Stereocontrolled intramolecular meta-arene-alkene photocycloaddition reactions using chiral tethers: Efficiency of the tether derived from 2,4-pentanediol

Article abstract of DOI:10.1016/j.tetasy.2004.11.086

Photochemical reactions of substrates consisting of phenyl and vinyl groups, which are tethered with a chiral diol, resulted in intramolecular meta-arene-alkene cycloaddition; the reaction efficiency as well as the stereoselectivity was studied. 1,3-Butanediol, 2-substituted 1,3-propanediols, 2-methyl-2,4-penetanediol, and 2,6-dimethyl-3,5-heptanediol were employed as tethers, and the results are compared with those obtained with 2,4-pentanediol (PD) tether, which are known to show high stereoselectivity and moderate efficiency. All the reactions with the lower analogues were less efficient than with PD, although one of the butanediol-tethered reactions afforded a single stereoisomer as PD did. The dimethylheptanediol tether showed similar efficiency but lower stereoselectivity than PD. The results suggest that the PD tether has an optimized structure having a proper flexibility.

Full text of DOI:10.1016/j.tetasy.2004.11.086

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 675–683
Stereocontrolled intramolecular meta-arene–alkene
photocycloaddition reactions using chiral tethers: efficiency
of the tether derived from 2,4-pentanediol
Takashi Sugimura,* Akiko Yamasaki and Tadashi Okuyama
Graduate School of Material Science, Himeji Institute of Technology, University of Hyogo, 3-2-1 Kohto,
Kamigori, Ako-gun, Hyogo 678-1297, Japan
Received 16 October 2004; accepted 9 November 2004
Available online 22 January 2005
Abstract—Photochemical reactions of substrates consisting of phenyl and vinyl groups, which are tethered with a chiral diol,
resulted in intramolecular meta-arene–alkene cycloaddition; the reaction efficiency as well as the stereoselectivity was studied.
1,3-Butanediol, 2-substituted 1,3-propanediols, 2-methyl-2,4-penetanediol, and 2,6-dimethyl-3,5-heptanediol were employed as teth-
ers, and the results are compared with those obtained with 2,4-pentanediol (PD) tether, which are known to show high stereoselec-
tivity and moderate efficiency. All the reactions with the lower analogues were less efficient than with PD, although one of the
butanediol-tethered reactions afforded a single stereoisomer as PD did. The dimethylheptanediol tether showed similar efficiency
but lower stereoselectivity than PD. The results suggest that the PD tether has an optimized structure having a proper flexibility.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
group to give a pair of the regioisomers, 4 and 5, but
their stereoisomers, 2 and 3, were not produced (Scheme
1).3 The stereochemistries of the photoproducts indicate
that the PD tethers in 1a and 1b exclusively promote the
addition at the si-face of the vinyl group. The regioiso-
meric ratio 4/5 is different between 1a and 1b. The ratio
originates not only from the reactivities of the generated
biradical intermediates, but largely from the difference
in extinction coefficients of the products, which affects
their interconversion, and so it depends on the reaction
conditions.
The chiral tethered reaction is applicable to a wide range
of asymmetric syntheses when the tether is made of opti-
cally active 2,4-pentanediol (PD).1 The meta-arene–alk-
ene photocycloaddition2 is one of such examples that
display high stereoselectivities unattainable by intermo-
lecular reactions. By the photoirradiation of 1a having
(2R,4S)-PD or 1b having (2R,4R)-PD, the vinyl group
adds to the 2,6-position of the phenyl group under suf-
ficient differentiation of the stereofaces of the vinyl
2R
O
4S
O
2S
O
4R
O
Rn
Rn
O
O
O
O
O
O
O
O
1c
or
1a
or
2R
hν
hν
4
5
2
3
O
O
+
+
4R
O
2S
O
hν
hν
4S
O
O
O
O
Rn
Rn
1d
1b
Scheme 1. The PD-tethered meta-arene–alkene photocycloadditions.
*
Corresponding author. Tel.: +81 791 58 0168; fax: +81 791 58 0115; e-mail: sugimura@sci.himeji-tech.ac.jp
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.086

676
T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
The essential difference between the two substrates is in
the efficiency of their intermolecular photocycloaddi-
tion. Under the same reaction conditions, the transform-
ation of 1a to 4a and 5a is 2.6 times faster than that
of 1b to 4b and 5b. Considering the equal absorption
of 1a and 1b, the quantum yield of the addition reaction
(/add) is larger with 1a than that with 1b by the same
ratio of 2.6. The efficiency in this reaction system is a
crucial factor to obtain the product in a good yield be-
cause of the potential formation of polymeric products
under photoirradiation. The isolated product yield was
70% in the reaction of 1a, while 55% in that of 1b under
the optimized conditions. Although those yields are very
high for meta-arene–alkene photocycloadditions, the
performance of the PD-tether to promote the intramo-
lecular addition is still not always high. For example,
when the reaction of 1a was applied to either isomer
of the tolyl analogues, the yield of the photoadducts is
only in a range of 29–33%, which further decreases to
19% when the substrate has a 3,5-xylyl group.3b
other products were assigned by comparison of the CD
spectra and the photoconversion to the corresponding
regioisomers.
Under the present photochemical conditions, the total
yields with 1c and 1d were a little lower than the re-
ported yields with 1a and 1b under the optimized condi-
tions (Table 1, entries 1–4). The stereochemical
outcomes observed suggest that the stereodirection by
the 2-methyl group (a-methyl) on the tether is stronger
than that by the 4-methyl group (c-methyl). This postu-
lation can be proved by the reaction with substrates 1e
and 1f having a singly methylated tether. The reaction
of 1e having (R)-a-methyl proceeded through the addi-
tion exclusively at si-face of the vinyl group to give a
regioisomeric mixture of 4e and 5e (entry 5). The strict
stereocontrol attained by the single methyl group indi-
cates strong stereocontrollability of the chiral tethered
reactions.5 In the case of 1f having (R)-c-methyl, the
addition at re-face was preferred to the si-face addition,
but the stereocontrol was not rigorous to give pairs
of regioisomers in a ratio of (2f + 3f)/(4f + 5f) = 79/21
(entry 6). The stereodirection as well as its degree ob-
served with 1e and 1f is well consistent with the results
obtained with 1c and 1d. The results indicate that the
reaction with a PD-tether is efficient when the two
methyl groups match in their stereodirection.
The PD-tether is flexible during the reaction, and the
flexibility regulated by the two methyl groups. Herein,
we consider the structure of the tether with regard to
its ability to cause the intramolecular meta-photocyclo-
addition, and found that the PD tether has an optimized
structure in terms of both selectivity and yield.4
The consumption rates of the reactants 1e and 1f were
even slower than that with 1d carrying the mismatched
PD-tether, but were obviously faster than that with 1g
having no methyl group on the tether (entry 7). Such
phenomena, the methyl substitution on a linear mole-
cule accelerates its cyclization, is known as the
Thorpe–Ingold effect.6,7 However, when substrate 1h, a
regioisomer of 1e and 1f, was photoirradiated under
the same reaction conditions, consumption of the reac-
tant was very slow and no internal cycloadduct was ob-
tained (entry 8). Its bulkier analogue 1i having t-butyl
group instead of the methyl group showed a similar con-
sumption rate to those with 1e and 1f. The total yield of
the adducts of 1i was moderately high, 32%, but the ste-
reoselectivity was poorer than that with 1f (entry 9).
2. Results and discussion
Substrates 1c–k for the photoreaction were prepared
according to the reported procedure with some modifi-
cations (Fig. 1). The PD-tethered substrates 1c and 1d
were prepared as standards for the present study, and
are the enantiomers of 1a and 1b. The photoreaction
was carried out in pentane (2 mM) with a low-pressure
mercury lamp and a Vycor filter at room temperature.
