Synthesis and chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols

Article abstract of DOI:10.1021/jo8020506

(Chemical Equation Presented) 1,4-Disubstituted 2,3-dioxabicyclo[2.2.2]oct- 5-enes were dihydroxylated with osmium tetroxide to yield diols anti to the peroxide linkage in a highly selective manner. Reduction of the peroxide bond furnished cyclohexane-1,2,3,4-tetraols with toxocarol relative stereochemistry in excellent yield. This new methodology was employed to synthesize the natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-tetrol (1) in a short sequence from (R)-α-phellandrene. Moreover, during the study of the chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols a hitherto unknown rearrangement was discovered which has wide applicability for the synthesis of 1,4-dicarbonyls, including optically enriched synthons. A broad range of mechanistic investigations applicable to this rearrangement are also reported.

Full text of DOI:10.1021/jo8020506

Synthesis and Chemistry of 2,3-Dioxabicyclo[2.2.2]octane-5,6-diols
Peter Valente,† Thomas D. Avery,† Dennis K. Taylor,*,‡ and Edward R. T. Tiekink§
Department of Chemistry, The UniVersity of Adelaide, South Australia 5005, Australia, Discipline of Wine
and Horticulture, The UniVersity of Adelaide, South Australia 5005, Australia, and Department of
Chemistry, The UniVersity of Texas, One UTSA Circle, San Antonio, Texas 78249-0698
dennis.taylor@adelaide.edu.au
ReceiVed September 17, 2008
1,4-Disubstituted 2,3-dioxabicyclo[2.2.2]oct-5-enes were dihydroxylated with osmium tetroxide to yield
diols anti to the peroxide linkage in a highly selective manner. Reduction of the peroxide bond furnished
cyclohexane-1,2,3,4-tetraols with toxocarol relative stereochemistry in excellent yield. This new
methodology was employed to synthesize the natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-
yl)cyclohexane-1,2,3,4-tetrol (1) in a short sequence from (R)-R-phellandrene. Moreover, during the study
of the chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols a hitherto unknown rearrangement was
discovered which has wide applicability for the synthesis of 1,4-dicarbonyls, including optically enriched
synthons. A broad range of mechanistic investigations applicable to this rearrangement are also reported.
Introduction
Cyclohexane-1,2,3,4-tetraols of the configuration in Figure
1 are relatively rare in nature except for the simple toxocarol-
like compounds such as (+)-pinitol, conduritol A, and (-)-
quebrachitol. Several more complex natural products exhibit this
toxocarol configuration such as altersolarol A,1 auxarthrol B,2
13,4 and 2,5 and many yet to be synthesized. The toxocarol
configuration also has appeared in several pharmacologically
6,7
active compounds
and as structures in the synthetic routes
to several natural products such as the otteliones8 and zeyle-
none.9
Of the compounds that have been synthesized, the general
approach has been to prepare them first by reduction of the
peroxide linkage of an appropriate 2,3-dioxabicyclo[2.2.2]oct-
5-ene 3, followed by dihydroxylation of the alkene (Scheme
† Department of Chemistry, The University of Adelaide.
‡ Discipline of Wine and Horticulture, The University of Adelaide.
§ The University of Texas at San Antonio.
(1) Stoessl, A. Can. J. Chem. 1969, 47, 777–784.
(2) Alvi, K. A.; Rabenstein, J. J. Ind. Microbiol. Biotechnol. 2004, 31, 11–
15.
(3) Jiang, H. X.; Gao, K. Chin. Chem. Lett. 2005, 16, 1217–1219.
(4) Jiang, H. X.; Li, Y.; Pan, J.; Gao, K. HelV. Chim. Acta 2006, 89, 558–
566.
FIGURE 1. Natural products displaying the toxocarol relationship of
hydroxyl groups.
1).10-14 In some cases, extra synthetic steps for protection and
deprotection of the diol (from the reduced peroxide linkage)
are employed to aid workup after dihydroxylation.6,10,12-14
(5) Iwagoe, K.; Kakae, T.; Konishi, T.; Kiyosawa, S.; Fujiwara, Y.; Shimada,
Y.; Miyahara, K.; Kawasaki, T. Chem. Pharm. Bull. 1989, 37, 124–128.
274 J. Org. Chem. 2009, 74, 274–282
10.1021/jo8020506 CCC: $40.75 2009 American Chemical Society
Published on Web 11/26/2008

2,3-Dioxabicyclo[2.2.2]octane-5,6-diols
SCHEME 1
SCHEME 3
SCHEME 2
Furthermore, it has been found that facial selectivity of dihy-
droxylation for the previous common route is extremely dependent
on the steric environment of the alkene with mixtures sometimes
observed (Scheme 1).6,7 High selectivity of dihydroxylation was
observed for 6 (R and R1 ) H). In these cases, one of the hydroxyl
groups will sit axial in the lowest-energy half-chair conformation,
thus always yielding direct dihydroxylation “trans” to the hydroxyl
groups, giving the stereochemistry of tetraol 5. When R and R1 *
H, we expect that both faces would be hindered similarly, and a
mixture of tetraols 5 and 7 would be observed, a hypothesis which
turned out to be true (vide infra). Our methodology should offer
higher and in some instances alternate facial selectivity for
dihydroxylation in an approach to cyclohexane-1,2,3,4-tetraols of
toxocarol stereochemistry.
In addition to the use of 2,3-dioxabicyclo[2.2.2]octane-5,6-
diols 4 for the synthesis of cyclohexane-1,2,3,4-tetraols 5, the
synthesis of a broad range of substituted compounds of type 4
also provided us with the opportunity to investigate an under-
explored area of 2,3-dioxabicyclo[2.2.2]oct-5-ene chemistry.
Thermal,16-18 metal catalyzed,19,20 and photo-induced electron-
transfer-assisted21,22 decomposition of bicyclic endoperoxides
have been extensively studied; however, no such possible
transformations have been investigated for 2,3-dioxabicyclo-
[2.2.2]octane-5,6-diol substrates. Consequently, we report herein
new studies on the thermal and photochemical decomposition
of systems of type 4 for the ready construction of 1,4-dicarbonyl
derivatives.
Alternatively, photooxygenation of 3,5-cyclohexadiene-1,2-diol
and subsequent reduction of the peroxide linkage represents
another route to the toxocarol configuration.10,11
We have recently published a method for the dihydroxylation
of 1,2-dioxines 8 (Scheme 2) and their application to the
synthesis of tetraols of “allitol” stereochemistry and sugars such
as (()-psicose 11 in excellent overall yields.15
With the above results in mind, we now examined an
extension to this methodology for the ready construction of
cyclohexane-1,2,3,4-tetraols 5. Thus, we felt that the dihydroxy-
lation of bicyclic systems 3 (to give 4) followed by reduction
of the peroxide bond would afford cyclohexane-1,2,3,4-tetraols
5 in a highly stereoselective manner (Scheme 1). We anticipated
that dihydroxylation would occur anti to the peroxide bond
because of the steric bulk and repulsive effect of the electro-
negative oxygen atoms on the approach of osmium tetroxide, a
hypothesis found to be true (vide infra). Moreover, it was
considered that variation of the substituents R and R1 would
have little effect on the facial selectivity of dihydroxylation as
the groups have an identical steric presence on either face of
the alkene. This method also would have the advantage of simple
purification of the tetraol with no requirements for a protection-
deprotection protocol, as highlighted previously.6,10,12-14
Results and Discussion
Dihydroxylation of 1,4-Disubstituted 2,3-Dioxabicyclo-
[2.2.2]oct-5-enes. A broad range of 2,3-dioxabicyclo[2.2.2]oct-
5-enes (3a-f) were synthesized by standard methods, featuring a
range of H, alkyl, and aryl substituents (Scheme 3 and Table 1).
Treatment of compounds 3a-h under conditions previously
identified as suitable for dihydroxylation of 1,2-dioxines15 gave
diols 4b-h in moderate to high yields as single diastereomers;
however, the reaction of 3a resulted in a complex mixture of
unidentified products (Table 1). Yields of the diols 4a-h varied
considerably because of their susceptibility to rearrangement
(6) Kelebekli, L.; Kara, Y.; Balci, M. Carbohydr. Res. 2005, 340, 1940–
1948.
