Stereo- And regioselectivity in an intramolecular nitrone-alkene cycloaddition of hept-6-enoses with a trans-acetonide blocking group

Article abstract of DOI:10.1002/chem.200800867

The positional effect of the trans-acetonide blocking group and the effect of the stereochemistry of the substituents on the regio- and stereoselectivity in intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses are reported. Hept-6

Full text of DOI:10.1002/chem.200800867

FULL PAPER
DOI: 10.1002/chem.200800867
Stereo- and Regioselectivity in an Intramolecular Nitrone–Alkene
Cycloaddition of Hept-6-enoses with a trans-Acetonide Blocking Group
Tony K. M. Shing,*[a] Wai F. Wong,[a] Taketo Ikeno,[b] and Tohru Yamada*[b]
Abstract: The positional effect of the
trans-acetonide blocking group and the
effect of the stereochemistry of the
substituents on the regio- and stereose-
lectivity in intramolecular nitrone–
alkene cycloaddition (INAC) reactions
of hept-6-enoses are reported. Hept-6-
enoses with a 2,3-trans-acetonide group
were reacted with N-alkyl hydroxyl-
amine to give a mixture of exo and
endo cycloadducts (cyclohexanols and
cycloheptanols, respectively). Complete
formation of endo cycloadducts (cyclo-
heptanols) was realized for the INAC
reaction of hept-6-enoses containing a
3,4-trans-O-isopropylidene ring. Simi-
larly, reaction of a hept-6-enose pos-
sessing a 4,5-trans-acetonide group sur-
prisingly afforded exo cycloadducts (cy-
clohexanols) exclusively. The regio-
and stereochemical outcomes of these
reactions were rationalized on the basis
of transition-state energies obtained by
computation.
Keywords: alkenes · carbohydrates ·
cycloaddition
nitrones
·
cycloheptanes
·
Introduction
There are only two examples[3] of the synthesis of a bridg-
ed bicycloACTHNUTRGNEUG[N 4.2.1] system, that is, a cycloheptane skeleton,
Intramolecular nitrone–alkene cycloaddition (INAC) consti-
tutes a versatile and efficient synthetic protocol for the con-
struction of polyhydroxylated carbocycles from carbohy-
drates.[1] The exo or the endo mode of INAC cyclization af-
from branched sugars, however, there are many examples[1]
of unbranched hept-6-enose derivatives being used to form
the fused bicycloACTHNUTRGNEUNG[4.3.0] system, that is, a cyclohexane skele-
ton. However, the regio- and diastereoselectivity of these
INAC reactions have not been studied.
fords
a fused or a bridged isoxazolidine, respectively
(Scheme 1).[2]
Both the fused and bridged isoxazolidines are key inter-
mediates in the syntheses of natural products or analogues
with biological importance.[1] Upon hydrogenolysis of the
À
N O bond, bridged bicycloACTHNUTRGENU[GN 4.2.1]isoxazolidine 1 provides
the skeleton of aminocycloheptanol 2, which is a new class
of glycosidase inhibitor.[4] Further transformation of 2 could
give alkaloid tropane 3[5] and calystegine 4[6] that exhibits
specific glycosidase inhibition (Scheme 2).[7] Recently, we
have successfully developed a method for the facile conver-
Scheme 1. The a) exo and b) endo modes of INAC cyclization.
sion of the bridged bicycloACTHNURGTNE[NUG 4.2.1] systems into two calyste-
gines 5 and 6, one tropane 7, and one hydroxylated amino-
[a] Prof. Dr. T. K. M. Shing, Dr. W. F. Wong
Department of Chemistry and Center of Novel Functional Molecules
The Chinese University of Hong Kong
Shatin, NT, Hong Kong (China)
cycloheptane 8.[8]
Our previous studies[9] have shown that exo-INAC cycliza-
tion is the preferred pathway for hept-6-enoses containing a
cis-acetonide (erythro-diol-acetonide) to give fused isoxazo-
lidines exclusively, whereas hept-6-enoses with a 2,3-O-
trans-diacetal give a mixture of fused (cyclohexane) and
bridged (cycloheptane) isoxazolidines. High yielding and ex-
clusive endo-INAC reactions of hept-6-enoses have recently
been realized with a 3,4-O-trans-acetonide to give bridged
Fax : (+852)2603-5057
E-mail: tonyshing@cuhk.edu.hk
[b] Prof. Dr. T. Ikeno, Prof. Dr. T. Yamada
Department of Chemistry
Faculty of Science and Technology
Keio University
Hiyoshi, Kohoku-ku, Yokohama, 223-8522 (Japan)
Fax : (+81)455-661-716
bicyclo
ent article, the positional effect of a trans-acetonide (threo-
[4.2.1]isoxazolidines for the first time.[8] In the pres-
ACHTUNGTRENNUNG
E-mail: yamada@chem.keio.ac.jp
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following the latter sequence
gave aldehydes 20 and 21, re-
spectively, in good yields.
Individual aldehydes 12, 13,
16, 17, 20, and 21 underwent an
INAC reaction with MeNHOH
smoothly to give one exo and
one endo cycloadduct. The re-
sults are summarized in Table 1.
The INAC reactions of hepte-
noses 12, 16, or 20 proceeded
with excellent yields and cyclo-
heptanes (endo product) 23, 25,
or 27, respectively, were ob-
tained as the major cycload-
ducts (entries 1–3). As the size
Scheme 2. Transformation of isoxazolidine 1.
diol-acetonide) blocking group
on the stereo- and regioselectiv-
ity of INAC reactions of hept-
6-enoses derived from carbohy-
drates is reported. Hept-6-
enoses with a trans-acetonide
group placed in different posi-
tions (2,3-, 3,4-, or 4,5-position)
were synthesized from sugars
and then subjected to INAC re-
actions to give cycloadducts.
Theoretical analysis was carried
out and the transition state
(TS) energies of all the possible
cycloadducts were computed.
The present findings on the ste-
reochemical outcome of the
INAC reactions should assist
synthetic chemists in their
routes towards the preparation
of calystegines, tropanes, and
hydroxylated aminocyclohep-
tanes.
Scheme 3. Preparation of hept-6-enoses 12, 13, 16, 17, 20, and 2 (Bn=benzyl; TBS=tert-butylsilyl).
of the OR4 group increases from OH to OTBS, the endo se-
lectivity increases from 86:14 (entry 1) to 92:8 (entry 3). The
endo selectivity appears to be controlled by the OR group
Results and Discussion
À
Hept-6-enoses with a 2,3-trans-acetonide group: Diol 9, syn-
thesized from d-mannitol according to the literature,[10] un-
derwent oxidative cleavage of glycol[11] and then allylation
to afford alkenes 10 and 11 in 44 and 27% overall yields, re-
spectively (Scheme 3). Both alkenes 10 and 11 were trans-
formed into aldehydes 12 and 13, respectively, upon regiose-
lective terminal hydrolysis with aqueous acetic acid (AcOH)
and subsequent glycol oxidative cleavage. Aldehydes 16 and
17 were obtained from alkenes 10 and 11, respectively,
through a synthetic sequence of benzylation, acid hydrolysis,
and glycol-cleavage oxidation. With the same starting al-
kenes 10 and 11, replacing benzylation with silylation and
at C3 and the new C N bond is always anti to OR3 in all
entries. In cases in which the OR4 stereochemistry is syner-
getic, the endo cycloadduct was the major product (en-
tries 1–3), otherwise (entries 4–6) the endo selectivity is
poor and further diminishes as the size of the OR4 group in-
creases. The structures of cycloheptanes 25 and 29, and cy-
clohexane 28 were confirmed by X-ray crystallography anal-
yses.[12] Desilylation of 27 gave alcohol 23, which was benzy-
lated to give cycloheptane 25 (Scheme 4). The constitutions
of cycloheptanes 23 and 27 were therefore confirmed. Simi-
lar synthetic transformation on cycloheptanes 33 and 29
verified their structures.
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Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
Table 1. INAC reactions of hept-6-enoses with 2,3-trans-acetonide.
Entry Aldehyde[a]
Cycloadducts
Yield[b] [%]
94
1
22/23 14:86
95
2
3
24/25 11:89
Scheme 4. Structural confirmation of cycloheptanes 23, 27, 31, and 33.
94
26/27 8:92
94
4
5
28/29 33:67
Scheme 5. Conformation of cyclohexane 26.
tional arrangement that hinted at a distorted-chair confor-
mation for the cycloadduct 26. The heterocyclic ring was in
92
30/31 47:53
À
a cis arrangement and anti to the C O bond at C2.
Hept-6-enoses with a 3,4-trans-acetonide group: Diaceto-
nide 34, synthesized from d-ribose,[8] was acetylated to give
acetate 35 (Scheme 6). Regioselective acid hydrolysis of ace-
tate 35 gave a diol that was subjected to oxidative glycol
cleavage to furnish hept-6-enose 36 as an INAC precursor
with a 3,4-trans-isopropylidene blocking group.
86
6
32/33 48:52
[a] Not characterized. [b] Overall isolated yield from the corresponding
diol.
The C2 hydroxyl group was protected in advance to
obtain the desired hept-6-enose 36 instead of a hex-5-enose
by further glycol-cleavage oxidation. The C2 substituent
effect on the INAC reaction was then studied by converting
diacetonide 34 into hept-6-enose 38 with a tert-butylsilyl
(TBS) group by a reaction sequence involving silylation,
The stereochemistry of the cyclohexanes was established
with the evidence from 1D H NMR spectroscopy coupling
1
data, and 2D COSY and NOESY analysis. The assignment
of the stereochemistry of cyclohexane 26 is illustrated in
Scheme 5. The quasi-diaxial ar-
rangement of H2 and H3 was
supported by the large coupling
constant (JH2,H3 =10.2 Hz). The
small coupling constants of H3
with H4 (JH3,H4 =2.4 Hz) and
H4 with H5 (JH4,H5 =3.6 Hz)
suggested a quasi-equatorial po-
sitioning of H4. The quasi-
axial–axial coupling of H1 with
H2 (JH1,H2 =7.8 Hz) and quasi-
axial–equatorial coupling of H5
with H6 (JH5,H6 =6.6 Hz) dem-
onstrated that the isoxazolidine
ring was bending to the b face
as shown in Scheme 5. The
large coupling constant (JH1,H6
=
7.8 Hz) between H1 and H6
verified an eclipsed conforma- Scheme 6. Preparation of hept-6-enoses 36, 38, and 41 (Ac2O=acetic anhydride).
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2695

T. K. M. Shing, T. Yamada et al.
acid hydrolysis, and glycol oxidative cleavage. Performing
the same manipulation as with hept-6-enose 38, hept-6-
enose 41 was synthesized from the known diacetonide 39.[8]
Hept-6-enoses 42, 43, 44 (Bz=benzoyl), and 45 shown in
Table 2 were synthesized from sugars by following the
method detailed in our previous communication.[8]
Complete formation of the cycloheptanes was realized by
means of the endo mode of the INAC reaction in excellent
yields. The stereochemistry of the only/major heterocycle
with the stereochemistry mismatch at C2. The major cyclo-
adduct 53 further decreases in entry 6 as there is an addi-
tional mismatched stereochemistry at C5, whereas only cy-
cloadduct 55 was obtained with a synergetic C5 stereochem-
istry (entry 7).
The structures of cycloheptanes 48 and 49 were confirmed
by X-ray crystallography analyses.[13] Single crystals of a de-
benzoylated derivative of 55 confirmed its constitution by
X-ray crystallography analyses.[14] The stereochemistry of cy-
cloheptanes 46, 47, and 51 was assigned by protective-group
transformation of the C2 substituent as described before.
For cycloheptane 53,[15] strong NOE correlations of H4 with
H7 and H1 with H2 indicate that the bridgehead is pointing
to the b face (Scheme 7). The NOE correlations of H4 with
H5 and H5 with H6 demonstrate that the benzoyl group is
at the a face. The isoxazolidine ring of cycloheptane 53 is
syn to the C2 substituent and that of another cycloadduct 54
is anti to the C2 substituent by exclusion.
À
seems to be controlled by the OR group at C3. The new C
N bond is always anti to OR3 in all entries. In cases in
which the OR2 stereochemistry is synergetic only one cyclo-
adduct is formed (entries 1–3), otherwise the diastereoselec-
tivity is analogously reduced (entries 4 and 5). Different C2
substituents in aldehydes 36, 42, and 38 result in the same
regio- and stereochemical outcome. The amount of the
major diastereomer 51 (entry 5) decreases as the size of the
C2 substituent increases from a -OH group in aldehyde 43
(entry 4) to a -OTBS group in aldehyde 41, which is in line
Hept-6-enoses with a 4,5-trans-
acetonide group: Enoate 56 was
synthesized from d-xylose by
Table 2. INAC reactions of hept-6-enoses with 3,4-trans-acetonide.
Entry
Aldehyde[a]
Cycloadduct(s)
Yield[b] [%]
means of a Wittig reaction and
acetylation according to the lit-
erature
(Scheme 8).[16]
The
double bond in enoate 56 was
saturated by palladium-cata-
lyzed hydrogenation to give an
ester that underwent acid hy-
drolysis to afford diol 57. The
terminal alkene functionality in
alkene 58 was obtained in a
high yield from diol 57 on treat-
ment with triphenylphosphine,
iodine, and imidazole.[17] Reduc-
tion of alkene 58 with diisobu-
tylaluminum hydride (DIBAL-
H) afforded alcohol 59 in a
quantitative yield. 2-Iodoxyben-
zoic acid (IBX) oxidation[18] of
alcohol 59 gave hept-6-enose
60, which was subjected to the
INAC reaction. Unexpected re-
sults of three cyclohexanes 61,
62, and 63 were generated in a
moderate overall yield (67%).
The structure of cyclohexane 61
was confirmed by X-ray crystal-
lography[19] analyses and those
of cyclohexanes 62 and 63 were
established with the evidence
1
89
2
3
4
5
97
99
93
49/50 91:9
100
51/52 88:12
85
6
7
53/54 66:34
1
from 1D H NMR spectroscopy
coupling data and 2D COSY
and NOESY analysis. Strong
NOE correlations of H1 with
H6 and H4 with H6 of cyclo-
hexane 62 illustrate a cis-fused
93
[a] Not characterized. [b] Overall isolated yield from the corresponding diol or alcohol.
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Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
obtained structures were similar to those in previous re-
ports[23,24] and the imaginary frequencies were checked to
ensure that the vectors were directed toward the reaction
pathway. Intrinsic reaction coordinate (IRC) calculations
were performed for the most stable TSs. Only the concerted
pathway was calculated as this was reported to be more fa-
vorable than the biradical pathway.[23]
The results of nitrone 64 derived from hept-6-enose 12
with a 2,3-trans-diacetonide are shown in Table 3. The calcu-
lated results suggested that cycloheptanol 23 (experimental
Scheme 7. Conformation of cycloheptane 53 (Bn=benzyl, Bz=benzoyl).
heterocyclic ring bending to the
b face as shown in Scheme 9.