The reaction was continued until the substrate became
undetectable by TLC analysis. All possible internal ad-
ducts were isolated by silica gel column chromatogra-
1
phy, and their structures determined by H NMR and
MS spectra. The isolated yields of meta-cycloadducts
2–5 are given in Table 1 together with the previously re-
ported results with 1a and 1b. Stereochemistries of two
cycloadducts 4e and 2f were determined by their conver-
sion to optically active 8 as shown in Scheme 2,3 and the
Expecting a result contrasting to that with the lower and
simpler analogues 1e–h, we next studied substrates hav-
ing higher analogues of the PD tether, 1j and 1k. The
tether of 1j has an additional methyl group on the tether
of 1c (or 1d) at the a-position. The substrate 1j is also
considered to be a higher analogue of 1e with two
gem-methyl groups at the c-position. With three methyl
groups on the tether, the photoreaction of 1j was, how-
ever, slow and sluggish. The produced cycloadducts
were too little to be isolated (<5% for sum of the ad-
ducts, entry 10).
R
RS
R
R
O
O
O
O
O
O
1e
1f
1g. R = H
1h. R = Me
1i. R = t-Bu
With the above results in mind, two bulkier isopropyl
groups are introduced in place of the two methyl groups
in 1c to give the higher analogue 1k. Such a modification
is commonly employed in asymmetric synthesis to en-
hance the stereoselectivity, and the efficiency may also
be improved if the effect of the methyl groups in 1c
can simply be amplified.8 Substrate 1k was prepared
RS
O
O
O
O
1j
1k
Figure 1.

T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
Table 1. Isolated yield and stereoselectivity in the reaction of the tethered substrates
Rn
677
Rn
O
O
stereoisomers
O
O
O
O
O
O
2
4
5
Rn
3
Rn
Entry
Subst.
Concn/mM
Reaction time/h
Isolated yield/%
Stereoselectivity
(2 + 3):(4 + 5)
2
3
4
5
Total
1
1a
1b
1c
1d
1e
1f
1.1
0.8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
4a
9a
2
—
—
—
—
38
30
—
<1
—
—
—
—
40
<1
40
70
15
—
—
27
<1
—
—
—
—
—
70
55
60
45
43
43
19b
0
32c
<5
57
0:100
0:100
100:0
100:0
0:100
79:21
50:50
—
2
3
24
14
—
—
4
6
5
10
9
—
34
16
9
6
7
1g
1h
1i
44
30
10
10
2
(ꢀ)b
(ꢀ)b
8
—
—
9
(ꢀ)c
—
(ꢀ)c
—
72:28
—
89:11
10
11
1j
1k
11
(6)d—
a The reaction was carried out until the photostationary state of the equilibrium of the regioisomers.3
b Racemic product (a mixture of 2 and 4) was obtained.
c The cycloadducts 2i and 4i were not separable. The ratio of the isomers as well as their structure was determined by 1H NMR.
d Not isolated. The yield was calculated from the amount of the crude product and its 1H NMR spectra.
O
O
O
O
a
b, c
O
OH
OH
O
(–)-8
6
4e
O
O
O
O
a
b, d
OH
O
HO
O
2f
7
(+)-8
Scheme 2. Reagents and conditions: (a) 4 M HCl/acetone (or THF), and then H2/Pd–C; (b) ethylene glycol/TsOH; (c) PCC, and then K2CO3/MeOH;
(d) PDC, MeMgBr, PCC, and then K2CO3/MeOH.
1
from optically active (3S,5S)-2,6-dimethyl-3,5-heptane-
diol in a stereochemically pure form by a similar process
to that for 1c. The photoreaction of 1k proceeded
1c
2c+3c
1k
2k+3k
0.8
0.6
0.4
0.2
0
smoothly to give a mixture of 2k and 3k in 51% yield
(entry 11). However, the third isomeric product was de-
tected by 1H NMR and GC–MS analyses of the reaction
mixture. This isomer could not be isolated, but the struc-
ture was suggested to be 4k from the H NMR spectra.
The estimated amount of 4k was ca. 6%.
1
The efficiency of the photoreaction was compared be-
tween 1c and 1k by monitoring the reaction by GLC.
A pentane solution of the substrate (3.0 mM) containing
a standard compound (decane or tetradecane) was irra-
diated, and the consumption of the substrates and the
formation of the cycloadducts during the reaction deter-
mined. As shown in Figure 2, the consumption rates of
1c and 1k were confirmed to be similar to each other.
Considering the almost identical extinction coefficients
of 1c and 1k at the irradiation wavelength, the quantum
0
40
80
120
160
time/h
Figure 2. Normalized concentration of reactants, 1c (open circles) and
1k (open squares), and sum of the cycloadducts, 2c and 3c (filled
circles) and 2k and 3k (filled squares) during the photoreactions.

678
T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
R
R
R
R
O
O
O
R
R
1
O
*
1
O
O
2 + 3
*
h
ν
internal exciplex
9
1c or 1k
O
O
1
O
O
10
*
EtO
O
external exciplex
Figure 3.
yields for intramolecular addition (/add) of 1k is only
1.1-fold larger than that of 1c. The observed similarity,
however, does not mean a similarity in nature of the
two tethers for the intramolecular reaction as follows.
of 1c and 1k were different in the intensity; 1k was
much weaker (0.3 0.1-fold) but 1c was only slightly
weaker (0.8 0.2-fold) than anisole. The strong emis-
sion from the S1 state of 1c indicates a small /1 value,
and the weak emission with 1k indicates a larger /1.
This difference in /1, /1(1c) < /1(1k), leads to an inverse
relationship of /2, /2(1c) > /2(1k), since /add(1c) ꢁ
When a pentane solution of 1c (2 mM) was irradiated in
the presence of ethyl vinyl ether 9 (1 or 2 M), the prod-
ucts obtained were the internal adducts, 2c and 3c, and
an isomeric mixture of external adduct 10; the ethyl
vinyl ether adducts mainly at the 2,6-position of 1c.9
The ratio of 2c + 3c:10 = 50:50 at [9] = 2 M and 74:26
at [9] = 1 M. The relative rate of the internal against
the external addition given as [2c + 3c][9]/[10] was 2 M,
which corresponds to the effective molarity in ground
state reactions. In contrast, the photoreaction of 1k
was not affected by the presence of 9 (up to 10 M),
and 1k was consumed at a similar rate without produc-
ing any external adducts (<3%). The effective molarity
for the intramolecular reaction of 1k was calculated to
be >102 M. The large difference between 1c and 1k can
partly originate from a slower external reaction of 1k
than 1c due to the steric interference of the isopropyl
groups.
/
add(1k).
This explanation seems to be reasonable because the
addition to form the two r-bonds necessitates more
accurate geometrical arrangement of the phenyl and
vinyl groups than the exciplex formation, and the iso-
propyl groups can cause larger strain energy when the
two reactants are placed at proper positions for the for-
mation of the two r-bonds. The loss of the stereoselec-
tivity may also originate from this strain.
3. Conclusions
Through the study of the asymmetric meta-arene–alkene
photocycloaddition with various chiral tethers, we
found that the substituent on the tether must be prop-
erly designed in its number, position, and size to achieve
the efficient and stereocontrolled meta-arene–alkene-
photocycloaddition. A suitable tether part has a func-
tion to force the internal reaction sites closer, but too
much restriction of the tether flexibility may result in
lose of the efficiency of the intramolecular reaction. So
far studied for the meta-arene–alkene-photocycloaddi-
tion, the tether made of the optically active 2,4-pentane-
diol has the most appropriate structure. The
conformation of the PD tether is rightly regulated in
keeping the flexibility.
