Asymmetric synthesis by the intramolecular haloetherification reaction of ene acetal: Discrimination of prochiral dienes in cyclohexane systems

Article abstract of DOI:10.1248/cpb.53.952

A novel asymmetric synthesis of the cyclohexane derivative functionalized by some substituents has been developed from the diene acetals (1), prepared from the corresponding diene aldehyde and (+)-hydrobenzoin. The treatment of 1 with NBS in the presence

Full text of DOI:10.1248/cpb.53.952

952
Chem. Pharm. Bull. 53(8) 952—957 (2005)
Vol. 53, No. 8
Asymmetric Synthesis by the Intramolecular Haloetherification Reaction
of Ene Acetal: Discrimination of Prochiral Dienes in Cyclohexane Systems
Hiromichi FUJIOKA,* Naoyuki KOTOKU, Yoshinari SAWAMA, Hidetoshi KITAGAWA, Yusuke OHBA,
Tsung-Lung WANG, Yasushi NAGATOMI, and Yasuyuki KITA*
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan.
Received March 10, 2005; accepted May 7, 2005; published online May 13, 2005
A novel asymmetric synthesis of the cyclohexane derivative functionalized by some substituents has been de-
veloped from the diene acetals (1), prepared from the corresponding diene aldehyde and (ꢀ)-hydrobenzoin. The
treatment of 1 with NBS in the presence of MeOCH2CH2OH predominantly afforded 2 in a stereoselective man-
ner. Subsequent alkylation of the methoxyethoxy group produced the optically active cyclohexene compounds (3)
in good yields. The stereoselective chemical modification of the remaining olefin in 3 was made by OsO4-oxida-
tion.
Key words desymmetrization; cyclohexa-1,4-diene; intramolecular haloetherification; (ꢀ)-hydrobenzoin; ene acetal
1).19) The alkoxy group of the mixed acetals was then con-
Asymmetric synthesis based on the desymmetrization of
verted to an alkyl group. The obtained alkylated compounds
3 were subjected to several transformation reactions forming
optically active cyclohexane derivatives with multichiral cen-
ters. We now present the full details of our study.
symmetric compounds is one of the most powerful ways to
get optically pure compounds, especially for the substrates
having prochiral carbon atom(s), and many methodologies by
chemical reactions, for examples refs. 1—4,1—4) and enzy-
matic ones, for examples refs. 5—9,5—9) have already been
developed. Recently, we have developed a new asymmetric
synthesis of 1,4- and 1,5-diols from the ene aldehydes in-
volving the intramolecular haloetherification reaction of their
C2-symmetric acetals as a key step (Eq. 1).10,11)
Results and Discussion
The optically active monosubstituted cyclohexadiene ac-
etals (1a, b) were synthesized as follows (Chart 2). The cy-
clohexadiene acetals (4, 5) were prepared from benzoic acid
according to a literature procedure.20) Their transacetalization
with (ꢀ)-hydrobenzoin21) gave 1a and 1b in good yields. The
disubstituted cyclohexadiene acetals (1c, d) were synthesized
from compound 6, which was obtained by reductive alkyla-
tion22) of methyl benzoate followed by reduction with
DIBAL-H (Chart 3). Protection of the hydroxy group of 6 by
the tert-butyldiphenylsilyl (TBDPS) group and selective de-
protection of the resulting disilyl ether afforded 7 in good
yield. The Swern oxidation23) of 7 followed by acetalization
with (ꢀ)-hydrobenzoin produced the optically active 3,3-di-
substituted cyclohexadiene acetal silyl ether 1c. The desilyla-
(1)
We then planned to extend this methodology to the symmet-
ric compounds with two prochiral olefins. If the reaction can
successfully discriminate the diastereotopic groups and their
faces, it will be quite useful for constructing optically active
compounds because it can produce chiral non-racemic com-
pounds bearing multichiral centers and the remaining olefin
can be used for further transformations (Eq. 2). (For exam-
ples of discrimination of prochiral two olefinic groups by
halocyclization using chiral auxiliary, see refs 12—18.)12—18)
(2)
Chart 1
Based on this idea, we studied the intramolecular haloetheri-
fication reaction of cyclohexa-1,4-dienes 1 having the C2-
symmetric acetal on the side chain and found that the reac-
tion discriminated the two prochiral olefins in a highly di-
astereoselective manner to give 2 as the major product (Chart
Chart 2
© 2005 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp

August 2005
953
tion of 1c followed by methylation of the resulting hydroxy was eliminated via B leading to the aromatization.
group gave the methyl ether 1d.
Therefore, we studied the reaction in detail. The results are
The haloetherification reaction of 1a with I(coll)2ClO4, summarized in Table 1. A change in the reaction solvent
which was the best choice of an electrophile in our previous from CH2Cl2 to CH3CN was not effective (entry 1). We then
work,10,11) in the presence of MeOCH2CH2OH as a nucle- used N-iodosuccinimide (NIS), a rather more neutral reagent
ophile in CH2Cl2 did not give the desired product at all than I(coll)2ClO4 (entry 2). In this case, the desired product
(Chart 4). The only aromatic compound 10 was obtained in 2a (R1ꢁR2ꢁH, XꢁI) was obtained as a mixture of stereoiso-
43% yield. This disappointing result must be due to the ba- mers, but the yield was low. When N-bromosuccinimide
sicity of 2,4,6-collidine, which coexisted with the reagent. (NBS) was used as the electrophile, the reactions success-
That is, it must have worked as a base for deprotonation from fully proceeded to give 2a (R1ꢁR2ꢁH, XꢁBr) having the
the iodonium ion intermediate (A) before the oxygen atom of newly formed four chiral centers and other stereoisomers in
the acetal attacked the cationic part, then hydrogen iodide good yields with fairly good diastereoselective manners (en-
tries 3—5). A lower reaction temperature also gave better re-
sults (entries 3 vs. 4) and CH3CN was a better choice than
CH2Cl2 in terms of chemical yield (entries 3 vs. 5). For the
ketal 1b, the chemical yield was pretty low due to steric hin-
drance of the methyl group preventing the attack of
MeOCH2CH2OH on the acetal carbon in the intermediate
(C) (entry 6). The disubstituted cyclohexadiene acetals 1c
and 1d reacted with NBS in a similar diastereoselective
manner to give 2c (R1ꢁCH2OTBDPS, R2ꢁH, XꢁBr) and
2d (R1ꢁCH2OMe, R2ꢁH, XꢁBr) as the major products
in fairly good yields (entries 7, 8). Mixed solvent
(CH3CN/CH2Cl2ꢁ4/1) was used in entry 7 due to low solu-
bility of 1c to CH3CN. The stereochemistries of the major
stereoisomers, 2a and 2c, were determined by NOE experi-
ments (Fig. 1). The stereochemistries of the major stereoiso-
mers, 2b and 2d, were deduced from the stereochemistries of
Chart 3
2a and 2c, and a mechanistic consideration (Chart 5).