(7) Mehta, G.; Ramesh, S. S. Tetrahedron Lett. 2001, 42, 1987–1990.
(8) Araki, H.; Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.; Watanabe, K.;
Abe, H.; Katoh, T. Chem.sEur. J. 2007, 13, 9866–9881.
(9) Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L. Chin.
Chem. Lett. 2004, 15, 1433–1436.
(10) Carless, H. A. J.; Busia, K. Tetrahedron Lett. 1990, 31, 1617–1620.
(11) Carless, H. A. J.; Billinge, J. R.; Oak, O. Z. Tetrahedron Lett. 1989,
30, 3113–3116.
(12) Gu¨ltekin, M. S.; C¸ elik, M.; Turkut, E.; Tanyeli, C.; Balci, M.
Tetrahedron: Asymmetry 2004, 15, 453–456.
(13) Gu¨ltekin, M. S.; Salamci, E.; Balci, M. Carbohydr. Res. 2003, 338,
1615–1619.
(16) Coughlin, D. J.; Salomon, R. G. J. Am. Chem. Soc. 1979, 101, 2761–
2763.
(17) Moore, C. G. J. Chem. Soc. 1951, 234–235.
(18) Zand, R.; Mesrobian, R. B. J. Am. Chem. Soc. 1955, 77, 6523–6524.
(19) Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1982, 104, 2024–2025.
(20) Suzuki, M.; Ohtake, H.; Kameya, Y.; Hamanaka, N.; Noyori, R. J. Org.
Chem. 1989, 54, 5292–5302.
(14) Salamci, E.; Sec¸en, H.; Su¨tbeyaz, Y.; Balci, M. J. Org. Chem. 1997,
62, 2453–2457.
(15) Robinson, T. V.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2006,
71, 7236–7244.
(21) Akaba, R.; Kiyota, Y.; Nishimoto, S.; Kamata, M. Proc.sElectrochem.
Soc. 2004, 10, 201–204.
(22) Kamata, M.; Kaneko, J.; Hagiwara, J.; Akaba, R. Tetrahedron Lett. 2004,
45, 7423–7428.
J. Org. Chem. Vol. 74, No. 1, 2009 275

Valente et al.
TABLE 1. Osmium-Catalyzed Dihydroxylation of
2,3-Dioxabicyclo[2.2.2]oct-5-enes 3a-h
SCHEME 5
entry
cyclohexadiene
3 (% yield)
4 (% yield)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
54
27
70
95
65
89
73
51
0
63
66
85
83
55
75
68
we can draw on the observation that palladium(0) can induce
fragmentation in a free radical manner of the peroxide linkage.23
Thus, we propose that homolytic cleavage of 4f followed by ꢀ
scission and intramolecular H atom abstraction affords
dicarbonyl 13. Simple intramolecular cyclization affords
hemiacetals 14 and 15. Further cyclization of 15 leads to
the observed hemiacetal 16. Coordination of Pd appears to
be assisted by the proximal methyl ester groups, giving facile
rearrangement in preference to reduction, as Pd-induced
reduction of 4d and 4g proceeded as expected. Reduction of
the peroxide linkage of 4f also was attempted using Zn in
acetic acid. No evidence for the formation of diol 5f was
found presumably because of ester hydrolysis and decom-
position to diketone 29f (Scheme 9).
12g
12h
SCHEME 4
Dihydroxylation of Heavily Substituted 2,3-Dioxabicyclo-
[2.2.2]oct-5-enes. In order to investigate a highly sterically
hindered system, peroxide 17 was used as a model system for
dihydroxylation and reduction (Scheme 7). Tetraol 19 is also a
known compound, resulting from ring opening and dihydroxy-
lation of peroxide 17.24 In complete contrast to the anti
dihydroxylation observed for our other 1,4-disubsituted 2,3-
dioxabicyclo[2.2.2]oct-5-enes, dihydroxylation of 17 proceeded
in a syn fashion to afford diol 18, which is most likely because
of the sterically restricted environment of the steroid framework.
Hydrogenation of 18 afforded the all cis tetrol 19 in excellent
to 1,4-dicarbonyl compounds and acetaldehyde, vide infra. 1,4-
Dicarbonyls made up the bulk of the remaining isolable
products.
The anticipated orientation of the diols 4a-h formed was
anti, with respect to the peroxide linkage, in all cases. This was
confirmed through two-dimensional (2D) NMR spectroscopy
and by obtaining crystal structures of diol 4h and tetraol 5d.
No evidence for the formation of the syn product was observed
in any example.
24
yield with physical data matching that previously reported.
Synthesis of Natural Product 1. Terpenoid 1 has been
reported recently to have been isolated from Eupatorium
fortunei, which has been used for a long time as a Chinese
medicine for the treatment of dropsical swelling, chills, and
fever, and as a diuretic and antipyretic.25 In order to evaluate
the dihydroxylation of compounds of type 3 in the case where
R and R1 ) H and to investigate the synthesis of reported natural
product 1, we chose to look at the dihydroxylation of 2,3-
dioxabicyclo[2.2.2]oct-5-enes derived from R-phellandrene
(20).26,27 Peroxides 21 and 22 were synthesized in 65% overall
yield from optically pure R-phellandrene (20) in a similar ratio
(2:1) as reported in the literature26 and were easily separable.
Dihydroxylation of 21 gave two peroxide isomers (23 and 24)
with the syn isomer being favored, while dihydroxylation of
22 gave only the anti diol (25) along with a significant amount
of ketone 26 as the only other isolable product (Scheme 8).
The stereochemical outcome of the dihydroxylation of 21 and
22 is explained simply by the overriding steric bulk of the
isopropyl group illustrated in Figure 2.
Synthesis of Tetraols with Toxocarol Relative Configu-
ration. To directly compare the two synthetic routes to cyclohex-
ane-1,2,3,4-tetraols outlined in Scheme 1, we chose the easily
synthesized ascaridole 3d as a model system (Scheme 4).
Given that dihydroxylation of 3d is completely facially
selective, we expected to obtain tetraol 5d in good yield after
reduction of the peroxide linkage of 4d. Tetraol 5d was obtained
in 95% isolated yield, which is in complete contrast to the
alternative method of peroxide reduction followed by dihy-
droxylation (Scheme 4). The workup of the dihydroxylation of
6d resulted in a poorly combined overall yield of 64% because
of the difficulty in separating the water soluble tetraols from
the aqueous phase with no facial selectivity. Tetraols 5d and
7d were isolated as a 1:1 mixture inseparable by column
chromatography. This demonstrates clearly that our approach
to tetraols of type 5 is superior in both yield and ease of workup.
In order to demonstrate the synthetic scope, we next examined
tetraol formation from aryl substituted diol 4g, which was
obtained from endoperoxide 3g in 73% yield (Table 1, entry
7), and subsequently reduced to give tetraol 5g in 85% yield
(Scheme 5). Consequently, both alkyl and aryl substituents can
be tolerated in the 1,4-positions.
The formation of ketone 26 may have been initiated by trace
metal catalysis. Numerous metals are known to induce the
peroxide bond cleavage of cyclic endoperoxides, followed by
Interestingly, attempted reduction of 4f with 5% Pd/C and
hydrogen in methanol resulted in the formation of bicyclic diol
16 in 35% yield with no observation of tetraol 5f (Scheme 6).
This rearrangement was due solely to the 5% Pd/C because the
same major product was observed in the same yield when the
reaction was repeated in the absence of hydrogen. While
the mechanism for the transformation of 4f into 16 is unclear,
(23) Suzuki, M.; Oda, Y.; Noyori, R. Tetrahedron Lett. 1981, 22, 4413–
4416.
(24) Rodewald, W. J.; Bon˜cza-Tomaszewski, Z. Pol. J. Chem. 1979, 53,
1679–1682.
(25) Medicine, J. C. o. N. A Dictionary of the Traditional Chinese Medicines;
People Hygene Publisher: Shanghai, 1977.
(26) Atkins, R.; Carless, H. A. J. Tetrahedron Lett. 1987, 28, 6093–6096.
(27) Turner, J. A.; Herz, W. J. Org. Chem. 1977, 42, 1895–1900.
276 J. Org. Chem. Vol. 74, No. 1, 2009

2,3-Dioxabicyclo[2.2.2]octane-5,6-diols
SCHEME 6
SCHEME 7
SCHEME 8
SCHEME 9
tetraols was assigned by 2D NMR, and the structure of 28 was
further confirmed by X-ray crystallography.
