Auxiliary controlled singlet-oxygen ene reactions of cyclohexenes

Article abstract of DOI:10.1016/j.tet.2006.07.104

The photooxygenation of homochiral cyclohexene ketals, which are easily available from 2-cyclohexenone and l-tartrates, affords hydroperoxides and after reduction the corresponding allylic alcohols in good yields and high regioselectivities. This can be rationalized by electronic repulsions in a perepoxide intermediate and provides evidence for unfavorable 1,3 diaxial interactions with a dioxolane oxygen atom. Only low stereoselectivities were observed, due to the flexibility of the cyclohexene ring. However, the diastereomers could be separated and after cleavage of the auxiliary, 4-hydroxy-2-cyclohexen-1-one was isolated in enantiomerically pure form, which can serve as a building block for natural product synthesis.

Full text of DOI:10.1016/j.tet.2006.07.104

Tetrahedron 62 (2006) 10639–10646
Auxiliary controlled singlet-oxygen ene reactions of cyclohexenes
*
Werner Fudickar, Katja Vorndran and Torsten Linker
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam/Golm, Germany
Received 18 May 2006; revised 13 July 2006; accepted 14 July 2006
Available online 25 September 2006
Abstract—The photooxygenation of homochiral cyclohexene ketals, which are easily available from 2-cyclohexenone and L-tartrates, affords
hydroperoxides and after reduction the corresponding allylic alcohols in good yields and high regioselectivities. This can be rationalized by
electronic repulsions in a perepoxide intermediate and provides evidence for unfavorable 1,3 diaxial interactions with a dioxolane oxygen
atom. Only low stereoselectivities were observed, due to the flexibility of the cyclohexene ring. However, the diastereomers could be separated
and after cleavage of the auxiliary, 4-hydroxy-2-cyclohexen-1-one was isolated in enantiomerically pure form, which can serve as a building
block for natural product synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
R2
R2
R1
R2
R1
R1
1. Introduction
CH3
CH2
CH2
1O2
Singlet oxygen (1O2), which can be conveniently generated
by the sensitized photoreaction of molecular oxygen with
visible light (photooxygenation), has become an important
reagent for the synthesis of oxyfunctionalized products
from simple precursors.1 Especially the ene reaction of
1O2 with alkenes provides a powerful route to allylic hydro-
peroxides and after reduction to allylic alcohols. The regio-
selectivity of this transformation was studied in detail during
the last years2 and more recently, the selectivities were im-
proved by reactions in zeolites or polymeric containers.3
Singlet-oxygen ene reactions with high diastereoselectiv-
ities are based on the pioneering work of Adam.4 More
recently, auxiliary controlled5 and even organocatalytic6
enantioselective photooxygenations were realized. Finally,
singlet oxygen was applied for reversible light- and air-
driven lithography.7
+
CHCl3, - 30 °C
85 - 94%
OOH
OOH
trans-2
cis-2
< 4:96
1
R
R
1 = CO2H, CO2Me, CH2OH
dr = 88:12
2 = Me, Et, i-Pr
Scheme 1. Photooxygenations of the cyclohexadienes 1.
Furthermore, the reactions are strongly controlled by steric
and polar factors and especially carboxylic acids and esters
provide high selectivities. This prompted us to investigate
chiral auxiliaries with such functional groups in photooxy-
genations. Commercially available tartaric acid and esters
seemed to be the ideal candidates, since they are often
used in asymmetric synthesis.10 Herein we report our results
on the singlet-oxygen ene reaction of homochiral cyclo-
hexene ketals, in view of regio- and stereoselectivities as
well as synthetic applications.
Although the singlet-oxygen ene reaction of five- and seven-
membered cycloalkenes proceeds with high regioselectivity,
the photooxygenation of cyclohexenes affords hydroper-
oxides with only moderate yield and selectivities.2,8 During
our work on synthetic applications of singlet oxygen,9 we
found excellent regio- and high diastereoselectivities in the
photooxygenation of cyclohexadienes 1 to afford hydroper-
oxides 2 (Scheme 1).
2. Results and discussion
Homochiral ketals can be conveniently prepared by the reac-
tion of a ketone with a chiral diol by azeotropic removal of
water.10a,11 However, the ketalization of cyclic enones
with simple diols might proceed under migration of the
double bond, due to the acidic conditions.12 Indeed, the
reaction of 2-cyclohexenone (3) with commercially avail-
able tartrates 4a–c or glycol (4d) and catalytic amounts of
p-toluenesulfonic acid (PTS) afforded mixtures of 2-cyclo-
hexene ketals 5a–d and the rearranged 3-cyclohexene ketals
6a–d in moderate yields (Scheme 2). Unfortunately, the
regioisomers 5 and 6 could not be separated by column
Keywords: Singlet oxygen; Auxiliary control; Regioselectivity; Stereoselec-
tivity.
* Corresponding author. Tel.: +49 331 9775212; fax: +49 331 9775056;
e-mail: linker@chem.uni-potsdam.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.104

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W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
chromatography. Therefore, we developed a new procedure
for the selective synthesis of the rearranged products by sim-
ply increasing the amount of p-toluenesulfonic acid (PTS).
Under such conditions, the desired 3-cyclohexene ketals
6a–c were isolated in moderate yields in analytically pure
form (Scheme 2). Thus, this one-pot procedure is superior
to the literature-known process by a two-step elimination.13
This result is in accordance with our previous studies on the
photooxygenation of cyclohexadienes,9 which don’t react at
the bisallylic position (Scheme 1) and points out the impor-
tance of pseudo-axial oriented hydrogen atoms in singlet-
oxygen ene reactions.
Therefore, the photooxygenations were carried out with the
3-cyclohexene ketals 6a–e. Indeed, the reactions proceeded
smoothly with tetraphenylporphin (TPP) as sensitizer at
ꢀ30 ꢁC (Table 1). Complete conversion was achieved after
2–4 d and the labile hydroperoxides were directly reduced
by dimethylsulfide. To determine the product ratios, 1H
NMR spectra (500 MHz) were directly recorded on the
crude reaction mixtures after evaporation of the solvents.
Finally, the corresponding allylic alcohols 7 and 8 were
isolated in good overall yields by column chromatography
(Table 1).
R
R
R
R
O
O
O
O
O
R
R
PTS
toluene, 110 °C
+
+
HO
OH
3
4a-d
5a-d
6a-e
0.005 equiv.PTS
4a: R = CO2Me
4b: R = CO2Et
4c: R = CO2iPr
4d: R =H
56% (5a:6a = 8:92)
64% (5b:6b = 13:87)
66% (5c:6c = 15:85)
62% (5d:6d = 9:91)
The first photooxygenations were conducted with ketals
6a–c, derived from chiral tartrates 4a–c (Table 1, entries
1–3). Interestingly, a high degree of regioselectivity from
81:19 to 89:11 was observed for all substrates. Thus, the
allylic alcohols 7a–c were isolated as main products in
good yields. This result is in contrast to the singlet-oxygen
ene reaction of substituted cyclohexenes, which afford hy-
droperoxides with only moderate yield and selectivities.2,8
To exclude an influence of the stereogenic centers of the chi-
ral auxiliaries, the achiral ketal 6d was photooxygenated
next (entry 4). Indeed, the same degree of regioselectivity
was observed, which can only be rationalized by repulsive
0.07 equiv.PTS
4a: R = CO2Me
4b: R = CO2Et
4c: R = CO2iPr
4d: R = H
6a (63%)
6b (53%)
6c (56%)
6d (35%)
6e (95% from 6a)
R =CO2H
Scheme 2. Synthesis of the cyclohexene acetals 6.