The plausible reaction mechanism of the haloetherification
reaction in the case of 1a is shown in Chart 5. First, the addi-
tion of the bromonium ion to one of the double bonds fol-
lowed by attack of one of the acetal oxygen atoms forms the
tricyclic oxonium ion intermediates (possible intermediates
Fig. 1. NOE Experiments of 2a and 2c
Chart 4
Table 1. Haloetherification Reaction of 1
Entry
1
Electrophile
Solvent
2
Yield (%)a)
Selectivityb)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1d
I(coll)2ClO4
NIS
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
2a (R1ꢁR2ꢁH, XꢁI)
2a (R1ꢁR2ꢁH, XꢁI)
Trace
39
c)
NBS
NBS
NBS
NBS
NBS
NBS
2a (R1ꢁR2ꢁH, XꢁBr)
75
76 : (19ꢀ5)
73 : (22ꢀ5)
73 : (19ꢀ8)
79 : (12ꢀ9)
82 : (14ꢀ4)
75 : (17ꢀ8)
2a (R1ꢁR2ꢁH, XꢁBr)
54d)
41
2a (R1ꢁR2ꢁH, XꢁBr)
CH3CN
2b (R1ꢁH, R2ꢁMe, XꢁBr)
2c (R1ꢁCH2OTBDPS, R2ꢁH, XꢁBr)
2d (R1ꢁCH2OMe, R2ꢁH, XꢁBr)
44
77
76
CH3CN/CH2Cl2 (4/1)
CH3CN
a) Isolated yield involving minor isomers (ꢂ10%). b) Major isomer (2) vs. minor ones. The presence of two minor isomers was detected by 1H-NMR. The ratio was deter-
mined from the crude product by 1H-NMR and HPLC (chiral OD). c) Not determined. d) Carried out at 0 °C.

954
Vol. 53, No. 8
Chart 5
Chart 7
Chart 6
Table 2. Nucleophilic Replacement with Grignard Reagent
Substratea)
Product
Yield (%)b)
Chart 8
Entry
1
2
3
4
R1ꢁH (2a)
R3ꢁMe (3a)
81
77
89
78
R1ꢁH (2a)
R3ꢁallyl (3b)
R3ꢁPhCH2CH2 (3c)
R3ꢁMe (3d)
hand, although the Birch reduction of 3a itself resulted in the
formation of a complex mixture, the reaction of the debromi-
nated compound obtained by the reduction with tri-n-butyltin
hydride proceeded without any problems to afford the cyclo-
hexene diol derivative 12 with an olefin, which can be used
for further transformations.
R1ꢁH (2a)
R1ꢁOTBDMS (2c)
a) Substrates involving minor isomers (ꢂ10%) were used. b) Isolated yield of
only main isomer.
We also examined the chemical modification of the re-
maining olefin. Dihydroxylation of 3a with OsO4 stereose-
lectively proceeded in high yields to produce the a-dihydrox-
ylated compound 13 as the major product (Chart 8). The
stereochemistries of 13 and 14 were determined from the
coupling patterns. The methine proton Ha of compound 15,
the diacetate of 13, appears as a dd, Jꢁ8.9 and 3.0 Hz (d
5.40 ppm). The large coupling constant between Ha and Hb in
15 suggested the configurations of the diol as a.
In conclusion, we have developed a novel asymmetric syn-
thesis of the cyclohexane derivatives with multichiral centers
using the haloetherification reaction. Since optically active
cyclohexane ring units with multichiral centers are found in
many natural products, the applications of this work to their
asymmetric synthesis are now under investigation.
are C1, C2, C3 or C4). Among the four intermediates, C1 is
most preferable because C2 has a steric repulsion between
the phenyl ring and cyclohexene ring, C3 has repulsion be-
tween the dioxolane ring and cyclohexene ring, and C4 has
repulsion between the phenyl group and cyclohexene ring in
addition to the one between the dioxolane ring and cyclohex-
ene ring. The subsequent SN2-type attack of an alcohol on
the intermediate C1 would then occur to give the 8-mem-
bered mixed acetal 2a having four newly formed chiral cen-
ters. This result fitted the experimental fact well and corre-
sponded to the MO calculations for intermediates by SPAR-
TAN (ver. 3.1.2) using the AM1 Hamiltonian (Energy:
165.00 kcal/mol for C1, 166.28 kcal/mol for C2,
169.90 kcal/mol for C3, 178.43 kcal/mol for C4). These re-
sults suggested that the reaction mainly proceeded via the tri-
cyclic intermediate (C1).
The obtained mixed acetals 2 were converted to 3 by the
Grignard reaction controlled by chelation of Mg2ꢀ to two
oxygen atoms of the methoxyethoxy group (Chart 6). This
nucleophilic replacement reaction has already been reported
to proceed in a retentive stereospecific manner.11,12) The re-
sults are shown in Table 2. The reactions of 2a and 2c with
Grignard reagents afforded the alkyl substituted compounds
3a—d in good yields. At this stage, 3a—c were obtained
with purity by recrystallization and the yields shown in Table
2 are those of the pure compounds.
Experimental
All melting points are uncorrected. The NMR spectra were measured
using 270 and 500 MHz spectrometers with CDCl3 as the solvent and with
SiMe4 as the internal standard. The infrared (IR) absorption spectra were
recorded as a KBr pellet. All solvents were dried and distilled according to
standard procedures.
