Asymmetric desymmetrization based on an intramolecular haloetherification: A highly effective and recyclable chiral nonracemic auxiliary, 2-exo-methyl-3-endo-phenyl-5-norbornene-2-carboxaldehyde, for meso-1,3- and meso-1,4-diols

Article abstract of DOI:10.1002/chem.200400444

A new chiral auxiliary, a 3-endo-phenyl norbornene aldehyde derivative, which is a crystalline, very stable, and easily handled, was developed for the desymmetrization of meso-1,3- and meso-1,4-diols. The key step of the method, an intramolecular bromoeth

Full text of DOI:10.1002/chem.200400444

FULL PAPER
Asymmetric Desymmetrization Based on an Intramolecular
Haloetherification: A Highly Effective and Recyclable Chiral Nonracemic
Auxiliary,2- exo-Methyl-3-endo-phenyl-5-norbornene-2-carboxaldehyde,for
meso-1,3- and meso-1,4-Diols
Hiromichi Fujioka,* Tetsuya Fujita, Naoyuki Kotoku, Yusuke Ohba, Yasushi Nagatomi,
[a]
Atsushi Hiramatsu,and Yasuyuki Kita*
Abstract: A new chiral auxiliary, a 3-
endo-phenyl norbornene aldehyde de-
rivative, which is a crystalline, very
stable, and easily handled, was devel-
oped for the desymmetrization of
meso-1,3- and meso-1,4-diols. The key
step of the method, an intramolecular
2) intramolecular bromoetherification
followed by acid hydrolysis, 3) protec-
tion of the alcohol, and 4) retrobro-
tives. The 3-endo-phenyl norbornene
aldehyde derivative was simultaneously
reformed and could be used repeatedly.
This is the first chemical example of a
single auxiliary that is applicable for
highly enantioselective desymmetriza-
tion of meso-1,3- and meso-1,4-diols; to
the best of our knowledge, this is the
best chemical method available for the
desymmetrization of meso-1,4-diols.
moetherification,
transformed
the
meso-diols into optically active deriva-
Keywords: asymmetric synthesis ·
chiral auxiliaries · desymmetriza-
tion · diols · norbornene
bromoetherification, proceeded in
highly diastereoselective manner.
a
A
four-step sequence, 1) acetalization,
Introduction
Recently, we developed a new desymmetrization method
for meso-1,2-diols by using the chiral nonracemic methylnor-
bornene aldehyde 1a as an auxiliary.[5] We then succeeded
in the optical resolution of other norbornene aldehyde de-
rivatives and found that 3-exo-phenylnorbornene aldehyde
1b is a better choice as an auxiliary for the desymmetriza-
tion of meso-1,2-diols because it overcomes the disadvant-
age of 1a, that is, volatility.[6] In our method, the desymmet-
rization step of the meso-1,2-diols depends on the difference
between the activation energies of the two transition states
(i and ii) formed by the intramolecular bromoetherification
of acetals derived from 1a or 1b and the meso-1,2-diols. A
large difference in the activation energies between transition
state i and transition state ii causes the discrimination of the
two oxygen atoms of the acetals in a highly diastereoselec-
tive manner (Scheme 1).
Desymmetrization of meso-diols is a very useful way to get
optically active compounds and has been investigated in
many ways by using chemical or enzymatic methods.[1] For
the chemical methods, many good desymmetrization meth-
ods for meso-1,2-diols have been reported.[2] However, the
desymmetrization methods for meso-1,3-diols are few[3] and
only a few chemical desymmetrization methods for meso-
1,4-diols, to our best knowledge, have been reported.[4]
Quite recently, a new asymmetric catalyst was developed for
the desymmetrization of the meso-1,3- and meso-1,4-diols by
Trost and Mino.[4c]
[a] Prof. Dr. H. Fujioka, T. Fujita, N. Kotoku, Y. Ohba, Y. Nagatomi,
A. Hiramatsu, Prof. Dr. Y. Kita
We then applied this method to the desymmetrization of
the meso-1,3- and meso-1,4-diols by using 1b. However, the
results were fruitless. The acetalization of 1b with the meso-
1,3-diol, meso-2,4-pentanediol (2), gave the single acetal 3,
but its intramolecular bromoetherification afforded a dia-
stereomeric mixture of the nine-membered acetals 4 in a
ratio of 6.5:1. The insufficient discrimination of the two
oxygen atoms was ascertained by acid hydrolysis of 4 to give
the aldehyde, which was still a 6.5:1 mixture. In the case of
the meso-1,4-diol 5a, acetalization did even not produce the
Graduate School of Pharmaceutical Sciences
Osaka University
1–6, Yamadaꢀoka, Suita, Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
kita@phs.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It contains the
13C NMR spectra of the compounds that were also analyzed by high-
resolution mass spectra.
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DOI: 10.1002/chem.200400444
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5386 – 5397
Based on the above concept,
we first examined the desym-
metrization of meso-1,4-diols
because the chemical methods
for their desymmetrization are
rare, as mentioned before.[4] We
found that the 2-endo-aldehyde
norbornene aldehyde derivative
7a was a good auxiliary. A 2-
exo-methyl group was intro-
duced to prevent the epimeriza-
tion of the 3-endo-phenyl
group. The aldehyde 7a also
proved to be effective for the
desymmetrization of the meso-
Scheme 1. Desymmetrization of meso-1,2-diols by using 3-exo-substituted norbornene aldehydes (1a or 1b).
PG=protecting group, Bn=benzyl, Deriv.=derivative.
1,3-diols. Scheme 4 shows
a
summary of our transforma-
tions: 1) acetalization of 7a
with meso-diols, 2) intramolecu-
lar bromoetherification in the
presence of MeOHfollowed by
acid hydrolysis, 3) protection of
the alcohol, then 4) retrobro-
moetherification. In this trans-
formation, 7a was regenerated
along with the optically active
diol derivatives and could be
used again. This is completely
different from our previous
method (see Scheme 1) where
the ene acetals are regenerated
and it makes our new method
more effective. Although exo-
Scheme 2. Desymmetrization of meso-1,3-diol (2) and meso-1,4-diol (5a) by using 1b. NBS=N-bromosuccini-
mide, p-TsOH=toluene-4-sulfonic acid.
single acetal; instead acetals 6 were formed as a mixture in
a ratio of 13:1. We therefore required a new auxiliary for
the desymmetrization of meso-1,3- and meso-1,4-diols
(Scheme 2).
substituted norbornene aldehydes 1a and 1b need mixed-
acetal structures for good retrobromoetherification, 7a does
not need mixed-acetal structures for retrobromoetherifica-
tion and aldehydes are good precursors for retrobromo-
etherification. This is an advantage because the retrobro-
moetherification of the mixed acetals requires careful reac-
tion-temperature control (about 708C) to prevent reacetali-
zation of the resulting hydroxy acetals (see Scheme 1). On
the other hand, the retrobromoetherification depicted in
Crucial steps in our method are the acetalization and dis-
crimination of the two oxygen atoms, an intramolecular bro-
moetherification. Based on this requirement, especially the
discrimination step, a large difference in the activation ener-
gies between the two transition states is needed to realize
sufficient desymmetrization.[7] We therefore planned the
synthesis of 3-endo-substituted norbornene aldehyde deriva-
tives, which would produce a large difference between tran-
sition states iii and iv because the 3-endo substituent R1
might inhibit the rotation of the acetal moiety that would
lead to the formation of the endo isomer iv during the intra-
molecular bromoetherification (Scheme 3).
Scheme 3. Perspective view of the effect of the 3-endo substituent in the
intramolecular bromoetherification.
Scheme 4. Desymmetrization of meso-diols by using 3-endo-phenyl nor-
bornene aldehyde 7a. Tf=triflate=trifluoromethanesulfonyl.
Chem. Eur. J. 2004, 10, 5386 – 5397
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FULL PAPER
Scheme 4 does not require careful reaction-temperature
control, because the acetalization no longer occurs between
the resulting 7a and the optically active diol derivatives
when one of the two hydroxy groups is protected.
Results and Discussion
Design of new auxiliary: As mentioned before (see
Scheme 3), we speculated that the 3-endo substituent would
enhance the diastereoselectivity during the key step of de-
symmetrization, that is, the intramolecular bromoetherifica-
tion. We synthesized two 3-endo-substituted norbornene al-
dehyde derivatives, the phenyl-substituted and methyl-sub-
stituted compounds 7a and 7b. Aldehydes (ꢁ)-7a,b were
prepared by the usual way (Scheme 5): 1) Diels–Alder reac-
Scheme 6. Optical resolution of racemic 7a. DMA=N,N-dimethylacet-
amide.
Desymmetrization of meso-1,4-diols: All of the transforma-
tions for desymmetrization of the meso-1,4-diols by using 5-
norbornene-2-endo-3-endo-dimethanol 5a are depicted in
Schemes 7 and 9. Acetalization of (ꢀ)-7a with 5a afforded
the sole product 11a, whose stereochemistry was deter-
mined to be trans by X-ray crystal analysis and mechanistic
considerations (see below). Intramolecular bromoetherifica-
tion of 11a in the presence of MeOHgave the ten-mem-
bered mixed acetal 15a in a highly diastereoselective
manner (Scheme 7). Its stereochemistry was determined by
Scheme 5. Preparation of racemic 3-endo-substituted norbornene alde-
hydes 7a and 7b and their acetalization with 5a. LDA=lithium diisopro-
pylamide.
tion of methyl Z-cinnamate[8] or methyl isocrotonate with
cyclopentadiene to give 8, 2) methylation of 8 by treatment
with LDA followed by methyl iodide to give 9, 3) LiAlH4
reduction of 9 to give 10, and 4) Swern oxidation[9] of 10 to
give (ꢁ)-7a,b. Without the 2-exo-methyl group, the 2-endo-
aldehyde groups would easily epimerize to the exo confor-
mation because of the steric repulsion of 3-endo substitu-
ents. Although acetalization of 7b with 5a gave the trans-
acetal 11b and a small amount of the cis isomer, the phenyl-
substituted norbornene aldehyde 7a afforded the single
isomer 11a (Scheme 5). Compound 7a was therefore deter-
mined to be the auxiliary of choice.
Scheme 7. Acetalization of (ꢀ)-7a and its intramolecular bromoetherifi-
cation.
X-ray crystal analysis of 15b’, which was obtained by the in-
tramolecular bromoetherification of the ene acetal from 5b
and (+)-7a (Scheme 8, see Table 1). Since haloetherification
of the ene acetal with MeOHproceeds in an S N2 manner,[5]
Preparation of optically pure 2-exo-methyl-3-endo-phenyl-5-
norbornene-2-carboxaldehydes (ꢀ)-7a and (+)-7a: Optical-
ly pure 7a was obtained from (ꢁ)-7a by using our recently
developed method.[6] Two diastereomeric acetals 12 and 13,
obtained by the reaction of (ꢁ)-7a and (R,R)-hydroben-
zoin[10] were treated with NBS (0.5 equiv) in the presence of
H2O (5 equiv) to give the hydroxy aldehyde 14 from 12 and
intact 13. Retrobromoetherification of 14 gave the optically
pure (ꢀ)-7a and (R,R)-hydrobenzoin. Intact 13 was hydro-
lyzed with 80% aqueous CF3COOHto give
(Scheme 6).
( +)-7a
Scheme 8. X-ray crystal structure of 15b’.
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Asymmetric Desymmetrization
5386 – 5397
the stereochemistry of the acetal ring of 11a was determined
to be trans based on the X-ray crystal structure of 15b’.[11]
Next, we tried the retrobromoetherification reaction of
15a by using the conditions indicated in Scheme 1 (Zn
powder and MgBr2 or Zn(OTf)2), but the desired product
was not obtained. Therefore, we developed another method
of transformation as shown in Scheme 9. The hydrolysis of
Scheme 10. Conversion of 18a into lactone 19. 1) Swern oxdidation;
2) TBAF; 3) PCC. TBAF=tetrabutylammonium fluoride, PCC=pyri-
dinium chlorochromate.
is noteworthy that bromoetherification occurred only in an
intramolecular fashion, not only for acetals from saturated
diols but also for acetals from unsaturated diols.
Previous chemical desymmetrizations of meso-1,2-bis(hy-
droxymethyl)cyclopropane 5e or meso-4,5-bis(hydroxyme-
thyl)cyclohexene 5 f resulted in poor enantioselectivity.[4a]
However, when these compounds were used in our method,
good results were obtained (Schemes 11 and 12). The acetal-
ization of 5e and 5 f with (ꢀ)-7a gave two isomers; the iso-
mers of 11e were difficult to separate and of 11 f were in-
separable by the usual SiO2 column. However, their intra-
molecular bromoetherification in the presence of MeOHaf-
forded two ten-membered acetals whose Rf values are differ-
ent (15e: major 0.21, minor 0.14; 15 f: major 0.42, minor
0.35; TLC with hexane/AcOEt (10:1)). Easy separation of
these isomers by using the usual SiO2 column gave the pure
acetals (15e and 15 f). In our desymmetrization cycle, three
new chiral centers are formed when MeOHis used as the
nucleophile in the intramolecular bromoetherification and
this usually allows easy separation of the isomers. After ob-
taining the pure compounds, it is not difficult to get the opti-
cally pure diol derivatives (18e and 18 f). The optical rota-
tion value of 18e was in good agreement with the reported
value,[13] so the absolute configuration of 18e was deter-
mined and the relative stereochemistries of the other com-
pounds in Scheme 11 were deduced from mechanistic con-
siderations. The absolute and relative configurations of the
compounds in Scheme 12 were tentatively determined by
considering the results shown in Scheme 11.
Scheme 9. Conversion of 15a into 18a. 1) p-TsOH, acetone, H2O;
2) TBDPSCl, imidazole; 3) Zn, Zn(OTf)2, DMA. TBDPS=tert-butyldi-
phenylsilyl.