Figure 3displays the observed clear cross-peaks in the ROESY
spectrum and confirms the stereochemistry of tetraol 1.
Our synthesized tetraol 1, however, did not match the data
reported for this compound in the literature.3,4 There were a
a 1,5-hydrogen atom abstraction to yield 4-hydroxy ketones of
type 26.28,29 It is also possible that ketone byproduct, although
not isolated, may be responsible for the relatively low yields of
dihydroxylated compounds 23 and 24.
FIGURE 2. Illustration of the steric environment which directs the
dihydroxylation of 21 and 22.
The reduction of diols 23, 24, and 25 proceeded smoothly in
excellent yields providing the reported natural product 1 along
with related isomers 27 and 28. The stereochemistry of the three
(28) Suzuki, M.; Ohtake, H.; Kameya, Y.; Hamanaka, N.; Noyori, R. J. Org.
Chem. 1989, 54, 5292–5302.
(29) Kamata, M.; Kudoh, T.; Kaneko, J.-i.; Kim, H.-S.; Wataya, Y.
Tetrahedron Lett. 2002, 43, 617–620.
FIGURE 3. Through-space interactions of protons in tetraol 1.
J. Org. Chem. Vol. 74, No. 1, 2009 277

Valente et al.
1
TABLE 2. Comparison of Reported H and 13C NMR Data for 1 and for Synthesised 1 and 27 in CDCl3
carbon
1 (lit.)
δ H (J, Hz)
3.77 (t, 2.4)
1 (synthesized)
δ 1H (J, Hz)
3.77 (brs)
27 (synthesized)
1
1
δ
13C
δ
13C
δ H (J, Hz)
δ
13C
1
2
3
4
5
6
72.9
74.6
76.7
68.9
41.4
26.8
73.3
74.3
77.3
73.8
40.6
26.2
3.70 (brs)
78.1
73.0
70.6
74.3
37.9
26.4
3.69 (d, 9.3)
3.96 (dd, 11.4, 9.3)
1.97 (ddt, 11.7, 11.4, 3.0)
1.78 (m)
3.50 (d, 9.6)
3.53 (dd, 9.6, 9.6)
1.76 (m)
3.62 (brd, 7.2)
3.67 (brs)
1.77 (m)
1.78 (m)
1.78 (m)
1.70 (m)
1.39 (s)
2.30 (m)
0.92 (d, 7.2)
0.78 (d, 7.2)
1.56 (m)
1.39 (s)
2.18 (dsept, 6.6, 1.8)
0.95 (d, 6.6)
0.86 (d, 6.6)
1.41 (brt, 7.2)
1.18 (s)
2.08 (brs)
0.96 (d, 7.2)
0.87 (d, 7.2)
Me
iPr
iPr
iPr
23.9
27.8
20.9
14.9
23.7
25.6
20.8
16.0
22.8
25.5
20.9
16.9
TABLE 3. Thermal Rearrangement of
2,3-Dioxabicyclo[2.2.2]octane-5,6-diols 4b-h to Dicarbonyls 29b-h
number of noticeable differences between our tetraol 1 and that
previously reported. The melting point we obtained for our
tetraol 1 was 124-126 °C, whereas the compound reported in
the literature was an oil. In addition, our tetraol 1 was virtually
insoluble in chloroform and dichloromethane, which were the
solvents used to obtain NMR spectra and optical rotation,
respectively, for the reported literature compound. Therefore,
obtaining an optical rotation in dichloromethane for comparison
was not possible. The HRSIMS obtained for [M + H]+ of 1 by
Gao et al. was found as 205.05364 for a calculated mass peak
of C10H21O4+ 205.1434, which actually should be 205.1440. This
reported HRSIMS is outside the normal range for a match with
the calculated mass, while our value for compound 1 was within
the acceptable limits. The authors also report an IR resonance
at 1705 cm-1 in the compound characterization data which
contradicts the proposed structure. Once 1H and 13C NMR
spectra of 1 and isomer 21 were recorded in deuterated
chloroform, it was clear that the compound reported in the
literature was neither tetraol 1 nor isomer 21 (Table 2). We
were unable to obtain a good enough spectrum of 22 in
deuterated chloroform for comparison because of extremely poor
solubility. Consequently, we conclude that the reported tetraol
1 is not the compound isolated by Gao et al.
entry
diol
solvent/conditions
29 (% conversion)
1
2
3
4
5
6
7
8
4d
4d
4d
4d
4d
4d
4d
4e
4e
4e
4e
4c
4f
methanol/reflux 0.5 h
acetonitrile/reflux 2 h
ethylacetate/reflux 5.5 h
THF/reflux 16 h
benzene/reflux 16 h
DCM/reflux 24 h
neat/4 °C 1 week
acetonitrile/reflux 16 h
THF/reflux 16 h
DCM/reflux 16 h
neat/4 °C 48 h
acetonitrile/reflux 16 h
acetonitrile/reflux 16 h
acetonitrile/reflux 16 h
acetonitrile/reflux 16 h
100
100
100
100
0
0
25
100
50
0
100
100
100
100
100
9
10
11
12
13
14
15
4g
4h
SCHEME 10
Facile Rearrangement of 2,3-Dioxabicyclo[2.2.2]octane-
5,6-diols to 1,4-Dicarbonyls. As previously mentioned, the
stability of diols of type 4 was found to be extremely variable
during their formation and upon isolation (Table 1). Upon closer
examination, we found that diols of type 4 will undergo an
extremely clean thermal rearrangement to their 1,4-dicarbonyls
29 and glycoaldehyde (31) (Scheme 9), a rearrangement not
previously reported in the literature. (Note: glycoaldehyde was
detected as the dimeric and polymeric species by NMR.) We
examined this rearrangement for a range of peroxide diols 4b-h
under a variety of conditions as summarized in Table 3. It was
found that the thermally induced rearrangement of diols 4b-h
to dicarbonyls 29b-h proceeds quantitatively in acetonitrile and
can tolerate a broad range of substituents. Comparison of Table
3, entries 1-7 or 8-11, clearly indicates that the reaction rate
increases with solvent polarity.
It has been reported previously that thermal decomposition of
2,3-dioxabicyclo[2.2.2]octane proceeds in a radical manner involv-
ing first the homolytic cleavage of the peroxide linkage followed
by ꢀ scission.30 This process affords a range of products via a polar
transition state, with the rate-determining step being accelerated
with increasing solvent polarity and H-bonding ability. Moreover,
it has been demonstrated that ꢀ scission is the rate-determining
step in the decomposition of alkoxy radicals, which are generated
from homolytic cleavage of dialkylperoxides, and is accelerated
again with increasing solvent polarity and H-bonding ability.31
Therefore, mechanistically we propose that the rearrangement of
2,3-dioxabicyclo[2.2.2]octane-5,6-diols proceeds via the mechanism
outlined in Scheme 10.
To further confirm that decomposition was a radical process,
4d was heated in isopropanol, which is a solvent well-known
to inhibit free radical processes by competition via radical
abstraction of a hydrogen atom from isopropanol to give
acetone.19,20 Indeed, tetraol 5d (Scheme 4) was now isolated
in 30% yield, with the remainder of the yield being 1,4-diketone
29d, confirming the free radical nature of these rearrangements.
Concern about the stability of the 2,3-dioxabicyclo[2.2.2]octane-
5,6-diols 4b-h led us to investigate protection of the diol moiety
of 4d as the acetonide, a technique which previously allowed
stabilization of dihydroxylated 1,2-dioxines.15 Furthermore, this
would allow us to examine the importance of the “free” hydroxyl
(30) Coughlin, D. J.; Brown, R. S.; Salomon, R. G. J. Am. Chem. Soc. 1979,
101, 1533–1539.
(31) Tsentalovich, Y. P.; Kulik, L. V.; Gritsan, N. P.; Yurkovskaya, A. V.