On the other hand, the 2-cyclohexene ketal 5a, where the
double bond is closer to the stereogenic centers, was selec-
tively obtained by a multi-step procedure.14 To investigate
the influence of polar groups, the free dicarboxylic acid 6e
was synthesized by saponification of the methylester 6a in
95% yield (Scheme 2).
1
interactions of the attacking O2 with the dioxolane ring.
Four different allylic hydrogen atoms are available for the
ene reaction and thus four perepoxide intermediates 9 can
be discussed (Fig. 2).
For the ene reactions, singlet oxygen (1O2) was conveniently
generated at ꢀ30 ꢁC from molecular oxygen by irradiation
with a sodium lamp in the presence of catalytic amounts
of tetraphenylporphin (TPP) as sensitizer (photooxygena-
tions). To establish the influence of the ketal auxiliaries,
2-cyclohexenone (3) was employed as substrate for the first
photooxygenations. However, even after prolonged irradia-
tion for several days no conversion could be achieved, which
can be rationalized by the electron poor double bond.
Another explanation for the failure of the singlet-oxygen
ene reaction might be the unfavorable conformation of
2-cyclohexenone (3). To distinguish between these two
effects, the reaction of 2-cyclohexene ketal 5a was examined
next. Furthermore, this substrate should provide higher
stereoselectivities than the regioisomer 6a, since the double
bond is located closer to the stereogenic centers. Unfortu-
nately, again no conversion was achieved, which speaks
for a preferred conformation of the 2-cyclohexene ketal 5a
with pseudo-equatorial allylic hydrogen atoms, which can-
not undergo an ene reaction (Fig. 1).
The importance of pseudo-axial oriented hydrogen atoms in
the singlet-oxygen ene reaction was already pointed out in
Table 1. Photooxygenations of the 3-cyclohexene ketals 6
R
R
R
R
R
R
O
O
O
O
O
O
1. O2, TPP, h
2. Me2S
CHCl3, – 30 °C, 2-4d
+
OH
OH
7a-e
6a-e
8a-e
Entry Ketal
R
7:8a
dr 7a
dr 8a
Yield (%)b
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6e
6e
CO2Me
CO2Et
CO2i-Pr
H
CO2H
CO2Hd
COꢀ2 f
82:18 57:43 62:38 75
81:19 53:47 55:45 75
89:11 54:46 n.d.
73
77
87:13
n.d.
—
n.d.
—
n.d.
<10c
e
>95:5
>95:5
52:48 n.d.
56:44 n.d.
e
Ratios determined (dr¼diastereomeric ratio) by 1H NMR analysis of the
a
crude product (500 MHz).
Yield of isolated allylic alcohols. Main isomers were separated by column
chromatography in analytically pure form.
CO2Me
b
O
H
c
d
e
f
Low yield is due to cleavage of the ketal under the acidic conditions.
Addition of tetra-n-butylammonium hydroxide as base.
Products 7e were not isolated but are identical to saponified 7a.
Deprotonation with 4 equiv of NaOCD3, reaction in CD3OD with rose
bengal as sensitizer.
CO2Me
O
H
5a
Figure 1. Preferred conformation of the 2-cyclohexene acetal 5a.

W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
10641
R
added to the reaction mixture. Indeed, an increase in the
regioselectivity resulted due to the stronger 1,3 diaxial polar
repulsions, but no influence on the diastereoselectivity was
observed (entries 6 and 7).
R
O
R
O
O
O
R
H
O
O
O
Obviously, the homochiral cyclohexene ketals 6 are too flex-
ible (compare different structures in Fig. 2) to prefer one
conformation and induce a high stereoselectivity. Further-
more, the chiral auxiliary is too far away from the newly
formed stereogenic center and thus, only a 1,6 induction
results. This is in accordance with a somewhat higher stereo-
selectivity for the minor regioisomer 8a (Table 1, entry 1),
which is formed by a 1,5 induction. The best substrates for
a stereoselective photooxygenation would be the 2-cyclo-
hexene ketals 5, since the double bond is located closer to
the chiral auxiliaries. Indeed, alkene 5a exhibits a higher
stereoselectivity in cyclopropanations than the correspond-
ing isomer 6a.13,14 Unfortunately, the 2-cyclohexene ketal
5a does not undergo a singlet-oxygen ene reaction, due to
the pseudo-equatorial allylic hydrogen atoms (Fig. 1).
H
O
9a (disfavored)
9c (favored)
9c, 9d
8
9a, 9b
7
O
H
O
O
O
O
O
H
R
R
O
R
R
9b (disfavored)
9d (favored)
Figure 2. Four possible perepoxide intermediates 9.
To compare steric and polar interactions in the oxidation of
3-cyclohexene ketal 6a, we became interested in the epoxi-
dation with m-chloroperbenzoic acid (MCPBA). The reac-
tion proceeded smoothly at 0 ꢁC and the epoxides 10a
were isolated in high yield (Scheme 3). However, both dia-
stereomers were obtained in a ratio of almost 1:1. Thus,
the photooxygenation of ketal 6a proceeds with a higher
selectivity, although MCPBA is sterically more demanding
than singlet oxygen. This interesting result is a further proof
of the importance of polar interactions in the perepoxide
intermediates 9, leading to stereoselectivities of up to 57:43
for a 1,6 induction.
Figure 1. If the remote allylic position reacts (Fig. 2, perep-
oxides 9a and 9b), an unfavorable 1,3 diaxial interaction
between the negatively charged perepoxide and one dioxo-
1
lane oxygen atom results, irrespective of the attack of O2
from the top or bottom of the double bond. Both intermedi-
ates afford the regioisomers 8, which are therefore formed
only as side products. On the other hand, if the allylic posi-
tion adjacent to the ketal reacts (Fig. 2, perepoxides 9c and
9d), no unfavorable 1,3 diaxial interactions are operative
and the regioisomers 7 are obtained as the main products.
This result is in accordance with the large group effect,2 and
very recently steric interactions between 1O2 and a pseudo-
axial methyl group were discussed during the photooxygena-
tion of cyclogeranyl derivatives.15 However, the herein
investigated ketal auxiliaries increase the unfavorable 1,3
diaxial interactions by severe electronic repulsions between
the perepoxide and one dioxolane oxygen atom and
thus control the regioselectivity of the singlet-oxygen ene
reaction.
MeO2C
CO2Me
MeO2C
CO2Me
O
O
O
O
MCPBA
CH2Cl2, 0 °C
O
95%
6a
10a (dr = 51:49)
Scheme 3. Epoxidation of the 3-cyclohexene acetal 6a.
