Synthesis of 3,4-dimethylidene oxacycles through Prins-type cyclization of allenylmethylsilanes

Article abstract of DOI:10.1002/asia.201100162

An efficient synthesis of 3,4-dimethylidene oxacycles including oxolanes and oxepanes through Prins-type cyclization of hydroxy(allenylmethyl)silanes is described. We have shown that 2-substituted tetrahydrofuran derivatives could be produced by using thi

Full text of DOI:10.1002/asia.201100162

FULL PAPERS
DOI: 10.1002/asia.201100162
Synthesis of 3,4-Dimethylidene Oxacycles through Prins-Type Cyclization of
Allenylmethylsilanes
Punna Reddy Ullapu,[a, b] Young Seub Kim,[a] Jae Kyun Lee,[a] Ae Nim Pae,[a, b]
Youseung Kim,[a] Sun-Joon Min,*[a, b] and Yong Seo Cho*[a, b]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Abstract: An efficient synthesis of 3,4-dimethylidene oxacycles including oxolanes
and oxepanes through Prins-type cyclization of hydroxy(allenylmethyl)silanes is
À
described. We have shown that 2-substituted tetrahydrofuran derivatives could be
produced by using this strategy although the 5-endo-trig cyclization mode is stereo-
electronically disfavored. We also applied our method to the stereoselective syn-
thesis of 2,7-cis-3,4-dimethylidene oxepanes, which were used for constructing
more complex ring systems, such as polyether bicycles or tricycles.
Keywords: aldehydes · C C bond
formation · cyclization · heterocy-
cles · stereoselectivity
Introduction
The Prins reaction is a funda-
À
mental reaction for C C bond
formation involving the electro-
philic addition of a p bond to a
carbonyl compound.[1] Depend-
ing on the substrate structure
and the reaction conditions, a
variety of products thus can be
generated, for example, 1,3-
diols, 1,3-dioxanes, or unsatu-
rated alcohols (Scheme 1). Ad-
Scheme 1. General mode of Prins reactions.
dition of alkenes or alkynes to
[a] Dr. P. R. Ullapu, Y. S. Kim, Dr. J. K. Lee, Dr. A. N. Pae, Dr. Y. Kim,
the activated carbonyl compound can initially promote for-
mation of the carbocation 1, which can undergo proton
elimination to produce the unsaturated alcohol 5a/b or cap-
ture a nucleophilic species to give the 3-substituted alcohols
3 or 4. Alternatively, the cationic intermediate 1 can be
treated with an excess of the carbonyl component to pro-
duce the dioxane 2.
Dr. S.-J. Min, Dr. Y. S. Cho
Center for Neuro-Medicine
Korea Institute of Science and Technology (KIST)
Hwarangno 14-gil, Seongbuk-gu, Seoul, 136-791 (South Korea)
Fax : (+82)2-958-5173 (S.-J. Min)
Fax : (+82)2-958-5156 (Y. S. Cho)
E-mail: sjmin@kist.re.kr
ys4049@kist.re.kr
[b] Dr. P. R. Ullapu, Dr. A. N. Pae, Dr. S.-J. Min, Dr. Y. S. Cho
School of Science
Considerable effort has been made to change the operat-
ing conditions to obtain the desired product selectively.
Among the diverse modifications of the Prins reaction, the
Prins-type cyclization has been used effectively to construct
various ring structures (Scheme 2).[2] In particular, when the
electrophile is an oxocarbenium intermediate 6 generated
University of Science and Technology (UST)
176 Gajung-dong, 217 Gajungro, Yuseong-gu
Daejeon 305-333 (South Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100162.
2092
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2092 – 2100

Results and Discussion
In connection with our previous results, we first envisioned
that tetrahydrofurans 12 could be easily synthesized if the
allenyl alcohol 10 containing a trimethylsilyl group was used
as a substrate (Scheme 4).[6] However, the 5-exo-trig cycliza-
tion is stereoelectronically disfavored. In fact, we found that
Scheme 2. Typical Prins cyclization for the synthesis of tetrahydropyrans.
from the condensation of ole-
finic/acetylenic alcohols with al-
dehydes or acetals, the cycliza-
tion occurs to form a variety of
oxygenated heterocycles, such
as tetrahydropyrans or tetrahy-
drofurans.
Various Prins-type cyclization
Scheme 3. Preliminary study on Prins-type cyclizations. TMSOTf=trimethylsilyl trifluoromethanesulfonate.
methods have also been devel-
oped to introduce functionality
onto the oxacyclic compounds.
It has been reported that the
reaction of vinylsilane[3] or allyl-
silane[4] with aldehydes in the
presence of a Lewis acid afford-
ed the corresponding tetrahy-
dropyran derivatives bearing an
alkene moiety. In these cases,
the utility of the silicon group
not only increases the nucleo-
philicity of the p system, but
also facilitates alkene formation
in the termination step of the
cyclization process. Recently, Scheme 4. Intermolecular double Prins-type cyclizations.
we reported that the Prins-type
cyclization reaction of the alle-
nylmethylsilane 7 with an aldehyde led to tetrahydropyrans
9 with vicinal exo-methylene groups at C-3 and C-4 posi-
tions.[5] As depicted in Scheme 3, cyclization through the
chairlike transition state 8 was proposed to rationalize the
high diastereoselectivity. We herein report a more detailed
study on the stereoselective synthesis of oxacycles, including
oxolanes and oxepanes, through the Prins-type cyclization of
allenylmethylsilanes.
the cyclization of 10 with a series of aromatic aldehydes af-
forded 1,6-dioxecanes 15 (see reference [6] for characteriza-
tion including X-ray crystallographical structure), which
were presumably generated from dimerization (path a) or
from intermolecular addition followed by a second conden-
sation (path b).
