Solvent- and temperature-controlled inversion of π-facial selectivity in the 1,2-cycloaddition of singlet oxygen to hydroxyphenyl-substituted cyclohexadihydrofurans

Article abstract of DOI:10.1016/j.tet.2017.02.038

Singlet-oxygenation of 3-hydroxyphenyl-substituted dihydrofurans fused with a cyclohexane 1a?c exclusively gave the corresponding syn/anti-stereoisomeric mixtures of dioxetanes 2a?c. The syn/anti-π-facial selectivity in the 1,2-cycloaddition of singlet ox

Full text of DOI:10.1016/j.tet.2017.02.038

Accepted Manuscript
Solvent- and temperature-controlled inversion of π-facial selectivity in the 1,2-
cycloaddition of singlet oxygen to hydroxyphenyl-substituted cyclohexadihydrofurans
Nobuko Watanabe, Kiriko Hiragaki, Kunihiko Tsurumi, Hisako K. Ijuin, Masakatsu
Matsumoto
PII:
S0040-4020(17)30177-1
10.1016/j.tet.2017.02.038
TET 28479
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 January 2017
Revised Date: 13 February 2017
Accepted Date: 17 February 2017
Please cite this article as: Watanabe N, Hiragaki K, Tsurumi K, Ijuin HK, Matsumoto M, Solvent- and
temperature-controlled inversion of π-facial selectivity in the 1,2-cycloaddition of singlet oxygen to
hydroxyphenyl-substituted cyclohexadihydrofurans, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.038.
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ACCEPTED MANUSCRIPT

1
ACCEPTED MANUSCRIPT
Solvent- and temperature-controlled inversion of π-facial selectivity in
the 1,2-cycloaddition of singlet oxygen to hydroxyphenyl-substituted
cyclohexadihydrofurans
Nobuko Watanabe,* Kiriko Hiragaki, Kunihiko Tsurumi, Hisako K. Ijuin,
Masakatsu Matsumoto*
Department of Chemistry, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa
259-1293, Japan
ABSTRACT
Singlet-oxygenation of 3-hydroxyphenyl-substituted dihydrofurans fused with a
cyclohexane 1a−c exclusively gave the corresponding syn/anti-stereoisomeric mixtures
of dioxetanes 2a−c. The syn/anti-π-facial selectivity in the 1,2-cycloaddition of singlet
oxygen (1O2) was found to be remarkably sensitive to the solvent as well as the reaction
temperature. In fact, the solvent effect was so conspicuous that inversion of the
syn/anti-π-facial selectivity was observed in different solvents, such as chloroform and
toluene. An LSER (linear solvation energy relationships) analysis suggested that the
Lewis-acidity/basicity and HBD (hydrogen-bond donor)/HBA (hydrogen-bond
acceptor) ability as well as dipolarity/polarizability of the solvent played an important
role in this change in syn/anti-π-facial selectivity. An investigation of the
temperature-dependency of the singlet-oxygenation suggested that the
syn/anti-π-facial-selective
1,2-cycloaddition
of
1O2
to
1
was
a
conformationally-(entropy-) controlled process.
Keywords:
Singlet-oxygenation
1,2-Cycloaddition of singlet oxygen
Stereoselectivity
Solvent effect
Temperature effect
*Corresponding authors E-mail address: nwatanab@kanagawa-u.ac.jp (N. Watanabe),
matsumo-chem@kanagawa-u.ac.jp (M. Matsumoto).

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1. Introduction
Experimental and theoretical studies have shown that singlet oxygen (1O2) attacks a
carbon-carbon double bond side-on to give a perepoxide intermediate, which rearranges
to a 1,2-dioxetane ([2+2] cycloaddition) or abstracts an allylic hydrogen atom, when
present in a preferential conformation, to form an allylic hydroperoxide (‘ene’ reaction)
(Scheme 1).1-8 Thus, for the singlet-oxygenation of olefins, the substituents sterically
1
and/or electronically direct the incoming O2 to the π-face and the side of the double
bond (π-facial selectivity and side selectivity) to cause mode-,9-12 regio-,13-16 and/or
stereo-selectivity.17-20 In addition to these effects in the chemical reactivity, it has
recently been suggested that one stereochemical pathway is physically deactivated more
rapidly through quenching of the incoming 1O2 by C-H bond vibrations.19,20
O
1O2
O
O
O
[2+2]cycloaddition
H
H
or
H
O
OOH
O
"ene" reaction
H
mode selectivity
side selectivity
-facial selectivity
Scheme 1. Selectivities for the addition of singlet oxygen to an olefin.
These selectivities are often strongly affected by solvent and temperature.19,21-26 For
instance, a change in solvent has been known to cause the inversion of mode-selectivity
in 1,2-cycloaddition vs the ‘ene’ reaction23 or 1,2-cycloaddition vs 1,4-cycloaddition25
for the singlet-oxygenation of certain olefins (dienes). The solvent-dependent inversion
of chemoselectivity (diastereoselectivity) has also been reported for the
1,2-cycloaddition of 1O2 to a mixture of diastereoisomeric olefins.19,20 However, little is
known about a solvent effect so strong that it can cause an inversion of the π-facial
selectivity of 1O2 for 1,2-cycloaddition to an olefin.
In the course of our study on high-performance dioxetane-based chemiluminescent
compounds, we investigated the singlet-oxygenation of oxyphenyl-substituted
dihydrofurans 1 fused with a cyclohexane ring [3,4-cyclohexa-2,3-dihydrofuran:
8-oxabicyclo[4.3.0]non-1(9)-ene] which also had a substituent at the 3-position

3
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1
(Scheme 2). We unexpectedly found that inversion of the π-facial selectivity of O2
occurred to preferentially give dioxetane syn-2 or its stereoisomer anti-2 depending on
the type of solvent. We report here the features of this remarkable solvent effect on the
1
syn/anti-π-facial selectivity in the 1,2-cycloaddition of O2 to bicyclic dihydrofurans 1
together with the thermodynamic aspects of the present singlet-oxygenation.
Scheme 2. Stereoselective formation of syn/anti-dioxetanes
3,4-cyclohexa-2,3-dihydrofurans 1.
2
from
2. Results and discussion
2.1. Synthesis of 5-(hydroxyphenyl)-3,4-cyclohexa-2,3-dihydrofurans
The dihydrofurans bearing a 5-(3-hydroxy)phenyl investigated here possessed
further a substituent, Me (1a), Et (1b), or PhCH2- (1c), at the 3-position (Scheme 2).
4-Hydroxyphenyl-isomer 1d and 3-methoxyphenyl-analog 1e were also investigated for
comparison to 1a in singlet-oxygenation. The bicyclic dihydrofurans 1 were synthesized
through several steps starting from ethyl 3,3-dimethyl-2-oxocyclohexanecarboxylate 3
with a substituent (R) at the 1-position: R = Me for 3a, Et for 3b and PhCH2- for 3c
(Scheme 3). These keto esters were reduced with LiAlH4 to the corresponding diols
4a−4c. Williamson ether synthesis using diol 4a (R = Me) and 3-methoxybenzyl
chloride selectively gave cyclohexylmethyl 3-methoxybenzyl ether 5a. The remaining
OH group of 5a was in turn oxidized with pyridinium chlorochromate (PCC) to give