Preparation of Diene Acetal (4, 5) Diene acetal (4) was prepared ac-
cording to a known procedure.20) 5 was also prepared in a similar procedure.
Preparation of 1a and 1b To a solution of (ꢀ)-hydrobenzoin (1.0
mmol) and diene acetal (4 or 5, 1.0 mmol) in C6H6 (20 ml) was added a cat-
alytic amount of p-toluenesulfonic acid (0.05 mmol) under a nitrogen atmos-
phere. The reaction mixture was refluxed for 1 h under azeotropic condi-
tions. K2CO3 was added to the mixture at r.t. After stirring for 15 min, the
solution was filtered through Celite and concentrated in vacuo. The residue
was purified by SiO2 column chromatography with hexane–AcOEt as the
eluent to give the ene acetal (1).
Removal of the diphenylethylene unit was also examined
as follows using 3a as the substrate (Chart 7). The catalytic
hydrogenolysis of 3a smoothly proceeded to give the bromo
(4R,5R)-2-(2,5-Cyclohexadienylmethyl)-4,5-diphenyl-1,3-dioxolane (1a):
Eluent hexane–AcOEt (50/1); colorless oil; bp 185—195 °C (bath
diol 11 with four chiral centers in good yield. On the other temp.)/0.2 mmHg; [a]D25 ꢀ31° (cꢁ1.0, CHCl3); IR nmax (KBr) 1605, 1497,

August 2005
1456 cmꢃ1 1H-NMR d 2.02 (2H, dd, Jꢁ6.7, 4.8 Hz), 2.6—2.7 (2H, m),
3.1—3.2 (1H, m), 4.77 (2H, s), 5.63 (1H, t, Jꢁ4.8 Hz), 5.7—5.9 (4H, m),
7.2—7.4 (10H, m); Anal. Calcd for C22H22O2: C, 82.99; H, 6.96. Found: C,
82.93; H, 7.04.
955
;
(EI) m/z 587 (MꢀHꢀ); FAB-HR-MS Calcd for C39H43O3Si (MꢀHꢀ)
587.2982, Found 587.2958.
(4R,5R)-2-[(1-Hydroxymethyl-2,5-cyclohexadienyl)methyl]-4,5-
diphenyl-1,3-dioxolane (9) To a solution of 1c (507 mg, 0.86 mmol) in
(4R,5R)-2-(2,5-Cyclohexadienylmethyl)-2-methyl-4,5-diphenyl-1,3-diox- THF (4.3 ml) was added Bu4NF (TBAF) (1.0 M in THF, 1.7 ml) at r.t. After
olane (1b): Eluent hexane–AcOEt (20/1); colorless oil; [a]D20 ꢃ51° (cꢁ0.51, being stirred for 2 h, H2O was added to the solution. The reaction mixture
CHCl3); IR nmax (KBr) 1605, 1497, 1456 cmꢃ1
;
1H-NMR d 1.68 (3H, s),
was extracted with AcOEt. The organic phase was washed with brine, dried
2.05 (2H, d, Jꢁ6.3 Hz), 2.6—2.7 (2H, m), 3.1—3.3 (1H, m), 4.75 (1H, d, over MgSO4, and concentrated in vacuo. The residue was purified by SiO2
Jꢁ8.6 Hz), 4.78 (1H, d, Jꢁ8.6 Hz), 5.6—5.8 (2H, m), 5.8—6.0 (2H, m), column chromatography with hexane–AcOEt (8/1) as an eluent to give 9
7.1—7.3 (10H, m); FAB-MS m/z 333 (MꢀHꢀ); FAB-HR-MS Calcd for
C23H25O2 (MꢀHꢀ) 333.1855, Found 333.1847.
1-(2-tert-Butyldimethylsilyloxyethyl)-1-hydroxymethyl-2,5-cyclohexa- Jꢁ4.5 Hz), 2.7—2.8 (2H, m), 3.50 (2H, d, Jꢁ4.6 Hz), 4.73 (1H, d,
(300 mg, 99%). Colorless oil; [a]D22 ꢀ25° (cꢁ1.3, CHCl3); IR nmax (KBr)
1
3480, 1605, 1497, 1456 cmꢃ1; H-NMR d 1.8—1.9 (1H, br s), 2.02 (2H, d,
diene (6) To a solution of methyl benzoate (7.0 g, 51.4 mmol), MeOH
(2.3 ml, 56.8 mmol) and THF (30 ml) in liq. NH3 (300 ml) was added lithium
wire (1.2 g, 170 mmol) at ꢃ78 °C under a nitrogen atmosphere. After being
stirred for 10 min, TBDMSOCH2CH2I (15.6 g, 54.5 mmol) was added at the
Jꢁ7.6 Hz), 4.75 (1H, d, Jꢁ7.6 Hz), 5.53 (1H, t, Jꢁ4.5 Hz), 5.6—5.7 (2H,
m), 5.9—6.1 (2H, m), 7.1—7.4 (10H, m); FAB-MS m/z 349 (MꢀHꢀ); FAB-
HR-MS Calcd for C23H25O3 (MꢀHꢀ) 349.1804, Found 349.1815.
(4R,5R)-2-[(1-Methoxymethyl-2,5-cyclohexadienyl)methyl]-4,5-
same temperature. After additional 20 min, the reaction mixture was diphenyl-1,3-dioxolane (1d) To a solution of 9 (185 mg, 0.53 mmol) in
quenched with saturated aqueous NH4Cl. After removal of NH3 at r.t., the MeI (5.3 ml) was added Ag2O (1.23 g, 5.3 mmol) at r.t. The reaction mixture
solution was extracted with AcOEt. The organic phase was washed with was stirred for 20 h in the dark. The solution was filtered through Celite and
brine, dried over MgSO4, and concentrated in vacuo. The residue was dis-
solved in THF (100 ml). DIBAL-H (0.95 M in hexane, 118 ml) was slowly
added to the mixture at ꢃ78 °C for 30 min. After being stirred for 30 min,
the reaction mixture was poured into water. To the solution was added satu-
rated aqueous NH4Cl, then the resultant solution was extracted with AcOEt.