J. Phys. Chem. A 1998, 102, 7975–7980.
278 J. Org. Chem. Vol. 74, No. 1, 2009

2,3-Dioxabicyclo[2.2.2]octane-5,6-diols
SCHEME 11
SCHEME 12
formed as opposed to dialdehyde 34 because of the orientation
of the hydroxyl group and its proximity to the oxygen-centered
radical, resulting from homolytic cleavage. Confirmation of the
structures was made by examining the clear cross-peaks in the
ROESY spectrum (see compounds 38, 39, and 42 in Scheme
13).
groups on the outcome of the radical rearrangement. Acetonide
33 showed no signs of decomposition in refluxing acetonitrile
over 16 h, whereas the unprotected diol 4d showed complete
conversion within 2 h (Scheme 11). Thus, under thermal
conditions, the free hydroxyl groupings are vital for rearrange-
ment to occur.
Interestingly, under photolytic conditions, both the protected
(33) and unprotected (4d) diol underwent complete conversion
to dicarbonyl 29d in 4 h in refluxing dichloromethane, conditions
under which 4d is stable in the absence of light (compare with
Table 3, entry 6). To the best of our knowledge, this is the first
example of unassisted photolytic decomposition of 2,3-
dioxabicyclo[2.2.2]octanes, although ascaridole 3d has been
decomposed in this fashion32 along with many other acyclic
peroxides and hydroperoxides.33 The identical rates obtained
for photolytic decomposition of 4d and 33 and different rates
for their thermal decomposition can be explained by the fact
that photodissociation of the peroxide linkage initially affords
an excited dialkoxy radical, which undergoes decomposition via
ꢀ scission in an “early vibration” as opposed to thermal
decomposition, which is reversible.33
Synthesis of Optically Pure 1,4-Dicarbonyl Compounds.
Formation of 1,4-dicarbonyl compounds in this fashion opens
the opportunity for the synthesis of dicarbonyls containing other
stereochemical features such as chiral centers. As an example,
photooxidation and dihydroxylation of 22 provided 25. Heating
of 25 in acetonitrile under reflux followed by in situ trapping
of dialdehyde 34 with ethyl (triphenyl-λ5-phosphanylidene)
acetate afforded diester 35 in 90% yield (Scheme 12).
Diol Orientation with Respect to the Peroxide Bond
and Its Influence on Radical Rearrangement. Given that we
now have shown that anti diol 25 afforded dicarbonyl 34, and
that we also had the syn diastereomer 26 of R-phellandrene-
derived diol 22 in hand, this provided us with a unique
opportunity to examine the relationship of the peroxide bond
to the diol on product outcome during thermolysis (Scheme 13).
Thermal decomposition of 22 in acetonitrile under reflux resulted
in the formation of a 1:1 mixture of anomers 38 and 39, along
with bicyclic hemiacetal 42, with no dialdehyde 34 being
formed. Anomers 38 and 39 were heated under reaction
conditions and did not give rise to compound 42. The formation
of the mixture of anomers, 38 and 39, and 42 is rationalized
from intramolecular hydrogen atom abstraction of different chair
conformations of diradical 36 (Scheme 13). These compounds
Conclusion
Herein, we have demonstrated an alternative route to cyclo-
hexane-1,2,3,4-tetraols of toxocarol relative stereochemistry. The
method has higher selectivity in cases where the parent 2,3-
dioxabicyclo[2.2.2]oct-5-ene has functionality other than H at
the bridgehead position. The alternative route also allows for a
simplified workup, and the necessity in some literature proce-
dures for a protection-deprotection protocol is removed. Our
application of dihydroxylation of 2,3-dioxabicyclo[2.2.2]oct-5-
enes to the synthesis of tetraols 1, 27, and 28 demonstrated that
1 was not the natural product isolated by Gao et al. nor was it
the configuration of tetraols 27 or 28. We also have touched on
potential routes into stereochemically specific-substituted di-
carbonyl compounds and presented a mechanistic explanation
for the susceptibility of 2,3-dioxabicyclo[2.2.2]oct-5,6-diols to
rearrange to 1,4-dicarbonyl compounds.
Experimental Section
Compounds 3a,34 3d,35 12b,36 12c,37 12g,38 12h,39 21,27 and
2227 showed H NMR spectra identical to the literature.
1
General Procedure for the Synthesis of Endoperoxides. A
solution of the appropriate 1,3-diene (∼1 g) in CH2Cl2 (60 mL/g)
was photolyzed with 3 × 500 W halogen lamps in the presence of
Rose Bengal bis(triethylammonium) salt (100 mg) and oxygen until
a reaction was determined by TLC. The reaction was performed in
a flask fitted with an external cooling jacket. The solution was
concentrated in vacuo, and the resulting residue was purified by
flash chromatography.
(()-(1R,4S)-1-Phenyl-2,3-dioxabicyclo[2.2.2]oct-5-ene (3b):
yield 27%, colorless solid; mp 50-52 °C; Rf 0.48 (1:4 ethylacetate/
hexane); 1H NMR (300 MHz, CDCl3) δ 1.55-1.69 (m, 1H),
1.76-1.90 (m, 1H), 2.38-2.49, (m, 2H), 4.71-4.82 (m, 1H),
(34) Spivey, A. C.; Manas, C. G.; Mann, I. Chem. Commun. (Cambridge,
U.K.) 2005, 4426–4428.
(35) Fuchter, M. J.; Hoffman, B. M.; Barrett, A. G. M. J. Org. Chem. 2006,
71, 724–729.
(36) Reich, H. J.; Wollowitz, S. J. Am. Chem. Soc. 1982, 104, 7051–7059.
(37) Brady, W. T.; Norton, S. J.; Ko, J. Synthesis 1985, 704–705.
(38) Dale, J.; Kristiansen, P. O. Acta Chem. Scand. 1971, 25, 359–360.
(39) del Pilar Crespo, M.; Avery, T. D.; Hanssen, E.; Fox, E.; Robinson,
T. V.; Valente, P.; Taylor, D. K.; Tilley, L. Antimicrob. Agents Chemother. 2008,
52, 98–109.
(32) Russell, K. E.; Tobolsky, A. V. J. Am. Chem. Soc. 1954, 76, 395–399.
(33) Calvert, J. G.; Pitts, J. N., Jr. Photochemistry; John Wiley and Sons,
Inc: New York, 1966.
J. Org. Chem. Vol. 74, No. 1, 2009 279

Valente et al.
SCHEME 13
6.71-6.83 (m, 2H), 7.30-7.49 (m, 5H); 13C NMR (75 MHz,
CDCl3) 23.4, 27.9, 71.3, 78.0, 126.2, 128.5, 128.7, 132.9, 136.1,
140.0; IR (solid) 2932, 1493, 1447, 1016, 919, 695 cm-1; MS m/z
(+EI) 188 (M+, 4), 115 (15), 105 (100), 77 (33); HRMS (+EI) (M
+ Na)+ found 211.0723, (M + Na)+ calcd for C12H12O2Na,
211.0735.
was removed in vacuo, and the aqueous layer was extracted with
ethyl acetate. The combined organics were dried (MgSO4) and
filtered, and the solvent was removed in vacuo. The crude product
was purified by flash chromatography.
(()-(1S,4S,5S,6R)-1-Phenyl-2,3-dioxabicyclo[2.2.2]octane-5,6-
diol (4b): yield 63%, colorless solid; Rf 0.14 (3:7 ethylacetate/
hexane); 1H NMR (300 MHz, CDCl3) δ 2.06-2.29 (m, 3H),
2.46-2.57 (m, 1H), 2.68, (br, 1OH), 3.13 (br, 1OH), 4.28 (m, 2H),
4.47 (dd, 1H, J ) 7.5, 4.8 Hz), 7.30-7.50 (m, 5H); 13C NMR (75
MHz, CDCl3) 18.9, 22.4, 65.2, 69.6, 75.0, 80.3, 126.0, 128.3, 128.6,
128.8. Compound was too unstable to obtain HRMS or melting
point.
1,4-Dimethyl-2,3-dioxabicyclo[2.2.2]oct-7-ene (3c): yield 70%,
1
pale yellow oil; Rf 0.44 (1:4 ethylacetate/hexane); H NMR (300
MHz, CDCl3) δ 1.38 (s, 6H), 1.47-1.59 (m, 2H), 1.97-2.13 (m,
2H), 2.99 6.38 (s, 2H); 13C NMR (75 MHz, CDCl3) 21.6, 30.0,
74.8, 136.0; IR (neat) 2932, 1452, 1380, 1052, 874, 699 cm-1
;
HRMS (+EI) (M)+ found 140.0839, (M)+calcd for C8H12O2,
140.0837.