Besides the high regioselectivities, only low stereoselectiv-
ities were observed for the chiral esters 6a–c (Table 1, entries
1–3). The diastereomeric ratios could be determined from
From the synthetic point of view, it was important that the
major allylic alcohols 7 could be conveniently separated
by column chromatography and were isolated in diastereo-
merically and analytically pure form. The absolute configu-
ration of the newly formed stereogenic center could not be
established by the coupling constants or NOE effects. There-
fore, we examined the cleavage of the chiral auxiliary from
the ketal 7a (Table 2), to afford 4-hydroxy-2-cyclohexen-1-
one (11), which is literature-known.16 However, the lability
of the desired product under the acidic reaction conditions
was problematic. Thus, cleavage with diluted hydrochloric
acid led to the elimination of water and formation of phenol
(12) as the main product (entry 1). After optimization of the
reaction conditions, the best results were obtained with buff-
ered clay, which afforded 4-(S)-hydroxy-2-cyclohexen-1-
one (11) in high yield (Table 2, entry 3). The S configuration
was unequivocally determined by comparison of the optical
rotations and thus the major diastereomers 7 have the same
absolute configuration. Finally, from 2-cyclohexenone, the
1
the crude products by H NMR spectroscopy (500 MHz)
and all isomers showed distinctive chemical shifts. Further-
more, a separation and complete characterization of the
main products was possible by column chromatography.
Thus, the major diastereomers of the allylic alcohols 7
always have the S configuration at the newly formed stereo-
genic center, which was established by cleavage of the chiral
auxiliary (see below). However, because of the low selectiv-
ities, an explanation and discussion for the formation of
these isomers in excess is not possible.
To increase the stereoselectivities, the free dicarboxylic acid
6e was photooxygenated next, since strong directing effects
of such functional groups were found in the singlet-oxygen
ene reaction in our previous studies.9 However, the acidic
reaction conditions led to the cleavage of the chiral auxiliary
(Table 1, entry 5). To overcome this problem, bases were

10642
W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
Table 2. Cleavage of the chiral auxiliary from ketal S-7a
deuteromethanol (CD3OD) as internal standard. IR spectra
were recorded on a Perkin–Elmer 1600 FT-IR and optical ro-
tations on a JASCO P-1020 polarimeter. Elemental analyses
were performed on a Vario El 3 instrument (Elementar).
MeO2C
CO2Me
O
OH
O
O
conditions
+
4.2. General procedure for the ketalizations
OH
(S)-7a
OH
(S)-11
A solution of 2-cyclohexenone (3) (4 g, 42 mmol), the diol
(42 mmol), and p-toluenesulfonic acid (0.5 g, 2.9 mmol,
0.07 equiv) in dry toluene (200 mL) was refluxed by using
a Dean–Stark trap for 8 h. After cooling the reaction mixture
was washed with a saturated aqueous solution of NaHCO3
(100 mL) followed by washing with water (100 mL). After
drying (MgSO4) the solvent was evaporated and the crude
product was purified by flash chromatography.
12
Entry
Conditions
Conv. (%)
11 (%)
12 (%)
1
2
3
MeOH, dil HCl
Montmorillonite
Montmorillonite, NaOAc
>98
>98
76
32
70
64
18
—
74 (97)a
a
Yield based on reisolated starting material.
auxiliary controlled singlet-oxygen ene reaction offers an
easy access to the enantiomerically pure ketone 11, which
can serve as a precursor for natural product synthesis.16
4.2.1. Dimethyl 1,4-dioxa-spiro[4,5]dec-7-ene-2(R),3(R)-
dicarboxylate (6a). The ketalization was carried out as
described above using dimethyl L-tartrate (4a) (7.4 g,
42 mmol) to afford after chromatography (hexane/ethyl
acetate¼3:1, Rf¼0.43) a colorless oil (6.65 g, 63%).
3. Conclusions
1H NMR (300 MHz, CDCl3) d 1.84 (t, J¼6.3 Hz, 1H, 10-H),
2.26–2.50 (m, 4H, 6-H, 9-H), 3.82 (s, 6H, Me), 4.84 (d,
J¼5.0 Hz, 1H, 2-H), 4.88 (d, J¼5.0 Hz, 1H, 3-H), 5.58–
5.62, 5.69–5.74 (2dm, J¼10 Hz, 2H, 7-H, 8-H); 13C NMR
(75 MHz, CDCl3) d 24.4 (t, C-10), 31.6 (t, C-6), 36.2 (t,
C-9), 52.8, 52.8 (2q, Me), 76.9, 77.1 (2d, C-2, C-3), 113.6
(s, C-5), 123.6 (d, C-7), 126.4 (d, C-8), 170.1, 170.4 (2s,
COOMe); IR (film) 3034, 2976, 2945, 1765, 1478, 1372,
1237, 1047, 857, 759, 662 cmꢀ1; [a]D20 ꢀ43.2 (c 1.02,
CHCl3). Anal. Calcd for C12H16O6: C, 56.25; H, 6.29.
Found: C, 56.58; H, 6.61.
Homochiral cyclohexene ketals were conveniently synthe-
sized from 2-cyclohexenone and L-tartrates. Under the acidic
reaction conditions an isomerization of the double bond was
observed, which afforded 3-cyclohexene ketals regioselec-
tively. The singlet-oxygen ene reactions proceeded smoothly
at ꢀ30 ꢁC and the corresponding allylic alcohols were iso-
lated in good yields after reduction. All reactions exhibited
a high degree of regioselectivity, which can be rationalized
by electronic repulsions in a perepoxide intermediate and
gives evidence for unfavorable 1,3 dipolar interactions
with a dioxolane oxygen atom. On the other hand, the photo-
oxygenations proceeded with low stereoselectivities, due to
the flexibility of the cyclohexene ring. However, compared
with the epoxidation of the homochiral cyclohexene ketals,
the singlet-oxygen ene reaction provided higher stereoselec-
tivities by a 1,6 induction. The isomeric allylic alcohols
could be separated by column chromatography and the
major diastereomers were isolated in analytically pure form.
Finally, the S configuration of the newly formed stereogenic
center was unequivocally established by cleavage of the
chiral auxiliary with clay in high yield. In summary, starting
from 2-cyclohexenone, the auxiliary controlled singlet-
oxygen ene reaction offers an easy access to an enantio-
merically pure hydroxycyclohexenone, which can serve as
a precursor for natural product synthesis.
4.2.2. Diethyl 1,4-dioxa-spiro[4,5]dec-7-ene-2(R),3(R)-
dicarboxylate (6b). The ketalization was carried out as de-
scribed above using diethyl L-tartrate (4b) (8.6 g, 42 mmol)
to afford after chromatography (hexane/ethyl acetate¼3:1,
Rf¼0.51) a colorless oil (6.2 g, 53%).