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2-[(3-methoxy)benzyloxymethyl]cyclohexanone 6a in high yield. Lithium
diisopropylamide (LDA)-mediated cyclization27 of 6a effectively took place to give
hydroxytetrahydrofuran fused with cyclohexane ring 7a, which was successively
dehydrated with SOCl2/pyridine to give 3-methoxyphenyl-substituted bicyclic
dihydrofuran 1e in good yield. Finally, a methoxy group in 1e was deprotected with
CH3SNa/DMF to give the bicyclic dihydrofuran 1a. As shown in Scheme 3, the bicyclic
dihydrofurans 1b and 1c were similarly synthesized starting from 3b and 3c,
respectively. By using p-methoxybenzyl chloride instead of its m-isomer, we prepared
(4-methoxy)phenylmethyl ether 5d via the Williamson synthesis from 4a. Thus,
5-(4-methoxyphenyl)dihydrofuran 1d was synthesized starting from 5d through four
steps 5d→6d→7d→8d→1d (Scheme 3).
Scheme 3. Synthetic pathway starting from 2-oxocyclohexanecarboxylates 3 to
3,4-cyclohexa-2,3-dihydrofurans 1.
2.2.
Solvent effect on the stereoselective 1,2-cycloaddition of singlet oxygen to
5-(oxyphenyl)-3,4-cyclohexa-2,3-dihydrofurans
For the singlet-oxygenation of dihydrofurans 1, dioxetanes syn-2 can be produced
1
when O2 attacks the π-face where a substituent R lies, while stereoisomers anti-2 can
1
form when O2 attacks the opposite π-face (Scheme 2). When a solution of bicyclic

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ACCEPTED MANUSCRIPT
dihydrofuran 1a was irradiated together with a small amount of tetraphenylporphin
(TPP) in toluene with a 940 W Na lamp under an oxygen atmosphere at 0 °C for 30 min,
a mixture of dioxetane syn-2a and its isomer anti-2a (syn/anti = 79/21) was exclusively
produced. Dioxetane syn-2a was isolated in pure form by recrystallization of the
stereoisomeric mixture. On the other hand, the singlet-oxygenation of 1a in chloroform
at 0 °C gave a mixture mainly consisting of anti-2a (syn/anti = 13/87), which was also
isolated in pure form by recrystallization. The structures of syn-2a and anti-2a were
1
determined by H NMR, 13C NMR, IR, Mass, and HRMass spectral analyses. In
addition, X-ray single crystallographic analysis was successfully performed for both
syn-2a and anti-2a: ORTEP views of these dioxetanes are shown in Figure 1. These
results indicate that inversion of the syn/anti-π-facial selectivity occurred between the
1
use of chloroform and toluene for the 1,2-cycloaddition of O2 to 1a. Notably, the
syn/anti-ratios of 2a did not meaningfully change when CDCl3 or toluene-d8 was used
instead of non-deuterated solvents, though the rates of the singlet-oxygenation appeared
1
to be accelerated: the lifetime of O2 is significantly prolonged in a deuterated solvent
1
[lifetime of O2 (x 10-6 s): 60−415 in CHCl3 vs. 300−3600 in CDCl3, and 25−29 in
toluene vs. 310−320 for toluene-d8].28
syn-2a
anti-2a
Figure 1. ORTEP views of dioxetanes syn-2a and anti-2a.
We were surprised to observe such a remarkable solvent effect on stereoselectivity
1
in the 1,2-cycloaddition of O2 to dihydrofuran 1a, even though the syn/anti-π faces of
1a differed from each other only sterically by a 3-methyl group on the bridgehead or a
6-methylene of a cyclohexane ring. We first considered that the change in
syn/anti-π-facial selectivity was related to rotational isomerism of the 3-hydroxyphenyl
group that accompanied a change in the dipole moment, which would be affected by the
solvent polarity. Thus, we examined the singlet-oxygenation of dihydrofuran 1d bearing

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ACCEPTED MANUSCRIPT
a 4-hydroxyphenyl that was symmetric around the bond axis, the rotation of which
might cause only a slight change in the dipole moment. The singlet-oxygenation of
dihydrofuran 1d gave a 10/90 syn/anti-mixture of dioxetane 2d in chloroform, and a
97/3 syn/anti-mixture of 2d in toluene at 0 °C: anti-2d was isolated in pure form,
though syn-2d was unstable and partly decomposed during purification (Scheme 2).
This result showed that rotational isomerism of the aromatic ring did not meaningfully
participate in the solvent-dependent change in syn/anti-π facial selectivity in the
singlet-oxygenation of 1a.
Next, to understand the steric interaction of 1O2 with a 3-substituent (Me for 1a), we
investigated the singlet-oxygenation of dihydrofurans possessing an ethyl 1b or benzyl
1c at the 3-position, which are larger than a methyl group. Under singlet-oxygenation in
chloroform or toluene at 0 °C, ethyl-analog 1b and benzyl-analog 1c exclusively gave
the corresponding syn/anti-mixtures of dioxetane 2b and 2c (Scheme 2). The
syn/anti-ratios for 2b and 2c are summarized together with those for 2a in Table 1. As
1
shown, toluene was rather preferable for syn-π-facial attack by O2, while chloroform
1
was preferable for anti-π-facial attack by O2, regardless of the 3-substituent on 1.
However, we should note the following points with respect of the substituent effect. The
ethyl group of 1b apparently acted to suppress syn-π-facial attack by 1O2 more strongly
than the methyl of 1a. On the other hand, although 1c had a benzyl group, which is far
larger than an ethyl group, 1c allowed syn-π-facial attack by 1O2 more favorably than 1b.
These results suggested that the usual steric interaction was not related to the substituent
1
effect on the syn/anti-π facial selectivity of O2 for the singlet-oxygenation of 1 (vide
infra).
To understand in more detail how the solvent influences the π-facial selectivity, we
investigated the singlet-oxygenation of 1a−1c in four different solvents, including
dichloromethane, acetonitrile, acetone, and methanol, in addition to chloroform and
toluene. In all of these solvents, syn/anti-isomeric mixtures of dioxetanes 2a−c were
selectively produced and their syn/anti ratios markedly changed depending on the
solvent, as summarized in Table 1.
Table 1 shows several notable features in the solvent effect on the
singlet-oxygenation of dihydrofurans 1:
a) Syn-π-facial selectivity (syn-2 selectivity) increased in the order chloroform ≤
methanol < dichloromethane < acetonitrile < toluene < acetone.
b) Syn-2, especially syn-2a and syn-2c, showed high selectivity in polar acetone as well
as in non-polar toluene.
c) Acetonitrile had a much different effect on the syn/anti-stereoselectivity than acetone,