15a afforded the hydroxy aldehyde 16a in high yield. Al-
though the use of H2O in place of MeOHfor the intramo-
lecular bromoetherification directly afforded 16a, the dia-
stereoselectivity decreased (66% de), maybe as a result of
the difference in nucleophilicity between MeOHand H O.
2
Protection of the alcohol group of 16a gave the silyl ether
17a. Retrobromoetherification of 17a by use of Zn powder
in the presence of Zn(OTf)2 afforded the optically active
diol derivative 18a and the starting aldehyde 7a, which was
reused. The absolute configuration of 18a was determined
by conversion into the known lactone 19, as shown in
Scheme 10. Thus, Swern oxidation of 18a followed by desi-
lylation gave the lactol, which was oxidized by PCC to give
the known lactone 19. The optical rotation value of our syn-
thetic 19 ([a]2D2 =ꢀ142.2 (CHCl3)) showed the opposite sign
to that of (2S,3R)-19 ([a]2D0 =
+143.2 (CHCl3)).[12]
Table 1. Desymmetrization of meso-1,4-diols 5 to form the optically active derivatives 18.
Table 1 shows the results of
the desymmetrization of vari-
ous bicyclo-meso-1,4-diols (see
Schemes 4, 7, and 9). In each of
these cases, acetalization of
(ꢀ)-7a with the meso-diols pro-
ceeded stereoselectively to give
sole products, whose stereo-
chemistries were determined as
trans by considering the result
of 5a and the absolute config-
uration of the diol derivative
18a. The subsequent intramo-
5
Yield [%]
18
Yield [%]
ee [%][a]
^98
11
16
17
(ꢀ)-7a
97
98
90
94
98
94
100
99
93
98
88
96
92
95
95
94
88
98
^98
89
86
^98
^99
lecular
bromoetherification,
protection of the alcohol, and
debromoetherificatin proceeded
smoothly without problems. It [a] Determined by HPLC analysis (Chiralpak AD-H or Chiralcel OD-H).
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Scheme 13. Desymmetrization of meso-1,3-diols 20a–c. 1) p-TsOH, tolu-
ene; 2) NBS, MeOH, then p-TsOH, acetone/H2O; 3) TBDPSCl, imida-
zole; 4) Zn, Zn(OTf)2, DMA.
Scheme 11. Desymmetrization of meso-1,2-bis(hydroxymethyl)-cyclopro-
pane (5e). 1) p-TsOH; 2) NBS, MeOH, CH 2Cl2; 3) separation by SiO2
column, then p-TsOH; 4) TBDPSCl, imidazole; 5) Zn, Zn(OTf)2, DMA.
Their stereochemistries were determined to be cis by NOE
experiments. Intramolecular bromoetherification of 21a–c in
the presence of MeOHfollowed by acid hydrolysis gave the
hydroxy aldehydes 22a–c in a highly diastereoselective
manner. The stereochemistries of compounds 22a–c were
deduced from the results of the desymmetrization of the
meso-1,4-diols in the preceding section and from our previ-
ous results.[5] Protection of the hydroxy function of 22a–c af-
forded the silyl ethers 23a–c. Retrobromoetherification of
23a–c with zinc in the presence of Zn(OTf)2 in DMA gave
the optically active diol derivatives 24a–c with the regener-
ated norbornene aldehyde (ꢀ)-7a. The optical purities of
24a–c were determined to be very high (>99% ee) by
chiral HPLC analysis (Scheme 13).
As the good desymmetrization of the meso-1,4- and meso-
1,3-diols has been achieved by using the 3-endo-phenyl nor-
bornene aldehyde derivative (ꢀ)-7a, desymmetrization of
the meso-1,2-diols was then studied. It was postulated that
the possibility of (ꢀ)-7a working as a chiral auxiliary was
low. Although exo isomers 1a and 1b needed a mixed-acetal
structure for good retrobromoetherification, such structures
from (ꢀ)-7a did not give a good retrobromoetherification
for the meso-1,4- and meso-1,3-diols. To our disappointment,
(ꢀ)-7a was only applicable for the acyclic diols, that is,
meso-2,3-butanediol 25 (see Scheme 14). For the cyclic
meso-1,2-diols, such as meso-1,2-cyclohexanediol, acetaliza-
tion with (ꢀ)-7a under the usual conditions gave the desired
products in low yields (<20%) together with unreacted
(ꢀ)-7a. Acetalization at a higher temperature (ꢂ508C) af-
forded a mixture of stereoisomers and the aldehyde (ꢀ)-7a
decomposed. The low reactivity of (ꢀ)-7a towards cyclic
meso-1,2-diols might be due to the steric hindrance of the 3-
endo-phenyl substituent.
Scheme 12. Desymmetrization of meso-4,5-bis(hydroxymethyl)-cyclohex-
ane (5 f). 1) p-TsOH; 2) NBS, MeOH, CH 2Cl2; 3) separation by SiO2
column, then p-TsOH; 4) TBDPSCl, imidazole; 5) Zn, Zn(OTf)2, DMA.
Desymmetrization of meso-1,3-diols and meso-1,2-diols:
Since (ꢀ)-7a showed a high ability in the desymmetrization
of meso-1,4-diols, we next applied it to the desymmetriza-
tion of meso-1,3-diols. We chose three 1,3-diols as the sub-
strates, meso-2,4-pentanediol (20a), meso-1,8-nonadiene-4,6-
diol (20b), and meso-2,6-dimethyl-3,5-heptanediol (20c).
Acetalization of these diols with (ꢀ)-7a afforded the cis-
acetals 21a–c, respectively, in good yields (Scheme 13).
The results with 25 are summarized in Scheme 14. Acetal-
ization proceeded stereoselectively to give the cis-acetal 26
in high yield. The stereochemistry was determined by an
NOE experiment. Intramolecular bromoetherification of 26
followed by acid hydrolysis afforded the hydroxy aldehyde
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Asymmetric Desymmetrization
5386 – 5397
of the steric repulsion of the acetal unit. Compound vii has
a 3-endo substituent while viii has a 3-exo substituent. To
recognize the actual factor required for the good retrobro-
moetherification of vii, we examined the reaction of alde-
hyde 30, which is obtained from the 3-exo-phenyl norbor-
nene aldehyde 1b (see Scheme 1) and acyclic meso-1,2-diol
25. The retrobromoetherification proceeded without a prob-
lem and afforded diol derivative 29 and aldehyde 1b in high
yield. When the results shown in Schemes 14 and 16 and our
previous work[5c] are taken into account, steric hindrance of
the acetal function in compounds like viii may inhibit the
formation of the chelation structure viiib and make the ret-
robromoetherification difficult.
Scheme 14. Desymmetrization of meso-2,3-butanediol 25. 1) p-TsOH, tol-
uene, RT; 2) NBS, MeOH, then p-TsOH, acetone/H2O; 3) TBDPSCl,
imidazole; 4) Zn, Zn(OTf)2, DMA.
27 in a highly diastereoselective manner. The stereochemis-
try of compound 27 was deduced from the results of the de-
symmetrization of the meso-1,4-diols described in the pre-
ceding section and from our previous results.[5] Protection of
the alcohol moiety as a silyl ether gave 28. To our surprise,
the retrobromoetherification reaction for 28 proceeded
smoothly to give the optically active diol derivative 29 and
(ꢀ)-7a. This result is in contrast to those obtained with 1a
and 1b.
Scheme 16. Debromoetherification of 3-exo-phenyl compound 30.
Conclusion
A new auxiliary, the 3-endo-phenyl norbornene aldehyde
derivative 7a, was developed. It was found that this auxili-
ary is applicable for the desymmetrization of meso-1,3- and
meso-1,4-diols. The methodology here is, to the best of our
knowledge, the best chemical desymmetrization method
available, especially for meso-1,4-diols. The significant ad-
vantage of our method is exemplified by our ability to
obtain enantiopure diol derivatives of 5e and 5 f, which
were not obtained by other chemical methods.[4a] The auxili-
ary, 7a, is a very stable (storage for one month at room tem-
perature produces no decomposition) and easily handled
crystal.[14] Furthermore, it is known that we can now choose
the proper chiral auxiliary among the 3-exo- and 3-endo-nor-
bornene aldehyde derivatives 1a, 1b, and 7a for the highly
enantioselective desymmetrization of meso-1,2-, meso-1,3-,
and meso-1,4-diols.
Consideration of retrobromoetherification: For the meso-
1,4-diols and meso-1,3-diols, chelation structures such as v
and vi (Scheme 15) do not cause any steric repulsion be-
tween the two side chains (see the reaction of 17a to form
18a in Scheme 9 and Table 1 for v and the reaction of 23a
to form 24a in Scheme 13 for vi). On the other hand, the
chelation structure of the acyclic meso-1,2-diol vii may cause
steric repulsion between the two side chains and seems to
be unfavorable. In fact, the acyclic meso-1,2-diol did not
give the debromoetherificated product through acetal com-
pounds like viii, possibly due to no formation of the chela-
tion structure viiib, in our previous report,[5c] whereas mixed
acetals gave the debromoetherificated products in good
yields by the formation of the chelation structure ix, irre-
spective of the system being cyclic or acyclic (see
Scheme 1).[5]
The results obtained here, with good retrobromoetherifi-
cation even in 28 from the acyclic meso-1,2-diol 25 in
Scheme 14, is completely different from our previous obser-
vations in ref. [5c]. A significant difference between vii and
viii is that viii has an acetal in place of the aldehyde in vii.
Also, viii might be present as viiia rather than viiib because
Experimental Section
All melting points are uncorrected. NMR spectra were measured on a
300 MHz spectrometer with CDCl3 as the solvent and with SiMe4 as an
internal standard. Chemical shifts are denoted in d (ppm). Infrared (IR)
absorption spectra were recorded from KBr pellets. Optical rotations
Scheme 15. Consideration of chelation structures v–ix. M=Zn or Mg.
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H. Fujioka, Y. Kita et al.
FULL PAPER
were measured in 0.5 dm cells with a JASCO P-1020 polarimeter. All sol-
vents were dried and distilled according to standard procedures. 13C
NMR spectra of the compounds that were also analyzed by high-resolu-
tion mass spectra can be found in the Supporting Information.
Norbornene diphenyldioxolanes 12 and 13: A catalytic amount of p-
TsOH(0.1 equiv) was added to a solution of ( ꢁ)-7a (54 mg) and (R,R)-
hydrobenzoin (65.4 mg) in toluene (2.6 mL) under N2 and the resulting
mixture was stirred for 3 h at RT. After completion of the reaction (TLC
check), the solution was quenched by the addition of saturated aqueous
NaHCO3 and extracted with AcOEt. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was puri-
fied by SiO2 flash column chromatography with hexane/AcOEt (20:1) as
the eluent to give a 1:1 diastereomeric mixture of 12 and 13 (89.7 mg,
86%). White powder; 1HNMR (300 MHz, CDCl 3): d=7.36–7.05 (m,
14H), 6.62–6.35 (m, 3H), 4.88 and 4.79 (both s, total 1H), 4.64–4.61/4.50–
4.47 (d, J=7.8 Hz, total 1H), 4.36–4.33/4.26–4.24 (d, J=7.8 Hz, total
1H), 3.26–3.24 (m, 1H), 3.13 (m, 1H), 2.84 (m, 1H), 1.90–1.86 (m, 1H),
1.64–1.59 (m, 1H), 1.63/1.60 ppm (both s, total 3H); 13C NMR (75 MHz,
CDCl3): d=141.6, 141.3, 139.9, 139.6, 138.0, 137.6, 137.1, 137.0, 135.3,
135.2, 129.5, 129.1, 128.6, 128.4, 128.2, 128.0, 127.9, 127.8, 127.4, 127.2,
127.1, 126.30, 126.27, 125.9, 125.8, 124.9, 107.9, 107.4, 86.6, 85.8, 85.1,
84.6, 56.9, 56.5, 53.5, 53.3, 50.7, 50.6, 49.6, 49.1, 49.0, 48.8, 22.6, 22.2 ppm;
MS (EI): m/z: 408 [M+]; HRMS (EI): m/z calcd for C29H28O2: 408.2089;
found: 408.2111; elemental analysis calcd (%) for C29H28O2: C 85.26, H
6.91; found: C 85.22, H6.98.
Methyl 3-endo-phenylnorbornene-2-carboxylate ((ꢁ)-8,R =Ph): Cyclo-
pentadiene (3.0 mL) and EtAlCl2 (44 mL, 0.98 mol in hexane) were
added slowly to a stirred solution of cis-methyl cinnamate (7.05 g), pre-
pared according to the literature procedure,[7] in CH2Cl2 (44 mL) at
ꢀ788C under N2. The mixture was allowed to warm to RT and stirred for
an additional 12 h. Ice-water and saturated aqueous NaHCO3 were
added to the mixture and the resulting solution was extracted with
CH2Cl2. The organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2 flash column
chromatography with hexane/AcOEt (20:1) as the eluent to give (ꢁ)-8
(R=Ph; 9.68 g, 40.0 mmol, 92%, endo:exo=17:1). 1HNMR (300 MHz,
CDCl3): d=7.32–7.04 (m, 5H), 6.66–6.63 (m, 1H), 6.15–6.11 (m, 1H),
3.79–3.74 (dd, J=10.8, 3.2 Hz, 1H), 3.67 (m, 1H), 3.50–3.45 (dd, J=10.8,
3.2 Hz, 1H), 3.21 (s, 3H), 3.02 (m, 1H), 1.54–1.49 ppm (m, 2H).
Methyl 2-exo-methyl-3-endo-phenylnorbornene-2-carboxylate ((ꢁ)-9,
R=Ph): nBuLi (0.68 mL) was added slowly to a stirred solution of diiso-
propylamine (146 mL) in THF (4.4 mL) at ꢀ788C under N2. After
30 min, a solution of (ꢁ)-8 (R=Ph; 198 mg) in THF (1 mL) was added
dropwise to the resulting mixture at ꢀ788C. After 1 h, methyl iodide
(0.27 mL) was added to the resulting mixture. The solution was allowed
to warm to RT and stirred for 12 h. The completion of the reaction was
confirmed by TLC. Ice-water was added to the mixture and the resulting
solution was extracted with Et2O. The organic layer was washed succes-
sively with ice-water, 10% aqueous Na2S2O3, and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by SiO2 flash
column chromatography with hexane/AcOEt (20:1) as the eluent to give
(ꢁ)-9 (R=Ph; 160 mg, 0.66 mmol, 76%). Colorless oil; 1HNMR
(300 MHz, CDCl3): d=7.25–7.02 (m, 5H), 6.72–6.69 (m, 1H), 6.19–6.16
(m, 1H), 3.19–3.18 (d, J=3.0 Hz, 1H), 3.15 (s, 3H), 2.92–2.88 (m, 2H),
1.82–1.79 (m, 1H), 1.60 (s, 3H), 1.58–1.52 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=176.1, 142.6, 140.0, 133.4, 128.4, 127.6, 126.1, 60.1,
58.4, 52.2, 50.8, 50.0, 47.9, 28.6 ppm; IR (KBr): n˜ =1728 cmꢀ1; MS (EI):
m/z: 242 [M+]; HRMS (EI): m/z calcd for C16H18O2: 242.1307; found:
242.1309.