1H NMR (300 MHz, CDCl3) d 1.33 (t, J¼7.1 Hz, 6H, CH3),
1.86 (t, J¼6.2 Hz, 1H, 10-H), 2.26–2.48 (m, 4H, 6-H, 9-H),
4.28 (q, J¼7.1 Hz, 4H, CH2CH3), 4.80 (d, J¼5.0 Hz, 1H, 2-
H), 4.85 (d, J¼5.0 Hz, 1H, 3-H), 5.61, 5.72 (2dm, J¼10 Hz,
2H, 7-H, 8-H); 13C NMR (75 MHz, CDCl3) d 14.1, 14.1 (2q,
CH3), 24.4 (t, C-10), 31.6 (t, C-6), 36.3 (t, C-9), 61.8, 61.9
(2t, CH2CH3), 77.0, 77.2 (2d, C-2, C-3), 113.4 (s, C-5),
123.6 (d, C-7), 126.4 (d, C-8), 169.7, 169.9 (2s, COOEt);
IR (film) 3030, 2981, 2934, 1759, 1448, 1371, 1218, 1137,
1047, 943, 857, 753, 662 cmꢀ1; [a]D20 ꢀ44.9 (c 1.07,
CHCl3). Anal. Calcd for C14H20O6: C, 59.14; H, 7.09.
Found: C, 59.33; H, 7.27.
4. Experimental
4.1. General
4.2.3. Diisopropyl 1,4-dioxa-spiro[4,5]dec-7-ene-2(R),
3(R)-dicarboxylate (6c). The ketalization was carried out
as described above using diisopropyl L-tartrate (4c) (9.8 g,
42 mmol) to afford after chromatography (hexane/ethyl
acetate¼3:1, Rf¼0.67) a colorless oil (7.3 g, 56%).
1H NMR (300 MHz, CDCl3) d 1.29 (d, J¼6.2 Hz, 12H,
CH3), 1.83 (m, 1H, 10-H), 2.24–2.53 (m, 4H, 6-H, 9-H),
4.71 (d, J¼5.2 Hz, 1H, 2-H), 4.78 (d, J¼5.2 Hz, 1H,
3-H), 5.12 (sept, J¼6.2 Hz, 2H, CH(CH3)2), 5.56, 5.64
Commercially available compounds were used without fur-
ther purification; solvents were dried according to standard
procedures. Flash chromatography was performed using
Merck Kieselgel 60 silica. TLC analysis was carried out
on Alugram silica gel 60 F254 plates (Macherey-Nagel).
Molybdatophosphate was used as developing reagent. NMR
spectra were measured on a Bruker AC 300 (300 MHz)
and AC 500 (500 MHz) spectrometers using deuterochloro-
form (CDCl3), deuterodimethylsulfoxide (DMSO-d6) or

W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
10643
(2dm, J¼9.9 Hz, 2H, 7-H, 8-H); 13C NMR (75 MHz,
4.3. General procedures for the photooxygenations
CDCl3) d 21.6, 21.6, 21.7, 21.7 (4q, CH3), 24.5 (t, C-10),
31.7 (t, C-6), 36.4 (t, C-9), 69.6, 69.7 (2d, CH(CH3)2),
77.2, 78.0 (2d, C-2, C-3), 113.4 (s, C-5), 123.7 (d, C-7),
126.4 (d, C-8), 169.3, 169.5 (2s, COOi-Pr); IR (film)
3030, 2981, 2935, 1753, 1467, 1376, 1220, 1107,
751, 657 cmꢀ1; [a]D20 ꢀ38.0 (c 0.98, CHCl3). Anal.
Calcd for C16H24O6: C, 61.52; H, 7.74. Found: C, 61.77;
H, 7.68.
4.3.1. Procedure A. The ketals 6a–d (2 mmol) and tetraphe-
nylporphin (1 mg) were dissolved in CHCl3 (4 mL) and
CCl4 (12 mL) in a glass tube. The tube was irradiated at
ꢀ30 ꢁC with two sodium lamps (250 W) for 2–4 d. During
the irradiation a slow stream of oxygen was bubbled through
the solution and additional portions of the sensitizer were
added, when the color of the solution faded. After comple-
tion, dimethylsulfide (1 mL) was added and the reaction so-
lution was kept for 24 h. The solvent was evaporated and the
ratio of the isomers was determined from the NMR spectra
(500 MHz).
4.2.4. 1,4-Dioxa-spiro[4,5]dec-7-ene (6d). The ketalization
was carried out as described above using ethylene glycol
(4d) (2.6 g, 42 mmol) to afford after chromatography (hex-
ane/ethyl acetate¼3:1, Rf¼0.60) a colorless oil (2.1 g, 35%).
1H NMR (300 MHz, CDCl3) d 1.51 (t, J¼6.4 Hz, 2H, 10-H),
1.98–2.06 (m, 4H, 6-H, 9-H), 3.72–3.75 (m, 4H, 2-H, 3-H),
5.36, 5.47 (2dm, J¼9.7 Hz, 2H, 7-H, 8-H); 13C NMR
(75 MHz, CDCl3) d 24.7 (t, C-10), 31.2 (t, C-6), 35.9 (t,
C-9), 64.4 (2t, C-2, C-3), 107.8 (s, C-5), 124.4 (d, C-7),
126.4 (d, C-8). IR (KBr) 3026, 2925, 1653, 1476, 1432,
1388, 1361, 1335, 1262, 1221, 1172, 1114, 1058, 1027,
948, 850 cmꢀ1. Anal. Calcd for C8H12O2: C, 68.55; H,
8.63. Found: C, 68.03; H, 9.16.
4.3.2. Procedure B. The ketal 6e (100 mg, 0.4 mmol) was
dissolved in 2 mL CD3OD in a glass tube. After addition
of rose bengal (1 mg) and sodium (40 mg, 1.7 mmol) the
tube was irradiated under the same conditions as described
for the general procedure for a period of 7 d. After comple-
tion, dimethylsulfide (1 mL) was added and the reaction so-
lution was kept for 24 h. The solvent was evaporated and the
ratio of the isomers was determined from the NMR spectra
(500 MHz) in CD3OD.
4.3.3. Photooxygenation of ketal 6a. Following procedure
A, compound 6a was irradiated for 4 d and the allylic
alcohols were isolated as colorless oils. The ratio 7a/8a
(82:18) and the diastereomeric ratios for 7a (57:43) and
8a (62:38) were determined from the crude spectra by
NMR spectroscopy (500 MHz). Chromatography (hexane/
ethyl acetate¼1:2, Rf¼0.42–0.50) afforded first the major
diastereomer of 8a, followed by the minor diastereomer
of 8a, the minor diastereomer of isomer 7a, and finally,
the major diastereomer of 7a (overall yield: 410 mg,
75%).
4.2.5. 1,4-Dioxa-spiro[4,5]dec-7-ene-2(R),3(R)-dicarbox-
ylic acid (6e). To a solution of the methylester 6a
(300 mg, 1.1 mmol) in methanol (10 mL) was added
NaOH (360 mg, 9 mmol) dissolved in water (2 mL). After
refluxing for 6 h the solvent was evaporated and water
(20 mL) and diethyl ether (20 mL) were added. After sepa-
ration the aqueous phase was acidified with 1 M aqueous
HCl and extracted three times with diethyl ether. The
combined ether extracts were washed with water,
dried (MgSO4), and the solvent was removed to afford the
carboxylic acid 6e as a yellow solid (240 mg, 95%); mp
114 ꢁC.
4.3.3.1. Dimethyl 8(S)-hydroxy-1,4-dioxa-spiro[4,5]-
dec-6-ene-2(R),3(R)-dicarboxylate (S-7a) (main product).