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even though these two solvents resemble each other in terms of measures of polarity,
such as dielectric constant (ε), dipole moment (µ), polarity parameter (ET), and
nucleophilicity/electrophilicity parameter [DN (donor number) /AN (acceptor
number)].29
d) Methanol favored the formation of anti-2 while acetone favored the formation of
syn-2, even though these two solvents have a similar DN/AN.
Table 1. Solvent effect on selectivity of syn/anti-stereoisomeric dioxetanes 2 for the
singlet-oxygenation of dihydrofurans 1.a)
Ratio of syn/anti-dioxetane 2
Solventb)
2a
2b
2c
2e
chloroform
methanolc)
dichloromethane
acetonitriled)
toluene
13 / 87
21 / 79
24 / 76
31 / 69
79 / 21
90 / 10
5 / 95
21 / 79
26 / 74
53 / 47
66 / 34
94 / 6
95 / 5
10 / 90
30 / 70
10 / 90
44 / 56
90 / 10
51 / 49
3 / 97
12 / 88
28 / 72
31 / 69
46 / 54
acetone
a) All reactions were carried out at 0 °C. b) Unless otherwise stated, TPP was used as a
sensitizer. c) Rose Bengal was used as a sensitizer. d) Methylene blue was used as a
sensitizer.
In conclusion, the solvent effect on syn/anti-π-facial selectivity for the
singlet-oxygenation of 1 did not appear to simply correlate with any particular polarity
index or parameter. Thus, we attempted to carry out an LSER (linear solvation energy
relationships) analysis according to the following equation:30
A = ln(syn-2/anti-2) = s(
π
* + d
δ
) + a
α
+ b
β
+ A0
(eq. 1)
where
π
* is an index of solvent dipolarity/polarizability,
α
β
is a measure of the
is a measure of the
solvent hydrogen-bond donor (HBD) and Lewis-acidity,
solvent hydrogen-bond acceptor (HBA) and Lewis-basicity, and
discontinuous polarization correction term (see SD).
δ is a
A multivariate analysis of the data in Table 1 showed that the syn/anti-π-facial
selectivity expressed as ln(syn-2/anti-2) was well correlated with LSER, as shown in

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eqs. 2~4:
ln(syn-2a/anti-2a) = −16.4(
ln(syn-2b/anti-2b) = −2.9(
ln(syn-2c/anti-2c) = −14.7(
π
* + 0.4
* − 0.1
* + 0.3
δ
) − 13.8
) − 4.5 + 4.2
) − 11.3 + 8.9
α
+ 11.4
− 0.2
+ 12.9
β
+ 14.5 (R2= 0.992) (eq. 2)
π
δ
α
β
(R2= 0.964) (eq. 3)
(R2= 0.950) (eq. 4)
π
δ
α
β
Equations 2~4 show negative coefficients for parameters
coefficient for parameter
selectivity was disfavored in a solvent with large dipolarity/polarizability (
and/or HBD ability/Lewis-acidity ( term), and favored in a solvent with large HBA
ability/Lewis-basicity ( term): a non-polar solvent favored syn-π-facial selectivity,
π
* and α, and a positive
β
. Therefore, the LSER analysis suggested that syn-π-facial
* term)
π
α
β
since the A0 term was positive especially for dihydrofurans 1a and 1c. Thus, the solvent
effect on syn/anti-π-facial selectivity for the singlet-oxygenation of 1a as an example
can be explained as follows (see SD):
a) High anti-π-facial selectivity may be mainly attributed to the solvent
dipolarity/polarizability in the case of chloroform, and to the solvent HBD
ability/Lewis-acidity in the case of methanol.
b) The HBA ability/Lewis-basicity (β term) of acetone may play an important role in
the high syn-π-facial selectivity.
According to suggestion b), a phenolic OH (a typical HBD/acid) of 1a may
participate in the expression of syn-π-facial selectivity in acetone (HBA/Lewis base).
Thus, we investigated the solvent effect on the singlet-oxygenation of dihydrofuran 1e
bearing a 3-methoxyphenyl without phenolic OH, which exclusively gave an syn/anti
mixture of dioxetane syn-2e and anti-2e. The results summarized in Table 1 showed that,
as expected, the syn/anti-π-facial selectivity [ratio of syn-2e/anti-2e] in acetone was, in
contrast to the case with 2a, similar to that in acetonitrile, though high syn- and
anti-π-facial selectivities were observed in toluene and chloroform, respectively.
Notably, LSER analysis in the case of 1e suggested that high anti-π-facial selectivity
was mainly attributed to the solvent dipolarity/polarizability: ln(syn-2e/anti-2e) =
−15.0(π*− 0.2δ) + 1.3α − 0.4β
+ 7.1 (R2= 0.981) (eq. 5).
1
For the oxygenation of 1 with small and short-lived O2, the stereochemical
(conformational) change in dihydrofurans 1 would be entirely responsible for the
change in syn/anti-π-facial selectivity. To understand the present singlet-oxygenation,

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the known reactions of the related 5-aryl-2,3-dihydrofurans 9−11 were suggestive:
dihydrofuran 9 selectively gave dioxetane 12, though it possessed an ‘ene’-active allylic
methyl,31 and dihydrofurans 10 and 11 selectively gave the corresponding dioxetanes 13
and 14 with anti-stereochemistry (Scheme 4).32,33 These singlet-oxygenations suggested
that the incoming 1O2 was guided to the side of the dihydrofuran ring, but not to the side
of the 5-aryl group presumably by a “directing effect (cis-effect)”11 of the dihydrofuran
O atom and by a “large-group effect (anti-cis-effect)”34 of the aryl group (Scheme 4).
These effects on the side-selectivity could also play a role in the case of dihydrofurans
1
1a−1e, for which the π-facial selectivity of the incoming O2 may be regulated by the
steric environment around the dihydrofuran ring.
R
R
R
OOH
O
O
1O2
CH3
CH3
CH2
S
R =
HO
HO
HO
N
O
O
O
12
9
"Ene" product
O
O
1O2
TBSO
TBSO
O
O
O
O
O
O
O
H
Ph
H
Ph
10
13
O
O
O
1O2
TBSO
TBSO
O
O
11
14
Scheme 4. Stereoselective 1,2-cycloaddition of singlet oxygen to dihydrofurans 9−11.
As illustrated in Scheme 5, the syn-π-face of dihydrofuran 1a leading to syn-2a is
surrounded by r-3-methyl, cis-9-methyl, and 5-(3-hydroxyl)phenyl groups, like a picket
fence, while the opposite anti-π-face leading to anti-2a is surrounded by 6-methylene,
trans-9-methyl, and 5-(3-hydroxyl)phenyl groups. Depending on the conformational
change in the cyclohexane ring of 1a, these groups may change their relative
stereochemistry such as the distances from the trigonal carbons of the 4,5-double bond,
bond angles, and dihedral angles to open a picket fence or block a π-face for the
incoming 1O2. A theoretical study (conformational search: MMFF and HF/6-31G(d))
suggested that, in the most stable conformer A (chair form), the anti-π-face was less

10
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1
crowded, so that it was more favorable for the incoming O2 than the syn-π-face, while
the steric environment of the syn/anti-π-faces reversed for the next-stable conformer B
with a twist-boat form (15~16 kJ mol-1 less stable), as illustrated in Scheme 5 (SD). The
equilibrium between conformers A and B would change with a change in the solvent
and temperature, and, accordingly, the syn/anti-π-facial selectivity would also change.35
Scheme 5. Steric regulation of the incoming singlet oxygen to the syn/anti-π-faces of
conformers A and B of dihydrofuran 1a.
In addition to steric control of the incoming 1O2 through a conformational change in
the singlet-oxygenation of 1a−1c, we should consider another factor to elucidate the
substituent effect on the syn/anti-π-facial selectivity. As already mentioned, anti-π-facial
selectivity increased in the order benzyl-analog 1c < methyl-analog 1a < ethyl-analog
1b (Table 1). This order did not coincide with the order of the bulkiness of the
3-substituent, i.e., benzyl > ethyl > methyl. However, this discrepancy may be explained
by considering the possible C-H bond-vibrational quenching of 1O2.20, If the
1
3-substituent acts to physically quench the incoming O2, the effect should increase in
the order benzyl < methyl < ethyl, and thus disfavor syn-π-facial selectivity in the same
order: a larger number of C-H bonds to which syn-π-face of the double bond exposes
may more effectively quench the incoming 1O2.