1
From the H NMR spectrum of
62, the coupling constant be-
tween H1 and H6 (JH1,H6
=
5.4 Hz) fell into the range of
axial–equatorial coupling. To-
gether with the axial–axial cou-
pling of H4 with H5 (JH4,H5
=
9.3 Hz) and H5 with H6
(JH5,H6 =9.3 Hz), it is suggested
that a chair conformation is
adopted by cyclohexane 62. In
the 1H NMR spectrum of 63,
the large coupling constant be-
tween H4 and H5 (JH4,H5
=
9.6 Hz) demonstrated a quasi-
diaxial arrangement and the
smaller one of H5 with H6
(JH5,H6 =6.0 Hz) fell into the Scheme 8. Preparation of hept-6-enose 60.
range of quasi-axial–equatorial
coupling. The coupling con-
stants of H1 with H6 and H1
with H2 were both 7.2 Hz
which suggested
a distorted-
chair conformation with the iso-
xazolidine ring bending to the a
face.
Scheme 9. Conformation of 62 and 63.
Theoretical
analysis:
The
ground-state structures were
calculated with molecular me-
chanics by using the CON-
FLEX program for conforma-
tional search.[20] Many conform-
ers were obtained and the rela-
tively stable conformers (within
10 kcalmolÀ1 compared with
the most stable one) were se-
lected for further analysis. The
ground states and all the transi-
tion states based on the
ground-state structures were
calculated by using B3LYP/6-
31G* with Gaussian 98.[21,22]
The obtained TS energies were
Table 3. Theoretical analysis of INAC of nitrone 64.[a]
ground state DE [kcalmolÀ1
]
3.07
4.62
0
2.90
bond length in TS [ꢁ][b]
À
C C
À
C O
2.25
2.07
14
2.05
1.27
2.22
2.07
0
4.94
4.84
2.17
2.21
86
0
0
2.08
2.33
0
1.66
2.14
experimental ratio [%]
TS DE [kcalmolÀ1
]
TS DG (1008C) [kcalmolÀ1
]
[a] B3LYP/6-31G* calculations were performed. Relative energies are shown. [b] The new bonds formed in
compared with each other. The the INAC reaction.
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2697

T. K. M. Shing, T. Yamada et al.
Table 4. Theoretical analysis of INAC of nitrone 67.[a]
ratio 86%) is the major isomer
because it had the lowest Gibbs
TS energy. The energy differ-
ence between the TSs of 23 and
22 was relatively smaller
(1.27 kcalmolÀ1) than that be-
tween 23 and 65 (4.84 kcal
molÀ1), and 23 and 66 (2.14 kcal
molÀ1). Therefore, cyclohexanol
22 (experimental ratio 14%)
was obtained in low yields. The
theoretical analysis is consistent
with the experimental results.
The results of nitrone 67 de-
rived from hept-6-enose 13 are
shown in Table 4. The TS lead-
ing to cycloheptane 29 is the
lowest, which implies that 29
should be formed as the major
cycloadduct and is in accord
with the experimental results.
The even smaller energy differ-
ence (0.69 kcalmolÀ1) between
the TSs of 29 and 28 suggested
that cyclohexanol 28 (experi-
mental ratio 34%) was ob-
tained in an appreciable yield.
ground state DE [kcalmolÀ1
]
0
1.86
2.38
2.78
4.43
bond length in TS [ꢁ][b]
À
C C
À
C O
2.17
2.19
67
0
0
2.12
2.27
0
3.27
3.03
2.26
2.05
33
1.80
0.69
2.20
2.07
0
4.79
4.92
2.15
2.14
0
4.66
3.92
experimental ratio [%]
TS DE [kcalmolÀ1
]
TS DG (808C) [kcalmolÀ1
]
[a] B3LYP/6-31G* calculations were performed. Relative energies are shown. [b] The new bonds formed in
the INAC reaction.
Table 5. Theoretical analysis of INAC of nitrone 71.[a]
ground state DE [kcalmolÀ1
]
0
3.15
5.84
6.73
9.36
bond length in TS [ꢁ][b]
À
C C
À
C O
2.15
2.27
100
0
2.06
2.33
0
5.46
5.81
2.23
2.05
0
4.54
4.18
2.23
2.12
0
5.01
4.45
2.16
2.14
0
6.33
5.83
The results of nitrones 71 and experimental ratio [%]
TS DE [kcalmolÀ1
TS DG (808C) [kcalmolÀ1
]
76, derived from hept-6-enoses
36 and 43, respectively, with a
3,4-trans-diacetonide are shown
in Tables 5 and 6, respectively.
The energy of the TS leading to
cycloheptanol 46 is significantly
lower than those of the rest of
the TSs. Consequently, the endo
cycloadduct 46 was the exclu-
sive product. For nitrone 76,
the energy of the TS leading to
endo cycloadducts 49 and 50 is
also appreciably lower than
those of the rest of the TSs.
]
0
[a] B3LYP/6-31G* calculations were performed. Relative energies are shown. [b] The new bonds formed in
the INAC reaction.
Table 6. Theoretical analysis of INAC of nitrone 76.[a]
ground state DE [kcalmolÀ1
]
0
1.02
5.78
4.79
7.47
bond length in TS [ꢁ][b]
The benzyl group of the ni-
trone derived from hept-6-
enose 60 was replaced with a
methyl moiety in the calcula-
tion for simplicity.[9] The calcu-
lation results for N-methyl ni-
trone 80 are illustrated in
Table 7. Since the energies of
the TSs leading to cyclohexa-
À
C C
À
C O
2.17
2.21
91
0
0
2.11
2.28
9
1.52
1.55
2.29
2.03
0
4.01
3.36
2.22
2.01
0
4.12
4.30
2.16
2.12
0
6.06
5.60
experimental ratio [%]
TS DE [kcalmolÀ1
]
TS DG (808C) [kcalmolÀ1
]
[a] B3LYP/6-31G* calculations were performed. Relative energies are shown. [b] The new bonds formed in
the INAC reaction.
nols 61–63 are relatively lower and the differences are not
larger than 0.8 kcalmolÀ1, we would expect the formation of
all of them.
The conformation of the most stable TSs leading to the
cycloadducts are showed in Figure 1. Only the skeleton
atoms are shown for simplicity.
With the 2,3-trans-diequatorial acetonide, the TS leading
to cyclohexanes 22 (TS-22a) and 28 (TS-28a) adopts a chair
conformation that results in less efficient bonding orbital
overlap as shown in TS-22b and TS-28b, respectively. Focus-
ing on the trans-fused C2 and C3 carbon atoms of TS-22a
and TS-28a revealed torsional strains, which is common in a
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Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
Table 7. Theoretical analysis of INAC of nitrone 80.[a]
of 2.16 kcalmolÀ1.[25] Such dif-
ference in the conformation of
the TS may account for the for-
mation of cycloheptane 49 (rel-
ative composition 91%) as the
major diastereomer.
With nitrone 71, the C2 sub-
stituent of TS-46a and TS-72a
is situated at the axial position.
The electronic and steric repul-
sion between the oxygen atom
of the C2 hydroxyl group and
that of the nitrone functionality
in TS-72a is highly unfavorable
and increases the TS energy.
Cycloheptane 46, with the het-
erocyclic ring anti to the C2
substituent, was therefore ob-
ground state DE [kcal
0
0.88
3.07
0.22
1.66
molÀ1
]
bond length in TS [ꢁ][b]
À
C C
2.09
2.30
0
6.91
6.84
2.14
2.23
0
3.02
3.40
2.19
2.10
20
0.95
0.32
2.24
2.03
35
0
2.24
2.07
12
1.38
0.80
À
C O
experimental ratio [%][c]
TS DE [kcalmolÀ1
]
TS DG (808C) [kcal
0
molÀ1
]
[a] B3LYP/6-31G* calculations were performed. Relative energies are shown. [b] The new bonds formed in
the INAC reaction. [c] Yield for the N-benzyl group.
trans-hydrindane system. On the other hand, the twist-chair
conformation of TS-23a and TS-29a allows the orientation
of bonding orbitals to be aligned on the same plane in space
and lowers the TS energy. The torsional strain of substitu-
ents on the trans-fused C2 and C3 carbon atoms in TS-23a
and TS-29a is relieved probably due to the twist-chair con-
formation of the cycloheptane and the torsional energy in-
volved becomes smaller when compared to that in TS-22a
and TS-28a. Cycloheptanes 23 and 29 were therefore
formed as the major cycloadduct. Moreover, TS-22a is de-
stabilized by a pseudo-1,3-diaxial interaction between the
C4 hydroxyl group and the developing isoxazolidine ring;
cycloheptane 23 was therefore harvested in a high relative
composition of 86%. The (R)-C4-OH group in TS-22a is sit-
uated at the axial position. When the size of the (R)-C4-OR
group increases from OH to OTBS, the endo selectivity in-
creases from 86:14 to 92:8, respectively, as cyclohexanes 22,
24, and 26 (exo product) are destabilized by the 1,3-diaxial
interaction. For the (S)-C4-OR group in TS-29a at the equa-
torial position, the endo cycloadducts 29, 31, and 33 might
be destabilized by the steric repulsion between the isoxazoli-
dine ring and the OR group at the same side. Consequently,
the endo selectivity decreased as the size of the (S)-C4-OR
group increased.
For nitrone 76, both the twist-chair and chair conforma-
tion of TS-49b and TS-50b, respectively, result in efficient
bonding orbital overlap. Among other exo cycloadducts, cy-
clohexane 77 has the lowest TS energy. To relieve the tor-
sional strain imposed by the 3,4-trans-isopropylidene ring,
TS-77a, which leads to cyclohexane 77, adopts a conforma-
tion in which the bonding orbitals are oriented in different
planes in space as shown in TS-77b. The less efficient orbital
overlap increases the TS energy, which may explain the ab-
sence of cyclohexane 77 experimentally. The twist-chair and
chair conformation of TSs leading to cycloheptane 49 and
50 are more easily observed from another angle of vision as
shown in TS-49a and TS-50a, respectively. The twist-chair
conformation of a seven-membered carbocycle is more
stable than the chair conformation with an energy difference
tained exclusively.
Apart from the trans-isopropylidene blocking group, there
are no other functional groups on the carbon chain of the
TSs leading to cyclohexanes 83, 84, and 85. The trans-aceto-
nide in the C4 and C5 position allows the unsubstituted
carbon chain to effect a conformation in which the bonding
orbitals of the nitrone and the alkene were aligned on the
same plane, to have efficient bonding orbital overlap. The
torsional strain on TS-82a imposed by the 4,5-trans-isopro-
pylidene ring is relieved by adopting a boatlike conforma-
tion, which has a relatively higher energy than the chair con-
formation. Moreover, the bonding orbitals are not oriented
closely on the same plane as shown in TS-82b and the orbi-
tal overlap is inefficient.
Concerning stereoselectivity, the cyclohexane cycload-
ducts were usually cis-fused as in the case of nitrones 64, 67,
and 80 because of more efficient overlap of bonding orbi-
tals.
Conclusion
A series of hept-6-enoses was synthesized from sugars to in-
vestigate the positional effect of the trans-acetonide block-
ing group and the stereochemistry of the substituents on the
regio- and stereoselectivity in INAC reactions. Hept-6-
enoses with a 2,3-trans-acetonide gave a mixture of exo and
endo cycloadducts. Complete formation of endo cycload-
ducts (cycloheptanes) was realized with a 3,4-trans-isopropy-
lidene ring. However, hept-6-enoses possessing a 4,5-trans-
acetonide, surprisingly, afforded exo cycloadducts (cyclohex-
anes) exclusively. The regio- and stereochemical outcomes
of these reactions were rationalized on the basis of transi-
tion-state energies obtained by computation.
By studying the transition state leading to the cycload-
ducts obtained by computation, the regioselectivity was
found to be controlled by the blocking groups that affect the
conformation of the transition states. The torsional strain
imposed by the trans-acetonide significantly affects the con-
Chem. Eur. J. 2009, 15, 2693 – 2707
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2699

T. K. M. Shing, T. Yamada et al.
Figure 1. Transition states of the cycloadducts.
formation of the TSs and therefore the extent of the overlap
of bonding orbitals.
A cycloheptane TS is more flexible and can exist in more
conformations than a cyclohexane TS. It is proposed that
2700
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2693 – 2707

Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
6H), 2.15 (d, J=9.0 Hz, 1H), 2.27–2.44 (m, 2H), 3.76 (q, J=7.8 Hz, 1H),
3.89–4.00 (m, 3H), 4.05 (ddd, J=8.1, 5.7, 4.5 Hz, 1H), 4.14 (dd, J=8.1,
6.0 Hz, 1H), 5.10–5.18 (m, 2H), 5.89 ppm (ddt, J=17.4, 10.2, 7.2 Hz,
1H); 1H NMR (CDCl3–D2O): d=1.34 (s, 3H), 1.38 (s, 3H), 1.41–1.42
(2s, 6H), 2.27–2.41 (m, 2H), 3.76 (t, J=6.3 Hz, 1H), 3.89–4.00 (m, 3H),
4.05 (dt, J=7.8, 4.8 Hz, 1H), 4.14 (dd, J=8.1, 5.7 Hz, 1H), 5.10–5.17 (m,
2H), 5.89 ppm (ddt, J=17.1, 10.2, 6.9 Hz, 1H); 13C NMR: d=25.7, 27.1,
27.5, 27.6, 39.7, 68.2, 69.9, 77.6, 82.7, 109.8, 110.2, 117.9, 135.2 ppm; IR
(thin film): n˜ =2496, 2986, 1371, 1214, 1067, 845, 511 cmÀ1; MS (CI): m/z
(%): 273 (78) [M+H]+, 257 (18) [MÀOCH3]+, 215 (76), 157 (100), 139
(57); HRMS (CI): m/z calcd for C14H24O5 [M+H]+: 273.1697; found:
273.1703.
the TSs leading to the cycloheptanes can better accommo-
date the 2,3- or 3,4-trans-isopropylidene group and the tor-
sional strain imposed by that blocking group is relieved. The
bonding orbitals of the TSs leading to the cycloheptanes are
oriented on the same plane in space, which results in more
efficient orbital overlap and lower TS energy. With a 3,4-
trans-diacetonide, endo cycloadducts (cycloheptane) were
synthesized exclusively and in excellent yield.
The stereochemistry of the isoxazolidine ring was corre-
lated to the C3 substituent. The cyclohexanes obtained are
usually cis-fused. In the case of the cycloheptanes, the major
isoxazolidine ring is always anti to the C3 substituent.