1H NMR (300 MHz, CDCl3) d 1.72–1.92 (m, 2H, 9-H),
2.08–2.2 (m, 2H, 10-H), 3.82, 3.83 (2s, 6H, CH3),
4.21 (m, 1H, 4-H), 4.81, 4.83 (2d, J¼4.5 Hz, 2H, 2-H,
3-H), 5.69 (d, J¼10.5 Hz, 1H, 6-H), 5.97–6.04 (dm,
J¼10.5 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3)
d 30.6 (t, C-9), 32.0 (t, C-10), 53.2, 53.3 (2q, Me),
66.4 (d, C-8), 77.8, 77.9 (2d, C-2, C-3), 111.0 (s, C-5),
129.0 (d, C-6), 137.5 (d, C-7), 170.8 (2s, CO2Me); IR
(KBr) 3425, 2975, 2920, 1738, 1402, 1234, 1156, 1042,
931, 745 cmꢀ1; [a]D25 ꢀ54.9 (c 0.25, CHCl3). Anal. Calcd
for C12H16O7: C, 52.94; H, 5.88. Found: C, 52.66; H,
5.88.
1H NMR (500 MHz, DMSO-d6) d 1.79–1.88 (m, 2H, 10-H),
2.16–2.51 (m, 4H, 6-H, 9-H), 4.81, 4.82 (2d, J¼9.2 Hz, 2H,
2-H, 3-H), 5.45–5.50 (m, J¼11.6 Hz, 1H, 8-H), 5.65–5.7 (m,
J¼11.6 Hz, 1H, 7-H); 13C NMR (125 MHz, DMSO-d6)
d 25.1 (t, C-9), 32.3 (t, C-10), 37.1 (t, C-6), 77.4, 77.6 (2d,
C-2, C-3), 112.8 (s, C-5), 124.4 (d, C-7), 127.1 (d, C-8),
172.0, 172.4 (2s, COOH); IR (film) 3038, 2934, 1737,
1425, 1361, 1271, 1142, 1042, 944 cmꢀ1; [a]D20 ꢀ2.6 (c
1.0, MeOH). Anal. Calcd for C10H12O6: C, 52.63; H, 5.26.
Found: C, 52.54; H, 4.97.
4.2.6. Dimethyl 1,4-dioxa-spiro[4,5]dec-6-ene-2(R),3(R)-
dicarboxylate (5a). The ene ketal was prepared via trans-
ketalization of 1,1-dimethoxy-2-cyclohexene.14
4.3.3.2. Dimethyl 8(R)-hydroxy-1,4-dioxa-spiro[4,5]-
dec-6-ene-2(R),3(R)-dicarboxylate (R-7a) (minor diaste-
reomer). 1H NMR (300 MHz, CDCl3) d 1.75–1.89 (m,
2H, 9-H), 2.09–2.19 (m, 2H, 10-H), 3.83, 3.84 (2s, 6H,
CH3), 4.27 (m, 1H, 8-H), 4.85, 4.87 (2d, J¼4.5 Hz, 2H,
2-H, 3-H), 5.73 (d, J¼10.4 Hz, 1H, 6-H), 5.99–6.03 (dm,
J¼10.4 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3) d 30.6
(t, C-9), 31.8 (t, C-10), 55.2, 55.3 (2q, Me), 66.0 (d, C-8),
77.2, 77.3 (2d, C-2, C-3), 110.8 (s, C-5), 128.8 (d, C-6),
136.8 (d, C-7), 170.3 (2s, CO2Me); IR (KBr) 3425, 2975,
2920, 1738, 1402, 1234, 1156, 1042, 931, 745 cmꢀ1; [a]D20
+2.3 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3) d 1.75–1.84 (m, 2H, 9-H),
1.87–1.97 (m, 2H, 10-H), 1.98–2.07 (m, 2H, 8-H), 3.80 (s,
6H, CH3), 4.83 (s, 2H, 2-H, 3-H), 5.65 (d, J¼10.0 Hz, 1H,
6-H), 6.02 (dt, J¼3.5, 10.0 Hz, 1H, 7-H); 13C NMR
(75 MHz, CDCl3) d 20.7 (t, C-9), 24.9 (t, C-10), 34.4 (t,
C-8), 53.2, 53.1 (2s, Me), 77.4, 77.2 (2d, C-2, C-3), 111.4
(s, C-5), 127.1 (d, C-6), 134.8 (d, C-7), 170.4, 170.5 (2s,
COOMe); IR (film) 3033, 2978, 2945, 1764, 1478, 1371,
1237, 1045, 857, 759, 662 cmꢀ1; [a]D20 ꢀ7.3 (c 1.0,
CHCl3), lit.:14 [a]D24 ꢀ8.5 (c 3.5, CHCl3).

10644
W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
4.3.3.3. Dimethyl 7-hydroxy-1,4-dioxa-spiro[4,5]dec-
8-ene-2(R),3(R)-dicarboxylate (8a) (major diastereo-
mer). H NMR (300 MHz, CDCl3) d 1.95–2.14 (m, 2H,
4.30 (q, J¼7.1 Hz, 4H, OCH2), 4.35 (m, 1H, 7-H), 4.8–
4.91 (m, 2H, 2-H, 3-H), 5.76–5.80 (dm, J¼9.89 Hz, 2H,
9-H), 5.89–5.97 (dm, J¼9.89 Hz, 1H, 8-H); 13C NMR
(75 MHz, CDCl3) d 13.6 (2q, CH3), 35.5 (t, C-10), 39.7 (t,
C-6), 62.2, 62.3 (2t, OCH2), 70.1 (d, C-7), 75.9, 76.1 (2d,
C-2, C-3), 112.2 (s, C-1), 124.5 (d, C-9), 128.3 (C-8),
168.6, 168.7 (CO2Et).
1
10-H), 2.25–2.46 (m, 2H, 6-H), 3.76, 3.77 (2s, 6H, CH3),
4.29 (m, 1H, 7-H), 4.79, 4.84 (2d, J¼4.7 Hz, 2H, 2-H,
3-H), 5.64–5.71 (dm, J¼9.7 Hz, 1H, 9-H), 5.8–5.87 (dm,
J¼9.7 Hz, 1H, 8-H); 13C NMR (75 MHz, CDCl3) d 36.8
(t, C-10), 40.1 (t, C-6), 53.3, 53.4 (2q, Me), 66.4 (d, C-7),
77.0, 77.1 (2d, C-2, C-3), 113.7 (s, C-5), 125.5 (d, C-9),
129.9 (d, C-8), 170.0, 170.5 (2s, CO2Me); [a]2D0 +14.8 (c
0.96, CHCl3).
4.3.4.4. Diethyl 7-hydroxy-1,4-dioxa-spiro[4,5]dec-8-
ene-2(R),3(R)-dicarboxylate (8b) (minor diastereomer).