11
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2.3.
Temperature effect on syn/anti-π-facial selectivity for the
1,2-cycloaddition
of
singlet
oxygen
to
3-hydroxyphenyl-substituted
cyclohexadihydrofurans
The results in the previous section suggested that the syn/anti-π-facial selectivity of
1
the 1,2-cycloaddition of O2 was controlled by a conformational change in the
cyclohexane ring in dihydrofurans 1. The conformers of a cyclohexane are generally in
a rapid equilibrium of chair ꢀ twist-boat ꢀ boat, which may be sensitively affected by
temperature. Thus, we carried out the singlet-oxygenation of 1 at various temperatures
ranging from 313 K to 215K in CDCl3 and toluene-d8, and the results are presented in
Figure 2. As shown, although the selectivity of anti-2 tended to increase at lower
temperature in both solvents, chloroform favored the anti-product regardless of the
reaction temperature. Next, using the data obtained regarding the syn/anti-2 ratios at
various temperatures, we estimated the differential activation parameters (∆∆H‡
syn-anti
and ∆∆S‡syn-anti) between the formation of syn-2 and anti-2 by means of the following
Eyring-relation.19,36
ln(ksyn/kanti) = ln(syn-2/anti-2) = ∆∆S‡syn-anti/R − ∆∆H‡syn-anti/RT (eq. 6)
100
80
0
2c in toluene
20
2a in toluene
60
40
60
2c in chloroform
40
2b in toluene
20
80
2a in chloroform
2b in chloroform
100
0
313
293
273
235
215
Reaction temperature /K
Figure 2. Temperature effect on the selectivity of syn/anti-stereoisomeric dioxetanes 2
for the singlet-oxygenation of dihydrofurans 1 in chloroform or toluene.
The results are summarized in Table 2, which shows that contribution of the differential
activation entropy term ∆∆S‡
is relatively high (30−67 J mol-1 K-1), while
syn-anti

12
ACCEPTED MANUSCRIPT
contribution of the differential activation enthalpy term ∆∆H‡syn-anti is appreciable (7−20
kJ mol-1) for a marked temperature dependence of the syn/anti-2 selectivity. Thus, the
syn/anti-π-facial-selective 1,2-cycloaddition of 1O2 to 1 is based on a crucial balance of
the enthalpy and the entropy terms, with the main contribution coming from the latter.
The plots of ln(syn-2/anti-2) vs 1/T according to Eyring equation (eq. 6) are shown in
Figure 3, from which we know that contribution of ∆∆S‡
increases at higher
syn-anti
temperature, while contribution of ∆∆H‡syn-anti relatively increases at lower temperature
and that the syn/anti-2 selectivity may be reversed at a critical temperature even for 2c
in toluene, 2a and 2b in chloroform. The main contribution of the entropy term suggests
that the ease of conformational motion of substrates 1/transition states and their
solvation are decisive in determining the preference for the syn/anti-π-face in the
present reaction.
Table 2. Differential activation parameters (∆∆H‡
and ∆∆S‡syn-anti) between the
syn-anti
formation of dioxetanes syn-2 and anti-2 from dihydrofurans 1a)
Chloroform
∆∆S‡
Toluene
∆∆H‡
∆∆H‡
∆∆S‡
syn-anti
/J mol-1 K-1
syn-anti
/ kJ mol-1
syn-anti
/J mol-1 K-1
syn-anti
/ kJ mol-1
12
19
15
30
49
46
13
20
58
67
48
1a
1b
1c
6.9
3
2
2c in toluene-d8
1
0
2b in toluene-d8
syn-2 > anti-2
2a in toluene-d8
anti-2 > syn-2
2c in CDCl3
-1
-2
-3
2a in CDCl3
-4
-5
2b in CDCl3
3.1
3.3
3.5
3.7
3.9
4.1
4.3
4.5
4.7
1/T x 103

13
ACCEPTED MANUSCRIPT
Figure 3. Eyring plots of the ratios of syn/anti-stereoisomeric dioxetanes 2 produced for
the singlet-oxygenation of dihydrofurans 1 in chloroform or toluene.
3. Conclusion
Singlet-oxygenation of oxyphenyl-substituted dihydrofurans fused with a cyclohexane
1a−1c proceeded smoothly to exclusively give the corresponding dioxetanes 2a−2c with
syn- and anti-stereochemistry with respect to the substituent R at a bridgehead. The
syn/anti-π-facial selectivity of dioxetane formation was remarkably affected by the
solvent. Indeed, the solvent effect was so strong that inversion of the syn/anti-π-facial
selectivity was observed in different solvents, such as chloroform and toluene. An LSER
analysis suggested that the Lewis-acidity/basicity and HBD/HBA ability as well as
dipolarity/polarizability of the solvent played an important role in the change in
syn/anti-π-facial selectivity. The reaction temperature also sensitively affected the
1
stereoselectivity of the 1,2-cycloaddition of O2 to 1, which was found to be an
entropy-controlled process. A change in the conformation of a cyclohexane ring fused to
a dihydrofuran ring was suggested to be responsible for the solvent- and
temperature-sensitive change in the syn/anti-π-facial selectivity for the
1,2-cycloaddition of 1O2 to dihydrofurans 1.
4. Experimental
4.1. General
Melting points were uncorrected. IR spectra were taken on a FT/IR infrared
spectrometer. 1H and 13C NMR spectra were recorded on a 400 MHz, 500 MHz and 600
MHz spectrometers. Mass spectra were obtained using double-focusing mass
spectrometers and an ESI-TOF mass spectrometer. Column chromatography was
carried out using silica gel.
4.2. Data for compounds
4.2.1.
5-(3-hydroxyphenyl)-3,9,9-trimethyl-3,4-cyclohexa-2,3-dihydrofuran (1a); Typical
procedure: solution of
9-(3-Methoxyphenyl)-2,2,6-trimethyl-8-oxabicyclo[4.3.0]non-1(9)-ene (1e) (see SD)
9-(3-Hydroxyphenyl)-2,2,6-trimethyl-8-oxabicyclo[4.3.0]non-1(9)-ene;
A