Alternatively, we assumed that electrophilic addition of
an aldehyde to the allenylsilane 10 and subsequent dehydra-
tion could produce a stabilized carbocation, which would
undergo cyclization to give a tetrahydrofuran (Scheme 5).[7]
In this case, the choice of aldehyde is important because the
Abstract in Korean:
Scheme 5. Concept for synthesis of tetrahydrofurans.
Chem. Asian J. 2011, 6, 2092 – 2100
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2093

S.-J. Min, Y. S. Cho et al.
FULL PAPERS
reaction of the aldehyde with the allenylsilane moiety of 10
should take place earlier than the oxocarbenium formation.
Thus, we selected a,b-unsaturated aldehydes as substrates
because they are less reactive, to suppress direct condensa-
tion of the alcohol and the aldehyde, and they are also able
to stabilize cationic intermediates.
Following the experimental procedure previously used in
intermolecular double Prins cyclizations, we attempted the
reaction of the hydroxy(allenylmethyl)silane 10[8] with cinna-
maldehyde in the presence of trimethylsilyl trifluorometha-
nesulfonate (TMSOTf) at À788C. To our delight, we ob-
tained the desired 3,4-dimethylidene tetrahydrofuran 18 in
56% yield (Table 1, entry 1). Inspired by this result, we
turated aldehydes, such as cyclohexene carboxaldehyde 19c
(entry 3), were treated with the (allenylmethyl)silane 10 to
furnish the cyclized product 18c in 62% yield.
After having established the protocol to synthesize the
five-membered oxacycles 18 and 21 along with the six-mem-
bered ones previously reported, we next decided to include
the preparation of the 3,4-dimethylidene oxepanes by using
the Prins-type cyclization of allenylmethylsilanes.
To demonstrate our methodology, we began with the syn-
thesis of the (allenylmethyl)silane 24 as shown in Scheme 6.
By starting from pent-4-yn-1-ol 22, tetrahydropyranyl (THP)
protection followed by hydroxymethylation on the terminal
alkyne moiety gave the corresponding propargylic alcohol
23[10] in 60% yield. The resulting alcohol was transformed
into the mesylate, which was subjected to TMSCH2MgCl in
the presence of LiCl and CuBr to afford the allenylmethylsi-
lane 24.[11] Finally, we could easily obtain the alcohol 25 by
removing the THP-protecting group by acid-catalyzed hy-
drolysis.
Table 1. Synthesis of 3,4-dimethylidene tetrahydrofurans through Prins-
type cyclizations.[a]
To find optimal reaction conditions, we tested several
acids, including TMSOTf, SnCl4, TiCl4, InCl3, TfOH, and
BF3·Et2O. We found that treatment of 25 with benzaldehyde
in the presence of 1.5 equivalents of TMSOTf at À788C for
2 h produced the desired oxepane 27a in excellent yield
(Table 2, entry 1; see the Supporting Information for de-
tails). As shown in Table 2, we then tested the cyclizations
of a series of aromatic or aliphatic aldehydes to obtain the
2-substituted 3,4-dimethylidene oxepanes 27. At first, the
Prins-type cyclization reactions with the aromatic aldehydes
(entries 1–8) led to the 2-aryl-substituted oxepane deriva-
tives 27 with good to high yields regardless of the nature of
the aldehydes. The electron-deficient benzaldehydes, such as
nitrobenzaldehydes 26b and 26c, were successfully trans-
Entry
Aldehyde
R1
Ph
4-NO2 Ph
À
AHCTUNGTRENNUNG
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
19a
19b
19c
20a
20b
20c
20d
20e
H
H
18a
18b
18c
21a
21b
21c
21d
21e
56
NR[c]
62
À
À
65
64
55
À
4-Me Ph
4-pentyl Ph
4-F Ph
4-MeO Ph
À
À
trace
NR[c]
À
[a] The reactions were performed in dry THF at À788C in the presence
of 2.0 equiv of TMSOTf and allowed to warm to room temp for 5 h.
[b] Isolated yield. [c] NR=No reaction.
tested a range of a,b-unsaturat-
ed aldehydes 19 and 20[9] as
shown in Table 1. Indeed,
a
series of tetrahydrofuran deriv-
atives 21 were readily obtained
Scheme 6. Synthesis of the hydroxy(allenylmethyl)silane 25: a) DHP, p-TsOH, CH2Cl2, 98%; b) nBuLi, paraf-
in good yields from both the al- ormaldehyde, Et2O, À788C, 60%; c) MsCl, Et3N, CH2Cl2, 08C, 90%; d) TMSCH2MgCl, LiCl, CuBr, HMPA,
THF, 82%; e) p-TsOH, aq. MeOH, 94%. DHP=dihydropyran; HMPA=hexamethylphosphoramide; THP=
tetrahydropyranyl.
kenyl and alkynyl aldehydes
under the reaction conditions.