(1R,2S,3S,4S)-2-exo-Methyl-3-endo-phenylnorbornene-2-carbaldehyde
((ꢀ)-7a): NBS (2.09 g, 0.5 equiv) was added to a stirred solution of 12
and 13 (9.50 g) in CH3CN containing 1% H2O (23.5 mL) at RT and the
reaction mixture was stirred for 20 h at the same temperature. After com-
pletion of the reaction (checked by TLC), saturated aqueous Na2S2O3
was added to the mixture and the resulting solution was extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2 flash column
chromatography with hexane/AcOEt (50:1!4:1) as an eluent to give 14
(4.28 g, 8.46 mmol, 36%) and 13 (4.75 g, 11.8 mmol, 50%). 13: [a]D24
=
ꢀ102.9 (c=1.04, CHCl3); 1HNMR (300 MHz, CDCl 3): d=7.39–7.25 (m,
10H), 7.15–7.04 (m, 3H), 6.58–6.56 (m, 1H), 6.38–6.35 (m, 2H), 4.79 (s,
1H), 4.64–4.61 (d, J=7.5 Hz, 1H), 4.36–4.33 (d, J=7.5 Hz, 1H), 3.26–
3.25 (d, J=3.0 Hz, 1H), 3.12 (brs, 1H), 2.83 (brs, 1H), 1.90–1.87 (d, J=
8.7 Hz, 1H), 1.62 (s, 3H), 1.61–1.58 ppm (d, J=8.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=141.6, 139.9, 138.0, 137.1, 135.2, 129.5, 128.6, 128.4,
128.0, 127.8, 127.2, 127.1, 125.9, 124.9, 107.4, 85.8, 85.1, 56.9, 53.3, 50.6,
49.6, 49.1, 22.2 ppm; elemental analysis calcd (%) for C29H28O2: C 85.26,
H6.91; found: C 85.22, H6.98.
2-exo-Methyl-3-endo-phenylnorbornene-2-methanol ((ꢁ)-10,R =Ph): A
solution of (ꢁ)-9 (R=Ph; 87 mg) in THF (1.0 mL) was added dropwise
to a stirred suspension of LiAlH4 (20.4 mg) in THF (2.6 mL) at 08C
under N2. The mixture was allowed to warm to RT and stirred for 1 h.
Excess reagent was quenched by careful addition of water and 1n aque-
ous NaOHat 0 8C. The precipitate was filtered off and the filtrate was
evaporated in vacuo. The residue was purified by SiO2 flash column chro-
matography with hexane/AcOEt (5:1) as the eluent to give (ꢁ)-10 (R=
Ph; 74.3 mg, 0.35 mmol, 97%). Colorless oil; 1HNMR (300 MHz,
CDCl3): d=7.26–7.16 (m, 5H), 6.51–6.48 (m, 1H), 6.35–6.32 (m, 1H),
3.11–2.98 (m, 4H), 2.59 (s, 1H), 1.83–1.80 (m, 1H), 1.61–1.57 (m, 1H),
1.45 (s, 3H), 0.70 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3): d=141.4,
137.1, 134.9, 128.3, 128.1, 126.2, 68.9, 56.3, 51.8, 49.3, 49.0, 48.9, 26.5 ppm;
IR (KBr): n˜ =3362 cmꢀ1; MS (FAB): m/z: 237 [M++Na]; HRMS (FAB):
m/z calcd for C15H18NaO: 237.1255 [M++Na]; found: 237.1261.
After
a solution of 14 (4.28 g, 8.46 mmol) and Zn(OTf)2 (18.5 g,
50.8 mmol) in DMA (85 mL) had been stirred for 30 min at 408C under
N2, Zn powder (11.1 g) was added to the mixture and the resulting so-
lution was stirred for 5 h at 708C. After completion of the reaction
(checked by TLC), Et2O was added to the reaction mixture and the pre-
cipitated salt and zinc were filtered out. The filtrate was evaporated in
vacuo. The residue was purified by SiO2 flash column chromatography
with hexane/AcOEt (10:1) as the eluent to give (ꢀ)-7a (1.5 g, 7.19 mmol,
85%). White crystals; m.p. 45–468C; [a]2D4 =ꢀ102.9 (c=1.04, CHCl3);
1HNMR (300 MHz, CDCl 3): d=8.99 (s, 1H), 7.24–7.11 (m, 5H), 3.42–
3.41 (m, 1H), 3.29–3.28 (m, 1H), 2.73 (brs, 1H), 1.90–1.87 (m, 1H), 1.70–
1.66 (m, 1H), 1.51 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=208.0,
139.8, 137.0, 135.4, 128.5, 127.8, 126.5, 58.5, 57.6, 52.9, 49.0, 48.1,
23.8 ppm; IR (KBr): n˜ =1715 cmꢀ1
.
2-exo-Methyl-3-endo-phenylnorbornene-2-carbaldehyde
((ꢁ)-7a):
Norbornene aldehyde norbornene acetal 11a: A catalytic amount of p-
TsOH(0.1 equiv) was added to a solution of ( ꢀ)-7a (320 mg) and 5a
(256 mg, 1.1 equiv) in toluene (15 mL) under N2 and the resulting mix-
ture was stirred for 24 h at RT. After completion of the reaction (checked
by TLC), the solution was quenched by the addition of saturated aqueous
NaHCO3 and extracted with AcOEt. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was puri-
fied by SiO2 flash column chromatography with hexane/AcOEt (50:1) as
DMSO (115 mL) was added carefully to a stirred solution of oxalyl chlo-
ride (70 mL) in CH2Cl2 (2.0 mL) at ꢀ788C under N2. After 30 min, a so-
lution of (ꢁ)-10 (R=Ph; 43.0 mg) in CH2Cl2 (1.0 mL) was added drop-
wise to the resulting mixture at ꢀ788C. After 1 h, Et3N (335 mL) was
added to the resulting solution. The solution was allowed to warm to
08C. Saturated aqueous NH4Cl was added to the mixture and the result-
ing solution was extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 flash column chromatography with hexane/AcOEt
(20:1) as the eluent to give (ꢁ)-7a (40.3 mg, 0.19 mmol, 95%). Colorless
oil; 1HNMR (300 MHz, CDCl 3): d=8.99 (s, 1H,), 7.24–7.11 (m, 5H),
3.42–3.41 (m, 1H), 3.29–3.28 (m, 1H), 2.73 (brs, 1H), 1.90–1.87 (m, 1H),
1.70–1.66 (m, 1H), 1.51 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
208.0, 139.8, 137.0, 135.4, 128.5, 127.8, 126.5, 58.5, 57.6, 52.9, 49.0, 48.1,
23.8 ppm; IR (KBr): n˜ =1715 cmꢀ1; MS (EI): m/z: 212 [M+]; HRMS
(EI): m/z calcd for C15H16O: 212.1201; found: 212.1218; elemental analy-
sis calcd (%) for C15H16O: C 84.87, H7.60; found: C 84.72, H7.65.
1
the eluent to give 11a (510 mg, 1.46 mmol, 97%). Colorless oil; HNMR
(300 MHz, CDCl3): d=7.26–7.11 (m, 5H), 6.51–6.48 (m, 1H), 6.24–6.21
(m, 1H), 6.02–5.99 (m, 1H), 5.89–5.86 (m, 1H), 3.99–3.93 (dd, J=12.3,
4.2 Hz, 1H), 3.58 (s, 1H), 2.98 (s, 1H), 2.95–2.90 (m, 2H), 2.88–2.84 (d,
J=12.5 Hz, 1H), 2.61 (brs, 2H), 2.56–2.51 (m, 1H), 2.45 (brs, 1H), 2.42–
2.37 (m, 1H), 2.10–2.06 (d, J=12.5 Hz, 1H), 1.74–1.72 (m, 1H), 1.50–1.35
(m, 3H), 1.35 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=142.5, 137.3,
135.2, 134.93, 134.91, 128.8, 127.2, 125.5, 112.4, 73.0, 71.9, 57.7, 53.0, 52.4,
51.3, 49.2, 48.9, 45.4, 45.3, 45.2, 44.9, 22.5 ppm; IR (KBr): n˜ =2963, 1105,
5392
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5386 – 5397

Asymmetric Desymmetrization
5386 – 5397
742 cmꢀ1; MS (EI): m/z: 348 [M+]; HRMS (EI): m/z calcd for C24H28O2:
348.2089; found: 348.2119.
1HNMR (300 MHz, CDCl 3): d=7.69–7.64 (m, 4H), 7.48–7.38 (m, 6H),
6.04–6.02 (m, 1H), 5.88–5.85 (m, 1H), 3.65 (brs, 1H), 3.60–3.46 (m, 4H),
2.82 (brs, 1H), 2.64 (brs, 1H), 2.62–2.49 (m, 2H), 1.59 (s, 1H), 1.36–1.35
(m, 1H), 1.04 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=135.6, 135.5,
135.1, 134.5, 129.9, 129.8, 127.80, 127.78, 65.2, 63.5, 49.8, 46.5, 46.3, 45.6,
44.8, 26.8, 19.1 ppm; IR (KBr): n˜ =3385 cmꢀ1; MS (FAB): m/z: 393 [M+
+H]; HRMS (FAB): m/z calcd for C25H33O2Si: 393.2250 [M++H]; found:
393.2244.
10-Membered mixed acetal 15a: NBS (48.0 mg, 0.55 equiv) was added to
a stirred solution of 11a (85.6 mg) in MeOH(2.4 mL) at ꢀ408C under N2
and the reaction mixture was allowed to warm slowly to RT. After com-
pletion of the reaction (checked by TLC), saturated aqueous Na2S2O3
was added to the mixture and the resulting solution was extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2 flash column
chromatography with hexane/AcOEt (10:1) as the eluent to give 15a
(2R,3S)-Lactone 19: DMSO (0.39 mL) was added carefully to a stirred
solution of oxalyl chloride (0.24 mL) in CH2Cl2 (7.0 mL) at ꢀ788C under
N2. After 30 min, a solution of 18a (272 mg) in CH2Cl2 (2.0 mL) was
added dropwise to the resulting mixture at ꢀ788C. After 1 h, Et3N
(1.16 mL) was added to the resulting solution. The solution was allowed
to warm to 08C. Saturated aqueous NH4Cl was added to the mixture and
the resulting solution was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo. The resi-
due was purified by SiO2 flash column chromatography with hexane/
AcOEt (15:1) as the eluent to give the aldehyde (268 mg, 0.686 mmol,
99%). 1HNMR (300 MHz, CDCl 3): d=9.40–9.39 (d, J=4.2 Hz, 1H),
7.64–7.60 (m, 4H), 7.40–7.38 (m, 6H), 6.26–6.25 (m, 1H), 6.04–6.03 (m,
1H), 3.61–3.43 (m, 2H), 3.08–2.80 (m, 4H), 1.53–1.51 (d, J=8.1 Hz, 1H),
1.39–1.36 (d, J=8.1 Hz, 1H), 1.03 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=205.7, 135.53, 135.47, 135.1, 133.55, 133.47, 129.7, 127.7, 64.3,
1
(115.2 mg, 0.243 mmol, 99%). Colorless oil; HNMR (300 MHz, CDCl 3):
d=7.27–7.17 (m, 5H), 6.09–6.04 (m, 2H), 5.11 (s, 1H), 4.62 (m, 1H),
4.35–4.32 (m, 1H), 4.08–4.05 (d, J=10.5 Hz, 1H), 3.85–3.80 (dd, J=12.6,
4.5 Hz, 1H), 3.57–3.40 (m, 2H), 2.94–2.92 (d, J=4.2 Hz, 1H), 2.84 (m,
1H), 2.78 (s, 3H), 2.70 (m, 2H), 2.57–2.56 (m, 1H), 2.41–2.38 (m, 2H),
1.99 (m, 2H), 1.43–1.41 (m, 2H), 1.24 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=139.7, 136.2, 134.0, 130.4, 127.9, 126.1, 109.7, 93.0, 74.3, 73.9,
58.3, 55.8, 55.1, 54.5, 54.4, 50.3, 48.4, 47.9, 46.0, 45.9, 42.5, 33.8, 23.8 ppm;
IR (KBr): n˜ =2963, 1117, 729 cmꢀ1; elemental analysis calcd (%) for
C25H31O3Br: C 65.36, H6.80; found: C 65.47, H6.69.
Norbornene aldehyde norbornene alcohol 16a: A catalytic amount of p-
TsOH(0.1 equiv) was added to a solution of 15a (55.8 mg) in acetone/
H2O (4:1; 1 mL) and the resulting mixture was stirred at RT. After com-
pletion of the reaction (checked by TLC), the solution was quenched by
the addition of saturated aqueous NaHCO3 and extracted with AcOEt.
