
60.33: H, 8.82.
4.9.4. 1,4-Dimethyl-4-methyldioxy-2,3-dioxabicylo-
[3.3.1]nonane +14c). An oil Aa 1:1 mixture of two stereo-
1
isomers); H NMR d 1.08 As)11.27 As)11.42 As)11.44 As)
A6H), 1.1±2.6 Am, 9H), 3.98 As)13.99 As) A3H); 13C NMR d
18.08, 19.79, 19.86, 20.58, 23.09, 26.35, 26.58, 26.99,
32.13, 33.96, 34.76, 35.51, 36.10, 37.74, 64.03, 64.17,
76.48, 78.46, 107.37, 109.40. Anal. Calcdfor C 10H18O4:
C, 59.39: H, 8.97. Found: C, 59.50: H, 8.91.
4.8.8. 4,4-Dimethyl-2,3-dioxabicylo[3.3.1]nonyl hydro-
peroxide +9e). An an oil; H NMR d 1.14 As, 3H), 1.3±
1
1.6 Am, 3H), 1.36 As, 3H), 1.6±2.0 Am, 3H), 2.1±2.4 Am,
3H), 8.56 As, 1H); 13C NMR d 20.88, 21.84, 25.43, 25.64,
29.40, 30.01, 39.25, 82.61, 108.79. Anal. Calcdfor
C9H16O4: C, 57.43: H, 8.57. Found: C, 57.28: H, 8.36.
4.9.5.
4-Methyl-4-methyldioxy-2,3-dioxabicylo[3.3.1]-
1
nonane +14d). An oil; H NMR d 1.2±1.6 Am, 4H), 1.39
As, 3H), 1.8±2.0 Am, 2H), 2.0±2.2 Am, 3H), 3.92 As, 3H), 4.5±
4.6 Am, 1H); 13C NMR d 18.62, 20.69, 23.78, 28.84, 29.47,
4.8.9. 4-Methoxy-4-methyl-2,3-dioxabicylo[3.3.1]nonyl
hydroperoxide +endo-9f). Mp 73±748C Afrom ethyl
35.82, 64.06, 74.43, 109.92. Anal. Calcdfor C H16O4: C,
9
57.43: H, 8.57. Found: C, 57.65: H, 8.50.
1
acetate±hexane); H NMR d 1.2±1.6 Am, 4H), 1.29 As,
3H), 1.8±2.1 Am, 3H), 2.2±2.4 Am, 1H), 2.4±2.5 Am, 1H),
3.34 As, 3H), 8.58 As, 1H); 13C NMR d 19.86 ACH3), 20.94
ACH2), 24.21 ACH2), 29.27 ACH2), 30.28 ACH2), 40.20 ACH),
49.33 ACH3), 105.88 AC), 109.11 AC). Anal. Calcdfor
C9H16O5: C, 52.93: H, 7.90. Found: C, 52.86: H, 7.76.
4.9.6. 4-Methoxy-4-methyl-1-methyldioxy-2,3-dioxabi-
cylo[3.3.1]nonane +endo-14f). An oil; H NMR d 1.2±1.6
1
Am, 4H), 1.29 As, 3H), 1.8±2.2 Am, 4H), 2.3±2.5 Am, 1H),
3.35 As, 3H), 3.96 As, 3H); 13C NMR d 19.89, 20.81, 24.21,
29.69, 30.68, 40.09, 49.24, 64.15, 105.52, 108.52. Anal.
Calcdfor C 10H18O5: C, 55.03: H, 8.31. Found: C, 55.58:
H, 8.49.
4.8.10. 4-Methoxy-4-methyl-2,3-dioxabicylo[3.3.1]nonyl
hydroperoxide +exo-9f). An oil; H NMR d 1.27 As, 3H),
1
1.3±2.0 Am, 5H), 2.1±2.3 Am, 2H), 2.4±2.6 Am, 2H), 3.34 As,
3H), 8.99 As, 1H); 13C NMR d 16.35 ACH3), 19.27 ACH2),
26.20 ACH2), 30.03 ACH2), 31.14 ACH2), 38.53 ACH), 48.48
ACH3), 103.38 AC), 106.29 AC).
4.9.7. 4-Methoxy-4-methyl-1-methyldioxy-2,3-dioxabi-
cylo[3.3.1]nonane +exo-14f). An oil; H NMR d 1.25 As,
1
3H), 1.3±2.0 Am, 5H), 2.1±2.3 Am, 2H), 2.4±2.6 Am, 2H),
3.35 As, 3H), 3.91 As, 3H); 13C NMR d 16.46, 19.37, 26.26,
30.39, 31.57, 38.53, 48.41, 64.62, 102.97, 106.36. Anal.
Calcdfor C 10H18O5: C, 55.03: H, 8.31. Found: C, 55.39:
H, 8.34.