It is worth noting that the
subtle change of electronic
character in the terminal aromatic moiety of the aldehydes
plays an important role in this cyclization process. For in-
stance, the reaction of 4-methylphenylpropiolaldehyde 20b
with 10 proceeded to afford the corresponding tetrahydro-
furan 21b in 64% yield (entry 5), whereas no expected
product was observed from the highly electron-rich (4-me-
thoxyphenyl)propiolaldehyde 20e (entry 8). On the contra-
ry, we could not obtain any desired product when the elec-
tron-deficient nitro group was on the aromatic ring of cinna-
maldehyde (entry 2). In addition, the use of a 4-fluoro sub-
stituent afforded only a trace amount of the tetrahydrofuran
21d (entry 7). On the other hand, simple aliphatic a,b-unsa-
formed into the corresponding cyclized products 27b and
27c although the yields were slightly decreased relative to
those of other aldehydes. These results implied that the elec-
tron density of the aromatic ring affected the process of
seven-membered ring formation, but not as significantly as
the above-mentioned tetrahydrofuran synthesis (see
Table 1). These cyclization reactions have also been validat-
ed with aliphatic aldehydes (Table 2, entries 9 and 10) and
heteroaromatic aldehydes (entries 11 and 12), which gave
the products in exceptionally high yields.
To further expand the scope of our strategy, we decided
to synthesize the 3,4-dimethylidene oxepanes 29 and 30 con-
2094
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2092 – 2100

Synthesis of 3,4-Dimethylidene Oxacycles
Table 2. Synthesis of 3,4-dimethylidene oxepanes through Prins-type cy-
clizations.[a]
anomeric protons of each compound, which indicates that
the stereochemistry of C-2 and C-7 is cis.
Oxepanes, often encountered in biologically active natural
products, exist as fused bicyclic systems in many cases.[12] In
connection with the stereoselective synthesis of 2,7-cis-dis-
ubstituted oxepanes through Prins-type cyclizations, we de-
vised a new proposal to construct such bicyclic polyether
structures derived from the cyclized products 29 and 30. In
the event, differentiation of the dimethylidene units in 29
and 30 would be a key transformation to reach the anticipat-
ed structure. Thus, we envisioned that synthesis of the 3,4-
dimethylidene oxepane containing a hydroxyalkyl chain at
the C-2 position and subsequent etherification would be a
suitable strategy to achieve this purpose.
Entry
Aldehyde
R1
Ph
2-NO2 Ph
4-NO2 Ph
4-F Ph
4-Cl Ph
4-Me Ph
3-MeO Ph
4-MeO Ph
nC6H13
cyclopentyl
thiophene-2-
furan-3-
Product
Yield [%][b]
1
2
3
4
5
6
7
8
26a
26b
26c
26d
26e
26 f
26g
26h
26i
27a
27b
27c
27d
27e
27 f
27g
27h
27i
90
55
86
94
98
95
90
96
92
96
90
94
À
À
À
À
À
À
À
9
To execute this idea, we treated 25 and 28a with 3-oxo-
propyl acetate in the presence of TMSOTf to obtain the 2-
acetyloxyalkyl oxepanes 31 and 32 in 66 and 69% yield, re-
spectively. Additionally, 4-oxobutyl acetate was also subject-
ed to the same reaction conditions to afford the oxepane de-
rivative 33 in 70% yield as a single stereoisomer. After un-
masking the acetyl groups from the cyclized products 31–33,
we explored etherification reactions of the corresponding
free alcohols 34–36. Initially, we attempted the cyclization
reactions of 34–36 catalyzed by Lewis acids, such as
10
11
12
26j
26k
26l
27j
27k
27l
[a] The reactions were performed in dry Et2O at À788C for 2 h in the
presence of 1.5 equiv of TMSOTf. [b] Isolated yield.
taining substituents at the C-2 and C-7-positions (Scheme 7).
Initially, the precursors 28a/b for cyclization were prepared
in two steps: oxidation by Dess–Martin periodinane and ad-
dition of Grignard reagents to the resulting aldehydes. The
results of the Prins-type cyclizations of the secondary alco-
hols 28a/b with several aldehydes are presented in
Scheme 7. Under the optimized conditions, the reactions of
28a with several benzaldehydes promoted by TMSOTf af-
forded 2,7-disubstituted oxepanes 29 in excellent yields. In
the case of aliphatic aldehydes, such as hexanal, the expect-
ed cyclized product 29c was cleanly obtained in 91% yield.
It is worth noting that only single diastereomers were pro-
duced in all cases. We also attempted the cyclization reac-
tions by using the more acid-sensitive alcohol 28b as the
substrate. Indeed, it turned out that this alcohol was tolerat-
ed under our reaction conditions to give the desired 2,7-dis-
ubstituted oxepanes 30a/b as single isomers in high yields.
The stereochemical outcome of the present cyclization reac-
tion was confirmed by NOE experiments on 29a and 29c.
We could observe an NOE correlation between the two
ACTHNUTRGNEUNG
AgOTf[13] and Sn(OTf)4,[14] but they proved to be ineffective
in our system. Alternatively, we found that treatment of 34
with I2 (10 equiv) and NaHCO3 (20 equiv) in Et2O/water
(4:1) afforded a 5:1 mixture of the bicyclic compounds 37a/
b in 88% yield, which were separated by column chroma-
tography.[15] It is noteworthy that two adjacent olefins were
substantially discriminated, generating a new quaternary
center. At this moment, we have tentatively assigned the
stereochemistry of the major isomer 37a to the cis configu-
ration because it is expected that the formation of the five-
membered ring in the cis-fused bicyclic ring structure is ther-
modynamically preferred. Under the same reaction condi-
tions, the 2,7-disubstituted oxepane 35 was also subjected to
iodoetherification to give a mixture of the two isomers 38a/
b in a ratio of 3:1. However, cyclization of the oxepane 36
did not provide any desired product. Presumably, the 6-exo-
tet cyclization mode is disfavored due to the inherent struc-
tural rigidity of the dimethylidene oxepane.