The reactions of 1c and 1k to give the meta-cycloadducts
start with the excitation at the phenyl moiety. The
excited phenyl produced is quenched by a vinyl moiety
to form an exciplex, and then the exciplex converted
to the adduct of a ground-state biradical intermediate,
which then transformed into the final products (Fig.
3).2a The chiral tether having the bulky isopropyl groups
in the appropriate stereochemistry must have better effi-
ciency to access the vinyl moiety to the excited phenyl,
and thus, the internal quenching of 1k is faster than 1c
to result in the higher effective molarity. The quantum
yield of the overall reaction (/add) is governed by the
quantum yields of the exciplex formation (/1) and its
reaction (/2) following the equation, /add = /1 · /2.
To estimate the /1 values, the relative intensity of emis-
sion from the S1 state of the phenyl group was deter-
mined. Compared to anisole (/fl = 0.24), synthetic
precursors of 1c and 1k (hydroxy analogues at the vinyl-
4. Experimental
4.1. General
All products were characterized by NMR spectrometry
using a JEOL EXcalibur-400 spectrometer at 400 MHz
for proton and 100 MHz for carbon, and by IR with a
oxy group) showed a similar emission efficiency
(1.1 0.2 times of anisole), while the emission spectra

T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
679
JASCO IR-88 or IR-810 spectrophotometer. A JEOL
ECA-600 recorded at 600 and 150 MHz was employed
for some compounds as indicated in the spectral data.
UV spectra were obtained by an Agilent 8453, and fluo-
rescence was observed by a JASCO FP-770. Optical
rotations were measured with a Perkin-Elmer 243B
polarimeter. CD spectra were obtained using a JASCO
J-720. High resolution MS was obtained by a JEOL
JMS-AX505HF (EI) or a JEOL JMS-T100LC (APCI).
13C NMR (150 MHz, CDCl3) d 158.78, 129.44, 120.83,
114.46, 71.11, 66.14, 35.62, 13.59. HRMS (EI) m/z
(M+) calcd for C10H14O2 166.0993, found 166.0987.
4.2.3.
3,3-Dimethyl-2-phenoxymethyl-1-butanol. 2-
Hydroxymethyl-3,3-dimethylbutyl acetate was obtained
by the mono-acetylation of 2-hydroxymethyl-3,3-di-
methyl-1-butanol10 in 38.5% yield. To a solution of the
acetate ester (1.02 g), phenol (0.58 g, 1.0 equiv), and tri-
phenylphosphine (1.68 g, 1.1 equiv) in THF (45 mL) was
added diisopropyl azodicarboxylate (1.3 mL, 1.1 equiv)
at rt, and the reaction monitored by TLC analysis. After
15 h, the mixture was concentrated and purified by col-
umn chromatography on silica gel (elution with 6%
ethyl acetate in hexane) to give 1.19 g of 3,3-dimethyl-
Analytical GLC was performed on
a Shimadzu
GC17A. MPLC was carried out using FMI pump
(10 mL minꢀ1) and a Lover column (Merck Si-60, type
B). Pentane for the photoreactions was treated with
concentrated H2SO4 before distillation. All other sol-
vents were purified by distillation with proper drying
agents.
2-(phenoxymethyl)butyl acetate as
a colorless oil
(81.6% yield). A solution of the acetate obtained
(0.993 g) and K2CO3 (2.3 mg) in methanol (40 mL)
and water (13 mL) was stirred for 1.5 h, and extracted
with ether (·3). The combined organic layer was washed
with water (·2), and then dried over Na2SO4. The fil-
trate was concentrated to give 0.762 g of 3,3-dimethyl-
2-phenoxymethyl-1-butanol (81.5% yield). IR (neat,
cmꢀ1) 3392, 2960, 1600, 1576, 1498, 1496, 1471, 1456,
1244, 1029, 753; 1H NMR (CDCl3) d 7.28 (m, 2H),
6.97–6.91 (m, 3H), 4.19 (dd, J = 9.3, 3.9 Hz, 1H), 4.03
(dd, J = 9.3, 7.8 Hz, 1H), 3.79 (br s, 1H), 3.75 (m,
1H), 2.53 (s, 1H, OH), 1.75 (tt, J = 7.8, 3.9 Hz, 1H),
0.96 (s, 9H); 13C NMR (CDCl3) d 158.5, 129.3, 129.2,
120.8, 114.4, 68.0, 62.3, 49.82, 49.80, 31.8, 28.41,
28.39, 28.35; HRMS (EI) m/z (M+) calcd for C13H20O2
208.1463, found 208.1440.
4.2. Preparation of the mono-phenyl ethers as precursors
of 1e–k
4.2.1. (R)-3-Phenoxy-1-butanol and (R)-4-phenoxy-2-
butanol. To a solution of cyclohexanone acetal of
(R)-1,3-butanediol (5.20 g, >99% ee) in THF (100 mL)
was added pyridinium perbromide (26.8 g, 2.7 equiv)
at ꢀ78 ꢁC. The mixture was warmed up to rt for 2 h,
and pyridine (1.5 mL), sodium bicarbonate (10% aque-
ous solution, 15 mL), and then sodium sulfite (ca. 1 g)
added to the mixture. The organic layer was separated,
and the resulting aqueous solution extracted with benz-
ene (50 mL · 3). The combined organic layer was
washed with brine (150 mL), dried over MgSO4, concen-
trated, and passed through a short silica gel column to
give a pale yellow oil (6.02 g, 60%). This oil was added
to a solution of sodium methoxide (6.16 g, 6.2 equiv)
in DMSO (100 mL), and the mixture stirred for 3 days
at rt. After the addition of water (50 mL), the mixture
was extracted with ether (100 mL · 4). The combined
extract was washed with brine (150 mL), dried over
MgSO4, and purified by column chromatography on sil-
ica gel (elution with 3% ethyl acetate in hexane) to give a
mixture of the phenyl ethers as a colorless oil (1.40 g,
45.9%). This mixture was separated by MPLC (elution
4.2.4. 2-Methyl-4-phenoxy-2-pentanol. To a solution of
diphenyliodonium chloride (4.14 g) and 2-methyl-2,4-
pentanediol (7.54 g) in THF was added Na (0.31 g)
under argon, and the mixture heated at 60 ꢁC. After
18 h, the mixture was cooled to rt, poured into water,
and extracted with dichloromethane (·3). The combined
organic layer was washed with water (·2) and dried over
Na2SO4. The solvent was removed, and the residue puri-
fied by column chromatography on silica gel (elution
with 30% ethyl acetate in hexane) to give 2-methyl-4-
phenoxy-2-pentanol (1.08 g, 41.2% yield) as a colorless
oil. IR (neat, cmꢀ1) 3410, 2970, 1600, 1500, 1380,
with 25% ethyl acetate in hexane) to give (R)-3-phen-
25
D
methanol)} and (R)-4-phenoxy-2-butanol {489 mg,
oxy-1-butanol {782 mg, 25.6%, ½aꢂ ¼ ꢀ61:9 (c 1.0,
25
1
16.0%, ½aꢂ ¼ ꢀ79:2 (c 1.1, methanol)}. The spec-
1240, 1150, 1050, 910, 880, 750; H NMR (CDCl3) d
D
tral data are identical with those reported for the prod-
uct prepared by another method.5b
7.29–7.25 (m, 2H), 6.97–6.91 (m, 3H), 4.69 (m, 1H),
2.97 (s, 1H), 2.00 (dd, J = 14.9, 10.0 Hz, 1H), 1.66 (dd,
J = 14.9, 2.4 Hz, 1H), 1.25 (s, 3H), 1.23 (s, 3H), 1.21 (s,
2H); 13C NMR (CDCl3) d 156.7, 129.5, 121.2, 116.1,
71.9, 70.3, 49.1, 49.0, 30.5, 29.0, 20.4; HRMS (EI) m/z
(M+) calcd for C12H18O2 194.1307, found 194.1308.