1H NMR (300 MHz, CDCl3) d 1.33 (t, J¼7.1 Hz, 6H,
CH3), 2.05–2.22 (m, 2H, 10-H), 2.32–2.56 (m, 2H, 6-H),
4.30 (q, J¼7.1 Hz, 4H, OCH2), 4.29 (m, 1H, 7-H), 4.83–
4.96 (m, 2H, 2-H, 3-H), 5.76–5.80 (dm, J¼9.9 Hz, 2H,
9-H), 5.82–5.91 (dm, J¼9.9 Hz, 1H, 8-H); 13C NMR
(75 MHz, CDCl3) d 13.6 (2q, CH3), 35.7 (t, C-10), 39.3 (t,
C-6), 65.1, 65.2 (2t, OCH2), 70.9 (d, C-7), 75.9, 76.1 (2d,
C-2, C-3), 112.3 (s, C-1), 124.2 (d, C-9), 128.5 (C-8),
168.6, 168.7 (CO2Et).
4.3.3.4. Dimethyl 7-hydroxy-1,4-dioxa-spiro[4,5]dec-
8-ene-2(R),3(R)-dicarboxylate (8a) (minor diastereo-
mer). H NMR (300 MHz, CDCl3) d 2.05–2.22 (m, 2H,
1
10-H), 2.32–2.52 (m, 2H, 6-H), 3.84, 3.85 (2s, 6H, CH3),
4.37 (m, 1H, 8-H), 4.86, 4.92 (2d, J¼4.7 Hz, 2H, 2-H,
3-H), 5.72–5.8 (dm, J¼9.7 Hz, 1H, 9-H), 5.89–5.97 (dm,
J¼9.7 Hz, 1H, 8-H); 13C NMR (75 MHz, CDCl3) d 36.8
(t, C-10), 39.9 (t, C-6), 53.3, 53.4 (2q, Me), 66.4 (d, C-7),
77.1, 77.6 (2d, C-2, C-3), 113.2 (s, C-5), 125.8 (d, C-9),
129.6 (d, C-8), 170.2, 170.5 (2s, CO2Me).
4.3.5. Photooxygenation of ketal 6c. Following procedure
A, compound 6c was irradiated for 4 d and the allylic alco-
hols were isolated as colorless oils. The ratio 7c/8c (89:11)
and the diastereomeric ratio for 7c (54:46) were determined
from the crude spectra by NMR spectroscopy (500 MHz).
Chromatography (hexane/ethyl acetate¼1:2, Rf¼0.65–
0.72) afforded first the major diastereomer of 8c, followed
by the minor diastereomer of isomer 7c, and finally, the
major diastereomer of 7c. The minor diastereomer of 8c
could not be isolated (overall yield: 480 mg, 73%).
4.3.4. Photooxygenation of ketal 6b. Following procedure
A, compound 6b was irradiated for 4 d and the allylic alco-
hols were isolated as colorless oils. The ratio 7b/8b (81:19)
and the diastereomeric ratios for 7b (53:47) and 8b (55:45)
were determined from the crude spectra by NMR spec-
troscopy (500 MHz). Chromatography (hexane/ethyl
acetate¼1:2, Rf¼0.50–0.58) afforded first the major diaste-
reomer of 8b, followed by the minor diastereomer of 8b, the
minor diastereomer of isomer 7b, and finally, the major
diastereomer of 7b (overall yield: 450 mg, 75%).
4.3.5.1. Diisopropyl 8(S)-hydroxy-1,4-dioxa-spiro[4,5]-
dec-6-ene-2(R),3(R)-dicarboxylate (S-7c) (major dia-
stereomer). 1H NMR (300 MHz, CDCl3) d 1.23 (d,
J¼6.1 Hz, 12H, CH3), 1.50–2.14 (m, 4H, 10-H, 12-H),
4.14 (m, 1H, 8-H), 4.59 (m, 2H, 2-H, 3-H), 5.06 (sept,
J¼6.1 Hz, 2H, CH), 5.62–5.72 (d, J¼10.0 Hz, 1H, 6-H),
5.89–5.96 (d, J¼10.0 Hz, 1H, 7-H); 13C NMR (75 MHz,
CDCl3) d 21.8 (q, CH3), 30.3 (t, C-9), 32.0 (t, C-10), 65.7
(d, C-8), 70.1 (2d, CHMe2), 77.7, 78.1 (2d, C-2, C-3),
110.6 (s, C-5), 128.5 (d, C-6), 137.0 (d, C-7), 169.4, 169.5
(2s, COOi-Pr). Anal. Calcd for C16H24O7: C, 58.53; H,
7.37. Found: C, 58.26; H, 7.29.
4.3.4.1. Diethyl 8(S)-hydroxy-1,4-dioxa-spiro[4,5]dec-
6-ene-2(R),3(R)-dicarboxylate (S-7b) (major diastereo-
1
mer). H NMR (300 MHz, CDCl3) d 1.33 (t, J¼6.6 Hz,
6H, CH3), 1.73–1.92 (m, 2H, 9-H), 2.0–2.17 (m, 2H, 10-
H), 4.21 (m, 1H, 8-H), 4.25 (t, J¼6.6 Hz, 4H, CH2), 4.76
(m, 2H, 2-H, 3-H), 5.69 (d, J¼10.1 Hz, 1H, 6-H), 5.94
(dm, J¼10.1 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3)
d 13.6 (q, CH3), 29.3 (t, C-9), 30.7 (t, C-10), 61.1 (2t,
OCH2), 64.6 (d, C-8), 76.1 (d, C-2, C-3), 109.1 (s, C-5),
127.4 (d, C-6), 135.3 (d, C-7), 168.6 (2s, CO2Et); IR
(KBr) 3420, 2982, 2940, 1740, 1445, 1395, 1221, 1127,
1022, 939 cmꢀ1. Anal. Calcd for C14H20O7: C, 55.99; H,
6.71. Found: C, 55.85; H, 6.72.
4.3.5.2. Diisopropyl 8(R)-hydroxy-1,4-dioxa-spiro-
[4,5]dec-6-ene-2(R),3(R)-dicarboxylate (R-7c) (minor dia-
stereomer). 1H NMR (300 MHz, CDCl3) d 1.21 (d,
J¼6.1 Hz, 12H, CH3), 1.62–2.19 (m, 4H, 10-H, 12-H),
4.11 (m, 1H, 8-H), 4.61–5.13 (m, 2H, 2-H, 3-H), 5.06
(sept, J¼6.1 Hz, 2H, CH), 5.62–5.72 (d, J¼10.0 Hz, 1H,
6-H), 5.89–5.96 (d, J¼10.0 Hz, 1H, 7-H); 13C NMR
(75 MHz, CDCl3) d 21.9 (q, CH3), 30.3 (t, C-9), 31.9 (t,
C-10), 65.6 (d, C-8), 70.0 (2d, CHMe2), 77.2, 77.6 (2d,
C-2, C-3), 110.4 (s, C-5), 128.3 (d, C-6), 136.9 (d, C-7),
169.3, 169.4 (2s, COOi-Pr).