The organic layer was washed with brine, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by SiO2 flash column chroma-
tography with hexane/AcOEt (5:2) as the eluent to give 16a (53.6 mg,
54.9, 49.6, 48.0, 46.2, 45.0, 26.8, 19.2; IR (KBr): n˜ =1715 cmꢀ1
.
TBAF (0.36 mL, 0.1m in THF) was added to a solution of the aldehyde
(141 mg) in THF (3.6 mL) at RT under N2, and the mixture was stirred
for 30 min at the same temperature. After completion of the reaction
(checked by TLC), water was added to the mixture and the resulting so-
lution was extracted with Et2O. The organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was used in the
next reaction without purification. A mixture of the crude product and
PCC (85.4 mg) in CH2Cl2 (3.6 mL) was stirred for 3 h at RT. After com-
pletion of the reaction (checked by TLC), Et2O was added to the result-
ing mixture. The precipitate was removed through a short pad of Florisil.
The filtrate was evaporated in vacuo. The residue was purified by SiO2
flash column chromatography with hexane/AcOEt (2:3) as the eluent to
give 19 (25.8 mg, 0.172 mmol, 48% over two steps). Colorless crystals;
m.p. 104–1058C; [a]2D2 =ꢀ142.2 (c=0.99, CHCl3); literature value for
(2S,3R)-lactone:[12] [a]D25 =+143.2 (c=5.2, CHCl3); 1HNMR (300 MHz,
CDCl3): d=6.30 (brs, 2H), 4.29 (dd, J=9.5, 8.2 Hz, 1H), 3.78 (dd, J=
9.5, 3.1 Hz, 1H), 3.37–3.00 (m, 4H), 1.64 (brd, J=8.4 Hz, 1H), 1.45 ppm
(brd, J=8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=136.9, 134.4, 70.3,
51.8, 47.6, 46.1, 45.7, 40.3 ppm; IR (KBr): n˜ =1759 cmꢀ1; MS (EI): m/z:
150 [M+]; HRMS (EI): m/z calcd for C9H10O2: 150.0681; found: 150.067.
0.120 mmol, 99%). Colorless oil; IR (KBr): n˜ =3398, 1710 cmꢀ1
;
1HNMR (300 MHz, CDCl 3): d=9.46 (s, 1H), 7.37–7.09 (m, 5H), 6.07–
5.99 (m, 2H), 4.18–4.10 (m, 2H), 3.41–3.34 (m, 3H), 3.18–3.13 (m, 2H),
3.07–3.02 (t, J=9 Hz, 1H), 2.82–2.76 (m, 2H), 2.48 (m, 1H), 2.41–2.29
(m, 2H), 2.14–2.10 (d, J=11.1 Hz, 1H), 1.93–1.90 (d, J=11.1 Hz, 1H),
1.51 (s, 3H), 1.40–1.24 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=
204.8, 136.3, 135.1, 134.9, 129.1, 127.3, 126.7, 91.9, 70.6, 63.1, 56.1, 55.8,
51.1, 50.8, 50.4, 49.5, 46.2, 46.1, 44.9, 41.3, 34.0, 25.6 ppm; MS (EI): m/z:
444 [M+]; HRMS (EI): m/z calcd for C24H29O3Br: 444.1300; found:
444.1297.
Norbornene aldehyde norbornene silylether 17a: Imidazole (33.0 mg)
and TBDPSCl (64 mL) were added to a stirred solution of 16a (49.2 mg)
in DMF (0.5 mL) at RT under N2 and the resulting mixture was stirred
for an additional 1 h at the same temperature. After completion of the
reaction (checked by TLC), the solution was quenched by the addition of
saturated aqueous NH4Cl and extracted with AcOEt. The organic layer
was washed with brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by SiO2 flash column chromatography with hexane/
AcOEt (10:1) as the eluent to give 17a (68.0 mg, 0.10 mmol, 99%). Col-
orless oil; 1HNMR (300 MHz, CDCl 3): d=9.40 (s, 1H), 7.64–7.08 (m,
15H), 5.97–5.96 (m, 1H), 5.87–86 (m, 1H), 4.13–4.12 (m, 1H), 3.99–3.96
(m, 1H), 3.52–3.46 (dd, J=9.9, 6.3 Hz, 1H), 3.35 (m, 1H), 3.20–3.14 (t,
J=9.6 Hz, 1H), 3.08–3.05 (m, 2H), 2.91 (m, 1H), 2.88–2.81 (t, J=9.6 Hz,
1H), 2.72 (m, 1H), 2.38–2.21 (m, 3H), 2.08–2.04 (m, 1H), 1.86–1.83 (m,
1H), 1.47 (s, 3H), 1.39–1.19 (m, 2H), 1.04 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=204.6, 136.6, 135.60, 135.56, 135.3, 134.0, 129.49,
129.46, 129.0, 127.6, 127.4, 126.6, 91.9, 70.5, 63.8, 56.3, 56.1, 51.2, 51.0,
50.9, 48.9, 45.4, 45.3, 44.2, 41.3, 34.0, 26.9, 25.5, 19.2 ppm; IR (KBr): n˜ =
1712 cmꢀ1; MS (FAB): m/z: 705 [M++Na]; HRMS (FAB): m/z calcd for
C40H47BrNaO3Si: 705.2576 [M++Na]; found: 705.2371.
Norbornene aldehyde norbornane acetal 11b: By use of the same proce-
dure as for 11a, 11b (134.0 mg, 98%) was obtained from 5b (67.2 mg)
and (ꢀ)-7a (83 mg). Eluent for chromatography: AcOEt/hexane (1:50).
White solid; m.p. 978C; 1HNMR (300 MHz, CDCl 3): d=7.21–7.10 (m,
5H), 6.55–6.53 (m, 1H), 6.31–6.28 (m, 1H), 5.30 (s, 1H), 3.88–3.82 (dd,
J=12.3, 4.5 Hz, 1H), 3.71 (s, 1H), 3.48–3.40 (t, J=12 Hz, 1H), 3.01 (m,
2H), 2.85–2.79 (dd, J=12.3, 4.5 Hz, 1H), 2.69–2.60 (m, 2H), 2.23–2.04
(m, 2H), 2.08 (m, 1H), 1.92 (m, 1H), 1.76–1.73 (d, J=8.6 Hz, 1H), 1.51–
1.49 (d, J=8.6 Hz, 1H), 1.44–1.15 (m, 5H), 1.35 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=142.5, 137.4, 135.3, 128.9, 127.3, 125.5, 112.1, 71.0,
69.7, 57.8, 53.0, 52.4, 49.2, 49.0, 43.7, 43.4, 41.6, 39.6, 39.3, 23.0, 22.6,
22.5 ppm; IR (KBr): n˜ =2957, 1107, 739 cmꢀ1; MS (EI): m/z: 350 [M+];
HRMS (EI): m/z calcd for C24H30O2: 350.2246; found: 350.2267.
Norbornene aldehyde bicyclooctene acetal 11c: By use of the same pro-
cedure as for 11a, 11c (77.1 mg, 88%) was obtained from 5c (44.6 mg)
and (ꢀ)-7a (51.2 mg). Eluent for chromatography: AcOEt/hexane (1:50).
White crystals; m.p. 104–1058C; 1HNMR (300 MHz, CDCl 3): d=7.21–
7.09 (m, 5H), 6.50–6.48 (m, 1H), 6.25–6.22 (m, 1H), 6.07–5.94 (m, 2H),
3.81–3.75 (dd, J=12.6, 3.9 Hz, 1H), 3.55 (s, 1H), 3.51–3.07 (t, J=12 Hz,
1H), 2.99–2.98 (m, 2H), 2.81–2.75 (dd, J=12.6, 3.9 Hz, 1H), 2.60 (m,
1H), 2.32–2.04 (m, 5H), 1.74–1.72 (m, 1H), 1.33 (s, 3H), 1.49–1.09 ppm
(m, 5H); 13C NMR (75 MHz, CDCl3): d=142.4, 137.3, 135.2, 133.0, 132.8,
128.8, 127.3, 125.5, 111.2, 74.2, 73.3, 57.8, 53.1, 52.1, 49.2, 48.9, 45.3, 44.9,
33.1, 32.5, 25.2, 24.9, 22.5 ppm; IR (KBr): n˜ =2936, 1111, 746 cmꢀ1; MS
(EI): m/z: 362 [M+]; HRMS (EI): m/z calcd for C25H30O2: 362.2246;
found: 362.2259.
Norbornene silylether 18a: A solution of 17a (82 mg) and Zn(OTf)2
(262 mg) in DMA (0.37 mL) was stirred at 408C under N2. After 30 min,
Zn powder (156 mg) was added to the mixture and stirring was continued
at 708C for 5 h. After completion of the reaction (checked by TLC),
Et2O was added to the reaction mixture and the precipitated salt and
zinc were filtered out. The filtrate was evaporated in vacuo. The residue
was purified by SiO2 flash column chromatography with hexane/AcOEt
(4:1) as the eluent to give 18a (46.6 mg, 0.118 mmol, 99%) and (ꢀ)-7a
(25.4 mg, 0.12 mmol, 100%). 18a: Colorless oil; [a]2D5 =+11.03 (c=0.67,
CHCl3); the optical purity of 18a (98% ee) was determined by HPLC
ꢀ1
analysis (Chiralpak AD-H, hexane/iPrOH(150:1), 0.5 mLmin
flow
rate, 264 nm wavelength; retention times: 33.73 min and 37.24 min for
(ꢁ)-18a and 37.91 min for (+)-18a); 7a: [a]2D6 =ꢀ101.9 (c=0.68, CHCl3);
Chem. Eur. J. 2004, 10, 5386 – 5397
www.chemeurj.org
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
5393

H. Fujioka, Y. Kita et al.
FULL PAPER
Norbornene aldehyde oxohexene acetal 11d: By use of the same proce-
dure as for 11a, 11d (106.0 mg, 96%) was obtained from 5d (54.2 mg)
and (ꢀ)-7a (67.2 mg). Eluent for chromatography: AcOEt/hexane (1:8).
Colorless oil; 1HNMR (300 MHz, CDCl 3): d=7.23–7.12 (m, 5H), 6.53–
6.52 (m, 1H), 6.31–6.26 (m, 3H), 4.41 (s, 1H), 4.24 (s, 1H), 4.19–4.08 (m,
1H), 3.80 (s, 1H), 3.43–3.34 (t, J=12.6 Hz, 1H), 3.14–3.08 (dd, J=12.9,
5.4 Hz, 1H), 3.00 (m, 2H), 2.65–2.57 (m, 2H), 2.02–1.96 (m, 1H), 1.92–
1.83 (m, 1H), 1.75–1.73 (d, J=8.4 Hz, 1H), 1.52–1.49 (d, J=8.4 Hz, 1H),
1.33 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=142.4, 137.1, 135.7,
135.4, 128.8, 127.4, 125.6, 112.4, 80.6, 80.2, 72.5, 71.3, 60.4, 57.8, 53.0, 52.3,
49.2, 49.0, 43.2, 43.1, 22.3 ppm; IR (KBr): n˜ =2970, 1047, 739 cmꢀ1; MS
(FAB): m/z: 373 [M++Na]; HRMS (FAB): m/z calcd for C23H26NaO3:
373.1780 [M++Na]; found: 373.1776.
and NBS (37.8 mg). Eluent for chromatography: AcOEt/hexane (1:3).
White crystals; m.p. 107–1088C; 1HNMR (300 MHz, CDCl 3): d=9.45 (s,
1H), 7.37–7.09 (m, 5H), 6.17–6.09 (m, 2H), 4.17–4.10 (m, 2H), 3.52–3.06
(m, 6H), 2.48–2.41 (m, 3H), 2.14–1.89 (m, 4H), 1.59–1.47 (m, 5H),
1.51 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=204.7, 136.4, 133.21,
133.18, 129.1, 127.3, 126.7, 91.9, 71.7, 64.2, 56.1, 55.9, 51.1, 50.8, 50.5, 44.9,
41.7, 34.0, 33.5, 33.4, 25.6, 25.5, 25.0 ppm; IR (KBr): n˜ =3371, 1711 cmꢀ1
;
MS (FAB): m/z: 481 [M++Na]; HRMS (FAB): m/z calcd for
C25H31BrNaO3: 481.1354 [M++Na]; found: 481.1358.
Norbornene aldehyde oxohexene alcohol 16d: By use of the same proce-
dure as for 16b, 16d (51.7 mg, 95%) was obtained from 11d (41.1 mg)
and NBS (23.0 mg). Eluent for chromatography: AcOEt/hexane (1:1).
White solid; m.p. 119–1208C; 1HNMR (300 MHz, CDCl 3): d=9.44 (s,
1H), 7.38–7.10 (m, 5H), 6.31 (s, 2H), 5.30 (s, 1H), 4.77 (s, 1H), 4.60 (s,
1H), 4.19 (s, 2H), 3.79 (m, 1H), 3.62–3.58 (m, 1H), 3.50–3.41 (m, 3H),
3.15 (s, 1H), 2.49 (s, 1H), 2.16–2.13 (d, J=11.1 Hz, 1H), 1.94–1.91 (d, J=
11.1 Hz, 1H), 1.79–1.78 (m, 2H), 1.52 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=204.7, 136.4, 135.8, 135.4, 129.1, 127.3, 126.7, 92.1, 80.9, 80.7,
70.2, 62.3, 56.10, 56.07, 51.2, 50.8, 50.5, 42.1, 39.9, 34.0, 25.6 ppm; IR
(KBr): n˜ =3411, 1711 cmꢀ1; HRMS (FAB): m/z calcd for C23H28BrNaO4:
447.1113 [M+H+]; found: 447.1142.