With this novel blocking-group strategy, polyhydroxylated
cyclohexanes and cycloheptanes with a nitrogen functionali-
ty can be constructed regio- and stereoselectively from
sugars by means of the INAC approach.
Triol 10a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 5:1 to
1:3), alkene 10 (139 mg, 0.510 mmol)
gave firstly starting material 10
(6.90 mg, 5%) and secondly triol 10a
(108 mg, 96% based on recovering
starting material) as
a colorless oil.
Data for 10a: Rf =0.19 (hexane/
EtOAc 1:2); [a]2D0 =+5.33 (c=1.32 in
CHCl3); 1H NMR: d=1.37 (s, 6H),
Experimental Section
2.22 (dt, J=14.4, 8.1 Hz, 1H), 2.63
(dddd, J=14.4, 6.3, 2.7, 1.5 Hz, 1H),
NMR spectra were measured at 300.13 (1H) or 75.47 MHz (13C) in
CDCl3, unless stated otherwise. All chemical shifts were recorded in ppm
relative to tetramethylsilane (d=0.0 ppm).
3.07 (brs, 1H), 3.61–3.89 (m, 7H), 5.16–5.22 (m, 2H), 5.87 ppm (dddd,
J=18.3, 10.5, 8.1, 6.3 Hz, 1H); 1H NMR (CDCl3–D2O): d=1.37 (s, 6H),
2.22 (dt, J=14.4, 8.1 Hz, 1H), 2.62 (dddd, J=12.9, 6.3, 3.1, 1.5 Hz, 1H),
3.61–3.86 (m, 6H), 5.16–5.22 (m, 2H), 5.87 ppm (dddd, J=18.3, 10.5, 8.1,
6.3 Hz, 1H); 13C NMR: d=27.2, 27.3, 39.2, 64.2, 72.3, 73.0, 80.8, 82.5,
109.7, 119.2, 134.3 ppm; IR (thin film): n˜ =3339, 2986, 2935, 1372, 1214,
1071, 872 cmÀ1; MS (FAB): m/z (%): 233 (28) [M+H]+, 185 (100), 93
(85); HRMS (FAB): m/z calcd for C11H20O5 [M+H]+: 233.1384; found:
233.1386.
General procedure for the glycol-cleavage reaction: NaIO4 (3 equiv) was
dissolved in a minimum amount of hot water (ꢀ808C). Silica gel (230–
400 mesh, 10ꢂweight of diol) was added to this solution with vigorous
swirling and shaking. The mixture was suspended in CH2Cl2 and then a
solution of diol (1 equiv) in CH2Cl2 was added. After vigorous stirring at
room temperature for 1 h, the mixture was filtered. The filtrate was con-
centrated under reduced pressure to give the aldehyde product.
Triol 11a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 5:1 to
1:3), alkene 11 (200 mg, 0.734 mmol)
gave firstly starting material 11
(33.2 mg, 17%) and secondly triol 11a
General procedure for selective deprotection with aqueous acetic acid: A
solution of diol (1.0 mmol) in 80% aqueous AcOH (8 mL) was stirred at
room temperature. The solvent was removed under reduced pressure and
the residue was purified by using flash chromatography.
(136 mg, 95% based on recovering
1,2,3-Trideoxy-5,6:7,8-di-O-isopropylidene-d-manno-oct-1-enitol (10) and
1,2,3-trideoxy-5,6:7,8-di-O-isopropylidene-d-gluco-oct-1-enitol (11): Diol
9 (1.48 g, 5.63 mmol) was converted into an aldehyde by following the
glycol-cleavage procedure. A 1m solution of allylmagnesium bromide in
Et2O (16.9 mL, 16.9 mmol) was added dropwise to a stirred solution of
the aldehyde in Et2O (50 mL) at À788C under N2 over 30 min. After stir-
ring at À788C for a further 1 h and then at room temperature for 12 h,
the mixture was quenched with saturated NH4Cl solution and the aque-
ous phase was extracted with Et2O (2ꢂ50 mL). The combined organic
extracts were dried over anhydrous MgSO4 and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by
using flash chromatography (hexane/CH2Cl2/EtOAc 10:1:2) to afford
firstly alkene 10 (668 mg, 44% overall yield from 9) and secondly alkene
11 (408 mg, 27% overall yield from 9) as colorless oils.
starting material) as
a colorless oil.
Data for 11a: Rf =0.16 (hexane/
EtOAc 1:2); [a]2D0 =À8.06 (c=1.60 in
CHCl3); 1H NMR: d=1.39 (s, 3H),
1.42 (s, 3H), 2.30 (ddd, J=14.4, 8.7,
7.5 Hz, 1H), 2.47 (dt, J=14.1, 6.0 Hz, 1H), 2.57–2.64 (m, 2H), 3.36 (brs,
1H), 3.69–3.72 (m, 2H), 3.81–3.84 (m, 2H), 3.97 (t, J=6.6 Hz, 1H), 4.03
(dd, J=7.8, 2.4 Hz, 1H), 5.12–5.19 (m, 2H), 5.87 ppm (ddt, J=17.1, 10.2,
7.2 Hz, 1H); 13C NMR: d=27.4, 27.5, 38.9, 64.2, 69.8, 73.1, 81.7, 109.8,
118.5, 135.0 ppm; IR (thin film): n˜ =3387, 2986, 1373, 1215, 1068,
872 cmÀ1; MS (FAB): m/z (%): 233 (35) [M+H]+, 185 (85), 93 (100);
HRMS (FAB): m/z calcd for C11H20O5 [M+H]+: 233.1384; found:
233.138806.
Data for 10: Rf =0.35 (hexane/CHCl3/EtOAc 5:1:1); [a]2D0 =+6.20 (c=
1.75 in CHCl3); 1H NMR: d=1.36–1.38 (2s, 9H), 1.44 (s, 3H), 2.25 (dt,
J=15.3, 7.5 Hz, 1H), 2.53 (dd, J=14.4, 5.4 Hz, 1H), 3.44 (s, 1H), 3.68–
3.75 (m, 3H), 4.00 (dd, J=9.0, 5.1 Hz, 1H), 4.04–4.08 (m, 1H), 4.19 (dd,
J=8.1, 5.7 Hz, 1H), 5.10–5.21 (m, 2H), 5.94 ppm (dddd, J=16.8, 9.9, 7.5,
6.3 Hz, 1H); 1H NMR (CDCl3–D2O): d=1.36–1.38 (2s, 9H), 1.44 (s,
3H), 2.25 (dt, J=15.3, 7.5 Hz, 1H), 2.53 (dddd, J=15.6, 6.3, 3.0, 1.5 Hz,
1H), 3.66–3.74 (m, 3H), 4.00 (dd, J=7.8, 5.1 Hz, 1H), 4.05–4.10 (m, 1H),
4.19 (dd, J=7.8, 5.7 Hz, 1H), 5.10–5.20 (m, 2H), 5.94 ppm (dddd, J=
17.1, 10.2, 7.5, 6.6 Hz, 1H); 13C NMR: d=25.5, 26.8, 27.2, 27.3, 38.5, 68.3,
72.1, 76.8, 81.4, 83.2, 109.7, 110.6, 117.9, 135.1 ppm; IR (thin film): n˜ =
3473, 2987, 2936, 1372, 1215, 1070, 844, 512 cmÀ1; MS (CI): m/z (%): 273
(26) [M+H]+, 85 (56), 71 (89), 69 (100), 67 (70); HRMS (CI): m/z calcd
for C14H24O5 [M+H]+: 273.1697; found: 273.1695.
4-O-Benzyl-1,2,3-trideoxy-5,6:7,8-di-O-isopropylidene-d-manno-oct-1-
enitol (14): Sodium hydride (80%, 1.76 g, 43.2 mmol) was suspended in
dry THF (50 mL) under nitrogen at 08C. A solution of alkene 10 (2.31 g,
8.47 mmol) in THF (100 mL) was added dropwise over 1 h at 08C, and
then the mixture was stirred for 1 h at 08C. Benzyl bromide (2.56 mL,
21.6 mmol) was added dropwise over 20 min and tetra-n-butylammonium
iodide (319 mg, 0.863 mmol) was added. The reaction mixture was stirred
at room temperature for 12 h. Water was then added slowly at 08C to de-
stroy the excess of hydride, and this was followed by the addition of satu-
rated NH4Cl solution. The aqueous layer was extracted with Et2O (2ꢂ
50 mL). The combined organic extracts were washed with brine, dried
over MgSO4, and filtered. Concentration of the filtrate followed by pu-
rification using flash chromatography (hexane/Et2O 3:1) gave benzyl
ether 14 (3.07 g, 100%) as a colorless oil. Rf =0.53 (hexane/Et2O 3:1);
[a]2D0 =+11.7 (c=2.27 in CHCl3); 1H NMR: d=1.33–1.40 (4s, 12H), 2.44
(t, J=6.0 Hz, 2H), 3.65 (q, J=6.0 Hz, 1H), 3.92–4.00 (m, 2H), 4.03–4.17
Data for 11: Rf =0.26 (hexane/CHCl3/EtOAc 5:1:1); [a]2D0 =À2.77 (c=
1.44 in CHCl3); 1H NMR: d=1.34 (s, 3H), 1.38 (s, 3H), 1.41–1.42 (2s,
Chem. Eur. J. 2009, 15, 2693 – 2707
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2701

T. K. M. Shing, T. Yamada et al.
(m, 3H), 4.64 (2d, J=11.7, 11.7 Hz, 2H), 5.07 (dd, J=9.9, 1.5 Hz, 1H),
5.14 (dd, J=17.4, 1.8 Hz, 1H), 5.88 (ddt, J=17.1, 9.9, 6.9 Hz, 1H), 7.26–
7.37 ppm (m, 5H); 13C NMR: d=25.8, 26.9, 27.8, 35.1, 67.3, 72.6, 77.4,
79.1, 79.4, 81.1, 109.9, 110.2, 117.7, 128.0, 128.4, 128.7, 135.3, 138.7 ppm;
IR (thin film): n˜ =2986, 1371, 1213, 1069, 848, 698 cmÀ1; MS (EI): m/z
(%): 347 (32) [MÀOCH3]+, 143 (100), 91 (100); HRMS (EI): m/z calcd
for C21H30O5 [MÀOCH3]+: 347.1853; found: 347.1850.
Diol 14a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 10:1 to
3:1), benzyl ether 14 (1.02 g, 2.81 mmol) gave firstly starting material 14
(51.2 mg, 5%) and secondly diol 14a
J=17.1, 10.2, 7.2 Hz, 1H), 7.31–7.37 ppm (m, 5H); 13C NMR: d=27.3,
27.3, 35.1, 64.4, 73.0, 73.8, 77.0, 77.7, 80.8, 109.5, 118.0, 128.6, 129.0, 135.2,
137.5 ppm; IR (thin film): n˜ =3407, 2986, 1371, 1213, 1071, 871, 698 cmÀ1
;
MS (FAB): m/z (%): 323 (56) [M+H]+, 185 (27), 93 (32), 91 (100);
HRMS (FAB): m/z calcd for C18H26O5 [M+H]+: 323.1853; found:
323.1859.
1,2,3-Trideoxy-5,6:7,8-di-O-isopropylidene-4-O-silyl-d-manno-oct-1-enitol
(18): A solution of alkene 10 (105 mg, 0.387 mmol), imidazole (78.9 mg,
1.16 mmol), and TBSCl (117 mg, 0.773 mmol) in dry DMF (1 mL) was
stirred at room temperature for 15 h. The mixture was quenched with sa-
turated NaHCO3 solution and the aqueous phase was extracted with
Et2O (2ꢂ20 mL). The combined organic extracts were washed with
brine, dried over anhydrous MgSO4, and filtered. The filtrate was concen-
trated under reduced pressure and the residue was purified by using flash
chromatography (hexane/Et2O 1:5) to afford silyl ether 18 (150 mg,
100%) as a colorless oil. Rf =0.70 (hexane/Et2O 2:1); [a]2D0 =+4.81 (c=
1.53 in CHCl3); 1H NMR: d=0.08–0.09 (2s, 6H), 0.91 (s, 9H), 1.34–1.36
(2s, 6H), 1.39 (s, 3H), 1.41 (s, 3H), 2.35–2.39 (m, 2H), 3.86–4.00 (m,
4H), 4.06–4.17 (m, 2H), 5.05–5.13 (m, 2H), 5.85 ppm (ddt, J=17.1, 9.9,
7.2 Hz, 1H); 13C NMR: d=À4.3, À4.2, 18.2, 25.4, 26.0, 26.6, 27.2, 27.5,
37.7, 66.8, 72.5, 76.7, 77.1, 82.2, 109.5, 117.5, 134.8 ppm; IR (thin film):
n˜ =2987, 2933, 2858, 1371, 1256, 1066, 837, 776 cmÀ1; MS (FAB): m/z
(%): 387 (24) [M+H]+, 185 (50), 101 (64), 73 (100); HRMS (FAB): m/z
calcd for C20H38O5Si [M+H]+: 387.2561; found: 387.2573.
(821 mg, 95% based on recovering
starting material) as
a colorless oil.
Data for 14a: Rf =0.52 (hexane/
EtOAc 1:2); [a]2D0 =À49.6 (c=2.34 in
CHCl3); 1H NMR: d=1.35–1.36 (2s,
6H), 2.27 (brs, 1H), 2.49 (ddd, J=
15.0, 7.8, 4.2 Hz, 1H), 2.71 (ddd, J=
15.0, 6.0, 4.5 Hz, 1H), 3.54–3.62 (m,
3H), 3.70–3.74 (m, 2H), 3.82 (t, J=7.2 Hz, 1H), 3.92 (dd, J=8.4, 7.2 Hz,
1H), 4.47 (d, J=11.1 Hz, 1H), 4.76 (d, J=11.1 Hz, 1H), 5.15–5.29 (m,
2H), 5.93 ppm (dddd, J=16.8, 10.2, 7.8, 6.6 Hz, 1H); 1H NMR (CDCl3–
D2O): d=1.35–1.36 (2s, 6H), 2.49 (ddd, J=14.7, 7.8, 3.9 Hz, 1H), 2.71
(ddd, J=15.0, 6.3, 4.8 Hz, 1H), 3.55–3.66 (m, 3H), 3.71 (dd, J=11.1,
3.9 Hz, 1H), 3.82 (t, J=7.5 Hz, 1H), 3.92 (dd, J=8.4, 7.2 Hz, 1H), 4.47
(d, J=11.1 Hz, 1H), 4.76 (d, J=11.1 Hz, 1H), 5.15–5.25 (m, 2H),
5.93 ppm (dddd, J=17.1, 10.2, 7.8, 6.6 Hz, 1H); 13C NMR: d=27.1, 27.2,
34.8, 64.3, 72.0, 73.3, 79.8, 79.9, 80.9, 109.8, 118.8, 128.8, 128.9, 129.0,
133.3, 136.9 ppm; IR (thin film): n˜ =3408, 2986, 1381, 1213, 1076, 872,
699 cmÀ1; MS (FAB): m/z (%): 323 (67) [M+H]+, 265 (21), 185 (39), 91
(100); HRMS (FAB): m/z calcd for C18H26O5 [M+H]+: 323.1853; found:
323.1858.