14
ACCEPTED MANUSCRIPT
(8.87 g, 32.6 mmol) and sodium methanethiolate (95 %, 4.62 g, 62.6 mmol, 1.92 eq.) in
dry DMF (90 mL) was stirred under a N2 atmosphere at 130 ºC for 3 h. The reaction
mixture was poured into sat. aq. NH4Cl and extracted twice with AcOEt. The combined
organic layer was washed five times with sat. aq. NaCl, dried over anhydrous MgSO4
and concentrated in vacuo. The residue was chromatographed on silica gel and eluted
with
AcOEt−hexane
(1:4)
to
give
a
9-(3-hydroxyphenyl)-2,2,6-trimethyl-8-oxabicyclo[4.3.0]non-1(9)-ene (1a) as
colorless solid in 95 % yield (7.99 g). 6-Ethyl-analog 1b, 6-benzyl-analog 1c and
9-(4-hydroxyphenyl)-analog 1d were similarly synthesized.
1a: Colorless needles; mp 111.5−113.0 ºC (from hexane−AcOEt). 1H NMR (500 MHz,
CDCl3): δH 0.81 (s, 3H), 1.18−1.26 (m, 1H), 1.22 (s, 3H), 1.30 (s, 3H), 1.28−1.35 (m,
1H), 1.39−1.44 (m, 1H), 1.54−1.62 (m, 1H), 1.66−1.80 (m, 2H), 3.81 (d, J = 7.8 Hz,
1H), 4.06 (d, J = 7.8 Hz, 1H), 5.22 (broad s, 1H), 6.74 (ddd, J = 8.0, 2.5 and 0.9 Hz, 1H),
6.84 (s with fine coupling, 1H), 6.95 (d with fine coupling , J = 7.6 Hz, 1H), 7.16 (dd, J
= 8.0 and 7.6 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δC 19.1, 25.8, 29.5, 31.5,
31.5, 37.7, 42.5, 46.0, 83.7, 115.7, 117.1, 122.5, 123.4, 128.8, 135.6, 146.9, 155.0 ppm.
IR (KBr): ν̃
3348, 2924, 2860, 1595, 1205, 1045 cm-1. Mass (m/z, %): 258 (M+, 25), 243
(100), 173 (8), 121 (36). HRMS (ESI) (m/z): 259.1692, calcd for C17H23O2 [M + H+]
259.1698. 281.1511, calcd for C17H22O2Na [M + Na+] 281.1517. Anal. Calcd for
C17H22O2: C, 79.03; H, 8.58. Found: C, 79.18; H, 8.79.
1b: 97 % yield. Colorless needles; mp 97.5−100.0 °C (from hexane−AcOEt).
1H NMR (400 MHz, CDCl3): δH 0.81 (s, 3H), 0.99 (t, J = 7.4 Hz, 3H), 1.20 (s, 3H),
1.20−1.74 (m, 6H), 1.82−1.92 (m, 2H), 3.79 (d, J = 8.3 Hz, 1H), 4.20 (d, J = 8.3 Hz,
1H), 4.83 (broad s, 1H), 6.78 (dd, J = 8.1 and 2.7 Hz, 1H), 6.87 (s with fine coupling,
1H), 6.98 (d with fine coupling, J = 7.6 Hz, 1H), 7.18 (dd, J = 8.1 and 7.6 Hz, 1H) ppm.
13C NMR (125 MHz, CDCl3): δC 8.7, 19.3, 28.8, 31.0, 31.7, 31.9, 37.3, 43.0, 49.7, 81.2,
115.6, 117.2, 119.6, 122.8, 128.8, 136.0, 148.0, 155.0 ppm. IR (KBr): ν̃ 3322, 2977,
2961, 2926, 2862, 1593, 1445, 1209, 1048 cm-1. Mass (m/z, %): 272 (M+, 15), 257 (11),
244 (23), 243 (100), 173 (14), 139 (11), 121 (35). HRMS (ESI): 273.1882, calcd for
C18H25O2 [M + H+] 273.1855. 295.1683, calcd for C18H24O2Na [M + Na+] 295.1674.
Anal. Calcd for C18H24O2: C, 79.37; H, 8.88. Found: C, 79.63; H, 9.25.
1c: 95 % yield. Colorless needles; mp 161.0−162.0 °C (from AcOEt). 1H NMR (500
MHz, CDCl3): δH 0.86 (s, 3H), 1.04−1.12 (m, 1H), 1.26−1.35 (m, 1H), 1.36 (s, 3H),
1.49−1.54 (m, 1H), 1.60−1.66 (m, 1H), 1.85−1.97 (m, 2H), 2.76 (d, J = 13.3 Hz, 1H),
3.06 (d, J = 13.3 Hz, 1H), 3.45 (d, J = 8.5 Hz, 1H), 4.38 (d, J = 8.5 Hz, 1H), 5.42 (s,
1H), 6.74 (dd, J = 8.2 and 2.3 Hz, 1H), 6.86 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.16 (dd, J

15
ACCEPTED MANUSCRIPT
13
= 8.2 and 7.8 Hz, 1H), 7.18−7.32 (m, 5H) ppm. C NMR (125 MHz, CDCl3): δC 18.8,
30.0, 31.6, 31.9, 33.6, 41.0, 42.7, 50.3, 78.5, 115.7, 117.0, 122.7, 123.1, 126.1, 128.0
(CH x 2), 128.9, 130.8(CH x 2), 135.8, 138.4, 148.3, 155.0 ppm. IR (KBr): ν̃ 3307,
2985, 2927, 2863, 1597, 1442, 1318, 1212, 1018 cm-1. Mass (m/z, %): 334 (M+, trace),
244 (17), 243 (100), 173 (21), 121 (44), 115 (12), 107 (12), 93 (18), 91 (89), 69 (10), 65
(38), 55 (10). HRMS (ESI): 335.2096, calcd for C23H27O2 [M + H+] 335.2011.
357.1845, calcd for C23H26O2Na [M + Na+] 357.1830. Anal. Calcd for C23H26O2: C,
82.60; H, 7.84. Found: C, 82.75; H, 8.09.
1d: 92 % yield. Colorless columns; mp 155.5−157.0 °C (from AcOEt). 1H NMR (400
MHz, CDCl3): δH 0.79 (s, 3H), 1.17−1.44 (m, 3H), 1.22 (s, 3H), 1.29 (s, 3H), 1.52−1.79
(m, 3H), 3.77 (d, J = 7.8 Hz, 1H), 4.03 (d, J = 7.8 Hz, 1H), 4.95 (broad s, 1H),
6.73−6.78 (m, 2H), 7.24−7.28 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δC 19.2, 25.9,
29.6, 31.6, 31.6, 37.8, 42.6, 46.0, 83.5, 114.6 (x 2), 122.5, 126.9, 131.4 (x 2), 147.2,
155.9 ppm. IR (KBr): ν̃
3374, 2925, 1666, 1608, 1511, 1460, 1273, 1225 cm-1. Mass
(m/z, %): 258 (M+, 20), 244 (20), 243 (100), 173 (8), 121 (47), 107 (8), 93 (7). HRMS
(ESI): 259.1688, calcd for C17H23O2 [M + H+] 259.1698. 281.1511, calcd for
C17H22O2Na [M + Na+] 281.1517. Anal. Calcd for C17H22O2: C, 79.03; H, 8.58. Found:
C, 79.20; H, 8.97.
1
1e: Colorless plates; mp 52.5−55.0 ºC (from hexane). H NMR (600 MHz, CDCl3): δH
0.81 (s, 3H), 1.20−1.26 (m, 1H), 1.24 (s, 3H), 1.30−1.36 (m, 1H), 1.31 (s, 3H),
1.40−1.45 (m, 1H), 1.55−1.60 (m, 1H), 1.67−1.80 (m, 2H), 3.81 (s, 3H), 3.81 (d, J = 7.8
Hz, 1H), 4.05 (d, J = 7.8 Hz, 1H), 6.86 (dd with fine coupling, J = 8.3, and 2.7, 1H),
6.93 (s with fine coupling, 1H), 6.98 (d with fine coupling, J = 7.5 Hz, 1H), 7.23 (dd, J
= 8.3 and 7.5 Hz, 1H) ppm. 13C NMR (150 MHz, CDCl3): δC 19.2, 25.9, 29.6, 31.5,
31.6, 37.8, 42.6, 46.1, 55.2, 83.8, 114.4, 115.2, 122.7, 122.9, 128.6, 136.0, 147.5, 158.9
ppm. IR (KBr): ν̃ 2962, 2927, 2862, 1593, 1462, 1429, 1317, 1269, 1269, 1232, 1182,
1043 cm-1. Mass (m/z, %): 272 (M+, 25), 258 (20), 257 (100), 187 (7), 136 (8), 135 (23),
121 (9), 107 (8). HRMS (ESI): 295.1690, calcd for C18H24O2Na [M + Na+] 295.1674.
Anal. Calcd for C18H24O2: C, 79.37; H, 8.88. Found: C, 79.46; H, 9.14.
4.3. Singlet-oxygenation of dihydrofurans 1
4.3.1. Isolation
of
6-substituted
(2):
9-(3-hydroxyphenyl)-2,2-dimethyl-8,10,11-trioxatricyclo[5.4.0.01,4]undecane
Although the singlet-oxygenation of dihydrofurans 1 was carried out at 0 ºC in
chloroform or in toluene in an initial experiment, the improved procedures to
individually isolate anti- and syn-2 are described here.