(1R,4S,5S,6R)-1,4-Dimethyl-2,3-dioxabicyclo[2.2.2]octane-5,6-
diol (4c): yield 66%, white needles; mp 38-40 °C; Rf 0.3 (2:3
ethylacetate/hexane); 1H NMR (300 MHz, CDCl3) δ 1.18 (s, 6H),
1.72 (dd, 2H, J ) 13.5, 5.4 Hz), 2.00 (dd, 2H, J ) 13.2, 5.4 Hz),
2.99 (br, 2OH), 3.92 (s, 2H); 13C NMR (75 MHz, CDCl3) 21.7,
24.5, 69.5, 77.5. IR (neat) 3415, 3266, 2934, 1453, 1370, 1062,
980, 864, 652 cm-1; HRMS (+EI) (M - H)- found 173.0821, (M
- H)-calcd for C8H13O4, 173.0819.
(()-Methyl-3-(4-methyl-2,3-dioxabicyclo[2.2.2]oct-7-en-1-yl)-
propanoate (3e): yield 65%, colorless oil; Rf 0.29 (1:4 ethylacetate/
1
hexane); H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 1.44-1.57
(m, 2H), 1.97-2.17, (m, 4H), 2.39-2.57 (m, 2H), 3.69 (s, 3H),
6.42 (s, 2H); 13C NMR (75 MHz, CDCl3) 21.3, 28.1, 28.2, 29.5,
30.2, 51.7, 74.8, 76.2, 133.8, 136.6, 173.5; IR (neat) 1737, 1637,
1438, 1378, 1197, 1172, 883 cm-1; MS m/z (+EI) 211 (M+, 4),
181 (100), 148 (38), 123 (60), 106 (46); HRMS (+EI) (M + Na)+
found 235.0948, (M + Na)+calcd for C11H16O4Na, 235.0946.
Dimethyl 2,2′-[(1R,4S)-2,3-dioxabicyclo[2.2.2]oct-5-ene-1,4-
diyl]diacetate (3f): yield 89%, colorless solid; mp 32-34 °C; Rf
0.50 (1:1 ethylacetate/hexane); 1H NMR (300 MHz, CDCl3) δ
1.66-1.82 (m, 2H), 2.06-2.22 (m, 2H), 2.65 (d, 2H, J ) 15.0
Hz), 2.73 (d, 2H, J ) 15.0 Hz), 3.71 (s, 6H), 6.70 (s, 2H); 13C
NMR (75 MHz, CDCl3) 27.9, 39.5, 52.1, 75.7, 134.0, 169.4; IR
(solid) 2955, 1725, 1436, 1295, 1151, 1006, 698 cm-1; HRMS
(+EI) (M + Na)+ found 279.0853, (M+Na)+calcd for C12H16O6Na,
279.0853.
(()-(1R,4R,5S,6R)-1-Isopropyl-4-methyl-2,3-dioxabicyclo[2.2.2]-
octane-5,6-diol (4d): yield 85%, colorless oil; Rf 0.25 (3:7 ethy-
1
lacetate/hexane); H NMR (300 MHz, CDCl3) δ 0.97 (d, 3H, J )
6.9 Hz), 0.99 (d, 3H, J ) 6.9 Hz), 1.17 (s, 3H), 1.66-1.74 (m,
1H), 1.80 (sept, 1H, J ) 6.9 Hz), 1.85-2.05 (m, 3H), 3.00 (br s,
2OH), 3.91 (dd, 1H, J ) 7.8, 1.5 Hz), 4.19 (dd, 1H, J ) 7.8, 1.5
Hz); 13C NMR (75 MHz, CDCl3) 16.6, 16.9, 20.9, 21.2, 24.6, 33.1,
67.0, 69.8, 76.8, 80.6; IR (neat) 3437, 1454, 1388, 1371, 1085,
1019 cm-1; HRMS (+EI) (M + Na)+ found 225.1102, (M +
Na)+calcd for C10H18O4Na, 225.1103.
(()-Methyl-3-[(1S,4S,5R,6S)-5,6-dihydroxy-4-methyl-2,3-di-
oxabicyclo [2.2.2]octan-1-yl]propanoate (4e): yield 83%, colorless
oil; Rf 0.30 (1:1 ethylacetate/hexane); 1H NMR (300 MHz, CDCl3)
δ 1.17 (s, 3H), 1.62-1.83 (m, 3H), 1.91-2.09, (m, 3H), 2.34-2.58
(m, 2H), 3.65 (br, 2OH), 3.70 (s, 3H), 3.88 (dd, 1H, J ) 8.2, 1.5
Hz) 3.94 (dd, 1H, J ) 8.2, 1.5 Hz); 13C NMR (75 MHz, CDCl3)
General Procedure for the Synthesis of syn Diols. To a solution
of endoperoxide (3 mmol) and citric acid (6 mmol) in tert-butanol/
H2O (1:1) was added potassium osmate dihydrate (0.03mmol)
followed by 4-methylmorpholine N-oxide (3 mmol). The reaction
was stirred at 50 °C until TLC was determined. The tert-butanol
280 J. Org. Chem. Vol. 74, No. 1, 2009

2,3-Dioxabicyclo[2.2.2]octane-5,6-diols
1
21.4, 23.2, 24.3, 27.1, 29.4, 52.0, 66.4, 69.1, 77.7, 78.0, 175.1; IR
(neat) 3468, 2936, 1731, 1441, 1105 cm-1; MS m/z (+EI) 248 (M+,
5), 230 (19), 178 (39), 167 (53), 133 (65), 118 (42), 65 (39), 48
(100). HRMS (+EI) (M)+ found 246.1102, (M)+calcd for C11H18O6,
246.1103.
Dimethyl 2,2′-[(1R,4S,5R,6S)-5,6-dihydroxy-2,3-dioxabicyclo-
[2.2.2]octane-1,4-diyl]diacetate (4f): yield 55%, white solid; mp
92-94 °C; Rf 0.45 (4:1 ethylacetate/hexane); 1H NMR (300 MHz,
CDCl3) δ 1.82-1.98 (m, 2H), 2.09-2.26 (m, 2H), 2.55 (d, 2H, J
) 14.7 Hz), 2.59 (d, 2H, J ) 14.7 Hz), 3.71 (s, 6H), 4.22 (s, 2H),
4.72 (br, 2OH); 13C NMR (75 MHz, CDCl3) 23.4, 40.3, 52.4, 68.0,
78.6, 170.6; IR (solid) 3394, 3251, 2957, 2938, 1729, 1440, 1348,
1299, 1212, 1172, 1090, 1014, 955, 714 cm-1; MS m/z (+EI) 290
(M+, <1), 193 (15), 183 (60), 151 (58), 145 (100), 91 (39), 85
(35); HRMS (+EI) (M + Na)+ found 313.0901, (M+Na)+calcd
for C12H18O8Na, 313.0899.
ethylacetate/hexane); H NMR (600 MHz, CDCl3) δ 0.91 (d, 3H,
J ) 6.6 Hz), 0.98 (d, 3H, J ) 6.6 Hz), 1.49 (s, 3H), 1.60 (ddddd,
1H, J ) 10.8, 9.6, 7.8, 3.0, 2.4 Hz), 1.71 (ddd, 1H, J ) 13.8, 7.8,
3.0, Hz), 1.80 (ddsept, 1H, J ) 9.6, 6.6, 1.2 Hz), 2.27 (dddd, 1H,
J ) 13.8, 10.8, 3.0, 1.2 Hz), 2.52 (br, 1OH), 2.95 (br, 1OH), 3.89
(ddd, 1H, J ) 3.0, 3.0, 3.0 Hz), 3.92 (d, 1H, J ) 3.6 Hz) 4.00 (dd,
1H, J ) 3.6, 2.4 Hz); 13C NMR (75 MHz, CDCl3) 20.0, 20.2, 25.4,
26.2, 29.6, 33.7, 68.4, 70.6, 76.9, 79.0; IR (neat) 3415, 2961, 1370,
1078, 980, 940, 735 cm-1; HRMS (+EI) (M + H)+ found 203.1283,
(M + H)+calcd for C10H19O4, 203.1285.