Norbornene aldehyde cyclopropane acetal 11e: By use of the same pro-
cedure as for 11a, 11e (107.9 mg, 74%) and 11e’ (33.1 mg, 23%) were
obtained from 5e (100 mg) and (ꢀ)-7a (104 mg). Eluent for chromatog-
1
raphy: AcOEt/hexane (1:30). 11e: HNMR (300 MHz, CDCl 3): d=7.26–
7.10 (m, 5H), 6.53 (dd, J=5.6, 2.9 Hz, 1H), 6.23 (dd, J=5.6, 2.7 Hz, 1H),
4.15 (dd, J=12.6, 3.0 Hz, 1H), 3.60 (d, J=11.9 Hz, 1H), 3.20 (dd, J=
12.9, 2.4 Hz, 1H), 3.16 (s, 1H), 3.00 (s, 1H), 3.00 (d, J=7.2 Hz, 1H), 2.61
(brs, 1H), 2.31 (d, J=13.2 Hz, 1H), 1.73 (d, J=8.4 Hz, 1H), 1.50 (dt, J=
10.2, 1.8 Hz, 1H), 1.37 (s, 3H), 0.85–0.78 (m, 1H), 0.70–0.60 (m, 2H),
0.30–0.20 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=142.2, 137.0,
135.5, 129.0, 127.4, 125.6, 111.2, 68.0, 66.5, 57.5, 53.3, 52.8, 49.1, 49.0, 22.1,
16.7, 16.4, ꢀ0.2 ppm; IR (KBr): n˜ =2968, 1083, 733 cmꢀ1; MS (EI): m/z:
296 [M+]; HRMS (EI): m/z calcd for C20H24O2: 296.1776 [M+]; found:
296.1769; 11e’: 1HNMR (300 MHz, CDCl 3): d=7.26–7.05 (m, 5H), 6.50
(dd, J=5.6, 2.9 Hz, 1H), 6.23 (dd, J=5.6, 3.0 Hz, 1H), 4.48 (dd, J=13.2,
6.6 Hz, 1H), 3.57 (s, 1H), 3.42 (dd, J=13.5, 6.6 Hz, 1H), 3.01 (s, 1H),
2.99 (brs, 1H), 2.87 (dd, J=13.2, 10.5 Hz, 1H), 2.63 (brs, 1H), 2.01 (dd,
J=13.5, 10.8 Hz, 1H), 1.75 (d, J=8.7 Hz, 1H), 1.49 (dt, J=10.0, 2.0 Hz,
1H), 1.42 (s, 3H), 1.40–1.15 (m, 2H), 0.82–0.75 (m, 1H), 0.37–0.32 ppm
(m, 1H); 13C NMR (75 MHz, CDCl3): d=142.5, 137.2, 135.3, 128.8, 127.3,
125.5, 114.5, 74.8, 73.4, 57.8, 53.0, 52.6, 49.1, 49.0, 22.7, 18.3, 17.9,
Norbornene aldehyde cyclopropane alcohol 16e: By use of the same pro-
cedure as for 16b, 15e and 15e’ (99%) were obtained from 11e and 11e’
(132 mg) and NBS (87 mg). 15e (138 mg, 76%) was obtained by separa-
tion with SiO2 flash column chromatography with hexane/AcOEt (20:1)
as the eluent. 16e (133 mg, 100%) was obtained from 15e. Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.46 (s, 1H), 7.39–7.11 (m, 5H), 5.58–
5.57 (m, 2H), 4.21–4.09 (m, 2H), 3.46–3.41 (m, 3H), 3.32–3.27 (m, 1H),
3.19–3.14 (m, 2H), 2.76 (brs, 1H), 2.62–2.51 (m, 1H), 2.16–2.12 (m, 1H),
2.02–1.66 (m, 7H), 1.52 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
206.1, 136.4, 129.1, 127.3, 126.8, 125.63, 125.56, 91.8, 69.8, 63.1, 56.6, 56.0,
51.2, 50.9, 50.7, 37.3, 34.0, 33.3, 27.2, 25.9, 25.7 ppm; IR (KBr): n˜ =3402,
1709 cmꢀ1; MS (FAB): m/z: 455 [M++Na]; HRMS (FAB): m/z calcd for
C23H29BrNaO3: 455.1197 [M++Na]; found: 455.1189.
16.5 ppm; IR (KBr): n˜ =2966, 1092, 741 cmꢀ1
.
Norbornene aldehyde cyclohexene alcohol 16 f: By use of the same pro-
cedure as for 16b, 15 f and 15 f’ (98%) were obtained from 11 f and 11 f’
(96.4 mg) and NBS (56.0 mg). 15 f (99.6 mg, 78%) was obtained by sepa-
ration with SiO2 flash column chromatography with hexane/AcOEt
(20:1) as the eluent. 16 f (96.4 mg, 0.224 mmol, 100%) was obtained from
15 f. Colorless oil; 1HNMR (300 MHz, CDCl 3): d=9.46 (s, 1H), 7.39–
7.11 (m, 5H), 5.58–5.57 (m, 2H), 4.21–4.09 (m, 2H), 3.46–3.41 (m, 3H),
3.32–3.27 (m, 1H), 3.19–3.14 (m, 2H), 2.76 (brs, 1H), 2.62–2.51 (m, 1H),
2.16–2.12 (m, 1H), 2.02–1.66 (m, 7H), 1.52 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=206.1, 136.4, 129.1, 127.3, 126.8, 125.63, 125.56,
91.8, 69.8, 63.1, 56.6, 56.0, 51.2, 50.9, 50.7, 37.3, 34.0, 33.3, 27.2, 25.9, 25.7;
IR (KBr): n˜ =3402, 1709 cmꢀ1; MS (FAB): m/z: 455 [M++Na]; HRMS
(FAB): m/z calcd for C23H29BrNaO3: 455.1197 [M++Na]; found:
455.1189.
Norbornene aldehyde cyclohexene acetal 11 f: By use of the same proce-
dure as for 11a, 11 f and 11 f’ (65.6 mg, 76%, 60% de) were obtained
from 5 f (72.8 mg) and (ꢀ)-7a (54.4 mg) as an inseparable diastereomix-
ture. Eluent for chromatography: AcOEt/hexane (1:15). 1HNMR
(300 MHz, CDCl3): d=7.26–7.12 (m, 5H), 6.57–6.55 (m, 1H), 6.32–6.29
(m, 1H), 6.55–6.51 (m, 2H), 3.99 (s, 1H), 3.80–3.73 (dd, J=11.9, 6.2 Hz,
1H), 3.56–3.50 (dd, J=12.2, 3.8 Hz, 1H), 3.01–2.90 (m, 3H), 2.62 (m,
1H), 2.00–1.49 (m, 9H), 1.38 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=142.4, 137.2, 135.4, 129.1, 127.5, 125.9, 125.6, 125.5, 104.4, 70.9, 70.1,
57.3, 53.4, 53.1, 49.3, 49.1, 38.3, 37.2, 27.4, 27.0, 22.0 ppm; IR (KBr): n˜ =
2964, 1134, 741 cmꢀ1; MS (EI): m/z: 336 [M+]; HRMS (EI): m/z calcd for
C23H28O2: 336.2089 [M+]; found: 336.2084.
Norbornene aldehyde norbornane alcohol 16b: NBS (61.0 mg, 1.1 equiv)
was added to a stirred solution of 11b (109.2 mg) in MeOH(3.2 mL) at
ꢀ408C under N2 and the reaction mixture was allowed to warm slowly to
RT. After completion of the reaction (checked by TLC), saturated aque-
ous Na2S2O3 was added to the mixture and the resulting solution was ex-
tracted with EtOAc. The organic layer was washed with brine, dried over
Norbornene aldehyde norbornane silylether 17b: By use of the same pro-
cedure as for 17a, 17b (84.6 mg, 94%) was obtained from 16b (58.4 mg),
TBDPSCl (74 mL), imidazole (39.2 mg), and DMF (0.8 mL). Eluent for
chromatography: AcOEt/hexane (1:10). Colorless oil; 1HNMR
(300 MHz, CDCl3): d=9.35 (s, 1H), 7.64–7.07 (m, 15H), 4.13–4.01 (m,
2H), 3.75–3.69 (m, 1H), 3.56–3.50 (m, 1H), 3.34–3.31 (m, 3H), 3.22–3.16
(m, 1H), 3.09 (m, 1H), 2.35–2.28 (m, 2H), 2.17–1.98 (m, 3H), 1.87–1.83
(m, 1H), 1.46 (s, 3H), 1.27–1.19 (m, 7H), 1.02 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=204.6, 136.6, 135.62, 135.58, 134.1, 129.5, 129.0,
127.6, 127.5, 127.4, 126.6, 91.7, 68.5, 61.7, 56.3, 56.1, 51.2, 51.0, 50.8, 42.7,
39.7, 39.6, 39.5, 39.4, 34.0, 26.9, 25.5, 22.3, 22.1, 19.2 ppm; MS (FAB):
m/z: 707 [M++Na]; IR (KBr): n˜ =1713 cmꢀ1; HRMS (FAB): m/z calcd
for C40H49BrNaO3Si: 707.2532 [M++Na]; found: 707.2542.
Na2SO4, and evaporated in vacuo.
A catalytic amount of p-TsOH
(0.1 equiv) was added to a solution of the crude 15b in acetone/H2O
(4:1; 1 mL) and the resulting mixture was stirred at RT. After completion
of the reaction (checked by TLC), the solution was quenched by addition
of saturated aqueous NaHCO3 and extracted with AcOEt. The organic
layer was washed with brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2 flash column chromatography
with hexane/AcOEt (3:1) as the eluent to give 16b (64.1 mg, 0.143 mmol,
1
92% over 2 steps). Colorless oil; HNMR (300 MHz, CDCl 3): d=9.43 (s,
1H), 7.37–7.09 (m, 5H), 4.19–4.18 (m, 2H), 3.78–3.76 (m, 1H), 3.49–3.40
(m, 3H), 3.29–3.25 (m, 1H), 3.15 (m, 1H), 2.51 (m, 1H), 2.22–1.91 (m,
7H), 1.51 (s, 3H), 1.35–1.19 ppm (m, 6H); 13C NMR (75 MHz, CDCl3):
d=204.7, 136.3, 129.1, 127.3, 126.7, 91.9, 69.2, 61.3, 56.1, 55.8, 51.1, 50.7,
50.4, 43.1, 40.4, 40.2, 39.7, 39.5, 34.0, 25.6, 22.8, 22.4 ppm; IR (KBr): n˜ =
3395, 1711 cmꢀ1; MS (FAB): m/z: 447 [M++H]; HRMS (FAB): m/z calcd
for C24H32BrO3: 447.1535 [M++H]; found: 447.1544.
Norbornene aldehyde bicyclooctene silylether 17c: By use of the same
procedure as for 17a, 17c (108.2 mg, 98%) was obtained from 16c
(79.2 mg), TBDPSCl (98 mL), imidazole (51.6 mg), and DMF (1.2 mL).
Eluent for chromatography: AcOEt/hexane (1:10). Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.39 (s, 1H), 7.64–7.08 (m, 15H), 6.11–
5.96 (m, 2H), 4.12–4.10 (m, 1H), 3.99–3.96 (m, 1H), 3.54–3.49 (m, 1H),
3.36–3.34 (m, 1H), 3.28–3.16 (m, 2H), 3.10 (m, 1H), 2.92–2.86 (t, J=
9 Hz, 1H), 2.63 (m, 1H), 2.42 (m, 1H), 2.32 (m, 1H), 2.07–1.97 (m, 3H),
1.86–1.82 (m, 1H), 1.46 (s, 3H), 1.43–1.02 (m, 4H), 1.03 ppm (s, 9H);
Norbornene aldehyde bicyclooctene alcohol 16c: By use of the same pro-
cedure as for 16b, 16c (84.2 mg, 95%) was obtained from 11c (70.0 mg)
5394
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5386 – 5397

Asymmetric Desymmetrization
5386 – 5397
13C NMR (75 MHz, CDCl3): d=204.6, 136.6, 135.60, 135.56, 134.01,
133.99, 133.3, 133.2, 129.5, 129.0, 127.6, 127.4, 126.6, 91.9, 77.4, 77.0, 76.6,
70.7, 64.2, 56.3, 56.2, 51.2, 51.0, 50.9, 44.2, 41.5, 34.0, 32.3, 26.9, 25.45,
25.38, 25.0, 19.2; MS (FAB): m/z: 719 [M++Na]; IR (KBr): n˜ =
flow rate, 262 nm wavelength; retention times: 22.20 min and 24.33 min
for (ꢁ)-18c and 22.24 min for (+)-18c); 1HNMR (300 MHz, CDCl 3): d=
7.69–7.64 (m, 4H), 7.47–7.23 (m, 6H), 6.15–5.95 (m, 2H), 3.74–3.64 (m,
3H), 3.48–3.43 (m, 2H), 2.47 (m, 1H), 2.28–2.25 (m, 3H), 1.62–1.45 (m,
2H), 1.26–1.17 (m, 2H), 1.04 ppm (s, 9H); 13C NMR (75 MHz, CDCl3):
d=135.6, 135.5, 134.8, 133.2, 133.0, 132.7, 129.85, 129.80, 127.77, 127.75,
66.4, 64.9, 45.8, 45.2, 34.1, 33.9, 26.8, 25.6, 25.2, 19.1 ppm; IR (KBr): n˜ =
3406 cmꢀ1; MS (FAB): m/z: 407 [M++H]; HRMS (FAB): m/z calcd for
C26H35O2Si: 407.2406 [M++H]; found: 407.2428.