Next, we needed to verify the stereochemistry of the ring
juncture in the bicyclic products 38a/b (Scheme 8). Accord-
ingly, we accomplished the ozonolysis of a mixture of 38a/b
to obtain two isomeric ketones, which were independently
separated in a 3:1 ratio by column chromatography. Reduc-
tion of the major isomer 40a through a radical intermediate
gave the methyl ketone 41 in 80% yield. As anticipated, we
identified the cis stereochemical relationship between the
proton at the ring juncture and the angular methyl group in
41 by NOE enhancement.
Further transformation of the oxepanes 38a and 40a into
other valuable molecules was investigated in Scheme 9.
While we tried dihydroxylation of 38a by using OsO4 and
N-methylmorpholine-N-oxide (NMO), we could obtain only
the tricyclic ether 42 in 85% yield, which was generated by
Scheme 7. Synthesis of 2,7-cis-disubstitued 3,4-dimethylidene oxepanes:
a) Dess–Martin periodinane, CH2Cl2, 95%; b) R1 MgCl, THF, 87% (28a,
R1 =iPr), 91% (28b, R1 =Ph); c) R2CHO, TMSOTf, Et2O, À788C to RT,
2 h.
Chem. Asian J. 2011, 6, 2092 – 2100
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2095

S.-J. Min, Y. S. Cho et al.
FULL PAPERS
Conclusions
The Prins-type cyclization of
hydroxy(allenylmethyl)silanes
can be utilized to efficiently
prepare 3,4-dimethylidene oxa-
cyclic compounds, including ox-
olanes and oxepanes. Our work
shows that less reactive unsatu-
rated aldehydes can be applied
as the key substrates, thereby
allowing the synthesis of a five-
membered ring system, which is
stereoelectronically disfavored.
Mechanistically, we proposed
that the cationic species stabi-
lized by two neighboring p sy-
stems is generated prior to oxo-
carbenium formation. We also
successfully applied our cycliza-
Scheme 8. Synthesis of polyether bicyclic compounds: a) TMSOTf, AcOCH2CH2CHO or AcO
Et2O, À788C to RT; b) K2CO3, MeOH/H2O (4:1); c) I2 (10 equiv), NaHCO3 (20 equiv), Et2O/H2O (4:1), RT;
d) O3, CH2Cl2, À788C, 10 min, then Me2S, À788C to RT; e) Bu3SnH, AIBN, PhH, reflux, 2 h, 80%. AIBN=
azobisisobutyronitrile.
ACHTUGNERTN(NUNG CH2)3CHO,
tion strategy to the stereoselective synthesis of the 2,7-cis-
3,4-dimethylidene oxepanes. In particular, we could signifi-
cantly extend the utility of the oxepane products in the syn-
thesis of more complex ring structures, such as polyether bi-
cycles or tricycles. Further investigations toward preparing
other oxacycles and related oxygen-containing bioactive ma-
terials are currently in progress and will be reported in due
course.
Experimental Section
General information
Scheme 9. Synthesis of the polyether tricyclic compound 42 and the elimi-
nated product 43: a) OsO4, NMO, acetone/H2O, 85%; b) SmI2, HMPA,
THF, 60%; c) Zn or In, tert-amyl alcohol H2O, reflux, 80% (M=Zn) and
70% (M=In). NMO=N-methylmorpholine-N-oxide
All reactions were conducted by using oven-dried glassware under an at-
mosphere of nitrogen (N2). All commercially available reagents were pur-
chased and used without further purification. Solvents—Et2O, THF, and
CH2Cl2—were dried and distilled by following the usual protocols. Reac-
tions were followed by TLC analysis by using silica gel plates with a fluo-
rescent indicator (60F-254) by using a UV lamp and an anisaldehyde so-
lution with heat as visualizing agents. Flash chromatography was carried
out by using silica gel (60, particle size: 0.040–0.063 mm). The 1H NMR
spectra were measured at 300 and 400 MHz and 13C NMR spectra were
measured at 75 and 100 MHz by using CDCl3. 1H NMR spectroscopic
chemical shifts are expressed in parts per million (d) downfield from
CHCl3 (d=7.26 ppm), 13C NMR spectroscopic chemical shifts are ex-
pressed in parts per million (d) relative to the central CDCl3 resonance
(d=77.0 ppm). Coupling constants in 1H NMR spectra are in Hz. The
following abbreviations were used to designate multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, quint=quintet, m=multiplet, br=
broad. Melting points were recorded by using open capillary tubes and
are uncorrected. HRMS were obtained by using positive electrospray
ionization and mass/charge (m/z) ratios are reported as values in atomic
mass units. FTIR analyses were obtained on a Perkin–Elmer Spectrum
nucleophilic substitution of the resulting diol with the
nearby iodide. The stereochemistry of the tertiary hydroxy
group was provisionally assigned as syn because dihydroxy-
lation presumably occurred from the side opposite the angu-
lar iodomethyl group. On the other hand, we imagined that
the iodoketone 40a could be converted into either the exo-
methylene 43 through elimination or the bicyclic compound
44 containing an eight-membered oxacycle through ring ex-
pansion. In fact, the reaction of 40a with SmI2 (freshly pre-
pared from samarium powder and diiodomethane following
the literature procedure)[16] led to the unsaturated ketone 43
exclusively in 60% yield. At the same time, zinc and indium
metal-mediated reactions were also attempted. Again, only
the elimination product 43 was isolated in 80 and 70%
yield, respectively.