4.3.4.2. Diethyl 8(R)-hydroxy-1,4-dioxa-spiro[4,5]dec-
6-ene-2(R),3(R)-dicarboxylate (R-7b) (minor diastereo-
1
mer). H NMR (300 MHz, CDCl3) d 1.33 (t, J¼6.6 Hz,
6H, CH3), 1.73–1.92 (m, 2H, 9-H), 2.0–2.17 (m, 2H, 10-H),
4.21 (m, 1H, 8-H), 4.25 (t, J¼6.6 Hz, 4H, CH2), 4.78, 4.82
(2d, J¼4.7 Hz, 2H, 2-H, 3-H), 5.66 (d, J¼10.1 Hz, 1H,
6-H), 5.94 (dm, J¼10.1 Hz, 1H, 7-H); 13C NMR (75 MHz,
CDCl3) d 13.6 (q, CH3), 29.2 (t, C-9), 30.5 (t, C-10), 61.0
(2t, OCH2), 64.6 (d, C-8), 76.2 (d, C-2, C-3), 109.3 (s,
C-5), 127.5 (d, C-6), 135.4 (d, C-7), 168.4 (2s, CO2Et).
4.3.5.3. Diisopropyl 7-hydroxy-1,4-dioxa-spiro[4,5]-
dec-8-ene-2(R),3(R)-dicarboxylate (8c) (major diastereo-
mer). 1H NMR (300 MHz, CDCl3) d 1.29, 1.31 (2d,
J¼6.1 Hz, 12-H, CH3), 2.05–2.25 (m, 2H, 10-H), 2.25–
2.61 (m, 2H, 6-H), 4.41 (m, 1H, 7-H), 4.71, 4.80 (2d,
J¼5.2 Hz, 2H, 2-H, 3-H), 5.12 (sept, J¼6.2 Hz, 2H,
OCH), 5.70–5.79 (m, 1H, 9-H), 5.85–5.92 (m, 1H, 8-H);
4.3.4.3. Diethyl 7-hydroxy-1,4-dioxa-spiro[4,5]dec-8-
ene-2(R),3(R)-dicarboxylate (8b) (major diastereomer).
1H NMR (300 MHz, CDCl3) d 1.33 (t, J¼7.1 Hz, 6H,
CH3), 2.05–2.22 (m, 2H, 10-H), 2.32–2.56 (m, 2H, 6-H),

W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
10645
13C NMR (75 MHz, CDCl3) d 22.0 (q, CH3), 36.6 (t, C-10),
4.4. Epoxidation of the ketal 6a
40.1 (t, C-6), 66.3 (d, C-7), 70.3, 70.7 (2d, CHMe2), 77.7 (2d,
C-2, C-3), 113.4 (s, C-5), 125.5 (d, C-9), 129.9 (d, C-8),
169.6, 169.1 (2s, COOi-Pr); IR (KBr) 3415, 2980, 2957,
1738, 1365, 1245, 1098, 1024, 754 cmꢀ1; [a]D20 ꢀ4.8 (c
1.02, CHCl3). Anal. Calcd for C16H24O7: C, 58.53; H,
7.37. Found: C, 58.96; H, 6.89.
The cyclohexene ketal 6a (420 mg, 1.6 mmol) was dissolved
in dichloromethane (30 mL) and m-chloroperbenzoic acid
(440 mg, 1.9 mmol) was added at 0 ꢁC in several portions.
The course of the reaction was followed by TLC (hexane/
ethyl acetate¼3:1). After completion (4 h) a saturated solu-
tion of NaHCO3 (100 mL) was added. After separation, the
aqueous phase was washed with diethyl ether (100 mL), and
the combined organic extracts were washed with water,
dried (NaSO4), and the solvent was evaporated. The dia-
stereomeric ratio (51:49) was determined from the crude
spectra by NMR spectroscopy (500 MHz). The product
was purified by column chromatography (hexane/ethyl
acetate¼1:1, Rf¼0.19) to afford the epoxides 10 as white
solids (415 mg, 95%).
4.3.6. Photooxygenation of ketal 6d. Following procedure
A, compound 6d (200 mg, 1.4 mmol) was irradiated for
2 d and the allylic alcohols were isolated as colorless oils.
The ratio 7d/8d (87:13) was determined from the crude spec-
tra by NMR spectroscopy (500 MHz). Chromatography
(hexane/ethyl acetate¼1:2, Rf¼0.35) afforded 8d in the first
fractions, followed by 7d (overall yield: 170 mg, 77%).
4.3.6.1. 8-Hydroxy-1,4-dioxa-spiro[4,5]dec-6-ene (7d).
1H NMR (300 MHz, CDCl3) d 1.69–1.80 (m, 2H, 10-H),
1.91–2.18 (m, 2H, 9-H), 3.89–4.04 (m, 4H, 2-H, 3-H),
4.22 (br, 1H, 8-H), 5.63 (dt, J¼1.4, 10.0 Hz, 1H, 6-H),
5.95 (dd, J¼1.1, 10.0 Hz, 1H, 7-H); 13C NMR (75 MHz,
CDCl3) d 31.0 (t, C-10), 31.3 (t, C-9), 64.9, 65.0 (2d, C-2,
C-3), 66.3 (d, C-8), 105.4 (s, C-1), 129.5 (d, C-6), 135.3
(d, C-7). IR (KBr) 3032, 2948, 2883, 1675, 1396, 1346,
4.4.1. Dimethyl 7,8-epoxy-1,4-dioxa-spiro[4,5]decane-
2(R),3(R)-dicarboxylate (10) (major diastereomer). Mp
1
56.5 ꢁC; H NMR (300 MHz, CDCl3) d 1.47–1.56, 1.65–
1.77 (2m, 2H, 10-H), 2.10–2.32 (m, 4H, 6-H, 9-H), 3.12–
3.20 (m, 2H, 7-H, 8-H), 3.80, 3.81 (2s, 6H, Me), 4.75, 4.79
(2d, J¼5.1 Hz, 2H, 2-H, 3-H); 13C NMR (75 MHz,
CDCl3) d 22.8 (t, C-10), 28.1 (t, C-9), 35.8 (t, C-6), 51.1
(d, C-8), 52.1 (d, C-7), 53.1, 53.2 (2s, Me), 77.1, 77.2 (2d,
C-2, C-3), 112.5 (s, C-1), 170.1, 170.3 (2s, COOMe); [a]D20
ꢀ29.3 (c 0.98, CHCl3); IR (KBr) 3015, 2959, 1761, 1436,
1272, 1066, 1012, 939, 863 cmꢀ1
.
4.3.6.2. 7-Hydroxy-1,4-dioxa-spiro[4,5]dec-8-ene (8d).
1H NMR (300 MHz, CDCl3) d 1.96 (d, J¼4.4 Hz, 2H, 10-H),
2.23 (br, 2H, 6-H), 2.71 (d, J¼10.3 Hz, 1H, OH), 3.85–3.98
(m, 4H, 2-H, 3-H), 4.24 (m, 1H, 7-H), 5.69 (dt, J¼3.6,
9.8 Hz, 1H, 8-H), 5.79–5.89 (m, 1H, 9-H); 13C NMR
(75 MHz, CDCl3) d 36.1 (t, C-10), 39.4 (t, C-6), 64.7 (t,
C-2, C-3), 66.7 (d, C-7), 108.4 (s, C-1), 126.5 (d, C-8),
127.7 (d, C-9).
1373, 1344, 1254, 1217, 1164, 1125, 1086, 992, 933 cmꢀ1
.