Diol 18a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 10:1 to
3:1),
silyl
ether
18
(120 mg,
0.311 mmol) gave firstly starting mate-
rial 18 (40.1 mg, 33%) and secondly
diol 18a (48.7 mg, 68% based on re-
covering starting material) as a color-
less oil. Data for 18a: Rf =0.22
(hexane/Et2O 1:1); [a]2D0 =À25.3 (c=
4-O-Benzyl-1,2,3-trideoxy-5,6:7,8-di-O-isopropylidene-d-gluco-oct-1-
enitol (15): By following the same procedure for benzylation of alkene 10
to give benzyl ether 14, alkene 11 (763 mg, 2.80 mmol) was converted
into benzyl ether 15 (945 mg, 93%) as a colorless oil. Rf =0.37 (hexane/
Et2O 3:1); [a]2D0 =+12.0 (c=3.84 in CHCl3); 1H NMR: d=1.34 (s, 3H),
1.34 (s, 3H), 1.37 (s, 6H), 1.42 (s, 3H), 2.41–2.58 (m, 2H), 3.60 (td, J=
6.9, 2.4 Hz, 1H), 3.89 (dd, J=7.2, 4.2 Hz, 1H), 3.98–4.13 (m, 4H), 4.56
(d, J=11.7 Hz, 1H), 4.70 (d, J=11.7 Hz, 1H), 5.08 (ddd, J=10.2, 2.1,
0.9 Hz, 1H), 5.16 (ddd, J=17.1, 3.0, 1.2 Hz, 1H), 5.88 (ddt, J=17.1, 10.2,
7.2 Hz, 1H), 7.26–7.35 ppm (m, 5H); 13C NMR: d=25.6, 26.9, 27.3, 36.2,
67.9, 72.8, 77.6, 77.6, 77.9, 82.0, 109.7, 109.9, 117.8, 127.9, 128.0, 128.7,
135.2, 138.9 ppm; IR (thin film): n˜ =2987, 1371, 1214, 1070, 848, 698,
512 cmÀ1; MS (EI): m/z (%): 363 (38) [M+H]+, 362 (100) [M]+, 347 (50)
[MÀOCH3]+, 143 (100), 101 (55), 91 (99), 43 (64); HRMS (EI): m/z
calcd for C21H30O5 [M]+: 362.3088; found: 362.2085.
1.13 in CHCl3); 1H NMR: d=0.14–
0.15 (2s, 6H), 0.92 (s, 9H), 1.37–1.38
(2s, 6H), 2.23 (brs, 1H), 2.44–2.48 (m,
2H), 3.21 (d, J=3.6 Hz, 1H), 3.65–3.85 (m, 4H), 3.91–3.97 (m, 2H),
5.11–5.17 (m, 2H), 5.88 ppm (ddt, J=18.0, 9.6, 7.2 Hz, 1H); 13C NMR:
d=À3.9, À3.7, 18.5, 26.3, 27.3, 27.4, 38.7, 64.3, 73.5, 74.2, 80.0, 80.9, 110.0,
118.8, 133.3 ppm; IR (thin film): n˜ =3407, 2930, 1254, 1079, 836,
776 cmÀ1; MS (FAB): m/z (%): 347 (50) [M+H]+, 185 (82), 93 (64), 75
(67); HRMS (FAB): m/z calcd for C17H34O5Si [M+H]+: 347.2248; found:
347.2248.
1,2,3-Trideoxy-5,6:7,8-di-O-isopropylidene-4-O-silyl-d-gluco-oct-1-enitol
(19): By following the same procedure for silylation of alkene 10 to give
silyl ether 18, alkene 11 (730 mg, 2.68 mmol) was converted into silyl
ether 19 (708 mg, 100%) as a colorless oil. Rf =0.56 (hexane/Et2O 4:1);
1
[a]2D0 =+23.9 (c=3.46 in CHCl3); H NMR: d=0.08 (s, 6H), 0.90 (s, 9H),
Diol 15a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 10:1 to
3:1), benzyl ether 15 (187 mg,
1.34 (s, 3H), 1.41 (s, 6H), 2.30 (dddt, J=13.8, 7.2, 6.0, 1.2 Hz, 1H), 2.48
(ddt, J=13.8, 7.2, 1.2 Hz, 1H), 3.80 (ddd, J=7.5, 6.3, 3.0 Hz, 1H), 3.85–
3.92 (m, 2H), 3.99 (t, J=7.2 Hz, 1H), 4.04–4.14 (m, 2H), 5.04–5.15 (m,
2H), 2.83 ppm (ddt, J=17.1, 10.2, 7.2 Hz, 1H); 13C NMR: d=À3.9, À3.7,
18.6, 25.7, 26.3, 26.9, 27.4, 27.8, 39.3, 67.9, 72.0, 77.6, 77.6, 82.2, 109.8,
109.9, 117.8, 135.2 ppm; IR (thin film): n˜ =2933, 1371, 1254, 1073, 836,
776 cmÀ1; MS (EI): m/z (%): 371 (30) [MÀOCH3]+, 287 (62), 271 (83),
185 (83), 143 (83), 101 (96), 73 (100); HRMS (EI): m/z calcd for
C20H38O5Si2 [MÀOCH3]+: 371.2248; found: 371.2251.
Diol 19a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 10:1 to
3:1), silyl ether 19 (458 mg, 1.18 mmol) gave firstly starting material 19
(90.2 mg, 20%) and secondly diol 19a (206 mg, 63% based on recovering
0.512 mmol) gave firstly starting mate-
rial 15 (19.7 mg, 11%) and secondly
diol 15a (144 mg, 96% based on re-
covering starting material) as a color-
less oil. Data for 15a: Rf =0.59
(hexane/EtOAc 1:2); [a]2D0 =+3.17
(c=2.42 in CHCl3); 1H NMR: d=1.36
(s, 3H), 1.40 (s, 3H), 2.19 (t, J=
6.0 Hz, 1H), 2.40 (dt, J=14.4, 8.1 Hz,
1H), 2.54 (dddt, J=14.4, 6.6, 4.2, 1.5 Hz, 1H), 3.59–3.67 (m, 3H), 3.73–
3.82 (m, 2H), 3.92 (t, J=7.2 Hz, 1H), 4.00 (dd, J=8.1, 3.3 Hz, 1H), 4.59
(d, J=11.4 Hz, 1H), 4.73 (d, J=11.4 Hz, 1H), 5.10 (ddt, J=9.9, 1.8,
0.9 Hz, 1H), 5.18 (dq, J=17.1, 1.5 Hz, 1H), 5.87 (ddt, J=17.1, 9.9,
starting material) as
a colorless oil.
Data for 19a: Rf =0.27 (hexane/Et2O
1:2); [a]2D0 =À11.9 (c=1.50 in CHCl3);
1H NMR: d=0.11–0.13 (2s, 6H), 0.90
(s, 9H), 1.37 (s, 3H), 1.39 (s, 3H),
2.21–2.31 (brs, 1H; dt, J=14.1, 7.8 Hz,
1H), 2.52 (ddd, J=14.1, 6.3, 4.5 Hz,
1
7.2 Hz, 1H), 7.31–7.37 ppm (m, 5H); H NMR (CDCl3–D2O): d=1.36 (s,
3H), 1.40 (s, 3H), 2.40 (dt, J=14.4, 7.5 Hz, 1H), 2.54 (dddt, J=14.4, 6.6,
4.5, 1.5 Hz, 1H), 3.56–3.67 (m, 2H), 3.92 (t, J=7.5 Hz, 1H), 4.00 (dd, J=
8.1, 3.3 Hz, 1H), 4.59 (d, J=11.4 Hz, 1H), 4.73 (d, J=11.4 Hz, 1H), 5.10
(ddt, J=9.9, 1.8, 0.9 Hz, 1H), 5.18 (dq, J=17.1, 1.5 Hz, 1H), 5.87 (ddt,
2702
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2693 – 2707

Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
1H), 3.62 (dtd, J=8.4, 5.4, 1.5 Hz, 1H), 3.69–3.73 (m, 1H), 3.81–3.85
(brs, 1H; dd, J=8.4, 3.3 Hz, 1H), 3.93 (t, J=8.1 Hz, 1H), 3.99 (d, J=
1.5 Hz, 1H), 4.04 (dt, J=7.8, 3.9 Hz, 1H), 5.06–5.12 (m, 2H), 5.80 ppm
(dddd, J=17.1, 10.2, 7.8, 6.6 Hz, 1H); 1H NMR (CDCl3–D2O): d=0.11–
0.13 (2s, 6H), 0.90 (s, 9H), 1.37 (s, 3H), 1.39 (s, 3H), 2.26 (dt, J=14.4,
8.1 Hz, 1H), 2.52 (dddt, J=14.1, 5.7, 4.2, 1.5 Hz, 1H), 3.61 (dt, J=8.1,
3.9 Hz, 1H), 3.71 (dd, J=11.1, 4.5 Hz, 1H), 3.81–3.85 (dd, J=6.3, 3.9 Hz,
1H; dd, J=6.6, 3.0 Hz, 1H), 3.93 (t, J=8.1 Hz, 1H), 4.04 (dt, J=7.8,
3.9 Hz, 1H), 5.06–5.15 (m, 2H), 5.80 ppm (dddd, J=16.8, 10.2, 7.8,
6.6 Hz, 1H); 13C NMR: d=À4.1, À4.0, 18.5, 26.2, 27.3, 27.4, 37.5, 64.3,
71.9, 72.4, 76.9, 83.2, 109.2, 118.3, 135.3 ppm; IR (thin film): n˜ =3403,
2931, 1463, 1253, 1074, 836, 776 cmÀ1; MS (FAB): m/z (%): 347 (100)
[M+H]+, 185 (57), 75 (40), 73 (49); HRMS (FAB): m/z calcd for
C17H34O5Si [M+H]+: 347.2248; found: 347.2256.
Cycloheptane 23 from 27: A 1m solution of TBAF in THF (0.29 mL,
0.288 mmol) was added to
a solution of silyl ether 27 (66.0 mg,
0.192 mmol) in THF (6 mL). The reaction mixture was stirred at room
temperature for 5 d and the solvent was removed under reduced pres-
sure. Flash chromatography of the residue (CHCl3/MeOH 40:1) afforded
cycloheptane 23 (43.0 mg, 98%) as a white solid.
Isoxazolidines 24 and 25: By following the glycol-cleavage procedure,
diol 14a (1.04 g, 3.24 mmol) was converted into aldehyde 16 as a color-
less oil. By following the cyclization procedure of aldehyde 12 and purifi-
cation by using flash chromatography (hexane/EtOAc 1:1), aldehyde 16
gave firstly cycloheptane 25 (784 mg, 76% overall yield from 14a) as a
white solid and secondly cyclohexane 24 (193 mg, 19% overall yield from
14a) as a colorless oil.
Data for 25: Rf =0.33 (hexane/EtOAc 1:2); m.p. 53–548C; [a]2D0 =+7.06
(c=1.52 in CHCl3); 1H NMR: d=1.47 (s, 3H), 1.49 (s, 3H), 1.90 (ddd,
J=15.6, 3.3, 1.2 Hz, 1H), 2.00 (ddd, J=15.9, 5.7, 2.1 Hz, 1H), 2.34 (d, J=
12.6 Hz, 1H), 2.56 (ddd, J=12.6, 9.3, 7.5 Hz, 1H), 2.64 (s, 3H), 3.55 (dd,
J=7.5, 2.1 Hz, 1H), 4.06–4.12 (d, J=5.7 Hz, 1H; dd, J=9.0, 2.1 Hz, 1H),
4.32 (d, J=9.0 Hz, 1H), 4.56–4.62 (d, J=11.7 Hz, 1H; m, 1H), 4.79 (d,
J=11.7 Hz, 1H), 7.26–7.34 ppm (m, 5H); 1H NMR (CDCl3/C6D6 2:1):
d=1.37 (s, 3H), 1.42 (s, 3H), 1.65 (ddd, J=15.9, 3.6, 1.2 Hz, 1H), 1.80
(ddd, J=15.9, 6.0, 2.1 Hz, 1H), 2.11 (d, J=12.6 Hz, 1H), 2.26 (ddd, J=
12.6, 9.3, 7.2 Hz, 1H), 2.45 (s, 3H), 3.33 (dd, J=7.2, 2.1 Hz, 1H), 3.91 (d,
J=5.7 Hz, 1H), 3.97 (dd, J=6.0, 2.4 Hz, 1H), 4.28 (d, J=9.0 Hz, 1H),
4.33 (d, J=9.3 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 4.66 (d, J=12.0 Hz,
1H), 7.09–7.24 ppm (m, 6H); 13C NMR: d=27.3 (CH3), 27.4 (CH3), 31.1
(CH2), 38.2 (CH2), 47.4 (CH3), 64.1 (CH), 73.4 (CH2), 73.5 (CH), 75.6
(CH), 76.7 (CH), 78.3 (CH), 108.8 (C), 127.6 (CH), 127.8 (CH), 128.7
(CH), 139.3 ppm (C); MS (EI): m/z (%): 320 (6) [M+H]+, 319 (22)
[M]+, 154 (28), 91 (100), 84 (45); IR (thin film): n˜ =3983, 2922, 1368,
1236, 1236, 1075, 756 cmÀ1; HRMS (EI): m/z calcd for C18H25O4N [M]+:
319.1778; found: 319.1774; elemental analysis calcd (%) for C18H25O4N:
C 67.69, H 7.89, N 4.38; found: C 67.38, H 7.90, N 4.19.
Data for 24: Rf =0.26 (hexane/EtOAc 1:2); [a]2D0 =À16.3 (c=2.67 in
CHCl3); 1H NMR: d=1.45–1.46 (2s, 6H), 1.81 (ddd, J=15.3, 6.3, 4.5 Hz,
1H), 2.13 (d, J=15.6 Hz, 1H), 2.70 (s, 3H), 2.98–2.31 (m, 1H), 3.16 (t,
J=8.1 Hz, 1H), 3.51 (dd, J=10.2, 2.5 Hz, 1H), 3.85 (t, J=8.7 Hz, 1H),
4.12–4.22 (m, 3H), 4.57 (d, J=12.0 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H),
7.26–7.33 ppm (m, 5H); 13C NMR: d=27.1 (CH3), 27.6 (CH3), 29.1
(CH2), 38.4 (CH), 45.2 (CH3), 70.4 (CH), 71.1 (CH2), 73.2 (CH2), 73.3
(CH), 80.2 (CH), 110.6 (C), 127.4 (CH), 127.7 (CH), 128.7 (CH),
139.2 ppm (C); IR (thin film): n˜ =2984, 2929, 1369, 1227, 1101, 846, 736,
698 cmÀ1; MS (EI): m/z (%): 320 (30) [M+H]+, 319 (100) [M]+, 91 (100);
HRMS (EI): m/z calcd for C18H25O4N [M]+: 319.1778; found: 319.1775.