GX FTIR system and were reported in cmÀ1
.
(E)-3,4-Dimethylene-2-styryltetrahydrofuran (18a)
TMSOTf (199 mg, 0.90 mmol) was slowly added to a solution of the alco-
hol 10 (70 mg, 0.45 mmol) and cinnamaldehyde (59 mg, 0.45 mmol) in
THF (10 mL) cooled to À788C. The mixture was allowed to warm up to
room temperature over 2 h. The reaction was monitored by TLC,
quenched with saturated aqueous NaHCO3 (15 mL) after completion of
the reaction, and extracted with dichloromethane (3ꢁ20 mL). The organ-
2096
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2092 – 2100

Synthesis of 3,4-Dimethylidene Oxacycles
ic extracts were washed with water and brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (EtOAc/n-hexane 1:20) to afford
7.46 (ddd, 1H, J=7.5, 6.5, 1.4 Hz), 5.26 (s, 1H), 5.18 (d, 1H, J=1.6 Hz),
5.02–4.96 (m, 1H), 4.93 (s, 1H), 4.27 (s, 1H), 4.25–4.23 (m, 1H), 3.71–
3.62 (m, 1H), 2.67–2.62 (m, 2H), 1.91–1.84 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=152.09, 147.34, 139.72, 136.88, 133.18, 129.29,
128.07, 124.17, 112.52, 112.14, 78.36, 73.45, 34.65, 31.98 ppm; HRMS-CI:
m/z: calcd for C14H16NO3: 246.1130 [M+H]+; found: 246.1133.
the compound 18a (50 mg, 56%) as
a
colorless liquid. 1H NMR
(400 MHz, CDCl3): d=7.43–7.41 (m, 2H), 7.35–7.31 (m, 3H), 6.66 (d, J=
15.8 Hz, 1H), 6.16 (dd, 1H, J=15.8, 7.4 Hz), 5.53 (d, 1H, J=2.5 Hz),
5.48 (t, 1H, J=2.4 Hz), 5.01–5.00 (m, 2H), 4.94 (s, 1H), 4.60 (dt, 1H, J=
13.0, 1.8 Hz), 4.48 ppm (dt, 1H, J=13.0, 2.3 Hz); 13C NMR (100 MHz,
CDCl3): d=147.0, 144.4, 136.5, 133.1, 128.6, 128.1, 127.9, 126.7, 104.6,
103.1, 83.6, 71.3 ppm; HRMS-EI: m/z: calcd for C14H14O: 198.1045 [M]+;
found: 198.1043.
2-Methyl-6-[(trimethylsilyl)methyl]octa-6,7-dien-3-ol (28a)
Dess–Martin periodinane (759 mg, 1.79 mmol) was added to a solution of
the allenyl alcohol 25 (300 mg, 1.62 mmol) in dichloromethane (20 mL)
under argon. The suspension was stirred at 08C for 1 h and then an aque-
ous solution of sodium thiosulfate in saturated sodium bicarbonate
(20 mL) was added. The mixture was stirred vigorously until the organic
layer became clear. The organic layer was separated. The aqueous layer
was extracted with ether (3ꢁ25 mL). Both organic layers were washed
with saturated sodium bicarbonate and brine, respectively. The combined
organic layers were then dried over magnesium sulfate and concentrated
under reduced pressure. The crude product was purified by column chro-
matography on silica gel (EtOAc/n-hexane 1:15) to afford the allenyl al-
dehyde (290 mg, 98%) as a clear oil. 1H NMR (400 MHz, CDCl3): d=
9.78 (t, 1H, J=1.48 Hz), 4.71–4.68 (m, 2H), 2.58–2.54 (m, 2H), 2.25–2.21
(m, 2H), 1.35 (t, 2H, J=2.3 Hz), 0.04 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=206.1, 202.3, 99.9, 76.3, 41.6, 26.7, 21.8, À1.2 ppm. Isopropyl
magnesium bromide (0.78 mL, 2.0m in THF) was added to a solution of
this allenyl aldehyde (140 mg, 0.78 mmol) in THF (20 mL) cooled to
À788C. The solution was stirred at À788C for 2 h and allowed to warm
up to 08C. The reaction mixture was quenched with saturated NH4Cl
(20 mL) and extracted with diethyl ether (3ꢁ20 mL). The combined or-
ganic layer was washed with brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc/n-hexane 1:10) to give the
alcohol 28a (150 mg, 87%) as an oil. IR (thin film): n˜ =3393, 2957, 1953,
2-(Cyclohex-1-en-1-yl)-3,4-dimethylenetetrahydrofuran (18c)
By following the same procedure as that used for the synthesis of 18a,
the reaction of the alcohol 10 (50 mg, 0.32 mmol), cyclohex-1-enecarbal-
dehyde (35 mg, 0.32 mmol), and TMSOTf (142 mg, 0.64 mmol) in THF
(8 mL) gave tetrahydrofuran 18c (35 mg, 62%) as a colorless oil after pu-
rification by column chromatography on silica gel (EtOAc/n-hexane
1:15). 1H NMR (400 MHz, CDCl3): d=5.77–5.76 (m, 1H), 5.48 (d, 1H,
J=2.6 Hz), 4.94 (t, J=2.0 Hz, 1H), 4.85 (d, 1H, J=2.2 Hz), 4.78–4.77 (m,
1H), 4.53 (dt, 1H, J=12.8, 2.1 Hz), 4.42 (dt, 1H, J=12.8, 2.5 Hz), 2.09–
2.05 (m, 2H), 2.04–1.93 (m, 1H), 1.89–1.86 (m, 1H), 1.65–1.54 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=146.2, 145.0, 137.1, 126.8, 104.0
102.4, 87.7, 71.5, 25.2, 22.7, 22.6, 22.5 ppm; HRMS-EI: m/z: calcd for
C12H16O: 176.1204 [M]+; found: 176.1201.