4.2.2. 3-Phenoxy-2-methyl-1-propanol. To a solution of
2-methyl-1,3-propanediol (6.31 g), phenol (6.36 g,
1.1 equiv), triphenylphosphine (19.2 g, 1.1 equiv) in
THF (400 mL) was added a solution of diisopropyl azo-
dicarboxylate (14.5 mL, 1.1 equiv) in THF (400 mL) at
rt for 70 min. After 12 h, the mixture was concentrated
and purified by column chromatography on silica gel
(elution with 25% ethyl acetate in hexane) to give
4.2.5. (3S,5R)-2,6-Dimethyl-5-phenoxy-3-heptanol. To
solution of (3S,5S)-2,6-dimethyl-3,5-heptanediol
a
(0.60 g), phenol (0.39 g, 1.0 equiv), and triphenylphos-
phine (3.52 g, 1.1 equiv) in THF (16 mL), a solution of
diisopropyl azodicarboxylate (0.9 mL, 1.1 equiv) in
THF (15 mL) was added over 1.5 h at rt. The mixture
was stirred overnight. The concentrated mixture was
purified by column chromatography on silica gel (elu-
tion with 6% ethyl acetate in hexane) to give 0.55 g
7.89 g of a colorless oil (67% yield). IR (neat, cmꢀ1
)
3360, 2960, 2930, 2880, 1600, 1500, 1390, 1300, 1250,
1
1170, 1040, 750, 690; H NMR (600 MHz, CDCl3) d
7.28–7.26 (m, 2H), 6.95–6.92 (m, 1H), 6.89 (d,
J = 8.2 Hz, 2H), 3.96–3.90 (m, 2H), 3.69 (br s, 2H),
2.19 (m, 1H), 1.97 (br s, 1H), 1.02 (d, J = 7.6 Hz, 3H);
of (3S,5R)-2,6-dimethyl-5-phenoxy-3-heptanol as
a

680
T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
20
D
colorless oil (61.5% yield). ½aꢂ ¼ ꢀ24 (c 1.2, methanol);
2.0 Hz, 1H), 4.09 (dd, J = 9.8, 4.4 Hz, 1H), 4.03 (dd,
J = 9.5, 6.1 Hz, 1H), 3.95 (dd, J = 6.8, 2.0 Hz, 1H),
3.90 (dd, J = 9.8, 4.4 Hz, 1H), 3.85 (dd, J = 10.3,
6.3 Hz, 1H), 1.85 (tt, J = 6.3, 4.4 Hz, 1H), 1.02 (s, 9H);
13C NMR (CDCl3) d 159.0, 152.0, 129.4, 120.5, 114.5,
111.8, 86.3, 65.9, 65.6, 47.4, 44.3, 32.1, 28.6; HRMS
(M+) m/z calcd for C15H22O2N 234.1620, found
234.1577. Compound 1j: (colorless oil, 50.2% yield) IR
(neat, cmꢀ1) 2976, 1652, 1637, 1634, 1243, 753; 1H
NMR (CDCl3) d 7.24 (m, 2H), 6.91–6.87 (m, 3H), 6.43
(dd, J = 13.7, 6.4 Hz, 1H), 4.61 (br s, 1H), 4.40 (d,
J = 13.7 Hz, 1H), 4.03 (d, J = 6.4 Hz, 1H), 2.02 (dd,
J = 14.2, 7.8 Hz, 1H), 1.83 (dd, J = 14.2, 2.9 Hz, 1H),
1.29 (m, 9H); 13C NMR (CDCl3) d 145.9, 129.4, 120.6,
116.1, 91.4, 77.2, 76.7, 70.6, 48.3, 27.4, 25.9, 21.2;
HRMS (M+) m/z calcd for C14H20O2 220.1463, found
220.1465. Compound 1k: (colorless oil, 79.8% yield)
IR (neat, cmꢀ1) 2960, 1630, 1600, 1490, 1470, 1390,
1370, 1290, 1240, 1110, 1030, 820; 1H NMR
(600 MHz, CDCl3) d 7.24 (m, 2H), 6.91–6.87 (m, 3H),
6.30 (dd, J = 7.3, 6.8 Hz, 1H), 4.31 (dd, J = 14.2,
1.5 Hz, 1H), 4.19 (td, J = 6.1, 4.1 Hz, 1H), 3.95 (dd,
J = 6.8, 1.5 Hz, 1H), 3.67 (dt, J = 6.8, 1.5 Hz, 1H),
2.01 (tt, J = 6.8, 2.9 Hz, 1H), 1.93 (dt, J = 14.6, 6.8 Hz,
1H), 1.84 (dt, J = 14.6, 6.8 Hz, 1H), 1.77 (dt, J = 14.6,
6.8 Hz, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.87 (d,
J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 6H); 13C NMR
(150 MHz, CDCl3) d 158.6, 152.1, 129.5 (·2), 120.4,
115.8 (·2), 87.8, 82.1, 78.8, 31.4, 30.4, 18.3, 18.1, 17.4,
17.3; HRMS (EI) m/z (M+) calcd for C17H26O2
262.1933, found 262.1890.
IR (neat, cmꢀ1) 3445, 2961, 1597, 1493, 1469, 1387,
1290, 1242, 1172, 1028, 876; 1H NMR (CDCl3) d
7.27–7.24 (m, 5H), 6.95–6.92 (m, 3H), 4.36 (m, 1H),
3.58 (td, J = 8.8, 4.9 Hz, 1H), 2.61 (d, J = 2.4 Hz, 1H),
2.07 (m, 1H), 1.74–1.66 (m, 4H), 0.93–0.90 (m, 13H);
13C NMR (CDCl3) d 126.9 (·2), 121.2, 116.5 (·2),
82.7, 75.9, 33.9, 32.9, 29.9, 18.5, 17.9, 17.2, 16.8. HRMS
(EI) m/z (M+) calcd for C15H24O2 236.1176, found
231.1155.