Isoxazolidines 22 and 23: By following the glycol-cleavage procedure,
triol 10a (66.5 mg, 0.286 mmol) was converted into aldehyde 12 as a col-
orless oil. N-Methylhydroxylamine hydrochloride (71.7 mg, 0.859 mmol)
and NaHCO3 (120 mg, 1.43 mmol) were added to a solution of aldehyde
12 in CH3CN (15 mL). The reaction mixture was stirred at room temper-
ature for 30 min until the disappearance of the starting material as shown
by using TLC analysis. The mixture was then heated under reflux for
24 h. After cooling, the mixture was partitioned between EtOAc (20 mL)
and water (20 mL). The aqueous layer was extracted with EtOAc (2ꢂ
20 mL). The combined organic extracts were washed with brine, dried
over anhydrous MgSO4, and filtered. Concentration of the filtrate fol-
lowed by using flash chromatography (CH3Cl/MeOH 40:1) gave firstly
cycloheptane 23 (53.5 mg, 81% overall yield from 10a) as a white solid
and secondly cyclohexane 22 (8.50 mg, 13% overall yield from 10a) as a
white solid.
Data for 23: Rf =0.26 (EtOAc); m.p. 113–1148C; [a]2D0 =+24.6 (c=1.61
in CHCl3); 1H NMR: d=1.42 (s, 3H), 1.48 (s, 3H), 1.80 (dd, J=16.2,
3.0 Hz, 1H), 2.05–2.15 (m, 2H), 2.21 (d, J=12.9 Hz, 1H), 2.56–2.65 (m,
4H), 3.54 (dd, J=7.2, 2.1 Hz, 1H), 3.92 (dd, J=8.7, 2.1 Hz, 1H), 4.24–
1
4.30 (m, 2H), 4.56 ppm (dt, J=9.3, 2.7 Hz, 1H); H NMR (CDCl3–D2O):
d=1.42 (s, 3H), 1.48 (s, 3H), 1.79 (dd, J=15.9, 3 Hz, 1H), 2.09 (ddd, J=
16.2, 6.9, 2.7 Hz, 1H), 2.22 (d, J=12.6 Hz, 1H), 2.56–2.65 (m, 4H), 3.54
(dd, J=7.2, 1.8 Hz, 1H), 3.93 (dd, J=9.0, 2.1 Hz, 1H), 4.25–2.29 (m,
2H), 4.56 ppm (dt, J=9.3, 2.7 Hz, 1H); 13C NMR: d=27.3 (CH3), 27.4
(CH3), 31.4 (CH2), 38.8 (CH2), 47.3 (CH3), 63.9 (CH), 65.7 (CH), 75.4
(CH), 76.3 (CH), 78.3 (CH), 108.6 ppm (C); IR (thin film): n˜ =3468,
2984, 2929, 1379, 1230, 1073, 856, 754 cmÀ1; MS (ESI): m/z (%): 230
(100) [M+H]+; HRMS (ESI): m/z calcd for C11H19O4N [M+H]+:
230.1387; found: 230.1386; elemental analysis calcd (%) for C11H19O4: C
57.63, H 8.35, N 6.11; found: C 57.51, H 8.40, N 6.08.
Data for 22: Rf =0.17 (EtOAc); m.p. 87–888C; [a]2D0 =À51.7 (c=1.42 in
CHCl3); 1H NMR: d=1.44–1.45 (2s, 6H), 1.89–2.05 (dt, J=15.0, 5.4 Hz,
1H; dt, J=15.3, 4.5 Hz, 1H), 2.36 (brs, 1H), 2.70 (s, 3H), 3.03–3.05 (m,
2H), 3.45 (dd, J=10.2, 3.3 Hz, 1H), 3.71 (m, 1H), 4.04 (t, J=9.0 Hz,
1H), 4.15 (t, J=8.4 Hz, 1H), 4.32 ppm (q, J=3.9 Hz, 1H); 1H NMR
(CDCl3–D2O): d=1.44–1.45 (2s, 6H), 1.87–2.05 (dt, J=15.6, 5.7 Hz, 1H;
dt, J=15.3, 4.8 Hz, 1H), 2.70 (s, 3H), 2.92–3.06 (m, 2H), 3.42 (dd, J=
10.2, 3.3 Hz, 1H), 3.71 (t, J=8.1 Hz, 1H), 4.04 (t, J=9.6 Hz, 1H), 4.15 (t,
J=8.4 Hz, 1H), 4.30 ppm (q, J=3.6 Hz, 1H); 1H NMR (CDCl3/C6D6
5:1): d=1.41–1.42 (2s, 6H), 1.78–1.83 (m, 1H), 1.93 (dt, J=15.3, 3.9 Hz,
1H), 2.30 (brs, 1H), 2.66 (s, 3H), 2.87–2.96 (m, 2H), 3.37 (dd, J=10.2,
3.0 Hz), 3.66 (brs, 1H), 3.99–4.12 (dd, J=9.6, 7.8 Hz, 1H; m, 1H),
4.25 ppm (q, J=3.3 Hz, 1H); 1H NMR (CDCl3/C6D6 (5:1)–D2O): d=
1.41–1.42 (2s, 6H), 1.80 (dt, J=15.0, 5.7 Hz, 1H), 1.93 (ddd, J=15.3, 4.8,
3.9 Hz, 1H), 2.66 (s, 3H), 2.85–2.97 (m, 2H), 3.36 (dd, J=10.2, 3.0 Hz,
1H), 3.66 (t, J=7.8 Hz, 1H), 3.99–4.10 (m, 2H), 4.23 ppm (q, J=3.6 Hz,
1H); 13C NMR: d=27.1 (CH3), 27.6 (CH3), 30.3 (CH2), 38.9 (CH), 45.0
(CH3), 65.3 (CH), 70.5 (CH), 71.6 (CH2), 73.2 (CH), 79.2 (CH),
111.3 ppm (C); MS (FAB): m/z (%): 230 (20) [M+H]+, 186 (87), 185
(74), 93 (100); IR (thin film): n˜ =3430, 2984, 2932, 1439, 1372, 1229, 1095,
1031, 845, 789 cmÀ1; HRMS (FAB): m/z calcd for C11H19O4N [M+H]+:
230.1387; found: 230.1390; elemental analysis calcd (%) for C11H19O4: C
57.63, H 8.35, N 6.11; found: C 57.55, H 8.39, N 6.06.
Cycloheptane 25 from 23: By following the same procedure for benzyla-
tion of alkene 10 to give benzyl ether 14, cycloheptane 23 (11.6 mg,
0.051 mmol) was converted into cycloheptane 25 (9.90 mg, 61%) as a
white solid.
Isoxazolidines 26 and 27: By following the glycol-cleavage procedure,
diol 18a (25.8 mg, 0.0745 mmol) was converted into aldehyde 20 as a col-
orless oil. By following the cyclization procedure of aldehyde 12 and pu-
rification by using flash chromatography (hexane/Et2O 2:3), aldehyde 20
gave firstly cycloheptane 27 (22.2 mg, 87% overall yield from 18a) and
secondly cyclohexane 26 (2.00 mg, 7% overall yield from 18a) as white
solids.
Data for 27: Rf =0.44 (hexane/EtOAc 1:1); m.p. 50–518C; [a]2D0 =À2.80
1
(c=3.84 in CHCl3); H NMR: d=0.05 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H),
1.39 (s, 3H), 1.46 (s, 3H), 1.62–1.69 (m, 3H), 2.00 (ddd, J=15.6, 5.7,
2.1 Hz, 1H), 2.36 (d, J=12.6 Hz, 1H), 2.54 (ddd, J=12.3, 9.0, 7.2 Hz,
1H), 2.63 (s, 3H), 3.53 (dd, J=7.2, 2.1 Hz, 1H), 3.97 (dd, J=9.0, 2.4 Hz,
1H), 4.18 (d, J=9.0 Hz, 1H), 4.24 (d, J=5.4 Hz, 1H), 4.56 ppm (d, J=
9.6 Hz, 1H); 1H NMR (CDCl3–D2O): d=0.05 (s, 3H), 0.08 (s, 3H), 0.89
(s, 9H), 1.39 (s, 3H), 1.46 (s, 3H), 1.65 (ddd, J=15.6, 3.6, 1.2 Hz, 1H),
2.00 (ddd, J=15.6, 5.4, 2.1 Hz, 1H), 2.37 (d, J=12.6 Hz, 1H), 2.54 (ddd,
J=12.6, 9.3, 7.5 Hz, 1H), 2.63 (s, 3H), 3.53 (dd, J=7.2, 2.1 Hz, 1H), 3.97
(dd, J=8.7, 2.1 Hz, 1H), 4.18 (d, J=9.0 Hz, 1H), 4.24 (d, J=5.1 Hz, 1H),
4.56 ppm (d, J=9.3 Hz, 1H); 13C NMR: d=À4.7, À4.2, 18.4, 26.2, 27.4,
27.4, 30.8, 41.1, 47.5, 64.1, 66.7, 75.6, 76.4, 77.9, 108.7 ppm; IR (thin film):
Chem. Eur. J. 2009, 15, 2693 – 2707
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2703

T. K. M. Shing, T. Yamada et al.
n˜ =2955, 2930, 2857, 1238, 1118, 1077, 990, 837, 776 cmÀ1; MS (FAB): m/z
(%): 344 (24) [M+H]+, 343 (35) [M]+, 99 (69), 75 (56), 73 (100); HRMS
(FAB): m/z calcd for C17H33O4NSi [M+H]+: 344.2252; found: 344.2252.
gave firstly cyclohexane 30 (44.2 mg, 44% overall yield from 15a) as a
colorless oil and secondly cycloheptane 31 (49.4 mg, 49% overall yield
from 15a) as a white solid.
Data for 26: Rf =0.30 (hexane/EtOAc 1:1); m.p. 69–708C; [a]2D0 =À50.6
(c=1.61 in CHCl3); 1H NMR (CDCl3/C6D6 1:5): d=0.05 (s, 3H), 0.09 (s,
3H), 0.89 (s, 9H), 1.41–1.43 (2s, 6H), 1.57 (ddd, J=15.3, 6.9, 3.9 Hz,
1H), 1.82 (d, J=14.7 Hz, 1H), 2.61 (s, 3H), 2.79–2.86 (m, 1H), 3.00 (brs,
1H), 3.21 (dd, J=9.9, 2.1 Hz, 1H), 3.85 (dd, J=9.3, 6.9 Hz, 1H), 4.01
(dd, J=9.3, 7.2 Hz, 1H), 4.10 (brs, 1H), 4.21 ppm (q, J=2.7 Hz, 1H);
13C NMR: d=À4.8, À4.2, 18.5, 26.1, 27.2, 27.7, 31.3, 38.4, 45.4, 67.3, 70.4,
71.0, 72.5, 79.8, 110.3 ppm; IR (thin film): n˜ =2930, 2857, 1229, 1102,
1052, 838, 777 cmÀ1; MS (FAB): m/z (%): 344 (42) [M+H]+, 185 (66), 93
(90), 73 (100), 57 (52); HRMS (FAB): m/z calcd for C17H33O4NSi
[M+H]+: 344.2252; found: 344.2256.
Data for 30: Rf =0.48 (hexane/EtOAc 1:1); [a]2D0 =À54.0 (c=2.48 in
CHCl3); 1H NMR: d=1.43 (s, 3H), 1.45 (s, 3H), 1.75 (ddd, J=15.0, 5.4,
3.9 Hz, 1H), 2.01 (ddd, J=14.7, 9.9, 6.3 Hz, 1H), 2.75 (s, 3H), 2.84 (t, J=
9.6 Hz, 1H), 3.03–3.16 (m, 1H), 3.38 (t, J=7.5 Hz, 1H), 3.54–3.69 (dd,
J=10.2, 8.4 Hz, 1H; dd, J=10.5, 7.2 Hz, 1H), 3.87 (td, J=6.6, 3.6 Hz,
1H), 4.15 (t, J=8.4 Hz, 1H), 4.58 (d, J=11.7 Hz, 1H), 4.74 (d, J=
12.0 Hz, 1H), 7.26–7.36 ppm (m, 5H); 13C NMR: d=27.5 (CH3), 27.6
(CH3), 31.3 (CH2), 39.9 (CH), 44.7 (CH3), 70.3 (CH), 71.3 (CH2), 71.5
(CH2), 75.9 (CH), 77.3 (CH), 82.5 (CH), 111.9 (C), 128.0 (CH), 128.1
(CH), 128.7 (CH), 138.6 ppm (C); IR (thin film): n˜ =2870, 1371, 1232,
1096, 842, 737, 698 cmÀ1; MS (EI): m/z (%): 319 (15) [M]+, 97 (33), 91
(100), 71 (55), 57 (72); HRMS (EI): m/z calcd for C18H25O4N [M]+:
319.1778; found: 319.1777; elemental analysis calcd (%) for C18H25O4N:
C 67.69, H 7.89, N 4.38; found: C 67.14, H 7.86, N 4.03.
Data for 31: Rf =0.26 (hexane/EtOAc 1:1); m.p. 79–808C; [a]2D0 =+12.1
(c=3.41 in CHCl3); 1H NMR: d=1.46 (s, 3H), 1.51 (s, 3H), 1.63 (d, J=
12.9 Hz, 1H), 1.88 (ddd, J=15, 8.7, 2.4 Hz, 1H), 2.02 (ddd, J=15.0, 7.2,
3.6 Hz, 1H), 2.53–2.61 (m, 1H), 2.63 (s, 3H), 3.32 (dd, J=8.4, 1.8 Hz,
1H), 3.48 (dd, J=7.2, 1.5 Hz, 1H), 3.55 (q, J=8.4 Hz, 1H), 4.33 (dd, J=
9.9, 8.7 Hz, 1H), 4.54 (dt, J=9.3, 2.7 Hz, 1H), 4.66 (d, J=12.6 Hz, 1H),
4.81 (d, J=12.6 Hz, 1H), 7.26–7.38 ppm (m, 5H); 13C NMR: d=27.1
(CH3), 27.6 (CH3), 31.9 (CH2), 39.1 (CH2), 47.2 (CH3), 63.3 (CH), 72.0
(CH2), 74.5 (CH), 74.5 (CH), 78.7 (CH), 82.0 (CH), 109.4 (C), 127.8
(CH), 128.0 (CH), 128.6 (CH), 139.3 ppm (C); IR (thin film): n˜ =2928,
1368, 1235, 1073, 737, 698 cmÀ1; MS (EI): m/z (%): 320 (5) [M+H]+, 319
(13) [M]+, 304 (100) [MÀOCH3]+, 153 (46), 91 (100); HRMS (EI): m/z
calcd for C18H25O4N [MÀOCH3]+: 304.1543; found: 304.1546.