3,4-Dimethylene-2-[(4-methylphenyl)ethynyl]tetrahydrofuran (21b)
By following the same procedure as that used for the synthesis of 18a,
the reaction of the alcohol 10 (40 mg, 0.26 mmol), 3-(4-methylphenyl)-
propiolaldehyde (37 mg, 0.26 mmol), and TMSOTf (113 mg, 0.51 mmol)
in THF (8 mL) gave tetrahydrofuran 21b (34 mg, 64%) as a colorless oil
after purification by column chromatography on silica gel (EtOAc/n-
hexane 1:20). 1H NMR (400 MHz, CDCl3): d=7.40 (d, 2H, J=8.0 Hz),
7.15 (d, 2H, J=8.0 Hz), 5.60 (s, 1H), 5.46 (brs, 1H), 5.42 (d, 1H, J=
2.0 Hz), 5.34 (brs, 1H), 5.21 (brs, 1H), 4.42 (d, 1H, J=11.8 Hz), 4.34 (d,
1H, J=11.8 Hz), 2.37 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
147.2, 143.7, 138.7, 131.7, 129.1, 120.4, 119.6, 116.2, 88.4, 84.5, 72.1, 69.1,
21.5 ppm; HRMS-CI: m/z: calcd for C15H15O: 211.1123 [M+H]+; found:
211.1125.
1
1719, 1385, 1248, 1161, 1053 cmÀ1; H NMR (400 MHz, CDCl3): d=4.65–
4.63 (m, 2H), 3.42–3.38 (m, 1H), 2.01–1.90 (m, 2H), 1.86–1.59 (m, 2H),
1.33–1.26 (m, 2H), 0.93 (d, 3H, J=6.8 Hz), 0.92 (d, 3H, J=6.7 Hz),
0.05 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=206.1, 100.6, 76.3,
75.4, 33.7, 31.9, 30.7, 21.6, 18.9, 17.2, À1.1 ppm; HRMS-CI: m/z: calcd for
C13H27OSi: 227.1831 [M+H]+; found: 227.1821.
(Æ)-(2S,7S)-7-Isopropyl-3,4-dimethylene-2-phenyloxepane (29a)
By following the same procedure as that used for the synthesis of 27a,
the reaction of alcohol 28a (25 mg, 0.11 mmol), benzaldehyde (13 mg,
0.121 mmol), and TMSOTf (37 mg, 0.165 mmol) in dry Et2O (5.0 mL)
gave the 2,7-disubstituted oxepane 29a (24 mg, 90%) as a colorless oil
after purification by column chromatography on silica gel (EtOAc/n-
hexane 1:15). IR (thin film): n˜ =3082, 2958, 2871, 1627, 1451, 1365, 1178,
3,4-Dimethylene-2-phenyloxepane (27a)
TMSOTf (196 mg, 0.88 mmol) was added to a solution of the alcohol 25
(100 mg, 0.587 mmol) and benzaldehyde 26a (69 mg, 0.66 mmol) in dry
Et2O (6.0 mL) at À788C for 10 min. The mixture was allowed to stir at
À788C for 2 h. The reaction was monitored by TLC analysis, quenched
with saturated aqueous NaHCO3 after completion of the reaction, and di-
luted with Et2O (10 mL). The organic solution was washed with water
and brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(EtOAc/n-hexane 1:20) to afford the compound 27a (106 mg, 90%) as a
colorless liquid. IR (thin film): n˜ =3045, 2940, 1720, 1450, 1275, 1196,
1086 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.37–7.25 (m, 5H), 5.23 (s,
;
1H), 5.12 (s, 1H), 5.05 (d, 1H, J=2.0 Hz), 4.87 (s, 1H), 4.43 (s, 1H),
3.36–3.31 (m, 1H), 2.64–2.58 (m, 1H), 2.43–2.36 (m, 1H), 1.98–1.91 (m,
1H), 1.72–1.65 (m, 1H), 1.64–1.54 (m, 1H), 0.92 (d, 3H, J=6.7 Hz),
0.90 ppm (d, 3H, J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=153.30,
149.98, 140.40, 127.87, 127.05, 112.52, 112.06, 101.43, 87.39, 84.28, 34.64,
34.53, 33.97, 19.23, 18.70 ppm; HRMS-EI: m/z: calcd for C17H22O:
242.1671 [M]+; found: 242.1671.
1099 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.34–7.27 (m, 5H), 5.24 (t,
;
1H, J=1.2 Hz), 5.10 (s, 1H), 5.06 (d, 1H, J=2.0 Hz), 4.90 (s, 1H), 4.46 (t,
1H, J=1.6 Hz), 4.21–4.17 (m, 1H), 3.73–3.66 (m, 1H), 2.64–2.58 (m,
1H), 2.46–2.39 (m, 1H), 1.90–1.84 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=153.81, 150.14, 141.63, 128.11, 127.38, 127.10, 113.63, 112.46,
84.83, 72.19, 35.00, 32.07 ppm; HRMS-EI: m/z: calcd for C14H16O:
200.1201 [M]+; found: 200.1206.