Oxohexene silylether 18d:[15] By use of the same procedure as for 18a,
18d (67.0 mg, 86%) and 7a (41 mg, 98%) were obtained from 17d
(135 mg), Zn(OTf)2 (430 mg), Zn (260 mg), and DMA (3.0 mL). Eluent
for chromatography: AcOEt/hexane (1:2). 18d: Colorless solid; m.p. 84–
858C; [a]2D0 =ꢀ17.73 (c=1.01, CHCl3); the optical purity of 18d (99%
ee) was determined by HPLC analysis (Chiralpak OD-H, hexane/iPrOH
(99:1), 0.5 mLminꢀ1 flow rate, 259 nm wavelength; retention times:
64.40 min and 70.43 min for (ꢁ)-18d and 69.33 min for (+)-18d);
1HNMR (300 MHz, CDCl 3): d=7.69–7.65 (m, 4H), 7.47–7.37 (m, 6H),
6.39–6.32 (m, 2H), 4.74 (s, 1H), 4.66 (s, 1H), 3.91–3.85 (m, 2H), 3.79–
3.73 (m, 1H), 3.67–3.66 (m, 1H), 3.10–3.08 (m, 1H), 1.97–1.93 (m, 2H),
1.05 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=135.8, 135.6, 135.52,
135.48, 132.9, 129.9, 127.8, 81.2, 80.8, 64.4, 62.5, 42.7, 42.5, 26.8, 19.1 ppm;
IR (KBr): n˜ =3422 cmꢀ1; MS (FAB): m/z: 395 [M++Na]; HRMS (FAB):
m/z calcd for C24H31NaO3Si: 395.2042 [M++Na]; found: 395.2036.
1713 cmꢀ1
; HRMS (FAB): m/z calcd for C41H49BrNaO3Si: 719.2732
[M++Na]; found: 719.2496.
Norbornene aldehyde oxohexene silylether 17d: By use of the same pro-
cedure as for 17a, 17d (102.2 mg, 94%) was obtained from 16d
(73.4 mg), TBDPSCl (90 mL), imidazole (47.4 mg), and DMF (1.2 mL).
1
Eluent for chromatography: AcOEt/hexane (1:6). Colorless oil; HNMR
(300 MHz, CDCl3): d=9.38 (s, 1H), 7.65–7.08 (m, 15H), 6.28–6.25 (m,
2H), 4.85 (s, 1H,), 4.59 (s, 1H), 4.11–4.03 (m, 2H), 3.75–3.70 (dd, J=9.9,
6.0 Hz, 1H), 3.61–3.55 (t, J=9.6 Hz, 1H), 3.43–3.36 (m, 2H), 3.23–3.17 (t,
J=9.6 Hz, 1H), 3.11–3.10 (m, 1H), 2.37–2.36 (m, 1H), 2.09–2.06 (m,
1H), 1.88–1.84 (m, 1H), 1.80–1.75 (m, 1H), 1.71–1.66 (m, 1H), 1.48 (s,
3H), 1.04 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=204.6, 136.6,
135.55, 135.52, 135.48, 135.4, 133.7, 133.6, 129.6, 129.0, 127.69, 127.67,
127.4, 126.6, 92.0, 80.5, 80.2, 69.9, 63.2, 56.2, 56.1, 51.3, 50.8, 50.7, 42.4,
39.7, 34.0, 26.9, 25.4, 19.2 ppm; IR (KBr): n˜ =1713 cmꢀ1; MS (FAB): m/z:
691 [M++Li]; HRMS (FAB): m/z calcd for C39H45BrLiO4Si: 691.2430
[M++Li]; found: 691.2427.
Norbornene aldehyde cyclopropane silylether 17e: By use of the same
procedure as for 17a, 17e (60.1 mg, 95%) was obtained from 16e
(39.2 mg), TBDPSCl (57 mL), imidazole (29.9 mg), and DMF (0.5 mL).
Eluent for chromatography: AcOEt/hexane (1:15). Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.43 (s, 1H), 7.67–7.63 (m, 4H), 7.43–
7.24 (m, 9H), 7.12–7.10 (m, 2H), 4.22–4.08 (m, 2H), 3.74–3.68 (m, 1H),
3.54–3.48 (m, 2H), 3.38–3.39 (m, 1H), 3.14–3.08 (m, 2H), 2.38 (brs, 1H),
2.11 (d, J=11.1 Hz, 1H), 1.88 (m, 1H), 1.49 (s, 3H), 1.29–0.97 (m, 2H),
1.03 (s, 9H), 0.67–0.14 (m, 1H), 0.10–0.08 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=204.6, 136.6, 135.6, 134.0, 133.9, 129.5, 129.0, 127.6,
127.5, 127.4, 126.6, 91.1, 70.0, 63.9, 56.4, 56.1, 51.4, 51.2, 50.8, 34.0, 26.9,
25.6, 19.2, 17.6, 15.0, 14.2, 8.7 ppm; IR (KBr): n˜ =1713 cmꢀ1; MS (FAB):
m/z: 653 [M++Na]; HRMS (FAB): m/z calcd for C36H43O3BrSiNa:
653.2028 [M++Na]; found: 653.2045.
Cyclopropane silylether 18e: By use of the same procedure as for 18a,
18e (33.0 mg, 92%) and 7a (18.8 mg, 94%) were obtained from 17e
(63.2 mg), Zn(OTf)2 (206 mg), Zn (122.8 mg), and DMA (0.8 mL).
Eluent for chromatography: AcOEt/hexane (1:4). 18e: Colorless oil;
[a]2D7 =ꢀ12.31 (c=1.14, CHCl3); the optical purity of 18e (99% ee) was
determined by HPLC analysis (Chiralpak OD-H, hexane/iPrOH(99:1),
0.5 mLminꢀ1 flow rate, 261 nm wavelength; retention times: 16.64 min
and 18.81 min for (ꢁ)-18e and 19.69 min for (+)-18e); 1HNMR
(300 MHz, CDCl3): d=7.69–7.65 (m, 4H), 7.47–7.36 (m, 6H), 5.57–5.52
(m, 2H), 3.77–3.53 (m, 4H), 2.76 (brs, 1H), 2.12–1.88 (m, 6H), 1.06 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=135.52, 135.47, 133.0, 129.71,
129.68, 127.6, 125.5, 125.3, 65.3, 64.1, 37.9, 37.3, 27.3, 26.9, 26.6, 19.2 ppm;
IR (KBr): n˜ =3344 cmꢀ1; MS (FAB): m/z: 381 [M++H]; HRMS (FAB):
m/z calcd for C24H33O2Si: 381.2250 [M++H]; found: 381.2260.
Cyclohexene silylether 18 f:[16] By use of the same procedure for 18a, 18 f
(33.0 mg, 92%) and 7a (18.8 mg, 94%) were obtained from 17 f
(63.2 mg), Zn(OTf)2 (206 mg), Zn (122.8 mg), and DMA (0.8 mL).
Eluent for chromatography: AcOEt/hexane (1:4). 18 f: Colorless oil;
[a]2D7 =ꢀ12.31 (c=1.14, CHCl3); the optical purity of 18 f (99% ee) was
determined by HPLC analysis (Chiralpak OD-H, hexane/iPrOH(99:1),
0.5 mLminꢀ1 flow rate, 263 nm wavelength; retention times: 27.69 min
and 33.20 min for (ꢁ)-18 f and 34.35 min for (+)-18 f); 1HNMR
(300 MHz, CDCl3): d=7.69–7.65 (m, 4H), 7.47–7.36 (m, 6H), 5.57–5.52
(m, 2H), 3.77–3.53 (m, 4H), 2.76 (brs, 1H), 2.12–1.88 (m, 6H), 1.06 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=135.52, 135.47, 133.0, 129.71,
129.68, 127.6, 125.5, 125.3, 65.3, 64.1, 37.9, 37.3, 27.3, 26.9, 26.6, 19.2 ppm;
IR (KBr): n˜ =3344 cmꢀ1; MS (FAB): m/z: 381 [M++H]; HRMS (FAB):
m/z calcd for C24H33O2Si: 381.2250 [M++H]; found: 381.2260.
Norbornene aldehyde cyclohexene silylether 17 f: By use of the same
procedure as for 17a, 17 f (63.2 mg, 98%) was obtained from 16 f
(41.6 mg), TBDPSCl (54 mL), imidazole (28.8 mg), and DMF (1.0 mL).
Eluent for chromatography: AcOEt/hexane (1:15). Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.34 (s, 1H), 7.66–7.62 (m, 4H), 7.41–
7.23 (m, 9H), 7.11–7.09 (m, 2H), 5.51 (m, 2H), 4.16–4.04 (m, 2H), 3.62–
3.48 (m, 2H), 3.36–3.35 (m, 1H), 3.33–3.20 (m, 2H), 3.11 (m, 1H), 2.32
(m, 1H), 2.11–1.72 (m, 8H), 1.57 (s, 3H), 1.03 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=204.3, 136.6, 135.61, 135.59, 133.89, 133.85, 129.52,
129.47, 129.0, 127.60, 127.57, 127.4, 126.6, 125.5, 125.4, 91.8, 71.5, 64.5,
56.6, 56.1, 51.4, 51.0, 50.7, 37.1, 34.9, 33.9, 26.9, 26.70, 26.66, 25.5,
19.2 ppm; IR (KBr): n˜ =1713 cmꢀ1; MS (FAB): m/z: 693 [M++Na];
HRMS (FAB): m/z calcd for C39H47BrNaO3Si: 693.2576 [M++Na];
found: 693.2362.
Norbornane silylether 18b: By use of the same procedure as for 18a, 18b
(69.0 mg, 94%) and 7a (36.5 mg, 93%) were obtained from 17b
(127.5 mg), Zn(OTf)2 (405 mg), Zn (245 mg), and DMA (2.0 mL). Eluent
for chromatography: AcOEt/hexane (1:5). 18b: Colorless oil; [a]D25
=
Norbornene aldehyde 1,3-dimethyl acetal 21a: By use of the same proce-
dure as for 11a, 21a (257 mg, 94%) was obtained from 20a (106 mg) and
(ꢀ)-7a (194 mg). Eluent for chromatography: AcOEt/hexane (1:50).
White solid; m.p. 78–798C; 1HNMR (300 MHz, CDCl 3): d=7.36–7.09
(m, 5H), 6.50–6.48 (m, 1H), 6.28–6.26 (m, 1H), 3.78 (s, 1H), 3.46–3.39
(m, 1H), 3.01 (brs, 2H), 2.67 (brs, 1H), 2.65–2.59 (m, 1H), 1.76–1.74 (m,
1H), 1.52–1.48 (m, 1H), 1.36 (s, 3H), 1.21–1.16 (m, 1H), 1.13–1.11 (d, J=
ꢀ8.31 (c=1.28, CHCl3); the optical purity of 18b (98% ee) was deter-
mined by HPLC analysis (Chiralpak OD-H, hexane/iPrOH(99:1),
0.5 mLminꢀ1 flow rate, 262 nm wavelength; retention times: 19.11 min
and 21.68 min for (ꢁ)-18b and 19.68 min for (+)-18b); 1HNMR
(300 MHz, CDCl3): d=7.69–7.65 (m, 4H), 7.43–7.39 (m, 6H), 4.02–3.95
(m, 2H), 3.64–3.59 (m, 3H), 2.26 (m, 3H), 2.08 (m, 1H), 1.61 (m, 1H),
1.44–1.17 (m, 5H), 1.04 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
135.5, 135.4, 132.9, 132.8, 129.8, 129.7, 127.72, 127.67, 63.8, 61.8, 43.7,
13
6 Hz, 3H), 0.96–0.85 (m, 1H), 0.61–0.59 ppm (d, J=6 H z, 3H ); C NMR
(75 MHz, CDCl3): d=142.4, 137.5, 134.9, 129.1, 127.0, 125.4, 103.7, 72.2,
71.7, 57.5, 52.5, 51.2, 49.1, 48.9, 40.4, 22.4, 21.9, 20.9 ppm; IR (KBr): n˜ =
2970, 1022, 745 cmꢀ1; MS (EI): m/z: 298 [M+]; HRMS (EI): m/z calcd for
C20H26O2: 298.1933; found: 298.1950; elemental analysis calcd (%) for
C20H26O2: C 80.50, H8.78; found: C 80.20; H8.80.
42.9, 40.8, 40.7, 40.0, 26.8, 22.8, 22.7, 19.2 ppm; IR (KBr): n˜ =3404 cmꢀ1
;
MS (FAB): m/z 395 [M++H]; HRMS (FAB): m/z calcd for C25H35O2Si:
395.2406 [M++H]; found: 395.2409.
Bicyclooctene silylether 18c: By use of the same procedure as for 18a,
18c (42.4 mg, 89%) and 7a (21.8 mg, 88%) were obtained from 17c
(81.8 mg), Zn(OTf)2 (256 mg), Zn (154 mg), and DMA (1.0 mL). Eluent
Norbornene aldehyde 1,3-diallyl acetal 21b: By use of the same proce-
dure as for 11a, 21b (75.2 mg, 90%) was obtained from 20b (50.0 mg)
and (ꢀ)-7a (58.8 mg): Eluent for chromatography: AcOEt/hexane (1:50).
Colorless oil; 1HNMR (300 MHz, CDCl 3): d=7.21–7.09 (m, 5H), 6.46
(dd, J=5.6, 2.4 Hz, 1H), 6.27 (dd, J=5.6, 3.2 Hz, 1H), 5.91–5.77 (m,
for chromatography: AcOEt/hexane (1:5). 18c: Colorless oil; [a]D24
=
+2.11 (c=1.48, CHCl3); the optical purity of 18c (98% ee) was determined
ꢀ1
by HPLC analysis (Chiralpak OD-H, hexane/iPrOH(99:1), 0.5 mLmin
Chem. Eur. J. 2004, 10, 5386 – 5397
www.chemeurj.org
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
5395

H. Fujioka, Y. Kita et al.
FULL PAPER
1H), 5.27–5.01 (m, 3H), 4.83–4.77 (m, 1H), 3.85 (s, 1H), 3.35–3.30 (m,
1H), 2.98 (brs, 2H), 2.70–2.59 (m, 2H), 2.30–2.04 (m, 2H), 1.75–1.70 (m,
3H), 1.48 (d, J=8.4 Hz, 1H), 1.35 (s, 3H), 1.20 (dt, J=12.9, 2.5 Hz, 1H),
0.99–0.91 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=142.3, 137.6,
134.8, 134.7, 134.6, 129.0, 127.3, 125.5, 116.5, 116.0, 103.4, 75.7, 74.9, 57.5,
52.5, 51.5, 49.3, 48.8, 40.4, 39.9, 35.9, 22.4 ppm; IR (KBr): n˜ =2974, 1342,
1020, 912, 742 cmꢀ1; elemental analysis calcd (%) for C24H30O2: C 82.24,
H8.63; found: C 82.11, H8.72.