Isoxazolidines 28 and 29: By following the glycol-cleavage procedure,
triol 11a (108 mg, 0.463 mmol) was converted into aldehyde 13 as a color-
less oil. By following the cyclization procedure of aldehyde 12 and purifi-
cation by using flash chromatography (CH3Cl/MeOH 40:1), aldehyde 13
gave firstly cyclohexane 28 (32.9 mg, 31% overall yield from 11a) and
secondly cycloheptane 29 (66.8 mg, 63% overall yield from 11a) as white
solids.
Data for 28: Rf =0.26 (EtOAc); m.p. 107–1088C; [a]2D0 =À32.8 (c=2.78
in CHCl3); 1H NMR: d=1.43–1.44 (2s, 6H), 1.61–1.70 (m, 4H), 2.14 (dt,
J=14.7, 6.0 Hz, 1H), 2.35 (brs, 1H), 2.72 (s, 3H), 3.04 (m, 1H), 3.17
(dtd, J=15.3, 7.8, 6.0 Hz, 1H), 3.39–3.55 (t, 2m, J=8.1 Hz, 3H), 4.05 (q,
J=6.6 Hz, 1H), 4.19 ppm (t, J=8.7 Hz, 1H); 1H NMR (CDCl3–D2O):
d=1.43–1.44 (2s, 6H), 1.65 (ddd, J=14.7, 6.6, 6.3 Hz, 1H), 2.14 (dt, J=
14.4, 6.0 Hz, 1H), 2.72 (s, 3H), 3.05 (t, J=7.2 Hz, 1H), 3.17 (dtd, J=15.6,
7.8, 6.0 Hz, 1H), 3.39–3.54 (t, J=8.1 Hz, 3H), 4.05 (q, J=6.6 Hz, 1H),
4.20 ppm (t, 2m, J=8.4 Hz, 1H); 1H NMR (CDCl3/C6D6 4:1): d=1.41–
1.53 (s, dt, J=14.1, 6.3 Hz, 7H), 1.97–2.04 (m, 2H), 2.66 (s, 3H), 2.89–
2.92 (m, 2H), 3.35–3.40 (m, 2H), 3.52 (t, J=9.6 Hz, 1H), 3.89 (brs, 1H),
4.05 ppm (t, J=8.4 Hz, 1H); 1H NMR (CDCl3/C6D6 (4:1)–D2O): d=
1.41–1.53 (2s, dt, J=14.4, 6.3 Hz, 7H), 1.97 (dt, J=15.0, 6.0 Hz, 1H),
2.65 (s, 3H), 2.92–2.99 (m, 2H), 3.29 (t, J=7.8 Hz, 1H), 3.37–3.40 (brs,
1H), 3.45 (t, J=8.7 Hz, 1H), 3.89 (q, J=6.6 Hz, 1H), 4.04 ppm (t, J=
8.1 Hz, 1H); 13C NMR: d=27.4 (CH3), 32.8 (CH2), 39.3 (CH), 44.9
(CH3), 68.8 (CH), 69.8 (CH), 70.7 (CH2), 82.6 (CH), 111.8 ppm (C); IR
(thin film): n˜ =3370, 2931, 1455, 1231, 1078, 1018, 843, 754, 509 cmÀ1; MS
(FAB): m/z (%): 230 (24) [M+H]+, 185 (100), 93 (76); HRMS (FAB):
m/z calcd for C11H19O4N [M+H]+: 230.1387; found: 230.1387; elemental
analysis calcd (%) for C11H19O4N: C 57.63, H 8.35, N 6.11; found: C
57.35, H 8.36, N 6.08.
Data for 29: Rf =0.22 (EtOAc); m.p. 137–1388C; [a]2D0 =+62.1 (c=3.73
in CHCl3); 1H NMR: d=1.42 (s, 3H), 1.48 (s, 3H), 1.71 (d, J=13.2 Hz,
1H), 1.80 (ddd, J=15.0, 8.4, 2.4 Hz, 1H), 2.13 (ddd, J=15.0, 7.2, 3.6 Hz,
1H), 2.27 (brs, 1H), 2.59–2.69 (m, 4H), 3.35 (dd, J=8.7, 2.1 Hz, 1H),
3.51 (dd, J=7.2, 1.8 Hz, 1H), 3.82 (q, J=8.4 Hz, 1H), 4.17 (dd, J=10.2,
9.0 Hz, 1H), 4.59 ppm (dt, J=9.6, 2.7 Hz, 1H); 13C NMR: d=27.1 (CH3),
27.5 (CH3), 32.1 (CH2), 39.9 (CH2), 47.2 (CH3), 63.3 (CH), 68.2 (CH),
74.6 (CH), 78.8 (CH), 81.4 (CH), 109.8 ppm (C); IR (thin film): n˜ =3455,
2980, 2940, 1370, 1232, 1076, 946, 808, 773, 576 cmÀ1; MS (FAB): m/z
(%): 230 (41) [M+H]+, 186 (64), 185 (100), 93 (75); HRMS (FAB): m/z
calcd for C11H19O4N [M+H]+: 230.1387; found: 230.1390; elemental anal-
ysis calcd (%) for C11H19O4N: C 57.63, H 8.35, N 6.11; found: C 57.26, H
8.35, N 6.01.
Cycloheptane 31 from 29: By following the same procedure for benzyla-
tion of alkene 10 to give benzyl ether 14, cycloheptane 29 (13.4 mg,
0.058 mmol) was converted into cycloheptane 31 (13.3 mg, 71%) as a
white solid.
Isoxazolidines 32 and 33: By following the glycol-cleavage procedure,
diol 19a (76.1 mg, 0.220 mmol) was converted into aldehyde 21 as a col-
orless oil. By following the cyclization procedure of aldehyde 12 and pu-
rification by using flash chromatography (hexane/Et2O 3:2), aldehyde 21
gave firstly cyclohexane 32 (30.9 mg, 41% overall yield from 19a) as a
colorless oil and secondly cycloheptane 33 (33.9 mg, 45% overall yield
from 19a) as a white solid.
Data for 32: Rf =0.38 (hexane/Et2O 1:1); [a]2D0 =À20.8 (c=2.21 in
CHCl3); 1H NMR: d=0.08–0.09 (2s, 6H), 0.88 (s, 9H), 1.38–1.39 (2s,
6H), 1.58 (dt, J=14.7, 5.4 Hz, 1H), 1.99 (ddd, J=14.1, 7.8, 6.0 Hz, 1H),
2.72 (s, 3H), 2.87–2.94 (m, 1H), 3.09 (dtd, J=15.9, 7.8, 6.0 Hz, 1H), 3.35–
3.50 (t, 2m, J=7.8 Hz, 3H), 3.98 (q, J=6.0 Hz, 1H), 4.16 ppm (t, J=
8.7 Hz, 1H); 13C NMR: d=À4.5 (CH3), À4.1 (CH3), 18.7 (C), 26.3 (CH3),
27.5 (CH3), 27.6 (CH3), 34.7 (CH2), 39.6 (CH), 44.9 (CH3), 69.9 (CH),
70.4 (CH), 71.3 (CH2), 77.0 (CH), 83.2 (CH), 111.4 ppm (C); IR (thin
film): n˜ =2933, 2858, 1462, 1233, 1099, 1061, 831, 778 cmÀ1; MS (EI): m/z
(%): 344 (15) [M+H]+, 343 (71) [M]+, 228 (100), 198 (90), 98 (100), 75
(92); HRMS (EI): m/z calcd for C17H33O4NSi [M]+: 343.2173; found:
343.2178.
Data for 33: Rf =0.21 (hexane/Et2O 1:1); m.p. 90–918C; [a]2D0 =+54.9
(c=2.20 in CHCl3); 1H NMR: d=0.05–0.06 (2s, 6H), 0.86 (s, 9H), 1.38
(s, 3H), 1.44 (s, 3H), 1.68 (d, J=12.9 Hz, 1H), 1.82 (ddd, J=15.0, 7.2,
3.6 Hz, 1H), 2.54–2.64 (m, 4H), 3.28 (dd, J=8.7, 2.1 Hz, 1H), 3.47 (dd,
J=7.2, 1.5 Hz, 1H), 3.76 (dt, J=9.9, 8.1 Hz, 1H), 4.12 (dd, J=9.6,
8.7 Hz, 1H), 4.52 ppm (dt, J=9.3, 2.7 Hz, 1H); 13C NMR: d=À4.6, À3.9,
18.8, 26.2, 27.1, 27.6, 32.0, 42.3, 47.3, 63.4, 69.4, 74.8, 78.7, 81.8,
109.0 ppm; IR (thin film): n˜ =2928, 2856, 1368, 1245, 1105, 1076, 837,
780 cmÀ1; MS (EI): m/z (%): 343 (8) [M]+, 228 (70), 84 (100), 75 (67);
HRMS (EI): m/z calcd for C17H33O4NSi [M]+: 343.2173; found: 343.2166.
Cyclohexane 28 from 32: By following the desilylation procedure of cy-
cloheptane 27 to give cycloheptane 23, silyl ether 32 (69.1 mg,
0.201 mmol) was converted into cyclohexane 28 (43.7 mg, 95%) as a
white solid.
Cycloheptane 29 from 33: By following the desilylation procedure of cy-
cloheptane 27 to give cycloheptane 23, silyl ether 33 (38.3 mg,
0.112 mmol) was converted into cycloheptane 29 (24.1 mg, 94%) as a
white solid.
6-O-Acetyl-1,2,3-trideoxy-4,5:7,8-di-O-isopropylidene-d-altro-oct-1-enitol
(35): Acetic anhydride (4.21 mL, 44.6 mmol), triethylamine (8.48 mL,
60.8 mmol), and 4-dimethylaminopyridine (DMAP; 248 mg, 4.46 mmol)
were added to a stirred solution of alkene 34 (11.0 g, 40.6 mmol) in
CH2Cl2 (150 mL) at room temperature. The reaction mixture was stirred
Isoxazolidines 164 and 165: By following the glycol-cleavage procedure,
diol 15a (103 mg, 0.319 mmol) was converted into aldehyde 17 as a color-
less oil. By following the cyclization procedure of aldehyde 12 and purifi-
cation by using flash chromatography (hexane/EtOAc 2:1) aldehyde 17
2704
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2693 – 2707

Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
for 12 h and quenched with saturated NaHCO3 solution. The aqueous
phase was extracted with Et2O (2ꢂ100 mL). The combined organic ex-
tracts were washed with brine, dried over anhydrous MgSO4, and filtered.
The filtrate was concentrated under reduced pressure and the residue
was purified by using flash chromatography (hexane/Et2O 7:2) to afford
acetate 35 (12.5 g, 98%) as a colorless oil. Rf =0.39 (hexane/Et2O 2:1);
1.386–1.394 (2s, 6H), 2.30 (dt, J=15.0, 7.2 Hz, 1H), 2.54 (dddd, J=14.7,
6.6, 3.0, 1.5 Hz, 1H), 3.67–3.85 (m, 5H), 4.04 (td, J=7.8, 3.3 Hz, 1H),
5.10–5.16 (m, 2H), 5.89 ppm (ddt, J=16.8, 10.2, 6.6 Hz, 1H); 13C NMR:
d=À3.9, À3.8, 18.5, 26.3, 27.5, 27.7, 38.8, 63.0, 73.8, 75.9, 78.9, 79.3, 109.6,
117.8, 134.6 ppm; IR (thin film): n˜ =2429, 2932, 2858, 1371, 1255, 1063,
837, 778 cmÀ1 MS (FAB): m/z (%): 347 (32) [M+H]+, 289 (100)
;
1
[a]2D0 =+38.1 (c=1.90 in CHCl3); H NMR: d=1.35 (s, 3H), 1.38 (s, 9H),
[MÀC4H9]+, 189 (54), 93 (64), 73 (80); HRMS (FAB): m/z calcd for
C17H34O5Si [M+H]+: 347.2248; found: 347.2247.
2.11 (s, 3H), 2.33 (dt, J=14.1, 6.9 Hz, 1H), 2.45 (dt, J=14.4, 5.4 Hz, 1H),
3.80 (dd, J=8.1, 4.5 Hz, 1H), 3.93 (dd, J=8.1, 6.9 Hz, 1H), 4.04–4.10 (m,
2H), 4.34 (td, J=6.9, 4.8 Hz, 1H), 5.11–5.18 (m, 2H), 5.21 (t, J=4.8 Hz,
1H), 5.86 ppm (ddt, J=17.1, 10.5, 7.2 Hz, 1H); 13C NMR: d=21.3, 25.7,
26.7, 27.2, 27.6, 37.9, 66.1, 72.4, 74.5, 77.7, 79.7, 109.6, 109.8, 118.3, 133.9,
1,2,3-Trideoxy-4,5:7,8-di-O-isopropylidene-6-O-tert-butyldimethylsilyl-d-
gluco-oct-1-enitol (40): By following the same procedure for silylation of
alkene 10 to give silyl ether 18, alkene 39 (424 mg, 1.56 mmol) was con-
verted into silyl ether 40 (568 mg, 95%) as a colorless oil. Rf =0.67
(hexane/Et2O 2:1); [a]2D0 =+0.619 (c=1.72 in CHCl3); 1H NMR: d=0.09
(s, 3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.33 (s, 3H), 1.37 (s, 6H), 1.41 (s, 3H),
2.31 (dt, J=14.4, 7.2 Hz, 1H), 2.40–2.48 (m, 1H), 3.68 (dd, J=8.1, 3.6 Hz,
1H), 3.85 (t, J=3.6 Hz, 1H), 3.90 (t, J=7.8 Hz, 1H), 4.02 (dd, J=8.1,
6.3 Hz, 1H; td, J=7.8, 4.2 Hz, 1H), 4.12 (ddd, J=7.2, 6.3, 4.5 Hz, 1H),
5.09–5.16 (m, 2H), 5.87 ppm (ddt, J=17.1, 10.2, 6.9 Hz, 1H); 13C NMR:
d=À3.7, À3.5, 18.7, 25.5, 26.4, 26.9, 27.3, 27.7, 37.9, 66.4, 72.3, 76.1, 77.4,
82.6, 108.8, 117.9, 134.5 ppm; IR (thin film): n˜ =2986, 2933, 2859, 1370,
1254, 1077, 837, 777 cmÀ1; MS (ESI): m/z (%): 409 (100) [M+Na]+;
HRMS (ESI): m/z calcd for C20H38O5Si [M+Na]+: 409.2381; found:
409.2383.