4.3. Preparation of the substrates 1c–k
General procedure for the formation of the vinyl ethers,
1c–k, from the corresponding mono-phenyl ethers is as
follows: A solution of the phenyl ether (0.10–0.88 g)
with 0.3 equiv of mercuric acetate in ethyl vinyl ether
(10–50 mL) was refluxed for 5–7 days. The ethanol gen-
erated was removed by azeotropic distillation with pen-
tane twice during the reaction. The concentrated
mixture was purified by column chromatography on
deactivated alumina with 10% water to give the vinyl
ether. For the details of the preparation of 1c and 1d,
see Ref. 3. Compound 1e: (colorless oil, 86.6% yield)
25
½aꢂ ¼ ꢀ51:7 (c 0.7, methanol); IR (neat, cmꢀ1) 2950,
D
2900, 1640, 1620, 1600, 1500, 1240, 1200; 1H NMR
(CDCl3) d 7.30–7.25 (m, 2H), 6.95–6.89 (m, 3H), 6.46
(dd, J = 14.3, 6.8 Hz, 1H), 4.57 (m, 1H), 4.19 (dd,
J = 14.3, 6.7 Hz, 1H), 3.99 (dd, J = 6.8, 2.0 Hz, 1H),
3.89–3.79 (m, 2H), 2.09 (m, 1H), 1.95 (m, 1H), 1.33 (d,
J = 6.1 Hz, 3H); Anal. Calcd for C12H16O2 C: 74.97,
H: 8.39. Found C: 75.41, H: 8.75. Compound 1f: (color-
25
D
less oil, 83.8% yield) ½aꢂ ¼ ꢀ57:4 (c 1.1, methanol); IR
4.4. Photoreaction of 1c–k
(neat, cmꢀ1) 2950, 2900, 1640, 1600, 1500, 1470, 1240,
1
1200, 1100; H NMR (CDCl3) d 7.27 (m, 2H), 6.97–
A solution of the vinyl ether 1 (40–160 mg) in pentane
(2.0 mmol dmꢀ3) was placed in a quartz photoreactor
and deareated by argon bubbling. This was irradiated
by a low-pressure mercury lamp (100 W, Eiko-sha,
Japan) through a Vycor filter at room temperature until
consumption of the substrate. The resulting mixture was
purified by MPLC on silica gel (elution with 10–15%
6.89 (m, 3H), 6.32 (dd, J = 14.0, 6.6 Hz, 1H), 4.31 (dd,
J = 14.0, 1.5 Hz, 1H), 4.21–4.01 (m, 3H), 3.99 (dd,
J = 6.6, 1.5 Hz, 1H), 2.09–1.92 (m, 2H), 1.30 (d, J =
6.4 Hz, 3H); Anal. Calcd for C12H16O2 C: 74.97, H:
8.39. Found C: 74.59, H: 8.28. Compound 1g: (colorless
oil, 94.3% yield) IR (neat, cmꢀ1) 2950, 1740, 1600, 1500,
1
1480, 1320, 1250, 1200, 1060; H NMR (CDCl3) d 7.29
ethyl acetate in hexane) to give a colorless oil. Com-
25
D
(m, 2H), 6.97–6.89 (m, 3H), 6.48 (dd, J = 14.2, 6.8 Hz,
1H), 4.21 (dd, J = 14.2, 2.2 Hz, 1H), 4.08 (t,
J = 6.1 Hz, 2H), 4.01 (dd, J = 6.8, 2.2 Hz, 1H), 3.88 (t,
J = 6.1 Hz, 2H), 2.14 (tt, J = 6.1, 6.1 Hz, 2H); Anal.
Calcd for C11H14O2 C: 74.13, H: 7.92. Found C:
73.81, H 7.95. Compound 1h: (colorless oil, 81.2%) IR
(neat, cmꢀ1) 2930, 2880, 1600, 1500, 1250, 1200, 1280,
pound 4e: (16.7% yield) ½aꢂ ¼ þ128:7 (c 0.8, methanol);
IR (neat, cmꢀ1) 2950, 1420, 1380, 1200, 1140, 1100, 770;
1H NMR (CDCl3) d 5.54 (dd, J = 5.6, 2.4 Hz, 1H), 5.47
(ddd, J = 5.6, 2.8, 1.6 Hz, 1H), 4.31 (m, 1H), 4.13 (d,
J = 4.3 Hz, 1H), 4.12 (m, 1H), 3.83 (m, 1H), 3.55 (m,
1H), 2.34 (d, J = 8.3 Hz, 1H,), 2.05–1.96 (m, 3H), 1.66
(ddd, J = 14.6, 4.3, 1.2 Hz), 1.25 (d, J = 6.6 Hz, 3H);
13C NMR (CDCl3) d 129.3, 128.5, 87.3, 85.0, 72.1,
61.8, 56.3, 39.2, 38.7, 34.5, 29.5, 22.4; HRMS (APCI)
1
1040, 1010, 1000, 753; H NMR (CDCl3) d 7.26 (m,
2H), 6.94–6.88 (m, 3H), 6.46 (dd, J = 14.2, 6.8 Hz,
1H), 4.18 (dd, J = 14.2, 6.8 Hz, 1H), 3.94 (dd, J = 9.0,
5.6 Hz, 1H), 3.86 (dd, J = 9.0, 5.6 Hz, 1H), 3.75 (dd,
J = 9.8, 5.9 Hz, 1H), 3.67 (dd, J = 9.8, 5.9 Hz, 1H),
2.31 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3) d 159.00, 151.94, 129.37, 120.59, 115.32,
114.48, 86.35, 69.69, 69.47, 33.47; HRMS (EI) m/z
(M+) calcd for C12H16O2 192.1150, found 192.1140.
Compound 1i: (colorless oil, 60.5% yield) IR (neat,
cmꢀ1) 3040, 2960, 1600, 1500, 1470, 1400, 1340, 1320,
m/z (M+) calcd for C12H16NaO2 215.1048, found
25
D
215.1040. Compound 5e: (27.3% yield) ½aꢂ ¼ þ74:1 (c
2.0, methanol); IR (neat, cmꢀ1) 2950, 1420, 1220,
1
1160, 1100, 1080, 880, 780; H NMR (CDCl3) d 5.65
(dddm, J = 5.6, 2.9, 1.0 Hz, 1H), 5.44 (dd, J = 5.6,
2.3 Hz, 1H), 4.51 (dd, J = 6.8, 2.0 Hz, 1H), 4.51(dd,
J = 6.8, 1.2 Hz, 1H), 4.13–4.03 (m, 2H), 3.94 (ddd,
J = 14.0, 6.6, 1.4 Hz, 1H), 3.31 (ddm, J = 8.5, 2.9,
1.5 Hz, 1H), 2.48 (dddm, J = 14.7, 8.5, 2.0 Hz, 1H,),
2.36–2.30 (m, 2H), 2.04–1.96 (m, 2H), 1.85 (ddd,
J = 14.7, 6.8, 1.5 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H); 13C
NMR (CDCl3) d 139.0, 123.6, 87.0, 81.0, 76.9, 61.4,
1
1250, 1170, 1080, 1030, 960; H NMR (CDCl3) d 7.26
(dd, J = 8.3, 7.3 Hz, 2H), 6.91 (dd, J = 10.7, 7.3 Hz,
3H), 6.45 (dd, J = 14.2, 6.8 Hz, 1H), 4.18 (dd, J = 14.2,

T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
681
53.9, 43.9, 42.5, 39.6, 38.0, 22.9; HRMS (APCI) m/z
13C NMR (150 MHz, CDCl3) d 129.1, 128.3, 86.9,
85.4, 83.4, 80.1, 52.82, 38.1, 36.5, 35.6, 34.7, 34.7, 33.6,
19.1, 18.4, 18.2, 18.0; HRMS (EI) m/z (M+) calcd for
(M+) calcd for C12H16NaO2 215.1048, found 215.1044.
Compound 2f: (34% yield) mp 53.0–55.5 ꢁC;
25
½aꢂ ¼ ꢀ140 (c 0.6, methanol); IR (KBr) 2950, 2870,
C17H26O2 262.1933, found 262.1911. Compound 3k:
D
20
1460, 1400, 1380, 1200, 1140, 1100, 760 cmꢀ1
;
1H
(55.7% yield) ½aꢂ ¼ ꢀ15:2 (c 0.3, methanol); CD (pen-
D
NMR (CDCl3) d 5.55 (dd, J = 5.6, 2.4 Hz, 1H), 5.44
(ddd, J = 5.6, 2.9, 1.5 Hz, 1H), 4.13 (m, 1H), 4.05 (m,
1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.44 (m, 1H), 2.51
(dm, J = 8.1 Hz, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.84
(ddd, J = 13.9, 6.4, 2.7 Hz, 1H), 1.61 (m, 1H), 1.44 (m,
1H), 1.18 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d
128.6, 87.4, 87.0, 66.7, 65.5, 56.8, 42.2, 39.6, 31.4, 30.0,
25.5; HRMS (APCI) m/z (M+) calcd for C12H16NaO2
tane) kext 220 nm (De ꢀ44.9); IR (neat, cmꢀ1) 2957,
1469, 1421, 1384, 1292, 1261, 1098; 1H NMR
(600 MHz, CDCl3) d 5.61 (dd, J = 5.4, 2.4 Hz, 1H),
5.42 (d, J = 5.4 Hz, 1H), 4.49 (dd, J = 6.8, 2.4 Hz),
3.92 (dd, J = 6.3, 3.4 Hz, 1H), 3.69 (dd, J = 7.3,
3.4 Hz, 1H,), 3.21 (dd, J = 8.3, 2.4 Hz, 1H), 2.47–2.41
(m, 2H), 2.06–1.92 (m, 2H), 1.79–1.68 (m, 2H), 1.56
(d, J = 17.6 Hz, 1H), 0.89 (m, 12H); 13C NMR
(150 MHz, CDCl3) d 138.7, 123.6, 87.8, 87.3, 81.5,
79.8, 54.4, 48.6, 40.9, 40.7, 35.9, 34.4, 33.4, 17.8 (·2),
17.7 (·2); HRMS (EI) m/z (M+) calcd for C17H26O2
262.1933, found 262.1909.