16
ACCEPTED MANUSCRIPT
4.3.1.1. Isolation of syn-2; general procedure: A solution of 1 (ca 1.0 mmol) and TPP
(ca 2.0 mg) in acetone (15 mL) was irradiated externally with 940W Na lamp under an
O2 atmosphere at 0 ºC for 7.5 h. After concentration, the photolysate was
chromatographed on silica gel (ether-CH2Cl2, 1 : 40) to exclusively give a mixture of
syn-2 (major) and anti-2 (minor) as a pale yellow solid. Pure syn-2 was isolated by
recrystallization from hexane-CH2Cl2.
syn-2a: Colorless plates; mp 145.0−148.0 ºC (dec.) (from hexane−CH2Cl2). 1H NMR
(500 MHz, CDCl3): δH 0.82 (s, 3H), 0.84 (s, 3H), 1.13 (s, 3H), 1.20−1.30 (m, 2H),
1.44−1.50 (m, 1H), 1.56−1.82 (m, 3H), 3.78 (d, J = 8.2 Hz, 1H), 4.44 (d, J = 8.2 Hz,
1H), 5.20 (broad s, 1H), 6.85 (d with fine coupling, J = 8.2 Hz, 1H), 6.94−7.30 (m, 2H),
13
7.26 (dd, J = 8.2 and 7.3 Hz, 1H) ppm. C NMR (125 MHz, CDCl3): δC 15.6, 17.4,
21.3, 26.9, 34.9, 35.6, 37.2, 44.0, 77.6, 103.0, 114.7 (broad CH), 116.3, 116.8, 120.1
(broad CH), 129.4, 138.1, 155.4 ppm. IR (KBr): ν̃ 3448, 2977, 2917, 1604, 1218, 1034
cm-1. Mass (m/z, %): 290 (M+, 4), 152 (28), 138 (22), 121 (100). HRMS (ESI):
313.1410, calcd for C17H22O4Na [M + Na+] 313.1416. Anal. Calcd for C17H22O4: C,
70.32; H, 7.64. Found: C, 70.40; H, 7.81.
syn-2b: Colorless columns; mp 142.5−145.0 °C (dec) (from hexane−CH2Cl2).
1H NMR (500 MHz, CDCl3): δH 0.83 (s, 3H), 0.83 (s, 3H), 0.92 (t, J = 7.6 Hz, 3H),
1.19−1.31 (m, 2H), 1.42−1.69 (m, 4H), 1.75−1.84 (m, 1H), 1.93−1.99 (m, 1H), 3.83 (d,
J = 8.7 Hz, 1H), 4.57 (d, J = 8.7 Hz, 1H), 5.37 (broad s, 1H), 6.84 (dd, J = 8.7 and 2.3
13
Hz, 1H), 6.90−7.40 (m, 2H), 7.25 (dd, J = 8.7 and 6.9 Hz, 1H) ppm. C NMR (125
MHz, CDCl3): δC 8.89, 17.3, 21.4, 21.4, 27.2, 30.0, 35.6, 37.2, 48.0, 75.5, 103.8, 114.8
(broad CH), 116.3, 116.9, 120.0 (broad CH), 129.4, 138.1, 155.4 ppm. IR (KBr): ν
̃
3440, 2973, 2938, 1604, 1450, 1307, 1218, 1050, 1018 cm-1.Mass (m/z, %): 304 (M+, 4),
166 (31), 139(12), 138 (36), 121 (100), 109 (11), 95 (20), 93 (14), 82 (33), 69 (17).
HRMS (ESI): 327.1556, calcd for C18H24O4Na [M + Na+] 327.1572. Anal. Calcd for
C18H24O4: C, 71.03; H, 7.95. Found: C, 71.18; H, 8.16.
syn-2c: Colorless needless; mp 140.0−142.5 °C (dec.) (from hexane−CH2Cl2).
1H NMR (500 MHz, CDCl3): δH 0.87 (s, 3H), 0.96 (s, 3H), 1.28−1.38 (m, 2H),
1.49−1.60 (m, 2H), 1.73−1.85 (m, 1H), 2.02−-2.08 (m, 1H), 2.99 (qAB, J = 13.3 Hz, 2H),
3.26 (d, J = 8.9 Hz, 1H), 4.68 (d, J = 8.9 Hz, 1H), 4.96 (broad s, 1H), 6.84 (dd, J = 8.7
13
and 2.3 Hz, 1H), 6.88−7.50 (m, 8H) ppm. C NMR (125 MHz, CDCl3): δC 17.2, 21.7,
27.5, 30.5, 34.4, 35.8, 37.3, 48.4, 75.6, 103.3, 114.7 (broad CH), 116.4, 116.8,
120.1(broad CH), 126.6, 128.3 (CH x 2), 129.5, 130.3 (CH x 2), 137.6, 138.1, 155.4
ppm. IR (KBr): ν
(m/z, %): 229 (M+-137, 21), 228 (100), 213 (17), 144 (11), 131 (13), 129 (17), 121 (58),
̃
3470, 2936, 1604, 1453, 1310, 1225, 1077, 1048, 1025 cm-1. Mass