170.3 ppm; IR (thin film): n˜ =2987, 1751, 1371, 1227, 1060, 847, 512 cmÀ1
;
MS (EI): m/z (%): 299 (41) [MÀOCH3]+, 215 (42), 101 (42); HRMS
(EI): m/z calcd for C16H26O6 [MÀOCH3]+: 299.1489; found: 299.1482.
Diol 35a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/EtOAc 5:1 to
1:2), acetate 35 (341 mg, 1.08 mmol)
gave firstly starting material 35
(59.4 mg, 17%) and secondly diol 35a
(200 mg, 82% based on recovering
starting material) as
a colorless oil.
Data for 35a: Rf =0.19 (hexane/
EtOAc 1:1); [a]2D0 =+30.1 (c=0.82 in
Diol 40a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/Et2O 10:1 to
CHCl3); 1H NMR: d=1.40–1.42 (2s,
6H), 2.12 (s, 3H), 2.31 (dt, J=14.4,
1:2),
silyl
ether
40
(259 mg,
7.2 Hz, 1H), 2.45 (dt, J=14.7, 5.1 Hz, 1H), 2.56 (s, 1H), 3.05 (d, J=
5.1 Hz, 1H), 3.61–3.75 (m, 2H), 3.87 (dt, J=9.6, 5.4 Hz, 1H), 3.99 (t, J=
6.9 Hz, 1H), 4.09 (td, J=7.2, 3.6 Hz, 1H), 4.97 (t, J=6.3 Hz, 1H), 5.11–
5.16 (m, 2H), 5.86 ppm (ddt, J=17.4, 10.7, 6.9 Hz, 1H); 1H NMR
(CDCl3–D2O): d=1.40–1.42 (2s, 6H), 2.12 (s, 3H), 2.31 (dt, J=14.4,
7.2 Hz, 1H), 2.45 (dt, J=14.7, 5.1 Hz, 1H), 3.62 (dd, J=12.0, 4.2 Hz,
1H), 3.70 (dd, J=12.0, 3.6 Hz, 1H), 3.86 (dt, J=6.0, 4.2 Hz, 1H), 3.99 (t,
J=6.9 Hz, 1H), 4.09 (td, J=7.2, 3.6 Hz, 1H), 4.97 (t, J=6.3 Hz, 1H),
5.10–5.16 (m, 2H), 5.86 ppm (ddt, J=17.4, 10.5, 6.9 Hz, 1H); 13C NMR:
d=21.3, 27.2, 27.6, 38.2, 62.7, 71.8, 74.2, 78.6, 78.8, 110.1, 118.2, 134.0,
171.0 ppm; IR (thin film): n˜ =3436, 2984, 2934, 1738, 1372, 1234,
1046 cmÀ1; MS (FAB): m/z (%): 275 (74) [M+H]+, 217 (100), 185 (47),
92 (47); HRMS (FAB): m/z calcd for C13H22O6 [M+H]+: 275.1489;
found: 275.1493.
0.670 mmol) gave firstly starting mate-
rial 40 (60.2 mg, 23%) and secondly
diol 40a (145 mg, 82% based on re-
covering starting material) as a color-
less oil. Data for 40a: Rf =0.25
(hexane/Et2O 1:1); [a]2D0 =À10.6 (c=
0.84 in CHCl3); 1H NMR: d=0.10 (s,
3H), 0.14 (s, 3H), 0.92 (s, 9H), 1.40–
1.42 (2s, 6H), 2.30 (dt, J=15.6, 7.5 Hz, 1H; brs, 1H), 2.42 (m, 1H), 3.19
(d, J=4.8 Hz, 1H), 3.69–3.74 (m, 2H), 3.77–3.82 (m, 2H), 3.87 (dd, J=
4.8, 3.0 Hz, 1H), 4.15 (td, J=7.8, 4.2 Hz, 1H), 5.10–5.17 (m, 2H),
5.87 ppm (ddt, J=17.1, 10.5, 6.9 Hz, 1H); 1H NMR (CDCl3–D2O): d=
0.10 (s, 3H), 0.14 (s, 3H), 0.92 (s, 9H), 1.39–1.42 (2s, 6H), 2.30 (dt, J=
14.4, 7.2 Hz, 1H), 2.42 (m, 1H), 3.65–3.74 (m, 2H), 3.75–3.82 (m, 2H),
3.87 (dd, J=5.1, 3.3 Hz, 1H), 4.15 (td, J=8.1, 4.2 Hz, 1H), 5.10–5.17 (m,
2H), 5.87 ppm (ddt, J=17.1, 10.2, 6.9 Hz, 1H); 13C NMR: d=À4.2, À3.9,
18.6, 26.3, 27.2, 27.6, 37.8, 63.8, 71.3, 74.1, 76.3, 81.9, 109.2, 118.61,
134.2 ppm; IR (thin film): n˜ =3423, 2931, 2858, 1379, 1253, 1090, 835,
776 cmÀ1; MS (ESI): m/z (%): 369 (100) [M+Na]+; HRMS (ESI): m/z
calcd for C17H34O5Si [M+Na]+: 369.2068; found: 369.2069.
1,2,3-Trideoxy-4,5:7,8-di-O-isopropylidene-6-O-tert-butyldimethylsilyl-d-
altro-oct-1-enitol (37): By following the same procedure for silylation of
alkene 10 to give silyl ether 18, alkene 34 (251 mg, 0.922 mmol) was con-
verted into silyl ether 37 (324 mg, 98%) as a colorless oil. Rf =0.50
(hexane/Et2O 3:1); [a]2D0 =+34.1 (c=1.16 in CHCl3); 1H NMR: d=0.10–
0.11 (2s, 6H), 0.90 (s, 9H), 1.34 (s, 3H), 1.38–1.42 (3s, 9H), 2.32 (dt, J=
14.7, 7.2 Hz, 1H), 2.45 (dddd, J=14.4, 5.4, 3.9, 1.2 Hz, 1H), 3.73 (dd, J=
8.1, 3.9 Hz, 1H), 3.90 (t, J=7.8 Hz, 1H), 3.95 (t, J=4.2 Hz, 1H), 3.99–
4.16 (dd, J=7.8, 6.6 Hz, 1H; td, J=7.8, 4.2 Hz, 1H), 4.17 (ddd, J=7.5,
6.3, 4.8 Hz, 1H), 5.10–5.17 (m, 2H), 5.88 ppm (ddt, J=17.1, 10.2, 6.66 Hz,
1H); 13C NMR: d=À3.8, À3.5, 18.5, 25.7, 26.4, 26.9, 27.5, 38.6, 66.4, 72.7,
76.3, 77.2, 82.1, 109.1, 109.1, 117.8, 134.6 ppm; IR (thin film): n˜ =2986,
2933, 2859, 1371, 1254, 1077, 837, 778 cmÀ1; MS (EI): m/z (%): 371 (27)
[MÀOCH3]+, 271 (55), 213 (100), 141 (50), 101 (97), 73 (50); HRMS
(EI): m/z calcd for C20H38O5Si [MÀOCH3]+: 371.2248; found: 371.2240.
Diol 37a: By following the aqueous acetic acid deprotection procedure
and purification by using flash chromatography (hexane/Et2O 10:1 to
1:2), silyl ether 37 (324 mg, 0.839 mmol) gave firstly starting material 37
(79.4 mg, 25%) and secondly diol 37a (151 mg, 69% based on recovering
starting material) as a colorless oil. Data for 37a: Rf =0.24 (hexane/Et2O
1:1); [a]2D0 =+13.6 (c=0.91 in CHCl3); 1H NMR: d=0.12–0.15 (2s, 6H),
0.91 (s, 9H), 1.39–1.40 (2s, 6H), 2.25–
Cycloheptane 46: By following the glycol-cleavage procedure, diol 35a
(64.5 mg, 0.235 mmol) was converted into aldehyde 36 as a colorless oil.
By following the cyclization procedure of aldehyde 12 and purification
by using flash chromatography (CHCl3/MeOH 40:1), aldehyde 36 was
converted into cycloheptane 46 (47.9 mg, 89% overall yield from 35a) as
a white solid. Rf =0.23 (EtOAc); m.p. 97–988C; [a]2D0 =À163.0 (c=2.21 in
CHCl3); 1H NMR: d=1.40 (s, 6H), 1.65 (dd, J=14.1, 9.9 Hz, 1H), 2.13
(ddd, J=14.1, 6.3, 4.2 Hz, 1H), 2.26 (d, J=13.5 Hz, 1H), 2.37–2.49 (m,
2H), 2.65 (s, 3H), 3.47 (t, J=5.7 Hz, 1H), 4.01 (dd, J=9.3, 2.7 Hz, 1H),
4.08–4.20 (m, 2H), 4.65 ppm (dd, J=9.3, 1.5 Hz, 1H); 1H NMR (CDCl3–
D2O): d=1.398–1.401 (2s, 6H), 1.65 (ddd, J=14.1, 9.9, 1.2 Hz, 1H), 2.13
(ddd, J=13.8, 6.3, 3.9 Hz, 1H), 2.26 (d, J=13.5 Hz, 1H), 2.42 (ddd, J=
13.5, 9.3, 6.9 Hz, 1H), 2.65 (s, 3H), 3.47 (dd, J=6.9, 5.1 Hz, 1H), 4.01
(dd, J=9.3, 2.7 Hz, 1H), 4.08–4.20 (m, 2H), 4.65 ppm (dd, J=9.3, 1.5 Hz,
1H); 13C NMR: d=27.2 (CH3), 27.6 (CH3), 28.2 (CH2), 34.7 (CH2), 46.9
(CH3), 67.6 (CH), 68.1 (CH), 70.9 (CH), 74.7 (CH), 79.2 (CH),
108.6 ppm (C); IR (thin film): n˜ =3467, 2985, 2930, 1370, 1240, 1071,
1013, 824, 799 cmÀ1; MS (FAB): m/z (%): 230 (7) [M+H]+, 185 (100), 93
(74); HRMS (FAB): m/z calcd for C11H19O4 [M+H]+: 230.1387; found:
230.1384; elemental analysis calcd (%) for C11H19O4: C 57.63, H 8.35, N
6.11; found: C 57.64, H 8.39, N 6.10.
2.35 (m, 3H), 2.54 (dddd, J=14.7, 6.3,
3.0, 1.5 Hz, 1H), 3.73–3.89 (m, 5H),
4.04 (td, J=8.1, 3.3 Hz, 1H), 5.10–5.16
(m, 2H), 5.88 ppm (ddt, J=17.1, 10.5,
6.9 Hz, 1H); 1H NMR (CDCl3–D2O):
d=0.12–0.15 (2s, 6H), 0.91 (s, 9H),
Chem. Eur. J. 2009, 15, 2693 – 2707
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2705

T. K. M. Shing, T. Yamada et al.
Cycloheptane 48: By following the glycol-cleavage procedure, diol 37a
(41.0 mg, 0.118 mmol) was converted into aldehyde 38 as a colorless oil.
By following the cyclization procedure of aldehyde 12 and purification
by using flash chromatography (hexane/Et2O 2:1), aldehyde 38 was con-
verted into cycloheptane 48 (40.3 mg, 99% overall yield from 37a) as a
white solid. Rf =0.45 (hexane/Et2O 1:1); m.p. 71–728C; [a]2D0 =À120.8
(c=1.26 in CHCl3); 1H NMR: d=0.08–0.11 (2s, 6H), 0.90 (s, 9H), 1.36
(s, 6H), 1.62 (dd, J=14.1, 9.6 Hz, 1H), 2.11 (ddd, J=14.1, 6.3, 4.2 Hz,
1H), 2.27–2.42 (m, 2H), 2.64 (s, 3H), 3.18 (t, J=5.7 Hz, 1H), 4.01 (dd,
J=9.6, 2.4 Hz, 1H), 4.09–4.18 (m, 2H), 4.62 ppm (ddd, J=8.7, 4.2,
2.1 Hz, 1H); 13C NMR: d=À4.7 (CH3), À3.9 (CH3), 18.5 (C), 26.3 (CH3),
27.5 (CH3), 27.7 (CH3), 28.3 (CH2), 35.7 (CH2), 47.4 (CH3), 68.9 (CH),
69.7 (CH), 71.0 (CH), 75.0 (CH), 78.5 (CH), 108.5 ppm (C); IR (thin
Ester 58: Triphenylphosphine (2.59 g, 9.87 mmol) was added in one por-
tion to a stirred solution of iodine (1.90 g, 7.40 mmol) and imidazole
(672 mg, 9.87 mmol) in dry toluene/acetonitrile (1:1, 20 mL). Diol 57
(645 mg, 2.47 mmol) dissolved in toluene (10 mL) was added to the re-
sulting yellow suspension with stirring. The reaction mixture was then
heated at 708C under N2 for 1 h and then filtered. The filtrate was
washed with saturated Na2S2O3 solution and then with saturated
NaHCO3 solution. The organic layer was concentrated under reduced
pressure and flash chromatography of the residue (hexane/Et2O 4:1) af-
forded ester 58 (505 mg, 90%) as a colorless oil. Rf =0.33 (hexane/Et2O
4:1); [a]2D0 =À2.61 (c=1.60 in CHCl3) (ref. [26]: [a]2D2 =0 (c=0.9 in
CHCl3)); 1H NMR: d=1.24 (t, J=7.2 Hz, 3H), 1.389–1.391 (2s, 6H),
1.80 (dtd, J=14.4, 8.4, 6.3 Hz, 1H), 1.95 (dddd, J=13.8, 9.3, 6.6, 3.6 Hz,
1H), 2.34–2.55 (ddd, J=16.2, 8.7, 6.6 Hz, 1H; ddd, J=16.2, 9.0, 6.0 Hz,
1H), 3.69 (td, J=8.4, 3.9 Hz, 1H), 3.99 (t, J=7.8 Hz, 1H), 4.09–4.16 (d,
J=7.2 Hz, 1H; d, J=7.2 Hz, 1H), 5.25 (dt, J=10.2, 0.6 Hz, 1H), 5.37 (d,
J=17.1 Hz, 1H), 5.79 ppm (ddd, J=17.1, 10.2, 7.2 Hz, 1H); 13C NMR:
d=14.6, 27.2, 27.3, 27.6, 31.1, 60.8, 79.9, 82.8, 109.2, 119.6, 135.4,
173.5 ppm; IR (thin film): n˜ =2986, 1736, 1371, 1242, 1167, 1070,
875 cmÀ1; MS (ESI): m/z (%): 251 (100) [M+Na]+; HRMS (ESI): m/z
calcd for C12H20O4 [M+Na]+: 251.1254; found: 251.1256.
film): n˜ =2930, 2856, 1367, 1251, 1123, 1073, 983, 894, 835, 778, 667 cmÀ1
;
MS (FAB): m/z (%): 344 (80) [M+H]+, 343 (10) [M]+, 185 (100), 93
(83); HRMS (FAB): m/z calcd for C17H33O4NSi [M+H]+: 344.2252;
found: 344.226228.