The organic phase was washed with brine, dried over MgSO4, and concen-
concentrated in vacuo. The residue was purified by SiO2 column chromatog-
raphy with hexane–AcOEt (20/1) as an eluent to give 1d (173 mg, 90%).
Colorless oil; [a]D22 ꢀ32° (cꢁ0.9, CHCl3); IR nmax (KBr) 1605, 1497,
1456 cmꢃ1 1H-NMR d 2.06 (1H, dd, Jꢁ14, 4.6 Hz), 2.09 (1H, dd, Jꢁ14,
;
4.6 Hz), 2.6—2.8 (2H, m), 3.29 (2H, s), 3.36 (3H, s), 4.70 (1H, d,
Jꢁ7.6 Hz), 4.73 (1H, d, Jꢁ7.6 Hz), 5.46 (1H, t, Jꢁ4.6 Hz), 5.6—5.8 (2H,
trated in vacuo. The residue was purified by SiO2 column chromatography m), 5.8—6.0 (2H, m), 7.2—7.4 (10H, m); Anal. Calcd for C24H26O3Si: C,
with hexane–AcOEt (20/1→10/1) as an eluent to give 6 (8.4 g, 67%). Color-
less oil; bp 185—190 °C (bath temp.)/15 mmHg; IR nmax (KBr) 3350, 1471,
79.53; H, 7.23. Found: C, 79.27; H, 7.19.
General Procedure for Haloetherification Reaction in Table 1 To a
solution of the diene acetal 1 (1.0 mmol) and MeOCH2CH2OH (5.0 mmol) in
CH3CN (10.0 ml) was added an electrophile (1.3 mmol) at ꢃ40 °C under a
nitrogen atmosphere. The reaction mixture was allowed to warm to 0 °C,
then stirred for over 4 h. The solution was quenched with saturated aqueous
Na2S2O3, then extracted with AcOEt. The organic phase was washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue was puri-
fied by SiO2 column chromatography with hexane–AcOEt to give the prod-
ucts 2 in the yields shown in Table 1. The products 2 involving impurities
(ꢂ10%) were used for the next nucleophilic substitution by Grignard
1
1464 cmꢃ1; H-NMR d 0.04 (6H, s), 0.88 (9H, s), 1.58 (2H, t, Jꢁ7.0 Hz),
2.0 (1H, br s), 2.6—2.7 (2H, m), 3.3 (2H, br s), 3.62 (2H, t, Jꢁ7.0 Hz), 5.49
(2H, dt, Jꢁ10, 2.0 Hz), 5.90 (2H, dt, Jꢁ10, 3.3 Hz); MS (EI) m/z 268 (Mꢀ);
Anal. Calcd for C15H28O2Si: C, 67.11; H, 10.51. Found: C, 67.06; H, 10.36.
1-(tert-Butyldiphenylsilyloxymethyl)-1-(2-hydroxyethyl)-2,5-cyclo-
i
hexadiene (7) To a solution of 6 (1.4 g, 5.3 mmol) and Pr2EtN (2.0 ml)
was added TBDPSCl (1.5 ml, 5.7 mmol) at 0 °C under a nitrogen atmo-
sphere. Slowly warming to r.t., the reaction mixture was stirred for 5 h, then
was poured into water. The solution was extracted with hexane for only one
time. The organic phase was washed with brine, dried over MgSO4, and con- reagent (Table 2). We supposed the contained impurities as minor stereoiso-
centrated in vacuo. Eighty percent aqueous acetic acid was added to the mers by considering the fact that they show the same polarity on TLC using
residue, and the mixture was refluxed for 2 h. The reaction mixture was di- various developing solvent systems (hexane–AcOEt, benzene–AcOEt,
rectly concentrated in vacuo. The residue was purified by SiO2 column chro-
matography with hexane–AcOEt (4/1) as an eluent to give 7 (1.7 g,
CH2Cl2–Et2O) and the result of the intramolecular haloetherification of more
simple ene acetals previously reported by us (see Eq. 1).10,11)
4.3 mmol, 81%). Colorless oil; IR nmax (KBr) 3400, 1589, 1487, 1464 cmꢃ1
;
The NMR data showed the signals of the major products (2a—d).
(1R,3R,4R,6R,8R,12R)-12-Bromo-6-methoxyethoxy-2,5-dioxa-3,4-
diphenylbicyclo[6.4.0]dodec-9-ene (2a) The ratio of the diastereoisomers
[2a : othersꢁ76 : (19ꢀ5)] was determined by HPLC analysis [Chiralcel OD,
1H-NMR d 1.05 (9H, s), 1.77 (2H, t, Jꢁ6.4 Hz), 2.6—2.7 (2H, m), 3.43
(2H, s), 3.67 (2H, t, Jꢁ6.4 Hz), 5.58 (2H, dt, Jꢁ10, 2.0 Hz), 5.85 (2H, dt,
Jꢁ10, 3.6 Hz), 7.3—7.5 (6H, m), 7.6—7.7 (4H, m); FAB-MS m/z 393
(MꢀHꢀ); FAB-HR-MS Calcd for C25H33O2Si (MꢀHꢀ) 393.2250, Found hexane–iPrOH (99/1), 0.7 ml/min flow rate]. Eluent hexane–AcOEt (4/1);
393.2226.
colorless oil; IR nmax (KBr) 1495, 1454 cmꢃ1 1H-NMR d 2.05 (2H, dd,
;
Jꢁ6.4, 5.5 Hz), 2.5—2.6 (1H, m), 2.8—2.9 (1H, m), 3.31 (3H, s). 3.3—3.6
(4H, m), 3.6—3.8 (1H, m), 4.03 (1H, dd, Jꢁ9.0, 5.5 Hz), 4.32 (1H, dt,
(1-tert-Butyldiphenylsilyloxymethyl-2,5-cyclohexadienyl) Acetaldehyde
(8) To a solution of oxalyl chloride (0.35 ml, 4.0 mmol) in CH2Cl2 (9.0 ml)
was carefully added a solution of dimethyl sulfoxide (0.57 ml, 8.0 mmol) in Jꢁ9.0, 6.1 Hz), 4.42 (1H, d, Jꢁ9.2 Hz), 4.43 (1H, d, Jꢁ9.2 Hz), 5.38 (1H, t,
CH2Cl2 (9.0 ml) at ꢃ78 °C under a nitrogen atmosphere. After being stirred
for 5 min, the reaction mixture was warmed to ꢃ20 °C. To the resulting so-
lution was added a solution of 7 (718 mg, 1.83 mmol) in CH2Cl2 (10.0 ml).