215.1048, found 215.1040. Compound 4f: (9.2% yield)
25
D
½aꢂ ¼ þ119 (c 0.8, methanol); IR (neat, cmꢀ1) 2950,
1
1420, 1380, 1240, 1200, 1160, 1100; H NMR (CDCl3)
d 5.50 (ddd, J = 5.6, 2.6, 1.6 Hz, 1H), 5.47 (dd, J = 5.6,
2.2 Hz, 1H), 4.16 (d, J = 5.1 Hz, 1H), 4.06–3.80 (m,
3H), 3.22 (t-like, J = 2.6 Hz, 1H), 2.33 (dm, J = 8.3 Hz,
1H), 2.23 (dt, J = 8.3, 1.2 Hz, 1H), 2.12 (m, 1H), 2.07
(dd, J = 6.4, 2.6 Hz, 1H), 1.79 (ddd, J = 15.6, 5.1,
1.2 Hz, 1H), 1.68 (dd, J = 16.8, 5.6 Hz, 1H), 1.21 (d,
J = 6.6 Hz, 3H); 13C NMR (CDCl3) d 130.8, 127.2,
88.1, 85.6, 71.4, 70.9, 60.5, 41.7, 40.1, 32.0, 28.6, 26.4;
HRMS (APCI) m/z (M+) calcd for C12H16NaO2
215.1048, found 215.1045. Compound 2g + 4g: (racemic
mixture, 19% yield) IR (neat, cmꢀ1) 3050, 2950, 2850,
4.5. Conversion of 4e to (ꢀ)-8
A solution of 4e (78 mg, 0.41 mmol) in acetone (8 mL)
and aqueous HCl (4 M, 2 mL) was stirred for 5 days.
The solution was heated to reflux for an additional
2 days. The mixture was diluted with water (15 mL),
and extracted with CH2Cl2 (15 mL · 3). The combined
organic layer was washed with satd aqueous NaHCO3,
and dried over MgSO4. Filtration, concentration, and
purification by MPLC on silica gel (elution with 65%
1
1460, 1420, 1240, 1200, 1140, 1100, 840, 780, 740; H
NMR (CDCl3) d 5.33 (dd, J = 5.6, 2.2 Hz, 1H), 4.13
(d, J = 4.6 Hz, 1H), 3.84–3.75 (m, 2H), 3.56 (t,
J = 11.4 Hz, 1H), 3.49 (ddd, J = 13.5, 7.4, 2.8 Hz, 1H),
3.22 (dm, J = 2.6 Hz, 1H), 2.34 (dm, J = 7.6 Hz, 1H),
1.99–1.89 (m, 3H), 1.63 (ddm, J = 13.4, 4.6 Hz, 1H),
1.37 (m, 1H); HRMS (APCI) m/z (M+) calcd for
C11H14NaO2 201.0891, found 201.0887. Compound 2i:
(23% yield) 1H NMR (CDCl3) d 5.58 (dd, J = 5.5,
2.7 Hz, 1H), 5.45 (d, J = 4.8, 2.7 Hz, 1H), 4.15 (s, 1H),
4.04 (t-like, J = 2.7 Hz, 1H), 3.90 (dd, J = 13.4, 8.6 Hz,
1H), 3.75 (dd, J = 13.8, 9.6 Hz, 1H), 3.53 (br s, 1H),
2.59 (d, J = 6.9 Hz, 1H), 1.99 (t-like, J = 6.9 Hz, 1H),
1.84 (ddd, J = 13.7, 6.9, 2.7 Hz, 1H), 1.46 (d,
J = 13.7 Hz, 1H), 0.98 (s, 9H); 13C NMR (CDCl3) d
128.6, 128.3, 87.8, 68.4, 62.6, 55.8, 52.1, 49.8, 43.6,
42.0, 33.2, 31.7, 29.4, 28.8, 27.1; HRMS (APCI) m/z
(M+) calcd for C15H22NaO2 257.1517, found 257.1510.
Compound 4i: (9% yield) 1H NMR (CDCl3) d 5.51
(dd, J = 5.5, 2.7 Hz, 1H), 5.45 (m, 1H), 4.06 (d,
J = 3.4 Hz, 1H), 3.90 (m, 2H), 3.78 (dd, J = 13.7,
6.2 Hz, 1H), 3.69 (dd, J = 13.7, 7.6 Hz, 1H), 3.36 (br s,
1H), 2.45 (d, J = 8.2 Hz, 1H), 2.03 (t-like, J = 7.6 Hz,
1H), 1.98–1.88 (m, 2H), 1.53–1.57 (m, 2H), 0.88 (s,
9H); 13C NMR (CDCl3) d 128.6, 128.3, 87.8, 68.4,
62.6, 55.8, 52.1, 49.8, 43.6, 42.0, 33.2, 31.7, 29.4, 28.8,
27.1; HRMS (APCI) m/z (M+) calcd for C15H22NaO2
ethyl acetate in hexane) gave 32 mg of a yellow oil
25
(40% yield). ½aꢂ ¼ ꢀ48:2 (c 0.3, methanol); IR (neat,
D
cmꢀ1) 3450, 3050, 2950, 1760, 1640, 1440, 1380, 1340,
1300, 1200, 1100, 1050, 940, 920, 880, 860, 780, 740,
680; 1H NMR (CDCl3) d 5.86 (m, 1H), 5.45 (dt,
J = 6.3, 3.2 Hz, 1H), 3.95–3.90 (m, 2H), 3.60–3.49 (m,
2H), 2.94 (m, 1H), 2.67–2.55 (m, 4H), 2.38 (m, 1H),
1.91 (m, 1H), 1.68–1.64 (m, 2H), 1.17 (d, J = 6.1 Hz,
3H); 13C NMR (CDCl3) d 215.2, 133.6, 124.9, 81.2,
67.7, 67.0, 49.4, 45.3, 41.0, 39.6, 38.3, 23.5; HRMS
(EI) m/z (M+) calcd for C12H18O3 210.1256, found
210.1240.
Hydrogenation of the above product (35 mg,
0.17 mmol) over Pd–C (ca. 30 mg) in ethyl acetate
(5 mL) proceeded smoothly to give essentially pure 6
25
(24 mg, 67.9% yield). Compound 6: ½aꢂ ¼ ꢀ17:7 (c
D
0.5, methanol); IR (neat, cmꢀ1) 3450, 2950, 2850,
1750, 1640, 1460, 1420, 1380, 1340, 1300, 1260, 1200,
1180, 1100, 1040, 1020, 960, 920, 840, 760; H NMR
1
(CDCl3) d 3.95 (q, J = 6.1 Hz, 1H), 3.90 (dd, J = 8.1,
2.4 Hz, 1H), 3.61 (m, 1H), 3.53 (m, 1H), 2.43 (m, 1H),
2.33 (m, 1H), 2.22 (dd, J = 14.4, 8.1 Hz, 1H), 2.05–
1.85 (m, 6H), 1.69–1.53 (m, 4H), 1.18 (d, J = 6.1 Hz,
3H); 13C NMR (CDCl3) d 220.5, 78.3, 67.22, 67.17,
51.3, 45.6, 38.3, 36.4, 34.6, 33.6, 23.5, 18.0; HRMS
(EI) m/z (M+) calcd for C12H20O3 212.1412, found
212.1412.