4.9. Ag2O-Mediated methylation of the cyclic peroxides 9
The methylation of the cyclic peroxide 9e is representative.

T. Tokuyasu et al. / Tetrahedron 57 22001) 5979±5989
5989
3. Ushigoe, Y.; Torao, Y.; Masuyama, A.; Nojima, M. J. Org.
Chem. 1997, 62, 4949.
4.10. X-Ray crystallographic analysis of the endoper-
oxides endo-9f and 13
4. Aa) Fielder, S.; Rowan, D. D.; Sherburn, M. S. Tetrahedron
1998, 54, 12907. Ab) Takahashi, Y.; Ando, M.; Miyashi, T.
J. Chem. Soc., Chem. Commun. 1995, 521. Ac) Courtneidge,
J. L. J. Chem. Soc., Chem. Commun. 1992, 1270. Ad) Yoshida,
J.; Nakatani, S.; Isoe, S. Tetrahedron Lett. 1990, 31, 2425.
Ae) Jefford, C. W.; Eschenhof, H.; Bernardinelli, G. Hetero-
cycles 1998, 47, 283. Af) Clennan, E. L.; Foote, C. S. In
Organic Peroxides; Ando, W., Ed.; Wiley: New York, 1992
Chapter 6. Ag) Dussault, P. H.; Davies, D. R. Tetrahedron Lett.
1996, 37, 463. Ah) Dussault, P. H.; Lee, H.-J.; Niu, Q. J. J. Org.
Chem. 1995, 60, 784. Ai) Kumabe, R.; Nishino, H.; Yasutake,
M.; Kurosawa, K. Tetrahedron Lett. 2001, 42, 69.
Ê
The X-ray diffraction data AMo±Ka lˆ0.71073 A) were
collectedon a Bruker AXS P4 diffractometer at 160 K.
Lorrentz andpolarisation corrections were appliedto the
data. The data from compound 13 were correctedfor
absorption. The structures were solved by direct methods
andre®nedby full least-squares techniques using aniso-
tropic temperature factors for the non-hydrogen atoms. All
crystallographic calculations andpreparation of structure
plots were carriedout using the shelxtl suite of progams.17
4.10.1. Crystal data for endo-9f. C9H16O5, Mˆ204.22,
colorless block Adata crystal dimensions 0.44£0.68£
0.49 mm), monoclinic, space group P21/c ANo 14), a
Â
Aj) Boukouvalas, J.; Pouliot, R.; Frechtte, Y. Tetrahedron
Lett. 1995, 36, 1467. Ak) Xu, X.-X.; Dong, H.-H. J. Org.
Chem. 1995, 60, 3039.
Ê
8.9418A13), b 10.873 A2), c 10.3033 A19) A, b 93.175
A128), U 1000.2 A3) A , Zˆ4, Dc 1.356 g cm23, FA000)
Ê 3
5. Tokuyasu, T.; Ito, T.; Masuyama, A.; Nojima, M. Hetero-
cycles 2000, 53, 1293.
440, mAMo±Ka) 0.110 mm21, ®nal discrepancy factors:
Rˆ0.037 and wR2ˆ0.094 for I.2sAI).
6. Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J.
J. Org. Chem. 2000, 65, 1069.
4.10.2. Crystal data for 13. C11H19IO3, Mˆ326.16, color-
less block Adata crystal dimensions 0.20£0.38£0.48 mm),
monoclinic, space group P21, a 9.5581 A17), b 5.8054 A9),
c 11.9491 A19) A, b 107.613 A138), U 631.96 A18) A , Zˆ2,
Dc 1.714 g cm23, FA000) 324, mAMo±Ka) 2.521 mm21, ®nal
discrepancy factors: Rˆ0.029 and Rwˆ0.082 for I.2sAI).
7. Aa) Xu, X.-X.; Zhu, J.; Haung, D.-Z.; Zhou, W.-S. Tetrahedron
Lett. 1991, 32, 5785. Ab) Bachi, M. D.; Korshin, E. E.; Hoos,
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8. Aa) O'Neill, P. M.; Searle, N. L.; Raynes, K. J.; Maggs, J. L.;
Ward, S. A.; Storr, R. C.; Park, B. K.; Posner, G. H.
Tetrahedron Lett. 1998, 39, 6065. Ab) Bachi, M. D.; Korshin,
E. E. Synlett 1998, 122. Ac) Hofheinz, W.; BuÈrgin, H.; Gocke,
E.; Jaquet, C.; Masciadri, R.; Schmid, G.; Stohler, H.;
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9. A part of this work was publishedin a preliminary form:
Tokuyasu, A.; Masuyama, A.; Nojima, M.; Kim, H.-S.;
Wataya, Y. Tetrahedron Lett. 2000, 41, 3145.
Ê
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