After being stirred for 15 min at the same temperature, the reaction mixture
was cooled to ꢃ78 °C, then quenched with Et3N (1.28 ml, 9.2 mmol). The
solution was warmed to 0 °C, then poured into water. The solution was ex-
Jꢁ5.5 Hz), 5.5—5.6 (1H, m), 5.6—5.7 (1H, m), 6.9—7.3 (10H, m); 13C-
NMR d 35.46, 35.62, 37.67, 47.80, 58.94, 66.56, 71.68, 81.94, 87.90, 88.50,
104.17, 124.42, 127.40, 127.48, 127.55, 127.75, 127.82, 129.18, 137.93,
138.10; FAB-MS m/z 473 (MꢀHꢀ); FAB-HR-MS Calcd for C25H30BrO4
(MꢀHꢀ) 473.1727, Found 473.1334.
(1R,3R,4R,6R,8R,12R)-12-Bromo-6-methoxyethoxy-6-methyl-2,5-
tracted with AcOEt. The organic phase was washed with brine, dried over dioxa-3,4-diphenylbicyclo[6.4.0]dodec-9-ene (2b) The ratio of the di-
MgSO4, and concentrated in vacuo. The residue was purified by SiO2 col-
umn chromatography with hexane–AcOEt (20/1) as an eluent to give 8
astereoisomers [2b : othersꢁ79 : (12ꢀ9)] was determined by HPLC analysis
[Chiralcel OD, hexane–iPrOH (99/1), 0.7 ml/min flow rate]. Eluent
(606 mg, 85%). Colorless oil; IR nmax (KBr) 1722, 1589, 1471 cmꢃ1
;
1H-
hexane–AcOEt (10/1); colorless oil; IR nmax (KBr) 1493, 1455 cmꢃ1 1H-
;
NMR d 1.06 (9H, s), 2.49 (2H, d, Jꢁ3.2 Hz), 2.6—2.7 (2H, m), 3.48 (2H, NMR d 1.26 (3H, s), 1.84 (1H, dd, Jꢁ14, 3.5 Hz), 2.2—2.4 (3H, m), 2.8—
s), 4.67 (2H, dt, Jꢁ10, 2.0 Hz), 5.87 (2H, dt, Jꢁ10, 3.3 Hz), 7.3—7.5 (6H, 3.0 (1H, m), 3.46 (3H, s), 3.3—3.5 (1H, m), 3.5—3.7 (2H, m), 3.9—4.0
m), 7.6—7.7 (4H, m), 9.66 (1H, t, Jꢁ3.2 Hz); FAB-MS m/z 391 (MꢀHꢀ); (1H, m), 4.2—4.3 (1H, m), 4.36 (1H, d, Jꢁ8.6 Hz), 4.43 (1H, d, Jꢁ8.6 Hz),
Anal. Calcd for C25H30O2Si: C, 76.88; H, 7.74. Found: C, 76.67; H, 7.77.
(4R,5R)-2-[(1-tert-Butyldiphenylsilyloxymethyl-2,5-cyclohexadienyl)-
4.94 (1H, t, Jꢁ4.3 Hz), 5.4—5.5 (1H, m), 5.6—5.7 (1H, m), 6.8—6.9 (4H,
m), 7.0—7.2 (6H, m); FAB-MS m/z 487 (MꢀHꢀ); FAB-HR-MS Calcd for
methyl]-4,5-diphenyl-1,3-dioxolane (1c) 1c was prepared by the same C26H32BrO4 (MꢀHꢀ) 487.1484, Found 487.1469.
procedure for 1a and 1b.
8
(296 mg, 0.76 mmol), (ꢀ)-hydrobenzoin
(1R,3R,4R,6R,8S,12R)-12-Bromo-8-tert-butyldiphenylsilyloxymethyl-
6-methoxyethoxy-2,5-dioxa-3,4-diphenylbicyclo[6.4.0]dodec-9-ene (2c)
The reaction was carried out in CH3CN–CH2Cl2 (v/vꢁ4/1) within 2 h. The
ratio of the diastereoisomers [2c : othersꢁ82 : (14ꢀ4)] was determined by
(162 mg, 0.76 mmol), C6H6 (7.5 ml), 1c (414 mg, 93%). Eluent hexane–
AcOEt (30/1); colorless oil; [a]D21 ꢀ17° (cꢁ1.3, CHCl3); IR nmax (KBr)
1605, 1497, 1456 cmꢃ1 1H-NMR d 1.07 (9H, s), 2.16 (1H, dd, Jꢁ14,
;
4.6 Hz), 2.19 (1H, dd, Jꢁ14, 4.6 Hz), 2.6—2.7 (2H, m), 3.53 (2H, s), 4.68 HPLC analysis [Chiralcel OD, hexane–iPrOH (99/1), 0.7 ml/min flow rate].
(1H, d, Jꢁ7.3 Hz), 4.74 (1H, d, Jꢁ7.3 Hz), 5.45 (1H, t, Jꢁ4.6 Hz), 5.7—5.8 Eluent hexane–AcOEt (10/1→8/1); colorless oil; IR nmax (KBr) 1495,
(2H, m), 5.8—5.9 (2H, m), 7.1—7.4 (16H, m), 7.6—7.7 (4H, m); FAB-MS
1455 cmꢃ1 1H-NMR d 1.14 (9H, s), 1.84 (1H, dd, Jꢁ15.5, 7.6 Hz), 2.10
;

956
Vol. 53, No. 8
(1H, dd, Jꢁ15.5, 4.6 Hz), 2.5—2.9 (2H, m), 3.27 (3H, s), 3.3—3.5 (3H, m), Jꢁ3.8, 6.6 Hz); Anal. Calcd for C9H17BrO2: C, 45.59; H, 7.23; Br, 33.70.