Cycloheptanes 51 and 52: By following the glycol-cleavage procedure,
diol 40a (65.8 mg, 0.190 mmol) was converted into aldehyde 41 as a col-
orless oil. By following the cyclization procedure of aldehyde 12 and pu-
rification by using flash chromatography (hexane/Et2O 3:1 to 1:2), alde-
hyde 41 gave firstly cycloheptane 52 (7.70 mg, 12% overall yield from
40a) and secondly cycloheptane 51 (57.8 mg, 88% overall yield from
40a) as white solids.
Data for 51: Rf =0.31 (hexane/Et2O 3:2); m.p. 93–948C; [a]2D0 =+56.3
(c=2.60 in CHCl3); 1H NMR: d=0.10–0.11 (2s, 6H), 0.89 (s, 9H), 1.34–
1.36 (2s, 6H), 1.71 (dd, J=13.8, 10.2 Hz, 1H), 1.86 (d, J=13.2 Hz, 1H),
2.11 (ddd, J=14.1, 6.3, 4.5 Hz, 1H), 2.50 (dt, J=13.8, 8.7 Hz, 1H), 2.66
(s, 3H), 3.19 (d, J=5.4 Hz, 1H), 3.51 (dd, J=8.7, 2.7 Hz, 1H), 3.66 (td,
J=9.6, 6.3 Hz, 1H), 4.03 (t, J=9.0 Hz, 1H), 4.61 ppm (dd, J=9.0, 3.9 Hz,
1H); 13C NMR: d=À4.7 (CH3), À3.7 (CH3), 18.7 (C), 26.3 (CH3), 27.3
(CH3), 27.6 (CH3), 30.1 (CH2), 35.6 (CH2), 47.7 (CH3), 70.5 (CH), 73.4
(CH), 74.4 (CH), 76.0 (CH), 80.3 (CH), 108.2 ppm (C); IR (thin film):
n˜ =2985, 2932, 2855, 1366, 1249, 1108, 857, 779, 671, 509 cmÀ1; MS (ESI):
m/z (%): 366 (55) [M+Na]+, 344 (100) [M+H]+; HRMS (ESI): m/z
calcd for C17H33O4NSi [M+H]+: 344.2252; found: 344.2245.
Data for 52: Rf =0.51 (hexane/Et2O 3:2); m.p. 70–718C; [a]2D0 =À47.8
(c=2.48 in CHCl3); 1H NMR (C6D6): d=0.18 (s, 3H), 0.26 (s, 3H), 1.04
(s, 9H), 1.12 (td, J=12.9, 1.2 Hz, 1H), 1.36–1.39 (2s, 6H), 1.78 (d, J=
12.9 Hz, 1H), 1.90 (dt, J=12.9, 8.1 Hz, 1H), 2.33 (dt, J=13.2, 4.5 Hz,
1H), 2.52 (s, 3H), 2.85 (d, J=8.7 Hz, 1H), 3.60 (dd, J=9.6, 6.9 Hz, 1H),
3.96 (d, J=7.2 Hz, 1H), 4.10 (t, J=5.7 Hz, 1H), 4.59 ppm (td, J=10.5,
4.2 Hz, 1H); 13C NMR: d=À4.5, À4.1, 18.6, 26.2, 27.5, 27.6, 32.9, 37.5,
48.6, 72.3, 72.7, 75.6, 84.7, 108.5 ppm; IR (thin film): n˜ =2929, 2856, 1248,
1095, 838, 778 cmÀ1; MS (ESI): m/z (%): 344 (100) [M+H]+; HRMS
(ESI): m/z calcd for C17H33O4NSi [M+H]+: 344.2252; found: 344.2250.
Alcohol 59: A solution of DIBAL-H (26.9 mL, 26.9 mmol) was added
dropwise over 30 min to a solution of ester 58 (2.05 g, 8.96 mmol) in dry
THF (80 mL) at À788C. The temperature of the resultant solution was
allowed to rise to 08C and was stirred for 3 h. It was then quenched with
saturated NH4Cl solution and filtered through a pad of Celite. The resi-
due was washed with EtOAc. Concentration of the filtrate followed by
purification using flash chromatography (hexane/Et2O 1:1) gave alcohol
59 (1.65 g, 100%) as a colorless oil. Rf =0.26 (hexane/Et2O 1:2); [a]D20
=
+2.48 (c=1.61 in CHCl3) (ref. [27]: [a]2D2 =À3.06 (c=0.49 in CHCl3));
1H NMR: d=1.40–1.41 (2s, 6H), 1.55–1.62 (m, 1H), 1.66–1.78 (m, 3H),
2.11 (brs, 1H), 3.64–3.72 (m, 3H), 3.98 (dd, J=8.1, 7.8 Hz, 1H), 5.25 (dt,
J=10.2, 0.6 Hz, 1H), 5.36 (dt, J=17.1, 0.9 Hz, 1H), 5.79 ppm (ddd, J=
17.4, 10.2, 7.5 Hz, 1H); 13C NMR: d=27.3, 27.6, 28.8, 29.8, 62.9, 81.0,
83.2, 109.1, 119.6, 135.4 ppm; IR (thin film): n˜ =3418, 2987, 2937, 1371,
1241, 1050 cmÀ1; MS (ESI): m/z (%): 209 (100) [M+Na]+, 111 (10);
HRMS (ESI): m/z calcd for C10H18O3 [M+Na]+: 209.1148; found:
209.1152.
Cyclohexanes 61, 62, and 63: IBX (458 mg, 1.63 mmol) was added to a
solution of alcohol 59 (102 mg, 0.545 mmol) in CH2Cl2/DMSO (1:1,
6 mL) and the mixture was stirred at room temperature for 8 h. The mix-
ture was partitioned between Et2O (30 mL) and water (30 mL). The
aqueous layer was extracted with Et2O (2ꢂ30 mL) and the combined or-
ganic extracts were concentrated under reduced pressure to give alde-
hyde 60 as a colorless oil. BnNHOH (73.8 mg, 0.600 mmol) was added to
a solution of aldehyde 60 in CH3CN (8 mL) and the mixture was stirred
at room temperature for 30 min and then heated under reflux for 40 h.
The reaction mixture was partitioned between EtOAc (20 mL) and water
(20 mL). The aqueous layer was extracted with EtOAc (2ꢂ20 mL). The
combined organic extracts were washed with brine, dried over anhydrous
MgSO4, and filtered. Concentration of the filtrate followed by purifica-
tion using flash chromatography (hexane/CH2Cl2/Et2O 2:1:1) gave firstly
cyclohexane 62 (51.0 mg, 32% overall yield from 59) as a colorless oil,
secondly cyclohexane 63 (18.3 mg, 12% overall yield from 59) as a color-
less oil, and cyclohexane 61 (32.1 mg, 20% overall yield from 59) as a
white solid.
Cycloheptane 49 from 51: By following the desilylation procedure of cy-
cloheptane 27 to give cycloheptane 23, silyl ether 51 (24.8 mg,
0.072 mmol) was converted into cycloheptane 49 (15.1 mg, 91%) as a
white solid.
Diol 57: 10% Pd on charcoal (148 mg, 0.139 mmol) was added to a solu-
tion of enoate 56 (1.39 g, 4.63 mmol) in EtOH (40 mL) and the mixture
was stirred under an atmosphere of H2 (balloon). After stirring at room
temperature under H2 for 1 h, the mixture was filtered and the filtrate
was concentrated to give an ester. A solution of the ester in 80% aque-
ous AcOH (30 mL) was stirred at room temperature for 5 h. The solvent
was removed under reduced pressure and the residue was purified by
using flash chromatography (hexane/EtOAc 1:2) to afford diol 57
Data for 61: Rf =0.27 (hexane/Et2O/CH2Cl2 1:1:1); m.p. 94–958C; [a]D20
=
1
(903 mg, 74%) as a colorless oil. Rf =0.30 (hexane/EtOAc 1:2); [a]D20
=
+68.3 (c=1.56 in CHCl3); H NMR: d=0.43–1.52 (m, 8H), 1.81–1.83 (m,
1H), 2.15–2.21 (m, 1H), 2.44–2.63 (m, 2H), 3.37 (dd, J=9.9, 8.4 Hz, 1H),
3.48 (ddd, J=12.3, 8.7, 4.2 Hz, 1H), 3.77 (dd, J=9.3, 7.2 Hz, 1H), 3.89
(d, J=13.5 Hz, 1H), 4.06 (d, J=13.5 Hz, 1H), 4.15 (t, J=6.3 Hz, 1H),
7.26–7.39 ppm (m, 5H); 13C NMR: d=25.8 (CH2), 26.0 (CH2), 27.2
(CH3), 51.1 (CH), 63.1 (CH2), 68.0 (CH2), 70.2 (CH), 80.3 (CH), 81.1
(CH), 111.1 (C), 127.8 (CH), 128.8 (CH), 129.4 (CH), 137.2 ppm (C); MS
(ESI): m/z (%): 290 (100) [M+H]+; IR (thin film): n˜ =2936, 2871, 1454,
1371, 1229, 1179, 1113, 1078, 835, 700 cmÀ1; HRMS (ESI): m/z calcd for
C17H23O3N [M+H]+: 290.1751; found: 290.1751.
À32.2 (c=1.49 in CHCl3); 1H NMR: d=1.26 (t, J=7.2 Hz, 3H), 1.39 (s,
6H), 1.81 (dtd, J=14.4, 8.4, 6.0 Hz, 1H), 1.97 (dddd, J=14.1, 9.0, 7.2,
3.3 Hz, 1H), 2.38–2.60 (ddd, J=16.5, 8.4, 7.2 Hz, 1H; ddd, J=16.5, 9.0,
6.0 Hz, 1H), 3.62–3.73 (m, 4H), 4.05 (td, J=8.1, 3.0 Hz, 1H), 4.13 (d, J=
7.2 Hz, 1H), 4.16 ppm (d, J=7.2 Hz, 1H); 13C NMR: d=14.6, 27.2, 27.7,
28.1, 31.0, 60.9, 65.2, 70.2, 76.5, 81.9, 109.6, 173.7 ppm; IR (thin film): n˜ =
3445, 2986, 1732, 1373, 1216, 1082, 880 cmÀ1; MS (ESI): m/z (%): 285
(100) [M+Na]+; HRMS (ESI): m/z calcd for C12H22O6 [M+Na]+:
285.1309; found: 285.1312.
2706
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2693 – 2707

Intramolecular Nitrone–Alkene Cycloaddition
FULL PAPER
Data for 62: Rf =0.50 (hexane/Et2O/CH2Cl2 1:1:1); [a]2D0 =À143.4 (c=
2.15 in CHCl3); 1H NMR: d=1.43 (s, 6H), 1.64–1.80 (m, 2H), 1.83–1.88
(m, 1H), 1.94–1.98 (m, 1H), 2.66 (ddd, J=10.5, 6.6, 1.8 Hz, 1H), 3.07–
3.09 (m, 1H), 3.43 (ddd, J=10.8, 9.3, 3.9 Hz, 1H), 3.73 (dd, J=10.2,
9.6 Hz, 1H), 3.82 (d, J=13.5 Hz, 1H), 3.97–4.07 (m, 3H), 7.23–7.39 ppm
(m, 5H); 1H NMR (C6D6): d=1.02–1.15 (m, 1H), 1.34–1.40 (m, 7H),
1.65–1.79 (m, 2H), 2.16 (dtd, J=10.8, 5.4, 1.5 Hz, 1H), 2.44 (ddd, J=6.9,
5.1, 2.1 Hz, 1H), 3.19 (td, J=9.3, 5.1 Hz, 1H), 3.57 (d, J=14.1 Hz, 1H),
3.65–3.73 (d, J=14.1 Hz, 1H; dd, J=7.8, 5.4 Hz, 1H), 3.84 (dd, J=10.2,
9.3 Hz, 1H), 3.92 (dd, J=7.5, 0.9 Hz, 1H), 7.03–7.18 (m, 4H), 7.34–
7.37 ppm (m, 2H); 13C NMR: d=24.9 (CH2), 25.0 (CH2), 27.4 (CH3),
27.4 (CH3), 48.3 (CH), 62.0 (CH2), 65.2 (CH), 68.4 (CH2), 78.9 (CH), 79.7
(CH), 109.8 (C), 127.7 (CH), 128.7 (CH), 129.4 (CH), 137.7 ppm (C); IR
(thin film): n˜ =2983, 2943, 2875, 1370, 1236, 1131, 1091, 700 cmÀ1; MS
(ESI): m/z (%): 290 (100) [M+H]+; HRMS (ESI): m/z calcd for
C17H23O3N [M+H]+: 290.1751; found: 290.1758.
Data for 63: Rf =0.43 (hexane/Et2O/CH2Cl2 1:1:1); [a]2D0 =+39.0 (c=1.06
in CHCl3); 1H NMR: d=1.41–1.51 (m, 7H), 1.53–1.64 (m, 1H), 1.96 (dt,
J=14.7, 5.4 Hz, 1H), 2.08 (ddd, J=11.7, 9.3, 4.5 Hz, 1H), 3.27 (q, J=
7.2 Hz, 1H), 3.47 (pentet, J=7.2 Hz, 1H), 3.66 (dd, J=9.0, 6.6 Hz, 1H),
3.78–3.83 (m, 2H), 3.91 (t, J=8.1 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 4.17
(t, J=8.7 Hz, 1H), 7.27–7.39 ppm (m, 5H); 13C NMR: d=25.3 (CH2),
27.3 (CH3), 27.4 (CH3), 60.4 (CH2), 64.3 (CH), 66.3 (CH2), 73.6 (CH),
79.0 (CH), 110.1 (C), 127.9 (CH), 128.9 (CH), 129.3 (CH), 137.5 ppm
(C); IR (thin film): n˜ =2945, 1455, 1369, 1236, 1166, 1131, 1089, 730,
699 cmÀ1; MS (ESI): m/z (%): 290 (100) [M+H]+; HRMS (ESI): m/z
calcd for C17H23O3N [M+H]+: 290.1751; found: 290.1751.
[12] CCDC-242454, CCDC-614145, and CCDC-245397 contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] CCDC-261413 and CCDC-262043 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] CCDC-614146 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Ref. [8] contains the experimental procedure for
the debenzoylation and the relevant spectroscopic data.
[15] Ref. [8] contains the spectroscopic data of cycloheptane 53.
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Acknowledgements
This work was partially supported by a CERG from the Research Grants
Council of HKSAR, China (project no. 402805) and was also partially
supported by a Grant-in-Aid for the 21st century COE program “KEIO
LCC” from the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan. The authors thank the Research Center for Computational
Science, Okazaki National Institute, for their support with the DFT cal-
culations.
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