(2R,3R,4S,5R)-2,3,4-Trihydroxy-2-methyl-5-(propan-2-yl)cy-
clohexanone methane (26): yield 22%, pale yellow solid; mp
72-74 °C; Rf 0.30 (1:1 ethylacetate/hexane); 1H NMR (600 MHz,
CDCl3) δ 0.94 (d, 3H, J ) 6.0 Hz), 1.01 (d, 3H, J ) 6.0 Hz), 1.52
(s, 3H), 1.80 (m, 1H), 1.85 (m, 1H), 2.44 (dd, 1H, J ) 13.2, 3.6
Hz), 2.70 (t, 1H, J ) 13.2 Hz), 3.93 (d, 1H, J ) 2.4 Hz), 4.27 (brs,
1H); 13C NMR (75 MHz, CDCl3) 20.6, 20.7, 24.1, 28.8, 36.1, 45.6,
69.3, 77.5, 79.4, 213.8.; IR (nujol) 3436, 1715, 1135, 1040, 948,
736 cm-1; HRMS (+EI) (M + H)+, found 203.1283, (M +
H)+calcd for C10H19O4, 203.1283.
General Methods for Peroxide Reduction. Method A. To a
stirred solution of endoperoxide (1 mmol) in methanol (5 mL) was
added 10% w/w of 5% palladium on carbon, and the mixture was
stirred under a hydrogen atmosphere until TLC was completed.
The suspension was then filtered through kenite and washed with
methanol, and the solvent was removed in vacuo to give crude
tetraol. The crude product was purified by flash column chroma-
tography or recrystallization.
Method B. To a stirred solution of endoperoxide (1 mmol) in
acetic acid (5 mL) was added zinc dust (5 mmol), and the mixture
was stirred for 24 h. The acetic acid was removed in vacuo, and
the solids were triturated with THF to give crude tetraol. The crude
product was purified by flash column chromatography or recrys-
tallization.
(1R,4S,5R,6S)-1,4-Diphenyl-2,3-dioxabicyclo[2.2.2]octane-5,6-
diol (4g): yield 65%, white solid; mp 138-140 °C; Rf 0.48 (2:3
1
ethylacetate/hexane); H NMR (200 MHz, CDCl3) δ 2.24-2.35
(m, 2H), 2.63-2.73 (m, 2H), 2.76 (br, 2OH), 4.47 (s, 2H),
7.35-7.46 (m, 6H), 7.51-7.57 (m, 4H); 13C NMR (75 MHz,
CDCl3) 24.7, 70.7, 81.1, 126.3, 128.8, 139.7, 199.0; IR (solid) 3366,
2943, 1497, 1447, 1100, 748, 695 cm-1; MS m/z (+EI) 296 (M+,
<1), 238 (30), 133 (24), 105 (100), 77 (37); HRMS (+EI) (M +
Na)+ found 321.1109, (M + Na)+calcd for C18H18O4Na, 321.1103.
(1R,4S,5R,6S)-1,4-Bis(4-fluorophenyl)-2,3-dioxabicyclo[2.2.2]-
octane-5,6-diol (4h): yield 68%, white solid; mp 120-122 °C; Rf
0.54 (2:3 ethylacetate/hexane); 1H NMR (300 MHz, CDCl3) δ
2.26-2.34 (m, 2H), 2.55-2.71 (m, 2H), 2.72 (br, 2OH), 4.43 (s,
2H), 7.06-7.11 (m, 4H), 7.48-7.53 (m, 4H); 13C NMR (75 MHz,
CDCl3): 24.7, 70.5, 80.8, 115.7 (d, J ) 21.0 Hz), 128.2 (d, J ) 8.3
Hz), 135.4, 163.0 (d, J ) 246.4 Hz); IR (nujol) 3484, 3379, 1598,
1505, 1462, 1377, 1230, 1160, 1107, 1092, 1005, 957, 837, 814
cm-1. Anal. Calcd for C18H16F2O4: C, 64.67; H, 4.82. Found: C,
64.66; H, 4.96.
(1S,2R,3S,4R,5R)-2-Methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-
tetrol (1): yield 92%, white solid; mp 124-126 °C (DCM); Rf 0.40
(1:9 methanol/ethylacetate); H NMR (600 MHz, CD3OD) δ 0.82
(d, 3H, J ) 6.6 Hz), 0.92 (d, 3H, J ) 6.6 Hz), 1.30 (s, 3H),
1.43-1.50 (m, 1H), 1.66-1.74 (m, 2H), 2.19 (dsept, 1H, J ) 6.6,
1.8 Hz), 3.35 (d, 1H, J ) 9.0 Hz), 3.46 (dd, 1H, J ) 9.0, 9.0 Hz),
3.59 (brt, 1H); 13C NMR (75 MHz, CD3OD) 16.7, 21.9, 24.4, 27.1,
27.2, 42.7, 74.2, 75.5, 76.2, 78.6; IR (solid) 3374, 2954, 1363, 1225,
1031 cm-1; HRMS (+EI) (M-H)- found 203.1289, (M - H)-calcd
for C10H19O4, 203.1289.
(3ꢀ,5r,6r,7r,8r)-6,7-Dihydroxycholestan-3-yl acetate (18):
1
yield 66%, white crystals; mp 174-176 °C (ethanol) Rf 0.70 (1:1
1
ethylacetate/hexane); H NMR (300 MHz, CDCl3) δ 0.85 (d, 3H,
J ) 0.9 Hz), 0.87 (d, 3H, J ) 0.9 Hz), 0.90 (d, 3H, J ) 6.6 Hz),
0.91 (s, 3H), 1.03 (s, 3H), 1.04-1.96 (m, 24H), 2.0 (s, 3H),
2.13-2.30 (m, 1H), 2.92 (brs, 2OH), 3.76 (d, 1H, J ) 7.8 Hz),
4.21 (d, 1H, J ) 7.8 Hz), 4.76 (tt, 1H, J ) 4.5, 11.7 Hz); 13C
NMR (75 MHz, CDCl3) 12.6, 17.5, 18.6, 20.4, 21.2, 22.0, 22.5,
22.8, 23.7, 25.9, 27.9, 28.2, 33.4, 33.8, 35.4, 35.9, 36.0, 39.4, 39.8,
44.2, 51.8, 55.7, 56.5, 66.9, 68.9, 69.3, 82.7, 83.4, 170.1; IR (solid)
3476, 2930, 1726, 1366, 1244, 1115, 1058, 1029 cm-1. Anal. Calcd
for C29H48O6: C, 70.70; H, 9.82. Found: C, 70.75; H, 9.79.
(1R,4S,5R,6R,7R)-5-Methyl-7-(propan-2-yl)-2,3-dioxabicyclo-
[2.2.2]octane-5,6-diol (23): yield 31%, colorless oil; Rf 0.30 (2:3
(1S,2S,3R,4S)-1-Methyl-4-(propan-2-yl)cyclohexane-1,2,3,4-
tetrol (5d): yield 95%, white solid; mp 122-124 °C (DCM); H
1
NMR (300 MHz, CDCl3) δ 0.88 (d, 3H, J ) 6.9 Hz), 0.93 (d, 3H,
J ) 6.9 Hz), 1.26 (s, 3H), 1.42-1.55 (m, 2H), 1.58-1.70 (m, 1H),
1.75-2.0 (m, 2H), 3.71-3.73 (m, 1H), 3.78 (d, 1H, J ) 3.6 Hz),
4.88 (s, 4OH); 13C NMR (75 MHz, CD3OD) 16.6, 16.7, 21.9, 29.5,
34.1, 35.3, 74.3, 75.0, 76.2, 76.6; IR (solid) 3482, 3375, 2959, 1454,
1368, 1164, 1088, 989, 694 cm-1. Anal. Calcd for C10H20O4: C,
58.80; H, 9.87. Found: C, 58.66; H, 9.65.
1
ethylacetate/hexane); H NMR (600 MHz, CDCl3) δ 0.96 (d, 3H,
J ) 6.6 Hz), 0.97 (d, 3H, J ) 6.6 Hz), 1.30-1.35 (m, 4H), 1.40
(ddsept, 1H, J ) 10.8, 6.6, 0.6, Hz), 1.91 (dddd, 1H, J ) 10.8,
10.2, 8.4, 2.4 Hz), 2.40 (dddd, 1H, J ) 14.4, 10.2, 6.0 Hz),
3.45-3.52 (m, 3H), 3.92 (dd, 1H, J ) 6.0, 2.4 Hz) 4.08 (dd, 1H,
J ) 2.4, 1.8 Hz); 13C NMR (75 MHz, CDCl3) 20.3, 20.4, 23.0,
27.1, 30.8, 40.8, 68.0, 69.4, 78.7, 82.0; IR (neat) 3431, 2960, 1387,
1370, 1094, 963, 733 cm-1; HRMS (+EI) (M + H)+ found
203.1287, (M + H)+calcd for C10H19O4, 203.1283.