3.5—3.7 (1H, m), 3.68 (1H, d, Jꢁ10 Hz), 4.28 (1H, dt, Jꢁ10, 5.6 Hz), 4.41
(1H, d, Jꢁ10 Hz), 4.46 (1H, d, Jꢁ9.2 Hz), 4.62 (1H, d, Jꢁ9.2 Hz), 4.94 (1H,
Found: C, 45.60; H, 7.02; Br, 33.39.
(1S,2R)-2-[(2S)-2-Hydroxypropyl]-3-cyclohexen-1-ol (12) To a solu-
d, Jꢁ10 Hz), 5.20 (1H, dd, Jꢁ7.6, 4.6 Hz), 5.5—5.6 (2H, m), 6.84 (2H, d, tion of 3a (95 mg, 0.22 mmol) in toluene (2.2 ml) was added Bu3SnH
Jꢁ6.9 Hz), 6.9—7.3 (18H, m); FAB-MS m/z 741 (MꢀHꢀ); FAB-HR-MS (0.092 ml, 0.34 mmol) and a catalytic amount of AIBN under a nitrogen at-
Calcd for C42H50BrO5Si (MꢀHꢀ) 741.2611, Found 741.2609.
mosphere. The reaction mixture was refluxed for 1 h. The resultant solution
(1R,3R,4R,6R,8R,12R)-12-Bromo-6-methoxyethoxy-8-methoxymethyl- was directly concentrated in vacuo. To a solution of Ca (26 mg, 0.66 mmol)
2,5-dioxa-3,4-diphenylbicyclo[6.4.0]dodec-9-ene (2d) The ratio of the in liq. NH3 (6.0 ml) was added the obtained residue at ꢃ78 °C under a nitro-
diastereoisomers [2d : othersꢁ75 : (17ꢀ8)] was determined by HPLC analy-
gen atmosphere. After being stirred for 15 min, a solution of EtOH (0.04 ml,
sis [Chiralcel OD, hexane–iPrOH (99/1), 0.7 ml/min flow rate]. Eluent 0.66 mmol) in THF (1.0 ml) was added at the same temperature. The solu-
hexane–AcOEt (6/1); colorless oil; IR nmax (KBr) 1603, 1495, 1455 cmꢃ1
;
tion was quenched with saturated aqueous NH4Cl. After removal of NH3 at
r.t., the resultant solution was extracted with AcOEt. The organic phase was
1H-NMR d 2.05 (1H, dd, Jꢁ15.5, 6.9 Hz), 2.11 (1H, dd, Jꢁ15.5, 4.6 Hz),
2.5—2.7 (1H, m), 2.7—2.9 (1H, m), 3.31 (3H, s). 3.45 (3H, s), 3.3—3.8 washed with brine, dried over MgSO4, and concentrated in vacuo. The
(3H, m), 4.2—4.3 (2H, m), 4.4—4.6 (3H, m), 5.4—5.7 (3H, m), 6.9—7.2 residue was purified by SiO2 column chromatography with hexane–AcOEt
(10H, m); FAB-MS m/z 539 (MꢀNaꢀ); FAB-HR-MS Calcd for (2/1→1/1) as an eluent to give 12 (28.0 mg, 78%). Colorless oil; [a]D20 ꢀ35°
1
C27H32BrNaO5 (MꢀNaꢀ) 539.1409, Found 539.1401.
(cꢁ0.56, CHCl3); IR nmax (KBr) 3300, 1641 cmꢃ1; H-NMR d 1.21 (3H, d,
Jꢁ5.9 Hz), 1.5—1.7 (6H, m), 2.0—2.5 (3H, m), 3.6—3.7 (1H, m), 3.8—3.9
(1H, m), 4.9—5.1 (2H, m), 5.8—5.9 (1H, m); MS (EI) m/z 156 (Mꢀ).
(1R,3R,4R,6S,8R,9R,10S,12R)-12-Bromo-9,10-dihydroxy-6-methyl-
2,5-dioxa-3,4-diphenylbicyclo[6.4.0]dodecane (13) To a solution of 3a
(74 mg, 0.17 mmol) and 4-methylmorpholine N-oxide (NMO) (50% in H2O,
0.04 ml) in acetone–H2O (v/vꢁ1/1, 2.0 ml) was added a catalytic amount of
General Procedure for the Grignard Reaction in Table 2 To a solu-
tion of the acetal [2a or 2c, 1.0 mmol, involving minor isomers (ꢂ10%)] in
toluene (50.0 ml) was added RMgX (5.0 mmol) at r.t. under a nitrogen atmo-
sphere. The reaction mixture was stirred for 12 h at r.t., then quenched with
saturated aqueous NH4Cl. The resulting solution was extracted with AcOEt.
The organic phase was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by SiO2 column chromatography OsO4 at r.t. The reaction mixture was stirred for 1.5 h. The solution was
with hexane–AcOEt as an eluent to give 3 involving minor isomers derived quenched with saturated aqueous Na2SO3, then stirred for 15 min at r.t. The
from those in substrates. Minor isomers of 3a—d were successfully removed resultant solution was extracted with AcOEt. The organic phase was washed
by recrystallization (hexane) to give 3a—d in the pure state.