2-(3,4-Dimethyleneoxepan-2-yl)ethyl acetate (31)
By following the same procedure as that used for the preparation of 27a,
the reaction of alcohol 25 (200 mg, 1.08 mmol), 3-oxopropyl acetate
(138 mg, 1.19 mmol), and TMSOTf (361 mg, 1.62 mmol) in dry Et2O
(10 mL) gave the compound 31 (150 mg, 66%) as a colorless oil after pu-
rification by column chromatography on silica gel (EtOAc/n-hexane
1:15). IR (thin film): n˜ =2939, 2863, 1741, 1626, 1433, 1367, 1242, 1105,
3,4-Dimethylene-2-(2-nitrophenyl)oxepane (27b)
By following the same procedure as that used for the synthesis of 27a,
the reaction of the alcohol 25 (50 mg, 0.293 mmol), 2-nitrobenzaldehyde
(49 mg, 0.322 mmol), and TMSOTf (98 mg, 0.44 mmol) in dry Et2O
(6.0 mL) gave the compound 27b (40 mg, 55%) as a colorless oil after
purification by column chromatography on silica gel (EtOAc/n-hexane
1:15). IR (thin film): n˜ =3085, 2958, 2860, 1725, 1528, 1345, 1274,
1
1041 cmÀ1; H NMR (400 MHz, CDCl3): d=5.18 (s, 1H), 5.01 (d, 1H, J=
2.0 Hz), 4.86 (s, 1H), 4.84 (s, 1H), 4.23–4.19 (m, 1H), 4.12–4.02 (m, 2H),
3.53–3.47ACTHNUTRGNE(UNG m, 1H), 2.56–2.50 (m, 1H), 2.39–2.26 (m, 1H), 2.06 (s, 3H),
1.96–1.91 (m, 2H), 1.78–1.72 ppm (m, 2H); HRMS-EI: m/z: calcd for
C12H18O3: 210.1256 [M]+; found: 210.1255.
1101 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.97 (dd, 1H, J=8.2,
1.3 Hz), 7.86 (dd, 1H, J=8.0, 1.3 Hz), 7.66 (ddd, 1H, J=7.5, 6.7, 1.1 Hz),
Chem. Asian J. 2011, 6, 2092 – 2100
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2097

S.-J. Min, Y. S. Cho et al.
FULL PAPERS
(Æ)-2-[(2S,7S)-7-Isopropyl-3,4-dimethyleneoxepan-2-yl]ethyl acetate (32)
(Æ)-3-[(2S,7S)-7-Isopropyl-3,4-dimethyleneoxepan-2-yl]propanol (36)
By following the same procedure as that used for the preparation of 27a,
the reaction of alcohol 28a (325 mg, 1.43 mmol), AcOCH2CH2CHO
(183 mg, 1.57 mmol), and TMSOTf (487 mg, 2.15 mmol) in dry Et2O
(10 mL) gave the compound 32 (250 mg, 69%) as a colorless oil after pu-
rification by column chromatography on silica gel (EtOAc/n-hexane
By following the same procedure as that used for the preparation of 34,
the reaction of the acetate 33 (625 mg, 2.34 mmol) and potassium carbon-
ate (648 mg, 4.69 mmol) in MeOHACHTNUTRGENNG(U 20 mL)/H2O (5 mL) gave the alcohol
35 (510 mg, 97%) as a colorless oil after purification by column chroma-
tography on silica gel (EtOAc/n-hexane 1:4); IR (thin film): n˜ =2956,
1:15). IR (thin film): n˜ =2959, 2856, 1742, 1366, 1240, 1040 cmÀ1
;
2867, 1756, 1636, 1456, 1324, 1248, 1145, 1056 cmÀ1
;
1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3): d=5.14 (s, 1H), 4.97 (d, 1H, J=2.0 Hz),
4.84 (s, 1H), 4.80 (s, 1H), 4.27–4.14 (m, 3H), 3.10–3.07 (m, 1H), 2.54–
2.50 (m, 1H), 2.26–2.19 (m, 1H), 2.06 (s, 3H), 1.98–1.92 (m, 2H), 1.84–
1.79 (m, 1H), 1.67–1.62 (m, 1H), 1.50–1.46 (m, 1H), 0.92 (d, 3H, J=
6.7 Hz), 0.89 ppm (d, 3H, J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=
171.11, 153.96, 150.14, 111.96, 110.32, 85.90, 78.06, 61.64, 34.94, 34.03,
34.01, 33.77, 21.03, 19.29, 18.37 ppm; HRMS-CI: m/z: calcd for C15H25O3:
253.1804 [M+H]+; found: 253.1797.
CDCl3): d=5.10 (s, 1H), 4.94 (d, 1H, J=2.4 Hz), 4.83ACHTUNGRTNE(NUGN s, 1H), 4.79 (s,
1H), 4.09–4.06 (m, 1H), 3.67(t, 2H, J=6.0 Hz), 3.21–3.16 (m, 1H), 2.56–
2.51 (m, 1H), 2.23–2.20 (m, 1H), 1.60 (s, 1H), 1.80–1.64 (m, 6H), 1.51–
1.48 (m, 1H), 0.94 (d, 3H, J=6.8 Hz), 0.90 ppm (d, 3H, J=6.8 Hz);
13C NMR (100 MHz, CDCl3): d=154.53, 150.32, 111.89, 110.61,85.54,
82.00, 62.99, 35.02, 34.05, 33.34, 32.09, 29.06, 19.16, 18.54 ppm.