(1R,2S,3R,4S)-1,4-Diphenylcyclohexane-1,2,3,4-tetrol (5g):
yield 85%, white solid; mp 162-164 °C (DCM); H NMR (200
1
MHz, CD3OD) δ 2.04-2.20 (m, 2H), 2.53-2.69 (m, 2H), 4.15 (s,
2H), 7.15-7.36 (m, 6H), 7.69-7.7.76 (m, 4H); 13C NMR (75 MHz,
CD3OD) 33.1, 76.3, 78.3, 127.9, 128.7, 146.7; IR (nujol) 3581,
3541, 3469, 3434, 1308, 1234, 787, 700 cm-1; HRMS (+EI) (M
- H)+ found 299.1281, (M - H)+calcd for C18H19O4, 299.1283.
Dimethyl 2,2′-(3,4-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-
1,5-diyl)diacetate (16): yield 35%, colorless oil; Rf 0.40 (4:1
(1R,4S,5S,6S,7R)-5-Methyl-7-(propan-2-yl)-2,3-dioxabicyclo-
[2.2.2]octane-5,6-diol (24): yield 6%, colorless oil; Rf 0.50 (2:3
1
ethylacetate/hexane); H NMR (300 MHz, CDCl3) δ 0.91 (d, 3H,
J ) 6.0 Hz), 0.97 (d, 3H, J ) 6.0 Hz), 1.50 (s, 3H), 1.77-1.91 (m,
4H), 2.15-2.32 (m, 1H), 3.07 (s, 1OH), 3.20 (d, 1OH, J ) 6.0
1
ethylacetate/hexane); H NMR (600 MHz, CDCl3) δ 1.60-1.68
Hz), 3.88-3.95 (m, 2H), 4.23 (ddd, 1H, J ) 2.4, 2.4, 4.8 Hz); 13
C
(m, 1H), 1.69-1.75 (m, 2H), 1.84-1.90 (m, 1H), 2.57 (d, 1H, J )
16.2 Hz), 2.86 (d, 1H, J ) 16.2 Hz), 2.88 (d, 1H, J ) 16.2 Hz),
2.90 (d, 1H, J ) 16.2 Hz), 3.71 (s, 3H), 3.72 (s, 3H), 4.06 (s, 1OH),
4.15 (s, 1H), 4.32 (d, 1OH, J ) 9.6 Hz), 5.65 (d, 1H, J ) 9.6 Hz);
13C NMR (75 MHz, CDCl3) 30.2, 31.7, 39.7, 40.0, 51.7, 67.0, 85.4,
95.6, 107.1, 169.5, 173.1; IR (solid) 3456, 2955, 1728, 1439, 1206,
NMR (75 MHz, CDCl3) 20.4, 21.2, 24.8, 27.0, 31.1, 40.5, 67.3,
71.8, 75.1, 78.8; HRMS (+EI) (M + H)+ found 203.1288, (M +
H)+calcd for C10H19O4, 203.1285.
(1S,4R,5R,6R,7R)-5-Methyl-7-(propan-2-yl)-2,3-dioxabicyclo-
[2.2.2]octane-5,6-diol (25): yield 48%, colorless oil; Rf 0.44 (2:3
J. Org. Chem. Vol. 74, No. 1, 2009 281

Valente et al.
1167, 1042 cm-1; HRMS (+EI) (M + Na)+ found 313.0887, (M
+ Na)+calcd for C12H18O8Na, 313.0899.
Diethyl (2E,4R,6E)-4-(Propan-2-yl)octa-2,6-dienedioate (35).
The dialdehyde decomposition product 34 was trapped by the
addition of ethyl (triphenyl-λ5-phosphanylidene) acetate (1 g, 2.9
mmol) to a solution of 25 (140 mg, 0.69 mmol) in acetonilrile (10
mL). The solution was boiled under reflux for 30 min. The resulting
product was purified by flash chromatography: yield 90%, slightly
yellow oil; Rf 0.25 (1:9 ethylacetate/hexane); 1H NMR (300 MHz,
CDCl3) δ 0.87 (d, 3H, J ) 6.6 Hz), 0.93 (d, 3H, J ) 6.6 Hz), 1.28
(t, 3H, J ) 7.2 Hz), 1.30 (t, 3H, J ) 7.2 Hz), 1.74 (septd, 1H, J )
6.6, 1.2 Hz), 2.12-2.46 (m, 3H), 4.18 (q, 2H, J ) 7.2 Hz), 4.19
(3ꢀ,5r,6r,7r,8r)-5,6,7,8-Tetrahydroxycholestan-3-yl acetate
(19): yield 96%, white crystals; mp 218-220 °C (ethanol) Rf 0.50
(1:1 ethylacetate/hexane); 1H NMR (300 MHz, CDCl3) δ 0.78 (s, 3H),
0.85 (d, 3H, J ) 1.2 Hz), 0.88 (d, 3H, J ) 1.2 Hz), 0.92 (d, 3H, J )
6.6 Hz), 1.08 (s, 3H), 1.04-1.96 (m, 24H), 2.03 (s, 3H), 2.13-2.30
(m, 1H), 3.40 (brs, 4OH), 3.70 (d, 1H, J ) 7.8 Hz), 4.04 (d, 1H, J )
7.8 Hz), 5.08-5.20 (m, 1H); 13C NMR (75 MHz, CDCl3) 11.7, 18.8,
20.8, 21.4, 22.5, 22.8, 23.2, 23.3, 23.8, 26.7, 27.5, 28.0, 33.7, 35.7,
35.9, 38.0, 38.8, 39.1, 39.4, 42.5, 48.0, 56.0, 60.2, 69.0, 70.1, 70.3,
74.8, 78.2, 170.6; IR (solid) 3445, 3335, 3145, 2929, 1717, 1462, 1380,
1264, 1243, 1100, 1039, 992 cm-1. Anal. Calcd for C29H50O6: C, 70.41;
H, 10.19. Found: C, 70.21; H, 10.16.
(q, 2H, J ) 7.2 Hz), 5.75-5.86 (m, 2H), 6.73-6.92 (m, 2H,); 13
C
NMR (75 MHz, CDCl3) 14.2, 18.6, 20.5, 31.1, 34.3, 47.9, 60.2,
60.3, 122.8, 122.9, 146.5, 149.4, 166.2; IR (neat) 2961, 1715, 1652,
1368, 1240, 1154, 1038, 984 cm-1; HRMS (+EI) (M)+ found
268.1681, (M)+calcd for C15H24O4, 268.1675.
(1S,2S,3R,4R,5R)-2-Methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-
tetrol (27): yield 79%, white solid; mp 48-50 °C (DCM); Rf 0.26
2,3,7-Trideoxy-3-propan-2-yl-L-arabino-heptopyranos-6-ul-
1
(1:9 methanol/ethylacetate); H NMR (600 MHz, CDCl3) δ 0.87
ose (38, 39): yield 65%, yellow oil; Rf 0.40 (1:1 ethylacetate/
1
(d, 3H, J ) 7.2 Hz), 0.96 (d, 3H, J ) 7.2 Hz), 1.18 (s, 3H), 1.41
(brt, 1H, J ) 12.6, Hz), 1.77-1.81 (m, 2H), 2.08 (brs, 1H), 3.53
(br, 1OH), 3.62 (brd, 1H, J ) 7.2 Hz), 3.67 (brs, 1H), 3.70 (brs,
1H), 4.16 (br, 1OH), 4.55 (br, 1OH), 4.65 (br, 1OH); 13C NMR
(75 MHz, CDCl3) 16.9, 20.9, 22.8, 25.5, 26.4, 37.9, 70.6, 73.0,
74.3, 78.1; IR (solid) 3364, 2956, 1442, 1386, 1142, 1039, 930
cm-1; HRMS (+EI) (M + H)+ found 205.1440, (M + H)+calcd
for C10H21O4, 205.1440.