with brine, dried over MgSO4, and concentrated in vacuo. The residue was
(1R,3R,4R,6S,8R,12R)-12-Bromo-6-methyl-2,5-dioxa-3,4-diphenylbicy- purified by SiO2 column chromatography with hexane–AcOEt (3/1) as an
clo[6.4.0]dodec-9-ene (3a): Eluent hexane–AcOEt (20/1); colorless crystal;
eluent to give 13 (68.3 mg, 85%) and 14 (6.0 mg, 8%). 13: colorless oil;
mp 98.5—99 °C (hexane); [a]D24 ꢃ402° (cꢁ0.56, CHCl3); IR nmax (KBr)
[a]D26 ꢃ59.6° (cꢁ2.36, CHCl3); IR nmax (KBr) 1493, 1453, 1437 cmꢃ1; H-
1
1
1493, 1454 cmꢃ1; H-NMR d 1.32 (3H, d, Jꢁ6.3 Hz), 1.53 (1H, dt, Jꢁ14, NMR d 1.23 (3H, d, Jꢁ6.0 Hz), 1.8—2.0 (1H, m), 2.2—2.7 (5H, m), 2.84
3.0 Hz), 2.3—2.4 (1H, m), 2.44 (1H, ddd, Jꢁ14, 4.6, 2.0 Hz), 2.8—3.0 (1H, (1H, br s), 3.9—4.2 (3H, m), 4.4—4.7 (3H, m), 4.7 (1H, br s), 6.8—7.2
m), 3.1—3.3 (1H, m), 4.0—4.2 (1H, m), 4.27 (1H, q, Jꢁ4.8 Hz), 4.42 (2H,
s), 4.76 (1H, t, Jꢁ4.8 Hz), 5.4—5.7 (2H, m), 6.8—7.2 (10H, m); MS (EI)
(10H, m); FAB-MS m/z 447 (MꢀHꢀ); FAB-HR-MS Calcd for C23H28BrO4
(MꢀHꢀ) 447.1171, Found 447.1173. 14: [a]D27 ꢃ48.7° (cꢁ0.48, CHCl3); IR
m/z 412 (Mꢀ), 414 (Mꢀ2ꢀ); HR-MS Calcd for C23H25BrO2 412.1039 (Mꢀ), nmax (KBr) 3499, 2922, 1088, 1069 cmꢃ1 1H-NMR d 1.30 (3H, d,
;
414.1019 (Mꢀ2ꢀ), Found 412.1042 (Mꢀ), 414.1027 (Mꢀ2ꢀ); Anal. Calcd
for C23H25BrO2: C, 66.83; H, 6.10; Br, 19.33. Found: C, 66.97; H, 6.09; Br, (3H, m), 3.60 (1H, d, Jꢁ10.0 Hz), 3.83 (1H, d, Jꢁ10.0 Hz), 3.9—4.1 (1H,
Jꢁ6.6 Hz), 1.8—1.9 (1H, m), 2.0—2.2 (2H, m), 2.46 (1H, br s), 2.6—2.8
18.94.
(1R,3R,4R,6S,8R,12R)-6-Allyl-12-bromo-2,5-dioxa-3,4-diphenylbicy-
clo[6.4.0]dodec-9-ene (3b): Eluent hexane–AcOEt (20/1); colorless crystal;
mp 74—74.5 °C (hexane); [a]D23 ꢃ215° (cꢁ0.57, CHCl3); IR nmax (KBr)
1495, 1455 cmꢃ1; 1H-NMR d 1.66 (1H, dt, Jꢁ15, 3.8 Hz), 2.2—2.6 (4H, m),
m), 4.2—4.4 (3H, m), 4.62 (1H, d, Jꢁ9.0 Hz), 5.10 (1H, s), 6.8—7.2 (10H,
m); FAB-HR-MS Calcd for C23H28BrO4 (MHꢀ) 447.1171, Found 447.1171.
(1R,3R,4R,6S,8R,9R,10S,12R)-12-Bromo-9,10-diacetoxy-6-methyl-2,5-
dioxa-3,4-diphenylbicyclo[6.4.0]dodecane (15) A mixture of 13 (160 mg,
0.36 mmol), Ac2O (0.18 ml), and pyridine (0.36 ml) was stirred for 3 h at r.t.
2.8—3.0 (1H, m), 3.1—3.3 (1H, m), 4.0—4.1 (1H, m), 4.29 (1H, q, Under a nitrogen atmospher. The resulting solution was evaporated in vacuo
Jꢁ5.0 Hz), 4.41 (1H, d, Jꢁ9.0 Hz), 4.42 (1H, d, Jꢁ9.0 Hz), 4.63 (1H, t, to give crude product, which was purified by SiO2 column chromatography
Jꢁ5.0 Hz), 4.9—5.1 (2H, m), 5.5—5.7 (2H, m), 5.7—5.9 (1H, m), 6.8—7.2 with hexane–AcOEt (5/1) as an eluent to give 15 (173 mg, 87%). 15: white
(10H, m); MS (EI) m/z 438 (Mꢀ), 440 (Mꢀ2ꢀ); Anal. Calcd for amorphous; [a]D24 ꢃ20.4° (cꢁ2.6, CHCl3); IR nmax (KBr) 1738, 1245 cmꢃ1
;
C25H27BrO2: C, 68.34; H, 6.19. Found: C, 68.16; H, 6.09.
1H-NMR d 1.18 (3H, d, Jꢁ6.0 Hz), 1.7—1.9 (1H, m), 1.9—2.1 (1H, m),
2.08 (3H, s), 2.10 (3H,s), 2.31 (1H, dt, Jꢁ13.5, 5.4 Hz), 2.49 (1H, dt,
(1R,3R,4R,6S,8R,12R)-12-Bromo-2,5-dioxa-3,4-diphenyl-6-(2-
phenylethyl)bicyclo[6.4.0]dodec-9-ene (3c): Eluent hexane–AcOEt (30/1); Jꢁ13.5, 4.1 Hz), 3.0—3.1 (1H, m), 4.0—4.2 (1H, m), 4.3—4.5 (1H, m),
colorless crystal; mp 160—161 °C (hexane); [a]D24 ꢃ187° (cꢁ1.1, CHCl3);
4.39 (1H, A part in ABq), 4.43 (1H, B part in ABq), 5.21 (1H, br s), 5.38
1
IR nmax (KBr) 1603, 1495, 1454 cmꢃ1; H-NMR d 1.5—1.6 (1H, m), 1.6— (1H, dd, Jꢁ8.9, 3.0 Hz), 6.8—7.2 (10H, m); FAB-MS m/z 530 (Mꢀ); FAB-
1.8 (1H, m), 2.0—2.2 (1H, m), 2.3—2.4 (2H, m), 2.5—2.7 (1H, m), 2.7— HR-MS Calcd for C27H31BrO6 (Mꢀ) 530.1303, Found 530.1314.