257.1517, found 257.1512. Compound 2k: (11.2% yield)
20
D
½aꢂ ¼ ꢀ65:6 (c 0.9, methanol); CD (pentane) kext
240 nm (De +19.3); IR (neat, cmꢀ1) 2959, 2873, 1405,
1
1385, 1097, 1082, 997; H NMR (600 MHz, CDCl3) d
A solution of 6 (23 mg, 0.11 mmol) and ethylene glycol
(2 mL) in benzene (40 mL) was heated to reflux in the
presence of TsOHÆpyridine and the generated water re-
moved by a Dean–Stark trap. After 2.5 h, the mixture
was cooled to rt, and extracted with ether (30 mL · 3).
The combined organic layer was dried over MgSO4,
5.55 (dd, J = 5.4, 2.4 Hz, 1H), 5.39 (ddd, J = 5.4, 2.4,
1.5 Hz, 1H), 4.06 (d, J = 2.9 Hz, 1H), 3.77 (m, 1H),
3.75 (br s, 1H), 3.53 (m, 1H), 2.26 (d, J = 5.4 Hz, 1H),
2.03 (dd, J = 7.3, 6.8 Hz, 1H), 1.89 (ddd, J = 13.7, 6.3,
2.9 Hz, 1H), 1.81–1.52 (m, 4H), 0.94–0.85 (m, 12H);

682
T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
filtered, and concentrated. The residue was purified by
column chromatography on silica gel (elution with 20%
ethyl acetate in hexane) to give the acetal as a color-
A solution of 7 (38.5 mg), ethylene glycol (2 mL), and
TsOHÆpyridine (10 mg) in benzene (40 mL) was heated
to reflux while removing generated water by a Dean–
Stark trap. After 2 h, the mixture was extracted with
ether (30 mL · 3), dried over MgSO4, and concentrated
to give a crude acetal (54.8 mg), which was purified by
column chromatography on silica gel (elution with
25
less oil (42 mg, 97% yield). ½aꢂ ¼ ꢀ13:9 (c 0.8, metha-
D
nol); IR (neat, cmꢀ1) 3450, 2950, 2850, 1720, 1450,
1380, 1260, 1240, 1180, 1120, 1020, 940, 860, 740; H
1
NMR (CDCl3) d 3.99–3.84 (m, 5H), 3.67–3.62 (m,
2H), 3.51 (td, J = 9.7, 3.2 Hz, 1H), 2.04 (m, 1H), 1.94
(m, 1H), 1.90–1.88 (m, 2H), 1.87–1.68 (m, 4H), 1.62
(m, 1H), 1.50 (m, 1H), 1.44–1.29 (m, 3H), 1.17 (d,
J = 6.1 Hz, 3H).
30% ethyl acetate in hexane) to give 45.3 mg of a color-
25
D
less oil (97.4% yield). ½aꢂ ¼ ꢀ43:9 (c 0.9, methanol); IR
(neat, cmꢀ1) 3450, 2950, 1450, 1380, 1240, 1180, 1120,
1
1080, 1060, 1020, 940, 760; H NMR (CDCl3) d 3.99–
3.87 (m, 4H), 3.81 (dd, J = 8.1, 3.9 Hz, 1H), 3.76–3.66
(m, 2H), 3.60 (m, 1H), 2.03 (m, 1H), 1.94–1.67 (m,
7H), 1.59 (m, 1H), 1.49 (m, 1H), 1.43–1.33 (m, 2H),
1.21 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H); 13C NMR
(CDCl3) d 115.9, 77.3, 74.6, 64.5, 63.9, 61.9, 44.6, 40.5,
39.3, 36.0, 28.2, 27.5, 19.6, 17.1.
A suspension of the acetal (42 mg, 0.16 mmol), PCC (ca.
60 mg), and powdered molecular sieves (3A) in dichlo-
romethane (25 mL) was stirred for 10 h. The mixture
was allowed to stand with additional PCC (ca. 30 mg)
for 6 h. The mixture was filtered and the filtrate was ex-
tracted with dichloromethane (30 mL · 5). The com-
bined organic layer was washed with water (50 mL)
and dried over MgSO4, filtered, and concentrated. The
residue was purified by flash column chromatography
on silica gel to give the ketone as a colorless oil
(44 mg, 106%). The ketone was dissolved in methanol
(4 mL), and stirred with K2CO3 (ca. 10 mg) at rt to give
(ꢀ)-8, the spectra of which were identical with the re-
ported ones.11 The optical rotation was observed after
The acetal obtained above (43 mg) was dissolved in
dichloromethane (30 mL) with powdered molecular
˚
sieves (3 A, 300 mg). To this suspension was added
PDC (104 mg, 1.6 equiv) at rt, and the mixture stirred
for 3 h. The filtrate was washed with satd aqueous NaH-
CO3, which was re-extracted with dichloromethane
(100 mL). The combined extract was dried over MgSO4,
concentrated and purified by column chromatography
on silica gel (elution with 30% ethyl acetate in hexane)
purification by the preparative GLC (NPGS, 160 ꢁC).
25
½aꢂ ¼ ꢀ15:2 (c 0.05, methanol), lit.11 for (1R,5S,6R)-
to give the aldehyde as a colorless oil (33.7 mg, 79%
)
D
25
D
8: [a]D = ꢀ16.
yield). ½aꢂ ¼ ꢀ46:0 (c 0.7, methanol); IR (neat, cmꢀ1
2950, 1730, 1440, 1380, 1310, 1240, 1200, 1180, 1120,
1080, 1060, 1020, 980, 950, 930, 870, 760; 1H NMR
(CDCl3) d 9.80 (t, J = 2.2 Hz, 1H), 3.95–3.84 (m, 5H),
3.81 (dd, J = 8.3, 3.8 Hz, 1H), 2.69 (ddd, J = 16.1, 8.3,
2.2 Hz, 1H), 2.38 (ddd, J = 16.1, 4.6, 2.2 Hz, 1H), 2.03
(m, 1H), 1.90–1.77 (m, 6H), 1.49–1.33 (m, 3H), 1.21
(d, J = 6.1 Hz, 3H); 13C NMR (CDCl3) d 202.5, 115.8,
78.5, 69.4, 64.3, 64.0, 50.7, 44.5, 40.9, 36.1, 28.3, 27.6,
20.3, 17.2; HRMS (EI) m/z (M+) calcd for C14H22O4
254.1218, found 254.1502.
4.6. Conversion of 2f to (+)-8
A solution of 2f (91 mg) in THF (10 mL) containing
aqueous HCl (4 mol dmꢀ3, 0.5 mL) was heated to reflux
for
2 days.