hexane). 38r: H NMR (600 MHz, CDCl3) 0.82 (d, 3H, J ) 6.6
Hz), 0.93 (d, 3H, J ) 6.6 Hz), 1.44 (ddd, 1H, J ) 13.2, 13.2, 3.0
Hz), 1.71 (dd, 1H, J ) 13.2, 3.0 Hz), 1.98 (dddd, 1H, J ) 13.2,
9.0, 3.0, 3.0 Hz), 2.21-2.28 (m, 1H), 2.27 (s, 3H), 3.53 (dd, 1H,
J ) 9.0, 9.0 Hz), 4.10 (d, 1H, J ) 9.0 Hz), 5.42 (d, 1H, J ) 3.0
Hz); 13C NMR (75 MHz, CDCl3) 15.8, 20.3, 24.9, 27.1, 28.1, 39.6,
68.8, 76.4, 91.7, 212.9; IR (neat) 3415, 2958, 1709, 1357, 1244,
1068, 1016, 736 cm-1; HRMS (+EI) (M)+ found 202.1201,
(M)+calcd for C10H18O4, 202.1205. 39ꢀ: 1H NMR (600 MHz,
CDCl3) 0.82 (d, 3H, J ) 7.2 Hz), 0.93 (d, 3H, J ) 7.2 Hz), 1.25
(ddd, 1H, J ) 13.8, 12.6, 9.0 Hz), 1.59 (dddd, 1H, J ) 13.8, 10.2,
3.6, 3.6 Hz), 1.86 (ddd, 1H, J ) 12.6, 3.6, 1.2 Hz), 2.21-2.28 (m,
1H), 2.32 (s, 3H), 3.48 (dd, 1H, J ) 10.2, 9.0 Hz), 3.62 (d, 1H, J
) 9.0 Hz), 4.90 (dd, 1H, J ) 9.0, 1.2 Hz); 13C NMR (75 MHz,
CDCl3) 15.9, 20.5, 25.1, 27.0, 30.7, 45.1, 68.0, 81.8, 96.7, 211.7.
(1S,2S,4R)-1-Methyl-4-(propan-2-yl)-6,8-dioxabicyclo[3.2.1]-
octane-2,7-diol (42): yield 25%, white solid; mp 110-112 °C
(1R,2S,3R,4S,5R)-2-Methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-
tetrol (28): yield: 88%, white solid; mp 176-178 °C (ethylacetate);
Rf 0.48 (1:9 methanol/ethylacetate); 1H NMR (300 MHz, CD3OD)
δ 1.68 (d, 6H, J ) 6.6 Hz), 1.90 (s, 3H), 1.93-2.17 (m, 2H),
2.24-2.46 (m, 2H), 4.08-4.21 (m, 1H), 4.29 (ddd, 1H, J ) 11.4,
4.2, 4.2 Hz), 4.51-4.58 (m, 1H), 4.71 (s, 1OH), 4.93 (d, 1OH, J
) 4.5 Hz), 5.14 (d, 1OH, J ) 2.7 Hz), 5.31 (d, 1OH, J ) 4.2 Hz);
13C NMR (75 MHz, CD3OD) 28.7, 30.5, 31.0, 37.1, 40.4, 51.4,
79.7, 81.9, 83.4, 87.4; IR (Solid) 3368, 2892, 1340, 1282, 1068,
1022, 973, 734, 693, 617 cm-1; HRMS (+EI) (M + H)+ found
409.2811, (M + H)+calcd for (C10H20O4)2H (dimer), 409.2801.
(3aS,4S,7S,7aR)-2,2,4-Trimethyl-7-(propan-2-yl)hexahydro-
4,7-epidioxy-1,3-benzodioxole (33). To a stirred solution of 4d
(0.5 g, 2.5 mmol) in dry CH2Cl2 (25 mL) was added 2,2-
dimethoxypropane (1.3 g, 12.4 mmol) followed by p-toluenesulfonic
acid (10 mol %), and the solution was stirred under nitrogen
overnight. The reaction mixture was washed with saturated NaHCO3
(20 mL), dried (MgSO4), and filtered, and the solvent was removed
in vacuo. The residue was purified by flash chromatography: yield
86%, colorless oil; Rf 0.69 (3:7 ethylacetate:hexane); 1H NMR (300
MHz, CDCl3) δ 0.94 (d, 3H, J ) 9.0 Hz), 0.97 (d, 3H, J ) 9.0
Hz), 1.17 (s, 3H), 1.37 (s, 3H), 1.50 (s, 3H), 1.58-1.80 (m, 1H),
1.90-2.05 (m, 3H), 4.10 (dd, 1H, J ) 7.8, 1.5 Hz), 4.30 (dd, 1H,
J ) 7.8, 1.5 Hz); 13C NMR (75 MHz, CDCl3) 17.1, 17.2, 19.6,
21.9, 23.9, 24.6, 26.4, 34.3, 74.5, 76.3, 77.1, 80.6, 110.2; IR (nujol)
1267, 1209, 1179, 1161, 1076, 1023, 874 cm1; (+EI) (M + Na)+
found 265.1414, (M+Na)+calcd for C13H22O4Na, 265.1416.
General Methods for Thermal and Photochemical Decom-
position of Endoperoxides. Thermal. A stirred solution of 2,3-
dioxine (1 mmol) was boiled under reflux in various solvents (5
mL) until decomposition was determined by TLC. The crude
products were purified by flash column chromatography.
1
(hexane/DCM) Rf 0.20 (1:1 ethylacetate/hexane); H NMR (300
MHz, CDCl3) δ 0.85 (d, 3H, J ) 6.6 Hz), 0.95 (d, 3H, J ) 6.6
Hz), 1.38 (s, 3H), 1.41 (m, 1H), 1.46 (m, 1H), 1.50 (m, 1H), 1.85
(ddd, 1H, J ) 6.6, 6.6, 3.6 Hz), 2.16 (brs, 1OH), 2.74 (brs, 1OH),
3.53 (s, 1H), 5.02 (s, 1H), 5.63 (s, 1H); 13C NMR (75 MHz, CDCl3)
15.6, 19.8, 20.3, 28.7, 30.1, 41.1, 67.7, 84.5, 96.2, 103.9 cm-1
;
HRMS (+EI) (M - H)- found 201.1132, (M - H)- calcd for
C10H17O4, 201.1132.
Acknowledgment. We thank the Australian Research Council
for funding. P.V. thanks the Faculty of Sciences and the School
of Chemistry and Physics for a postgraduate research scholarship.
Supporting Information Available: Experimental details for
compounds 3g, 3h, 6d, 12e, and 12f; 13C NMR spectra for
compounds 3b, 3c, 3e, 3f, 4b, 4c, 4e-h, 5d, 5g, 16, 19, 23-28,
1
1, 33, 35, 39, and 42; H NMR spectra for compounds 3b, 3c,
3e, 3f, 4b-h, 5d, 5g, 16, 19, 23-28, 1, 33, 35, 39, and 42; and
crystallographic data for compounds 4h, 5d, and 28. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8020506
Photochemical. A solution of 2,3-dioxine (1 mmol) in DCM (5
mL) was irradiated with a sun lamp under reflux until decomposition
was determined by TLC. The crude products were purified by flash
column chromatography.
(41) Nikishin, G. I.; Troyanskii, E. I.; Lazareva, I. Tetrahedron Lett. 1984,
25, 4987–4978.
(42) Moreau, J. L.; Couffignal, R. J. Organomet. Chem. 1985, 294, 139–
Compounds 29b,40 29c,41 29d,42 29e,43 29f,44 29g,45 and 29h45
144.
1
(43) Zschiesche, R.; Hafner, T.; Reissig, H. U. Liebigs Ann. Chem. 1988,
1169–1173.
showed H NMR spectra identical to the literature.
(44) Hirai, K.; Ojima, I. Tetrahedron Lett. 1983, 24, 785–788.
(45) Huang, J. T.; Su, T. L.; Watanabe, K. A. J. Org. Chem. 1991, 56, 4811–
4815.
(40) Cantrell, T. S.; Allen, A. C.; Ziffer, H. J. Org. Chem. 1989, 54, 140–
145.
282 J. Org. Chem. Vol. 74, No. 1, 2009