3.0 (2H, m), 3.1—3.3 (1H, m), 3.87 (1H, ddt, Jꢁ9.2, 5.0, 5.0 Hz), 4.28 (1H,
q, Jꢁ4.5 Hz), 4.39 (1H, d, Jꢁ8.9 Hz), 4.45 (1H, d, Jꢁ8.9 Hz), 4.72 (1H, t,
Acknowledgment This research was supported by a Grant-in-Aid for
Jꢁ4.5 Hz), 5.4—5.7 (2H, m), 6.8—7.3 (15H, m); Anal. Calcd for Scientific Research from the Ministry of Education, Culture, Sports, Science
C30H31BrO2: C, 71.57; H, 6.21; Br, 15.87. Found: C, 71.47; H, 6.31; Br, and Technology, Japan.
15.78.
(1R,3R,4R,6S,8S,12R)-12-Bromo-8-tert-butyldiphenylsilyloxymethyl-6- References and Notes
methyl-2,5-dioxa-3,4-diphenylbicyclo[6.4.0]dodec-9-ene (3d): Eluent
1) Mikami K., Yoshida A., J. Synth. Org. Chem. Jpn., 60, 732—739
(2002).
2) Willis M. C., J. Chem. Soc., Perkin Trans. 1, 1999, 1765—1784
(1999).
3) Maganus S. R., Tetrahedron, 51, 2167—2213 (1995).
4) Poss C. S., Schreiber S. L., Acc. Chem. Res., 27, 9—17 (1994).
5) Ward R. S., Chem. Soc. Rev., 19, 1—19 (1990).
6) Johnson C. R., Acc. Chem. Res., 31, 333—341 (1998).
7) Schoffers E., Golebiowski A., Johnson C. R., Tetrahedron, 52, 3769—
3826 (1996).
hexane–AcOEt (30/1); colorless oil; [a]D20 ꢃ155° (cꢁ0.50, CHCl3); IR nmax
(KBr) 1590, 1493, 1455 cmꢃ1
;
1H-NMR d 1.09 (12H, s), 1.82 (2H, d,
Jꢁ6.3 Hz), 2.5—2.7 (1H, m), 2.8—2.9 (1H, m), 3.78 (1H, d, Jꢁ10 Hz), 4.28
(1H, dt, Jꢁ2.8, 8.4 Hz), 4.41 (2H, t, Jꢁ8.8 Hz), 4.6—4.8 (3H, m), 5.2—5.3
(1H, m), 5.5—5.6 (1H, m), 6.7—6.8 (2H, m), 6.9—7.0 (2H, m), 7.0—7.2
(6H, m), 7.3—7.5 (6H, m), 7.6—7.8 (4H, m); FAB-MS m/z 681 (MꢀHꢀ);
FAB-HR-MS Calcd for C40H46BrO3Si (MꢀHꢀ) 681.2400, Found 681.2405.
(1R,2R,6S)-2-Bromo-6-[(2S)-2-hydroxypropyl]cyclohexanol (11) To a
solution of 3a (33.8 mg, 0.082 mmol) in EtOH–THF (3.5 ml, v/vꢁ6/1) was
added a catalytic amount of Pd(OH)2–C at r.t. under a medium pressure of
H2 (4 kgf/cm2). After the completion of the reaction, the product was puri-
fied by SiO2 column chromatography with hexane–AcOEt (2/1) as an eluent
to give 11 (16.5 mg, 86%). Colorless crystal; mp 71—71.5 °C (AcOEt–
8) Santaniello E., Ferraboschi P., Grisenti P., Manzocchi A., Chem. Rev.,
92, 1071—1140 (1992).
9) Ohno M., Kobayashi S., Kurihara M., J. Synth. Org. Chem. Jpn., 44,
38—48 (1986).
hexane); [a]D16 ꢃ23° (cꢁ0.66, CHCl3); IR nmax (KBr) 3330, 1456 cmꢃ1; 1H- 10) Fujioka H., Kitagawa H., Matsunaga N., Nagatomi Y., Kita Y., Tetra-
NMR d 1.22 (3H, d, Jꢁ6.2 Hz), 1.3—1.9 (7H, m), 2.2—2.5 (2H, m), 2.55
hedron Lett., 37, 2245—2248 (1996).
(2H, br s), 3.87 (1H, dd, Jꢁ6.6, 3.5 Hz), 3.9—4.1 (1H, m), 4.27 (1H, dt, 11) Fujioka H., Kitagawa H., Nagatomi Y., Kita Y., J. Org. Chem., 61,

August 2005
957
7309—7315 (1996).
Soc., 111, 7507—7519 (1989).
12) Kitagawa O., Momose S., Fushimi Y., Taguchi T., Tetrahedron Lett., 18) Takano S., Murakata C., Imamura Y., Tamura N., Ogasawara K., Hete-
40, 8827—8831 (1999).
rocycles, 16, 1291—1294 (1981).
13) Yokomatsu T., Iwasawa H., Shibuya S., Tetrahedron Lett., 33, 6999—
7002 (1992).
14) Yokomatsu T., Iwasawa H., Shibuya S., J. Chem. Soc., Chem. Com-
mun., 1992, 728—729 (1992).
19) For the communication related to the similar concept, see: Fujioka H.,
Kotoku N., Sawama Y., Nagatomi Y., Kita Y., Tetrahedron Lett., 43,
4825—4828 (2002).
20) Scholz D., Schmidt U., Chem. Ber., 107, 2295—2298 (1974).
15) Kitagawa O., Hanano T., Tanabe K., Shiro M., Taguchi T., J. Chem. 21) Wang Z.-M., Sharpless K. B., J. Org. Chem., 59, 8302—8303 (1994).
Soc., Chem. Commun., 1992, 1005—1007 (1992).
16) Fuji K., Node M., Naniwa Y., Kawabata T., Tetrahedron Lett., 31,
3175—3178 (1990).
22) Marshall J. A., Wuts P. G. M., J. Org. Chem., 43, 1086—1089 (1978).
23) Mancuso A. J., Huang S. L., Swern D., J. Org. Chem., 43, 2480—2482
(1978).
17) Hart D. J., Huang H.-C., Krishnamurthy R., Schwartz T., J. Am. Chem.