Extraction
with
dichloromethane
(20 mL · 2) and purification by MPLC (elution with
60% ethyl acetate in hexane) gave a colorless oil
25
(11 mg, 11% yield). ½aꢂ ¼ ꢀ0:5 (c 0.8, methanol); IR
D
(neat, cmꢀ1) 3400, 2950, 1760, 1640, 1440, 1380, 1320,
1300, 1200, 1120, 1080, 1020, 940, 740; 1H NMR
(CDCl3) d 5.88 (m, 1H), 5.48 (dt, J = 9.0, 2.9 Hz, 1H),
4.07 (dd, J = 8.3, 4.2 Hz, 1H), 3.63–3.59 (m, 3H), 2.95
(m, 1H), 2.65 (dd, J = 4.2, 3.2 Hz, 1H), 2.60 (m, 2H),
2.40 (m, 1H), 1.93 (m, 1H), 1.68–1.64 (m, 2H), 1.17 (d,
J = 6.1 Hz, 3H); 13C NMR (CDCl3) d 215.6, 133.7,
125.0, 78.0, 72.3, 59.8, 49.6, 45.3, 42.0, 39.5, 39.2, 19.7;
HRMS (EI) m/z (M+) calcd for C12H18O3 210.1256,
found 210.1244.
A solution of the aldehyde (30 mg) in ether (7 mL) was
added to a solution of methyl magnesium bromide (2 M
in ether, 1 mL). Extraction and column chromatography
on silica gel afforded 37 mg of a colorless oil (100%). To
a solution of this oil (29 mg) in dichloromethane
(20 mL) was added PCC (46 mg) and powdered molecu-
˚
lar sieves (3 A, 210 mg) at rt. After 2 h, the mixture was
filtered, extracted (CH2Cl2, 20 mL · 4), dried over
MgSO4, and purified by a flash column (silica gel, 20%
ethyl acetate in hexane) to give 27.9 mg of the ketone
A solution of this compound (39 mg) in ethyl acetate
(5 mL) was stirred vigorously under hydrogen atmo-
sphere in the presence of Pd–C (ca. 30 mg) for 30 min.
25
(97% yield). ½aꢂ ¼ ꢀ29 (c 0.6, methanol); IR (neat,
D
cmꢀ1) 2950, 1720, 1380, 1240, 1130, 1060, 1020; 1H
NMR (CDCl3) d 3.93–3.83 (m, 5H), 3.77 (dd, J = 8.1,
3.8 Hz, 1H), 2.76 (dd, J = 15.3, 8.1 Hz, 1H), 2.33 (dd,
J = 15.3, 4.8 Hz, 1H), 2.19 (s, 3H), 2.02 (br s, 1H),
1.92–1.77 (m, 5H), 1.48–1.34 (m, 2H), 1.30–1.18 (m,
2H), 1.16 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3) d
208.5, 115.8, 78.5, 77.3, 70.8, 64.2, 63.8, 50.9, 44.2,
41.0, 36.1, 28.3, 27.7, 20.2, 17.2.
Filtration and evaporation gave essentially pure 7 as a
25
D
3450, 2950, 1750,
colorless oil (39 mg, 99% yield). ½aꢂ ¼ ꢀ53:7 (c 0.8,
methanol); IR (neat, cmꢀ1
)
1460, 1380, 1340, 1200, 1140, 1100, 1060, 960, 870,
760; 1H NMR (CDCl3) d 4.01 (dd, J = 8.3, 2.4 Hz,
1H), 3.73–3.60 (m, 3H), 2.41–2.34 (m, 3H), 2.24 (dd,
J = 14.4, 8.3 Hz, 1H), 2.00–1.84 (m, 5H), 1.70–1.51 (m,
4H), 1.15 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3) d
221.1, 75.0, 71.5, 59.6, 51.3, 45.5, 39.1, 36.2, 34.5, 34.4,
19.8, 18.0; HRMS (EI) m/z (M+) calcd for C12H20O3
212.1412, found 212.1399.
The ketone obtained above (23 mg) was dissolved in
methanol (5 mL) with K2CO3 (50 mg). After stirring
for 3 days, the mixture extracted was identical to (ꢀ)-8

T. Sugimura et al. / Tetrahedron: Asymmetry 16 (2005) 675–683
683
except for the specific rotation obtained after the GLC
Acknowledgements
25
D
purification (NPGS, 160 ꢁC). ½aꢂ ¼ þ14 (c 0.1,
methanol).
The authors thank Mr. Junichi Osuga of JEOL Ltd. for
the APCI-Mass operation. Part of this work was sup-
port by JSPS (KAKENHI, no 13440192).
4.7. GLC analysis of the reaction of 1c and 1k
A solution of 1c (1.58 mg) in pentane (2.5 mL) contain-
ing decane (0.46 mg) was placed in a UV cell, de-aerated
by argon bubbling, and then this was photoirradiated by
a low-pressure mercury lamp. A part of solution was
taken out by a microsyringe every hour during the photo-
irradiation, and was subjected to GLC analysis. (OV-1,
0.25 mm i.d. · 30 m, 120 ꢁC, 30 cm sꢀ1). The retention
times were as follows (min); decane: 5.1, 1c: 12.9, 2c:
16.3, 3c: 20.1. The sensitivities among 1c, 2c, and 3c
were predicted to be the same. Photoreaction of 1k
was carried out in the same way except for the use of
tetradecane as a standard. The GLC analysis was per-
formed at 150 ꢁC. The retention times were as follows
(min); tetradecane: 5.3, 1k: 12.3, 2k: 17.1, 3k: 22.6.
The sensitivities among 1k–3k were predicted to be the
same. The results are shown in Figure 2.
References
1. Sugimura, T. In Recent Research Developments in Organic
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2. (a) For reviews of meta-arene-alkene photocycloaddition,
see: Wender, P. A.; Siggel, L.; Nuss, J. M. In Organic
Photochemistry; Padwa, A., Ed.; Dekker: New York, 1989;
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4.8. Determination of the effective molarity for the
reaction of 1c and 1k
4. A part of this report has been published in a preliminary
communication of Ref. 3a.
A solution of 1c (8.3 mg) and ethyl vinyl ether (3.8 mL
or 1.9 mL) in pentane (20 mL) was placed in a quartz
photo reactor, de-aerated by argon bubbling, and then
photo-irradiated for 16 h by the low pressure mercury
lamp. The mixture was subjected to GLC analysis
(OV-1, 120 ꢁC, 30 cm sꢀ1). The retention times for the
intermolecular products were at 59–67 (showing five
peaks). One of the intermolecular adducts was isolated
from the reaction mixture and used as a standard for
5. (a) Sugimura, T.; Tei, T.; Mori, A.; Okuyama, T.; Tai, A.
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1
the calibration of the GLC peaks. H NMR (CDCl3) d
6.27 (ddd, J = 14.6, 6.8, 1.5 Hz, 1H), 5.57 (dd, J = 5.9,
2.0 Hz, 1H), 5.45 (m, 1H), 4.25 (dtd, J = 14.2, 2.9,
1.5 Hz, 1H), 4.02 (q, J = 6.3 Hz, 1H), 3.95 (dq, J = 6.3,
1.5 Hz, 1H), 3.88 (td, J = 5.9, 1.5 Hz, 1H), 3.60 (dd,
J = 5.9, 4.4 Hz, 1H), 3.42 (dtd, J = 19.5, 6.8, 2.4 Hz,
2H), 3.20 (s, 1H), 2.16 (d, J = 3.4 Hz, 1H), 1.97 (dt,
J = 13.7, 7.3 Hz, 2H), 1.59 (dd, J = 14.6, 4.9 Hz, 1H),
1.45 (m, 1H), 1.24–1.16 (m, 6H), 0.86 (t, J = 6.8 Hz,
3H); 13C NMR (CDCl3) d 150.59, 129.27, 128.59,
88.89, 88.06, 87.48, 72.94, 71.87, 63.20, 58.12, 43.92,
37.77, 34.89, 30.58, 20.97, 19.96, 15.48; HRMS
(EI) m/z (M+) calcd for C17H26O3 278.1882, found
278.1826.