17
ACCEPTED MANUSCRIPT
109 (10), 93 (13), 91 (31), 69 (10). HRMS (ESI): 389.1701, calcd for C23H26O4Na [M +
Na+] 389.1729. Anal. Calcd for C23H26O4: C, 75.38; H, 7.15. Found: C, 75.25; H, 7.25.
syn-2d: Pale yellow oil. 1H NMR (600 MHz, CDCl3): δH 0.82 (s, 3H), 0.84 (s, 3H), 1.12
(s, 3H), 1.14−1.24 (m, 2H), 1.42−1.49 (m, 1H), 1.56−1.65 (m, 1H), 1.67−1.80 (m, 2H),
3.76 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 8.4 Hz, 1H), 5.24 (broad s, 1H), 6.82 (d with fine
13
coupling, J = 9.0 Hz, 2H), 7.34−7.60 (m, 2H) ppm. C NMR (150 MHz, CDCl3): δC
15.7, 17.4, 21.4, 26.7, 34.9, 35.6, 37.2, 43.9, 77.2, 102.6, 114.9 (broad CH x 2), 117.2,
128.6, 129.4 (broad CH x 2), 156.5 ppm. IR (liquid film): ν̃ 3379, 2933, 2871, 1608,
1693, 1517, 1514, 1460, 1275, 1165 cm-1. Mass (m/z, %): 291 (M++1, 6), 290 (M+, 15),
181 (26), 153 (23), 152 (29), 138 (15), 137 (31), 136 (23), 125 (10), 124 (19), 123 (14),
122 (13), 121 (100), 109 (13), 95 (17), 93 (10), 82 (13), 81(24), 69 (35), 55 (11). HRMS
(ESI): 313.1404, calcd for C17H22O4Na [M + Na+] 313.1416.
syn-2e: Colorless oil. 1H NMR (400 MHz, CDCl3): δH 0.81 (s, 3H), 0.84 (s, 3H), 1.14 (s,
3H), 1.20−1.32 (m, 2H), 1.44−1.51 (m, 1H), 1.56−1.85 (m, 3H), 3.78 (d, J = 8.4 Hz,
1H), 3.82 (s, 3H), 4.45 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.3 and 2.5 Hz, 1H), 7.00−7.36
(m, 2H), 7.31 (dd, J = 8.3 and 7.5Hz, 1H) ppm. 13C NMR (150 MHz, CDCl3): δC 15.6,
17.4, 21.3, 26.9, 34.9, 35.6, 37.2, 43.9, 55.3, 77.5, 102.8, 113.3, 114.9 (broad CH),
116.9, 120.0 (broad CH), 129.1, 137.9, 159.2 ppm. IR (liquid film): ν̃ 2935, 2887, 1603,
1586 cm-1. Mass (m/z, %): 304 (M+, 10), 152 (51), 135 (100), 124 (11), 107 (13).
HRMS (ESI): 327.1545, calcd for C18H24O4Na [M + Na+] 327.1572.
4.3.2. Isolation of anti-2; general procedure: A solution of 1 (ca 1.0 mmol) and TPP
(ca 2.0 mg) in CH2Cl2 (15 mL) was irradiated externally with 940 W Na lamp under an
O2 atmosphere at -78 ºC for 2.5 h. After concentration, the photolysate was
chromatographed on silica gel (ether−CH2Cl2, 1 : 40) to exclusively give of a mixture of
anti-2 (major) and syn-2 (minor) as a pale yellow solid. Pure anti-2 was isolated by
recrystallization from hexane−CH2Cl2.
anti-2a: Colorless column; mp 121.5−123.0 ºC (dec.) (from hexane−CH2Cl2). 1H NMR
(500 MHz, CDCl3): δH 0.76 (s, 3H), 1.10−1.16 (m, 1H), 1.26 (s, 3H), 1.35−1.50 (m, 3H),
1.38 (s, 3H), 1.54−1.64 (m, 2H), 3.97 (d, J = 7.8 Hz, 1H), 4.70 (d, J = 7.8 Hz, 1H), 5.11
(broad s, 1H), 6.86 (d with fine coupling, J = 8.5 Hz, 1H), 7.12 (s with fine coupling,
1H), 7.19 (d with fine coupling, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz 1H) ppm. 13C NMR
(125 MHz, CDCl3): δC 17.9, 22.1, 22.5, 27.2, 27.3, 35.5, 36.2, 44.6, 81.1, 105.5, 114.0,
114.6, 116.5, 120.0, 129.6, 136.3, 155.4 ppm. IR (KBr): ν̃ 3454, 2972, 2926, 1590,
1489, 1469, 1316, 1198 cm-1.Mass (m/z, %): 290 (M+, 7), 203 (15), 153 (13), 152 (44),
138 (33), 121 (100), 109 (22), 93 (19), 82 (37), 81 (27), 65 (10), 55 (11).HRMS (ESI):

18
ACCEPTED MANUSCRIPT
313.1426, calcd for C17H22O4Na [M + Na+] 313.1416. Anal. Calcd for C17H22O4: C,
70.32; H, 7.64. Found: C, 70.34; H, 7.81.
anti-2b: Colorless granules; mp 134.5−136.5 °C (dec.) (from hexane−CH2Cl2). 1H
NMR (500 MHz, CDCl3): δH 0.78 (s, 3H), 1.00 (t, J = 7.3 Hz, 3H), 1.13−1.17 (m, 1H),
1.28 (s, 3H), 1.35−1.55 (m, 5H), 1.62−1.65 (m, 1H), 1.85−1.92 (m, 1H), 4.33 (d, J = 7.8
Hz, 1H), 4.50 (dd, J = 7.8 and 1.8 Hz, 1H), 5.36 (s, 1H), 6.84 (dd, J = 7.8 and 2.7 Hz,
1H), 7.09 (s with fine coupling, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H)
ppm. 13C NMR (125 MHz, CDCl3): δC 9.42, 17.7, 22.3, 22.6, 22.8, 27.9, 35.6, 36.1,
48.8, 74.1, 106.3, 113.7, 114.6, 116.5, 120.0, 129.5, 136.1, 155.5 ppm. IR (KBr): ν
3449, 2967, 2940, 1604, 1218 cm-1. Mass (m/z, %): 304 (M+, 7), 217 (14), 166 (60), 138
̃
(81), 121 (100), 109 (23). HRMS (ESI): 327.1560, calcd for C18H24O4Na [M + Na+]
327.1572. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.01; H, 8.15.
anti-2c: Colorless plates; mp 142.5−145.0 °C (dec.) (from hexane−CH2Cl2). 1H NMR
(500 MHz, CDCl3): δH 0.88 (s, 3H), 1.22−1.27 (m, 1H), 1.34 (s, 3H), 1.36−1.58 (m, 3H),
1.72−1.77 (m, 1H), 1.82−1.92 (m, 1H), 2.69 (d, J = 13.3 Hz, 1H), 3.17 (d, J = 13.3 Hz,
1H), 4.22 (d, J = 8.2 Hz, 1H), 4.34 (d with fine coupling, J = 8.2 Hz, 1H), 5.20 (s, 1H),
6.86−6.91 (m, 1H), 7.22−7.38 (m, 8H) ppm. 13C NMR (125MHz, CDCl3): δC 17.8, 22.5,
23.2, 27.9, 35.5, 35.6, 36.3, 49.2, 73.7, 106.0, 113.7, 114.7, 116.7, 120.1, 126.7, 128.4
(x 2), 129.7, 130.9 (x 2), 136.1, 137.9, 155.5 ppm. IR (KBr): ν̃ 3428, 2939, 1604, 1220
cm-1. Mass (m/z, %): 229 (M+-137, 21), 228 (100), 213 (17). HRMS (ESI): 389.1728,
calcd for C23H26O4Na [M + Na+] 389.1729. Anal. Calcd for C23H26O4: C, 75.38; H, 7.15.
Found: C, 75.18; H, 7.29.
1
anti-2d: Pale yellow amorphous solid. H NMR (600 MHz, CDCl3): δH 0.73 (s, 3H),
1.11−1.14 (m, 1H), 1.24 (s, 3H), 1.34−1.48 (m, 3H), 1.37 (s, 3H), 1.54−1.65 (m, 2H),
3.95 (d, J = 7.5 Hz, 1H), 4.68 (d with fine coupling, J = 7.5 Hz, 1H), 5.19 (s, 1H), 6.84
(d with fine coupling, J = 8.8 Hz, 2H), 7.50 (d with fine coupling, J = 8.7 Hz, 2H) ppm.
13C NMR (150 MHz, CDCl3): δC 18.0, 22.0, 22.5, 27.1, 27.2, 35.5, 36.1, 44.6, 80.8,
105.1, 114.3, 115.1 (CH x 2), 126.9, 129.2 (CH x 2), 156.6 ppm. IR (KBr): ν̃ 3365,
2935, 1613, 1517, 1445, 1325, 1277, 1227, 1016, 983 cm-1. Mass (m/z, %): 290 (M+, 2),
258 (10), 243 (15), 152 (26), 138 (15), 124 (15), 123 (10), 121 (100), 82 (10), 69 (11).
HRMS (ESI): 313.1402, calcd for C17H22O4Na [M + Na+] 313.1416.
1
anti-2e: Colorless columns; mp 110.0-112.0 °C (from hexane−CH2Cl2). H NMR (600
MHz, CDCl3): δH 0.75 (s, 3H), 1.10−1.15 (m, 1H), 1.26 (s, 3H), 1.36−1.50 (m, 3H),
1.39 (s, 3H), 1.56−1.65 (m, 2H), 3.83 (s, 3H), 3.98 (d, J = 7.5 Hz, 1H), 4.71 (d, J = 7.5
Hz, 1H), 6.93 (dd, J = 8.2 and 2.6 Hz, 1H), 7.18 (s with fine coupling, 1H), 7.21 (broad
d with fine coupling, J = 7.7 Hz, 1H), 7.32 (dd, J = 8.2 and 7.7 Hz, 1H) ppm. 13C NMR