Anal. Calcd for C12H16O7: C, 52.94; H, 5.88. Found: C,
52.85; H, 6.24.
4.4.2. Dimethyl 7,8-epoxy-1,4-dioxa-spiro[4,5]decane-
2(R),3(R)-dicarboxylate (10) (minor diastereomer). 1H
NMR (300 MHz, CDCl3) d 1.44–1.56, 1.63–1.78 (2m, 2H,
10-H), 2.0–2.30 (m, 4H, 7-H, 8-H), 3.41 (br, 2H, 7-H, 8-
H), 3.77, 3.78 (2s, 6H, Me), 4.74 (m, 2H, 2-H, 3-H); 13C
NMR (75 MHz, CDCl3) d 23.5 (t, C-10), 29.2 (t, C-9),
36.3 (t, C-6), 52.0 (d, C-8), 52.8 (d, C-7), 53.1, 53.2 (s,
Me), 78.0, 78.1 (2d, C-2, C-3), 113.5 (s, C-1), 171.2, 171.3
(2s, COOMe).
4.3.7. Photooxygenation of ketal 6e. Following procedure
B, compound 6e was irradiated for 7 d. The NMR spectrum
(500 MHz) of the crude product showed exclusively
regioisomer 7e in a diastereomeric ratio of 56:44. The con-
figuration of the main diastereomer was established by sa-
ponification of the corresponding methylester 8a (MeOH/
H2O, catalytic amount of NaOH) and comparison of their
NMR spectra.
4.5. Cleavage of the chiral auxiliary from ketal 7a
4.5.1. Cleavage with HCl. The ketal (S)-7a (100 mg,
0.36 mmol) was dissolved in methanol (10 mL). Hydrochlo-
ric acid (1 N, 0.5 mL) was added dropwise at 0 ꢁC. After
12 h diethyl ether (20 mL) and water (10 mL) were added,
the organic phase was separated, dried (MgSO4), and the sol-
vent was evaporated. NMR analysis of the residue resulted in
a 1:2 mixture of the ketone 11 and phenol (12).
4.3.7.1. 8(S)-Hydroxy-1,4-dioxa-spiro[4,5]dec-6-ene-
2(R),3(R)-dicarboxylic acid (7e) (major diastereomer).
1H NMR (300 MHz, CD3OD) d 1.69–2.0 (m, 2H, 10-H),
2.02–2.30 (m, 2H, 9-H), 4.15 (m, 1H, 8-H), 4.54, 4.56 (2d,
J¼6.6 Hz, 2H, 2-H, 3-H), 5.77 (d, J¼10 Hz, 1H, 6-H),
5.87 (d, J¼10 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3)
d 30.3 (t, C-9), 32.0 (t, C-10), 65.7 (d, C-8), 80.4, 80.7
(2d, C-2, C-3), 107.4 (s, C-5), 129.9 (d, C-6), 135.1 (d,
C-7), 176.7, 176.8 (2s, COOH).
4.5.2. Cleavage with montmorillonite K-10. The ketal (S)-
7a (100 mg, 0.36 mmol) was dissolved in dichloromethane
(10 mL). Montmorillonite K-10 (800 mg) was added at
0 ꢁC and the mixture was stirred at room temperature for
24 h. After filtration and evaporation of the solvent NMR
analysis of the residue resulted in a 4:1 mixture of the ketone
11 and phenol (12).
4.3.7.2. 7(R)-Hydroxy-1,4-dioxa-spiro[4,5]dec-8-ene-
2(R),3(R)-dicarboxylic acid (7e) (minor diastereomer).
1H NMR (300 MHz, CD3OD) d 1.69–2.0 (m, 2H, 10-H),
2.02–2.30 (m, 2H, 9-H), 4.15 (m, 1H, 8-H), 4.48, 4.50 (2d,
J¼6.2 Hz, 2H, 2-H, 3-H), 5.77 (d, J¼10 Hz, 1H, 6-H),
5.87 (d, J¼10 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3)
d 30.2 (t, C-9), 31.7 (t, C-10), 65.7 (d, C-8), 80.4, 80.7
(2d, C-2, C-3), 107.6 (s, C-5), 130.0 (d, C-6), 134.7 (d,
C-7), 177.0, 177.1 (2s, COOH).
4.5.3. Cleavage with buffered montmorillonite K-10. The
ketal (S)-7a (100 mg, 0.36 mmol) was dissolved in dichloro-
methane (10 mL). Sodium acetate (45 mg, 0.4 mmol) and
montmorillonite K-10 (800 mg) were added at 0 ꢁC and

10646
W. Fudickar et al. / Tetrahedron 62 (2006) 10639–10646
E.-M.; Peters, K.; Wirth, T. J. Am. Chem. Soc. 1998, 120,
4091–4093; (c) Adam, W.; Peters, K.; Peters, E.-M.;
Schambony, S. B. J. Am. Chem. Soc. 2001, 123, 7228–7232;
(d) Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc.
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the mixture was stirred at room temperature for 24 h. The
conversion was followed by TLC but was not complete
even after longer reaction times. However, no phenol could
be detected. After filtration and evaporation of the solvent,
flash chromatography (hexane/ethyl acetate¼1:2, Rf¼0.3)
afforded the ketone 11 as a colorless oil (30 mg, 74%,
97% based on the conversion). In addition, unreacted ketal
(S)-7a was recovered (24 mg, 24%).
ꢀ
6. (a) Sunden, H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Cordova,
A. Angew. Chem., Int. Ed. 2004, 43, 6532–6535;
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(b) Cordova, A.; Sunden, H.; Engqvist, M.; Ibrahem, I.;
Casas, J. J. Am. Chem. Soc. 2004, 126, 8914–8915.
7. Fudickar, W.; Fery, A.; Linker, T. J. Am. Chem. Soc. 2005, 127,
9386–9387.
4.5.3.1. 4(S)-Hydroxy-2-cyclohexen-1-one (11). 1H
NMR (300 MHz, CDCl3) d 1.85–2.09 (m, 1H, 5-H), 2.22–
2.45 (m, 2H, 6-H), 2.55–2.68 (m, 1H, 5-H), 4.60 (br, 1H,
4-H), 5.99 (d, J¼10.2 Hz, 1H, 2-H), 6.95 (dt, J¼2.0,
10.2 Hz, 1H, H-3); 13C NMR (75 MHz, CDCl3) d 32.8 (t,
C-5), 35.7 (t, C-6), 66.7 (d, C-4), 129.6 (d, C-2), 153.0 (d,
C-3), 199.1 (s, CO); [a]2D5 ꢀ85.3 (c 0.16, CHCl3), lit.:16
[a]2D0 ꢀ90.0 (c 0.2, CHCl3).
8. (a) Dang, H.-S.; Davies, A. G. Tetrahedron Lett. 1991, 32,
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Acknowledgements
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(e) Frohlich, L.; Linker, T. Synlett 2004, 2725–2727.
This work was generously supported by the Fonds der
Chemischen Industrie and the Deutsche Forschungs-
gemeinschaft (DFG).
10. (a) Alexakis, A.; Mangney, P. Tetrahedron: Asymmetry 1990, 1,
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Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, NY,
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