57.5, 56.2, 51.9, 51.2, 51.2, 46.3, 34.2, 27.0, 25.3, 23.8, 19.5, 19.2 ppm; IR
(KBr): n˜ =3439 cmꢀ1; HRMS (FAB): m/z calcd for C36H45O3BrSiNa:
655.2219 [M++Na]; found: 655.2224.
Norbornene aldehyde 1,3-diallyl silylether 23b: By use of the same pro-
cedure as for 16a, 23b (120.2 mg, 96%) was obtained from 22b
(81.3 mg), TBDPSCl (140 mL), imidazole (75 mg), and DMF (0.5 mL).
Eluent for chromatography: AcOEt/hexane (1:15). Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.22 (s, 1H), 7.64–7.06 (m, 15H), 5.70–
5.40 (m, 2H), 4.90–4.80 (m, 4H), 4.16 (t, J=3.9 Hz, 1H), 4.07–4.05 (m,
1H), 3.80–3.74 (m, 1H), 3.55–3.48 (m, 1H), 3.33 (d, J=3.3 Hz, 1H), 3.10
(brs, 1H), 2.20–1.80 (m, 7H), 1.70–1.50 (m, 2H), 1.50 (s, 3H), 1.01 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=204.7, 136.5, 135.8, 135.7, 134.3,
134.2, 133.9, 133.7, 129.5, 129.5, 128.9, 127.5, 127.4, 127.3, 126.6, 117.4,
117.1, 90.6, 78.1, 69.9, 57.5, 56.2, 52.1, 51.3, 51.3, 41.0, 40.2, 37.9, 34.2,
27.0, 25.2, 19.3 ppm; IR (KBr): n˜ =2929, 1715, 1113, 912 cmꢀ1; HRMS
(FAB): m/z calcd for C40H49O3BrSiNa: 707.2532 [M++Na]; found:
707.2562.
Norbornene aldehyde 1,3-diisopropyl acetal 21c: By use of the same pro-
cedure as for 11a, 21c (147 mg, 88%) was obtained from 20c (83 mg)
and (ꢀ)-7a (100 mg). Eluent for chromatography: hexane. Colorless oil;
1HNMR (300 MHz, CDCl 3): d=7.15–7.06 (m, 5H), 6.42–6.41 (m, 1H),
6.30–6.27 (m, 1H), 3.91 (s, 1H), 2.95–2.92 (s, 3H), 2.71 (brs, 1H), 2.38–
2.35 (m, 1H), 1.72 (d, J=8.4 Hz, 1H), 1.57–1.55 (m, 3H), 1.43 (d, J=
8.4 Hz, 1H), 1.32 (s, 1H), 1.27–1.12 (m, 3H), 0.95 (d, J=6.6 Hz, 3H),
0.84 (d, J=6.6 Hz, 3H), 0.46 (d, J=6.6 Hz, 3H), 0.31 ppm (d, J=6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=142.6, 137.9, 134.7, 129.1, 127.5,
125.5, 102.9, 81.3, 80.1, 57.6, 52.9, 52.2, 49.8, 48.6, 33.2, 32.6, 31.2, 22.6,
18.4, 18.3, 17.9, 17.6 ppm; IR (KBr): n˜ =2959, 1109, 746 cmꢀ1; elemental
analysis calcd (%) for C24H34O2: C 81.31, H9.67; found: C 81.36, H9.71.
Norbornene aldehyde 1,3-diisopropyl silylether 23c: By use of the same
procedure for 16a, 23c (74 mg, 97%) was obtained from 22c (50 mg),
TBDPSCl (0.13 mL), imidazole (68 mg), and DMF (0.5 mL). Eluent for
chromatography: AcOEt/hexane (1:30); white crystal. M.p. 93–948C;
1HNMR (300 MHz, CDCl 3): d=9.07 (s, 1H), 7.56–7.54 (m, 4H), 7.27–
7.00 (m, 11H), 4.00–3.96 (m, 2H), 3.55 (m, 1H), 3.23 (brs, 1H), 3.02
(brs, 1H), 2.02–1.96 (m, 2H), 1.71–1.52 (m, 2H), 1.49–1.47 (m, 1H), 1.36
(s, 3H), 1.36–1.18 (m, 4H), 0.94 (s, 9H), 0.84 (d, J=7.5 Hz, 3H), 0.66 (d,
J=7.5 Hz, 3H), 0.46 (d, J=7.5 Hz, 3H), 0.35 ppm (J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=204.4, 136.5, 135.8, 135.7, 134.6, 134.3,
129.3, 129.2, 128.9, 127.3, 127.2, 126.5, 92.0, 84.9, 74.7, 57.5, 56.4, 52.7,
52.7, 51.6, 34.2, 34.2, 32.0, 29.9, 27.2, 25.1, 19.7, 18.7, 17.6, 16.6, 16.3 ppm;
IR (KBr): n˜ =1717, 1111 cmꢀ1; HRMS (FAB): m/z calcd for C40H53O3Br-
SiNa: 711.2845 [M++Na]; found: 711.2816.
Norbornene aldehyde 1,3-dimethyl alcohol 22a: By use of the same pro-
cedure as for 16a, 22a (52.5 mg, 99%) was obtained by p-TsOHhydroly-
sis of the product from the reaction of 21a (40.0 mg), NBS (26.0 mg), and
MeOH(1.5 mL). Eluent for chromatography: AcOEt/hexane (1:3). Col-
orless oil; 1HNMR (300 MHz, CDCl 3): d=9.39 (s, 1H), 7.36–7.08 (m,
5H), 4.29–4.26 (m, 1H), 4.18–4.17 (m, 1H), 3.83 (m, 1H), 3.73–3.66 (q,
J=6.2 Hz, 1H), 3.39 (m, 1H), 3.14 (m, 1H), 2.35 (m, 1H), 2.19–2.14 (d,
J=12 Hz, 1H), 1.93–1.89 (d, J=12 Hz, 1H), 1.78 (brs, 1H), 1.72–1.64 (m,
1H), 1.51 (s, 3H), 1.42–1.33 (m, 1H), 1.15–1.13 (d, J=6.8 Hz, 3H), 1.08–
1.06 ppm (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.1,
136.3, 128.9, 127.2, 126.6, 89.9, 77.5, 77.0, 76.5, 75.9, 66.0, 57.8, 56.3, 51.9,
51.4, 51.2, 45.6, 34.4, 25.5, 24.0, 20.1 ppm; IR (KBr): n˜ =3404, 1713 cmꢀ1
HRMS (EI): m/z calcd for C20H28O2Br: 395.1221; found: 395.1218.
;
1,3-Dimethyl silylether 24a: By use of the same procedure as for 18a,
24a (61.2 mg, 86%) and 7a (37.8 mg, 86%) were obtained from 23a
(132 mg), Zn(OTf)2 (453 mg), Zn (273 mg), and DMA (2.0 mL). Eluent
Norbornene aldehyde 1,3-diallyl alcohol 22b: By use of the same proce-
dure as for 16a, 22b (66.8 mg, 87%) was obtained by p-TsOHhydrolysis
of the product from the reaction of 21b (61.2 mg), NBS (18.6 mg), and
MeOH(1.74 mL). Eluent for chromatography: AcOEt/hexane (1:3). Col-
orless oil; 1HNMR (300 MHz, CDCl 3): d=9.37 (s, 1H), 7.35–7.07 (m,
5H), 5.79–5.57 (m, 2H), 5.10–4.99 (m, 4H), 4.30 (t, J=3.9 Hz, 1H), 4.21–
4.19 (m, 1H), 3.71–3.63 (m, 2H), 3.37 (d, J=3.3 Hz, 1H), 3.14 (d, J=
1.8 Hz, 1H), 2.33–1.87 (m, 8H), 1.65–1.50 (m, 2H), 1.49 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=204.9, 136.3, 134.4, 133.8, 128.9, 127.2,
126.6, 118.1, 117.7, 90.2, 78.7, 68.1, 57.3, 56.2, 51.9, 51.4, 51.2, 42.0, 40.3,
for chromatography: AcOEt/hexane (1:4). 24a: Colorless oil; [a]D24
=
ꢀ16.93 (c=1.33, CHCl3); the optical purity of 24a (99% ee) was deter-
mined by HPLC analysis (Chiralpak AD-H, hexane/iPrOH(150:1),
0.5 mLminꢀ1 flow rate, 264 nm wavelength; retention times: 20.11 min
and 22.21 min for (ꢁ)-24a and 20.31 min for (+)-24a); 1HNMR
(300 MHz, CDCl3): d=7.75–7.70 (m, 4H), 7.46–7.36 (m, 6H), 4.13–4.00
(m, 2H), 3.00 (brs, 1H), 1.74–1.49 (m, 2H), 1.04 (s, 9H), 1.15–1.12 (d,
J=6.2 Hz, 3H), 0.99–0.97 ppm (d, J=6.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=135.8, 135.8, 134.4, 133.5, 129.8, 129.6, 127.7, 127.5, 70.6, 67.0,
48.0, 26.9, 24.1, 23.6, 19.1 ppm; IR (KBr): n˜ =3439 cmꢀ1; elemental analy-
sis calcd (%) for C21H30O2Si: C 73.63, H8.83; found: C 73.32, H8.69.
37.9, 34.1, 25.2 ppm; IR (KBr): n˜ =3410, 2974, 1713, 1084, 914 cmꢀ1
;
HRMS (FAB): m/z calcd for C24H32O3Br: 447.1535 [M++H]; found:
447.1544.
1,3-Diallyl silylether 24b: By use of the same procedure as for 18a, 24b
(53.3 mg, 92%) and 7a (29.3 mg, 94%) were obtained from 23b
(101.0 mg), Zn(OTf)2 (321 mg), Zn (193 mg), and DMA (1.5 mL). Eluent
Norbornene aldehyde 1,3-diisopropyl alcohol 22c: By use of the same
procedure as for 16a, 22c (77 mg, 70%) was obtained by p-TsOHhydrol-
ysis of the product from the reaction of 21c (87 mg), NBS (49 mg), and
MeOH(1.8 mL). Eluent for chromatography: AcOEt/hexane (1:5). Col-
orless oil; 1HNMR (300 MHz, CDCl 3): d=9.29 (s, 1H), 7.28–7.23 (m,
3H), 7.04–7.01 (m, 2H), 4.21–4.20 (m, 1H), 4.16–4.15 (m, 1H), 3.40–3.39
(m, 1H), 3.30 (m, 1H), 3.09 (s, 1H), 2.22 (brs, 1H), 2.07 (d, J=10.8 Hz,
1H), 1.84–1.79 (m, 2H), 1.54–1.35 (m, 3H), 1.43 (s, 3H), 1.18–1.13 (m,
2H), 0.78 (d, J=6.9 Hz, 3H), 0.77 (d, J=6.9 Hz, 3H), 0.69 (d, J=6.9 Hz,
3H), 0.68 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=204.5,
136.4, 128.9, 127.2, 126.6, 91.8, 86.2, 74.9, 57.5, 56.4, 52.6, 51.7, 51.5, 35.1,
34.2, 33.6, 30.2, 25.3, 18.7, 17.5, 17.3, 16.7 ppm; IR (KBr): n˜ =3500,
1715 cmꢀ1; HRMS (FAB): m/z calcd for C24H36O3Br: 451.1848 [M++H];
found: 451.1853.
for chromatography: AcOEt/hexane (1:15). 24b: Colorless oil; [a]D24
=
ꢀ24.0 (c=2.03, CHCl3); the optical purity of 24b (99% ee) was deter-
mined by HPLC analysis (Chiralpak AD-H, hexane, 0.5 mLminꢀ1 flow
rate, 261 nm wavelength; retention times: 29.35 min and 32.33 min for
(ꢁ)-24b and 29.31 min for (+)-24b); 1HNMR (300 MHz, CDCl 3):
d=7.75–7.66 (m, 4H), 7.50–7.30 (m, 6H), 5.79–5.53 (m, 2H), 5.10–4.78
(m, 4H), 4.01–3.78 (m, 2H), 2.50 (brs, 1H), 2.20–2.06 (m, 4H), 1.70–1.56
(m, 2H), 1.06 ppm (9H, s); 13C NMR (75 MHz, CDCl3): d=135.9, 134.6,
134.1, 133.6, 129.8, 129.7, 127.7, 127.5, 117.7, 117.4, 72.7, 69.1, 42.4, 42.0,
41.8, 27.0, 19.2 ppm; IR (KBr): n˜ =3460, 2932, 1427, 1111, 914 cmꢀ1; ele-
mental analysis calcd (%) for C25H34O2Si: C 76.09, H8.68; found:
C 75.93, H8.72.
Norbornene aldehyde 1,3-dimethyl silylether 23a: By use of the same
procedure as for 17a, 23a (104.0 mg, 100%) was obtained from 22a
(65.0 mg), TBDPSCl (94 mL), imidazole (50 mg), and DMF (0.8 mL).