19
ACCEPTED MANUSCRIPT
(150 MHz, CDCl3): δC 17.9, 22.1, 22.5, 27.2, 27.3, 35.4, 36.1, 44.6, 55.3, 81.0, 105.4,
113.1, 114.1, 115.1, 119.9, 129.3, 136.1, 159.4 ppm. IR (KBr): ν̃ 2965, 2920, 1610,
1582 cm-1. Mass (m/z, %): 304 (M+, 7), 152 (49), 135 (100), 124 (11), 107 (14), 82 (12).
HRMS (ESI): 327.1526, calcd for C18H24O4Na [M + Na+] 327.1572.
4.3.3. Solvent dependency of syn/anti-π-facial selectivity for the singlet-oxygenation
of dihydrofuran 1; general procedure: A solution of dihydrofuran 1 (ca. 1x10-5 mol)
and TPP (ca. 5x10-7 mol) in chloroform, dichloromethane, acetone, or toluene (2mL)
was irradiated with 940 W Na lamp under an oxygen atmosphere at 0 °C for 30 min.
After concentration in vacuo, the photolysate was dissolved in CDCl3 and the
1
syn/anti-ratio of dioxetane 2 was measured by H NMR. In methanol, Rose Bengal
was used as a sensitizer, while, in acetonitrile, Methylene Blue was used as a sensitizer.
4.3.4. Temperature dependency of syn/anti-π-facial selectivity for the
singlet-oxygenation of dihydrofuran 1; general procedure: A solution of 1 (ca. 1x10-5
mol) and TPP (ca. 5x10-7 mol) in CDCl3 or toluene-d8 (2mL) was irradiated with 940 W
Na lamp under an oxygen atmosphere at 313, 293, 273, 235, or 215 K for 30 180 min.
In the case of the reactions in toluene-d8, after concentration in vacuo, the photolysate
1
was dissolved in CDCl3 and the syn/anti-ratio of dioxetane 2 was measured by H
NMR.
4.4. X-ray single crystallographic analysis
X-ray diffraction data were collected on a Rigaku Mercury CCD diffractometer with
graphite monochromated Mo Kα (λ=0.71070 Å) radiation. Data were processed using
CrystalClear.*1 The structures were solved by direct method (SIR2008) *2 and expanded
using Fourier techniques. All non-hydrogen atoms were refined anisotropically. The
hydrogen atoms were refined using the riding model. The final cycle of full-matrix
least-squares refinement on F2 was based on 3376 and 6407 observed reflections and
212 and 423 variable parameters respectively (for syn-2a and anti-2a). All calculations
were performed using the CrystalStructure crystallographic software package.*3,4
Crystal data for syn-2a: C17H22O4, (Mr = 290.36), colorless block, 0.20 x 0.20 x 0.10
mm, orthorhombic, space group Pbca (#61), a = 8.59(6) Å, b = 15.60(4) Å, c =
22.12(7) Å, V = 2964(25) Å 3, Z = 8, ρcalcd = 1.301 g cm-3, T = 150 K, F(000) = 1248.00,
reflections collected/unique 27618 / 3376 (Rint = 0.0915), ꢀ(MoKα) = 0.914 cm-1. An
empirical absorption correction was applied which resulted in transmission factors
ranging from 0.765 - 0.991. The data were corrected for Lorentz and polarization

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ACCEPTED MANUSCRIPT
effects. R1 = 0.0690 [ I >2σ(I)], wR2= 0.2014 (all data), GOF on F2 = 1.006, and
residual electron density 0.69 / -0.63 e-Å-3.
Crystal data for anti-2a: C17H22O4, (Mr = 290.36), colorless platelet, 0.10 x 0.05 x
0.05 mm, triclinic, space group P-1 (#2), a = 8.49(3) Å, b = 13.60(5) Å, c =13.60(5) Å,
α= 107.593º, β = 90.0000º, γ= 90.0000º, V = 1496(9) Å 3, Z = 4, ρcalcd = 1.289 g cm-3, T
= 150 K, F(000) = 624.00, reflections collected/unique 14956 / 6407 (Rint = 0.0523),
ꢀ(MoKα) = 0.905 cm-1. An empirical absorption correction was applied which resulted
in transmission factors ranging from 0.857-0.995. The data were corrected for Lorentz
and polarization effects. R1 = 0.0619 [I >2σ(I)], wR2= 0.0784 (all data), GOF on F2 =
1.011, and residual electron density 1.02 / -0.59 e-Å-3.
Crystallographic data for the structural analysis of compound syn-2a and anti-2a
has been deposited at the Cambridge Crystallographic Data Center, CCDC-1520410 and
1520409. Free Copies of the data can be obtained, via http//www.ccdc.cam.
ac.uk/conts/retrieving.html(or from the Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
*1; CrystalClear: Data Collection and Processing Software, Rigaku Corporation
(1998-2014). Tokyo 196-8666, Japan.
*2; SIR2008: Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L.,
De Caro, L., Giacovazzo, C., Polidori, G. Siliqi, D. and Spagna R. (2007). J. Appl.
Cryst. 40, 609-613.
*3; CrystalStructure 4.1: Crystal Structure Analysis Package, Rigaku and Rigaku /
MSC (2000-2003). 9009 New Trails Dr. The Woodlands TX 77381 USA.
*4; CRYSTALS Issue 11: Carruthers, J.R., Rollett, J. S., Betteridge, P.W., Kinna, D.,
Pearce, L., Larsen, A., and Gabe, E. Chemical Crystallography Laboratory,
Oxford, UK. (1999).
Acknowledgements
The authors gratefully acknowledge financial assistance in the form of Grants-in-aid
(Nos. 25350269, 25410056, 25410057 and 16K05707) for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Technology, Japan. The author
(NW) further acknowledges financial support from the Strategic Research Base
Development Program for Private Universities of the Ministry of Education, Culture,
Sports, Science and Technology of Japan.

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Supplementary data
Supplementary data associated with this article can be found in the online version, at
xxxxx.
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