Eluent for chromatography: AcOEt/hexane (1:15). Colorless oil;
1HNMR (300 MHz, CDCl 3): d=9.29 (s, 1H), 7.64–7.08 (m, 15H), 4.20–
4.08 (m, 2H), 3.80–3.78 (m, 1H), 3.58–3.52 (m, 1H), 3.36 (m, 1H), 3.12
(m, 1H), 2.23 (m, 1H), 2.14–2.10 (m, 1H), 1.89–1.75 (m, 3H), 1.47 (s,
3H), 1.00 (s, 9H), 1.04–1.01 (d, J=6.3 Hz, 3H), 0.83–0.81 ppm (d, J=
6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.1, 136.6, 135.8, 135.7,
134.6, 134.0, 129.5, 129.4, 128.9, 127.5, 127.3, 127.3, 126.5, 89.4, 73.9, 66.8,
1,3-Diisopropyl silylether 24c: By use of the same procedure as for 18a,
24c (99 mg, 99%) and (ꢀ)-7a (54 mg, 100%) were obtained from 23c
(174 mg), Zn(OTf)2 (552 mg), Zn (330 mg), and DMA (2.4 mL). Eluent
for chromatography: AcOEt/hexane (1:30!1:15). Colorless oil; [a]2D9 =+
4.29 (c=1.43); the optical purity of 24c (99% ee) was determined by
HPLC analysis (Chiralpak AD-H, hexane, 0.5 mLminꢀ1 flow rate,
261 nm wavelength; retention times: 25.24 min and 27.16 min for (ꢁ)-
24c and 25.01 min for (+)-24c); 1HNMR (300 MHz, CDCl 3): d=7.65–
7.63 (m, 4H), 7.35–7.18 (m, 6H), 6.30–6.27 (m, 1H), 3.80–3.75 (m, 1H),
3.27 (m, 1H), 1.97–1.18 (m, 4H), 1.00 (s, 9H), 0.83 (d, 6.9 Hz, 3H), 0.76
5396
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5386 – 5397

Asymmetric Desymmetrization
5386 – 5397
(d, 6.6 Hz, 3H), 0.74 (d, 6.6 Hz, 3H), 0.70 ppm (d, 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=136.0, 134.3, 134.2, 129.6, 129.6, 127.5, 127.5, 77.3,
74.6, 36.0, 33.5, 32.3, 27.1, 19.5, 18.4, 17.5, 17.1, 16.8 ppm; IR (KBr): n˜ =
3500, 1471, 1111 cmꢀ1; elemental analysis calcd (%) for C25H38O2Si: C
75.47, H9.80; found: C 75.32, H9.61.
thesis 1993, 1029–1056; f) E. Santaniello, P. Ferraboschi, P. Grisenti,
A. Manzocchi, Chem. Rev. 1992, 92, 1071–1140; g) T. Harada, A.
Oku, Synlett 1994, 95–104.
[2] For recent studies on desymmetrization of meso-1,2-diols, see: a) S.
Mizuta, M. Sadamori, T. Fujimoto, I. Yamamoto, Angew. Chem.
2003, 115, 3505–3507; Angew. Chem. Int. Ed. 2003, 42, 3383–3385;
b) N. Maezaki, A. Sakamoto, N. Nagahashi, M. Soejima, Y. Li, T.
Imamura, N. Kojima, H. Ohishi, K. Sakaguchi, C. Iwata, T. Tanaka,
J. Org. Chem. 2000, 65, 3284–3291; c) T. Oriyama, K. Imai, T. Sano,
T. Hosoya, Tetrahedron Lett. 1998, 39, 3529–3533; d) M. Kinugasa,
T. Harada, A. Oku, J. Am. Chem. Soc. 1997, 119, 9067–9068; e) E.
Vedejs, O. Daugulis, S. T. Diver, J. Org. Chem. 1996, 61, 430–431.
[3] a) T. Harada, K. Sekiguchi, T. Nakamura, J. Suzuki, A. Oku, Org.
Lett. 2001, 3, 3309–3312; b) T. Oriyama, T. Hosoya, T. Sano, Hetero-
cycles 2000, 69, 1054–1069; c) T. Harada, Y. Ikemura, H. Nakajima,
A. Oku, Chem. Lett. 1990, 1441–1444; d) T. Harada, K. Sakamoto,
Y. Ikemura, A. Oku, Tetrahedron Lett. 1988, 29, 3097–3100; e) J.
Ichikawa, M. Asami, T. Mukaiyama, Chem. Lett. 1984, 949–952.
[4] a) K. Ishihara, M. Kubota, H. Yamamoto, Synlett 1994, 611–614;
b) S. Yamada, H. Katsumata, Chem. Lett. 1998, 995–996; c) B. M.
Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, 2410–2411.
[5] a) H. Fujioka, Y. Nagatomi, H. Kitagawa, Y. Kita, J. Am. Chem.
Soc. 1997, 119, 12016–12017; b) H. Fujioka, Y. Nagatomi, N.
Kotoku, H. Kitagawa, Y. Kita, Tetrahedron Lett. 1998, 39, 7309–
7312; c) H. Fujioka, Y. Nagatomi, N. Kotoku, H. Kitagawa, Y. Kita,
Tetrahedron 2000, 56, 10141–10151.
Norbornene aldehyde 1,2-dimethyl acetal 26: By use of the same proce-
dure as for 11a, 26 (65.6 mg, 84%) was obtained from 25 (50.0 mg) and
(ꢀ)-7a (58.8 mg). Eluent for chromatography: AcOEt/hexane (1:50).
Colorless oil; 1HNMR (300 MHz, CDCl 3): d=7.19–7.15 (m, 5H), 6.47–
6.37 (m, 2H), 4.25 (s, 1H), 3.87–3.81 (m, 1H), 3.62–3.55 (m, 1H), 3.10
(m, 1H), 3.03 (m, 1H), 2.67 (m, 1H), 1.82–1.79 (m, 1H), 1.55–1.51 (m,
1H), 1.34 (s, 3H), 1.03–1.01 (d, J=6.3 Hz, 3H), 0.92–0.90 ppm (d, J=
6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=141.6, 137.2, 135.0, 129.2,
127.2, 125.6, 105.2, 74.4, 72.8, 56.7, 53.3, 49.4, 49.2, 49.0, 22.1, 15.6,
14.8 ppm; IR (KBr): n˜ =2972, 1094, 743 cmꢀ1; HRMS (EI): m/z calcd for
C19H24O2: 284.1776; found: 284.1774.
Norbornene aldehyde 1,2-dimethyl alcohol 27: By use of the same proce-
dure as for 16a, 27 (56.0 mg, 96%) was obtained by p-TsOHhydrolysis
of the product from the reaction of 26a (43.7 mg), NBS (30 mg), and
MeOH(1 mL). Eluent for chromatography: AcOEt/hexane (1:3). Color-
1
less oil; HNMR (300 MHz, CDCl 3): d=9.41 (s, 1H), 7.37–7.10 (m, 5H),
4.37–4.36 (m, 1H), 4.20–4.16 (m, 1H), 3.77 (brs, 1H), 3.55–3.54 (m, 1H),
3.40 (m, 1H), 3.16 (m, 1H), 2.36 (m, 1H), 2.19–2.14 (d, J=12.0 Hz, 1H),
1.93–1.89 (d, J=12.0 Hz, 1H), 1.82 (m, 1H), 1.52 (s, 3H), 1.04–0.98 ppm
(m, 6H); 13C NMR (75 MHz, CDCl3): d=205.2, 136.3, 129.0, 127.2, 126.6,
89.0, 79.2, 69.2, 57.5, 56.3, 51.5, 51.4, 51.0, 34.2, 25.5, 17.3, 13.0 ppm; IR
(KBr): n˜ =3456, 1710 cmꢀ1; MS (EI): m/z: 381 [M+]; HRMS (EI): m/z:
calcd for C19H25O3Br: 381.1065; found: 381.1088.
[6] a) H. Fujioka, N. Kotoku, Y. Nagatomi, Y. Kita, Tetrahedron Lett.
2000, 41, 1829–1832; b) H. Fujioka, N. Kotoku, T. Fujita, R. Inogu-
chi, K. Murai, Y. Nagatomi, Y. Sawama, Y. Kita, Chirality 2003, 15,
60–67.
Norbornene aldehyde 1,2-dimethyl silylether 28: By use of the same pro-
cedure as for 16a, 28 (49.7 mg, 94%) was obtained from 27 (32.4 mg),
TBDPSCl (49 mL), imidazole (25.5 mg), and DMF (0.6 mL). Eluent for
chromatography: AcOEt/hexane (1:10). Colorless oil; 1HNMR
(300 MHz, CDCl3): d=9.48 (s, 1H), 7.62–7.09 (m, 15H), 4.73–4.70 (m,
1H), 4.27–4.25 (m, 1H), 3.65–3.59 (m, 2H), 3.39–3.38 (m, 1H), 3.16–3.16
(m, 1H), 2.39–2.39 (m, 1H), 2.17–2.12 (m, 1H), 1.90–1.86 (m, 1H), 1.51
(s, 3H), 0.95 (s, 9H), 0.92–0.90 (d, J=6 Hz, 3H), 0.86–0.84 ppm (d, J=
6 H z, 3H );13C NMR (75 MHz, CDCl3): d=205.6, 136.6, 135.9, 135.8,
129.6, 129.5, 129.0, 127.6, 127.4, 127.3, 126.6, 88.9, 78.7, 73.5, 60.4, 56.9,
56.4, 51.8, 51.6, 27.0, 25.4, 19.0, 16.6, 16.0, 14.2 ppm; IR (KBr): n˜ =
1712 cmꢀ1; MS (FAB): m/z: 641 [M++Na]; HRMS (FAB): m/z calcd for
C35H43BrNaO3Si: 641.2263 [M++Na]; found: 641.2064.
[7] At the beginning of the work, we supposed that discrimination be-
tween the two oxygen atoms depends on the stability of the cationic
intermediates from intramolecular bromoetherification. (See ref. [5],
where the direction of discrimination expected from the activation
energy is the same as the direction from the stability of the cationic
intermediates.) Later, during the work on optical resolution
(ref. [6]), the obtained direction was found to be opposite to the di-
rection expected from the stability of the cation intermediates, but
the same as the order of activation energies. We therefore suppose
that the genuine factor for discrimination of the two oxygen atoms
of the acetal is the difference in the activation energies of the transi-
tion states.
1,2-Dimethyl silylether 29: By use of the same procedure as for 18a, 29
(62.4 mg, 96%) and 7a (39.9 mg, 95%) were obtained from 28
(122.1 mg), Zn(OTf)2 (429 mg), Zn (258 mg), and DMA (1.5 mL). Eluent
for chromatography: AcOEt/hexane (1:6). 29: Colorless oil; [a]2D3 =ꢀ9.67
(c=0.75, CHCl3); the optical purity of 29a (97% ee) was determined by
[8] H. Honig, P. Seufer-Wasserthal, H. Weber, Tetrahedron 1990, 46,
3841–3850.
[9] K. Omura, A. K. Sharma, D. Swern, J. Org. Chem. 1976, 41, 957–
962.
[10] Chiral hydrobenzoin is readily available in both enantiomeric forms
by asymmetric synthesis. See: Z.-M. Wang, K. B. Sharpless, J. Org.
Chem. 1994, 59, 8302–8303.
[11] CCDC-230171 contains the supplementary crystallo-graphic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK: fax: (+44)1223-336-033; or e-mail; deposit@ccdc.cam.ac.
uk).
ꢀ1
HPLC analysis (Chiralpak OD-H, hexane/iPrOH(150:1), 0.5 mLmin
flow rate, 263 nm wavelength; retention times: 13.60 min and 14.81 min
for (ꢁ)-29 and 13.81 min for (+)-29); 1HNMR (300 MHz, CDCl 3): d=
7.69–7.65 (m, 4H), 7.46–7.38 (m, 6H), 3.80–3.76 (m, 2H), 2.24 (brs, 1H),
1.70 (s, 9H), 1.05–1.03 (d, J=6 Hz, 3H), 1.00–0.98 ppm (d, J=6 H z, 3H );
13C NMR (75 MHz, CDCl3): d=135.8, 135.7, 134.1, 133.7, 129.8, 129.7,
127.7, 127.6, 73.0, 70.9, 27.0, 19.3, 17.2, 16.4 ppm; IR (KBr): n˜ =
3439 cmꢀ1; FAB MS: m/z: 351 [M++Na]; HRMS (FAB): m/z calcd for
C20H28NaO2Si: 351.1756 [M++Na]; found: 351.1752.
[12] K. P. Lok, I. J. Jakovac, J. B. Jones, J. Am. Chem. Soc. 1985, 107,
2521–2526.
[13] D. Grandjean, P. Pale, J. Chuche, Tetrahedron 1991, 47, 1215–1230.
[14] Compound 7a is stable when it stands at room temperature al-
though it has an aldehyde functionionality. Its stability may depend
on its crystallization at room temperature, although other norbor-
nene aldehydes, such as 1a, 1b, and 7b, are oils and need refrigera-
tion for prolonged storage.
Acknowledgement
Financial support from Monbusho (Grant-in-Aid for Scientific Research
on Priority Areas, No. 706: Dynamic Control of Stereochemistry) and
Promotion of Science is gratefully acknowledged
[15] K. Takano, G. Watanabe, H. Yasui, K. Tadano, Org. Lett. 2002, 4,
2941–2943.
[16] P. OꢁBrien, J. J. Tournayre, Tetrahedron 1997, 53, 17527–17542.
[1] For example, see: a) A. P. Davis, Angew. Chem. 1997, 109, 609–612;
Angew. Chem. Int. Ed. Engl. 1997, 36, 591–594; b) A. Fadel, P.
Arzel, Tetrahedron: Asymmetry 1997, 8, 283–291; c) E. Schoffers, A.
Golebiowski, C. R. Johnson, Tetrahedron 1996, 52, 3769–3826; d) F.
Theil, Chem. Rev. 1995, 95, 2203–2227; e) L. Banfi, G. Guanti, Syn-
Received: May 6, 2004
Published online: September 23, 2004
Chem. Eur. J. 2004, 10, 5386 – 5397
www.chemeurj.org
ꢀ 2004 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
5397