(Æ)-(3aS,8aS)-8a-(Iodomethyl)-8-methyleneoctahydrofuro
(37a) and (Æ)-(3aS,8aR)-8a-(iodomethyl)-8-
ACHTUNGTREN[NGNU 3,2-b]oxepine
(Æ)-3-[(2S,7S)-7-Isopropyl-3,4-dimethyleneoxepan-2-yl]propyl acetate (33)
methyleneoctahydrofuroACTHNUGRTNEUNG[3,2-b]oxepine (37b)
By following the same procedure as that used for the preparation of 27a,
the reaction of alcohol 28a (850 mg, 3.75 mmol), AcOCH2CH2CH2CHO
(537 mg, 4.13 mmol), and TMSOTf (1.25 g, 5.63 mmol) in dry Et2O
(30 mL) gave the compound 33 (700 mg, 70%) as a colorless oil after pu-
rification by column chromatography on silica gel (EtOAc/n-hexane
1:15). IR (thin film): n˜ =2959, 2874, 1742, 1626, 1446, 1365, 1243,
Iodine (1.20 g, 4.75 mmol) was added in one portion to a solution of the
alcohol 34 (80 mg, 0.48 mmol) and NaHCO3 (800 mg, 9.52 mmol) in Et2O
(8 mL) and H2O (2 mL) at room temperature. After having been stirred
for 2 h, the reaction mixture was washed with aqueous Na2S2O3 to
remove the excess iodine. The layers were separated and the aqueous
layer was extracted with diethyl ether (3ꢁ15 mL). The combined organic
extracts were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (EtOAc/n-hexane 1:15) to give the iodides 37a
(105 mg, 75%) and 37b (18 mg, 13%).
1
1050 cmÀ1; H NMR (400 MHz, CDCl3): d=5.11 (s, 1H), 4.94 (d, 1H, J=
2.0 Hz), 4.83 (s, 1H), 4.79 (s, 1H), 4.11–4.08 (m, 2H), 4.04–4.01 (m, 1H),
3.15 (m, 1H), 2.51 (m, 1H), 2.19 (s, 3H), 2.05 (m, 2H), 1.74–1.57 (m,
1H), 0.94 (d, 3H, J=6.7 Hz), 0.89 (d, 3H, J=6.7 Hz), 0.89 ppm (d, 3H,
J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=171.25, 154.31, 150.31,
111.75, 110.43, 85.42, 81.34, 81.34, 64.61, 35.03, 34.12, 33.59, 31.61, 25.08,
21.04, 19.33, 18.51 ppm; HRMS-EI: (m/z): calcd for C16H26O3: 266.1882
[M]+; found: 266.1881.
Product 37a
IR (thin film): n˜ =2937, 2867, 1433, 1196, 1101, 1063, 908 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=5.38 (s, 1H), 5.09 (s, 1H), 4.83 (s, 1H), 4.19–4.14
(m, 3H), 4.00–3.91 (m, 3H), 3.43–3.35 (m, 3H), 2.57–2.52 (m, 1H), 2.44–
2.36 (m, 1H), 2.06–1.978 (m, 2H), 1.79–1.74 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=147.33, 113.95, 89.70, 86.97, 74.11, 66.59, 35.42,
32.52, 14.78 ppm; HRMS-CI: m/z: calcd for C10H16IO2: 295.0195 [M+H]+
; found: 295.0191.
2-(3,4-Dimethyleneoxepan-2-yl)ethanol (34)
Potassium carbonate (197 mg, 1.42 mmol) was added to a solution of the
acetate 31 (150 mg, 0.71 mmol) in MeOH (8 mL) and H2O (2 mL) was
added at room temperature. The resulting mixture was stirred at room
temperature for 2 h, diluted with aqueous NH4Cl (10 mL), and concen-
trated under reduced pressure to remove the methanol. Diethyl ether
(15 mL) was added and the layers were separated. The aqueous layer
was extracted with diethyl ether (3ꢁ15 mL) and the combined organic
extracts were washed with brine, dried over MgSO4, and concentrated.
The residue was purified by column chromatography on silica gel
(EtOAc/n-hexane 1:4) to give the alcohol 34 (110 mg, 92%). IR (thin
Product 37b
IR (thin film): n˜ =2947, 2867, 1644, 1423, 1255, 1199, 1104, 1081,
914 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.20 (s, 1H), 5.11 (s, 1H),
;
4.42–4.40 (m, 1H), 4.08–4.03 (m, 1H), 3.81–3.71 (m, 1H), 3.68–3.60 (m,
3H), 3.57–3.54 (m, 1H), 2.31–2.27 (m, 1H), 2.07–1.99 (m, 2H), 1.68–1.84
(m, 1H), 1.64–1.58 (m, 1H), 1.37–1.31 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=146.91, 115.75, 76.54, 64.43, 58.91, 38.23, 33.66,
29.71, 27.34, 6.29 ppm; HRMS-CI: m/z: calcd for C10H16IO2: 295.0195
[M+H]+; found: 295.0190.
film): n˜ =2936, 2865, 1626, 1432, 1349, 1279, 1111, 1054 cmÀ1 1H NMR
;
(400 MHz CDCl3): d=5.13 (s, 1H), 4.97 (s, 1H), 4.84 (s, 1H), 4.82 (s,
1H), 4.27–4.23 (m, 1H), 3.77 (s, 2H), 3.56–3.49 (m, 1H), 2.76 (s, 1H),
2.5–2.48 (m, 1H), 2.29–2.21 (m, 1H), 1.93–1.85 (m, 2H), 1.75–1.71 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=153.70, 150.16, 112.21, 110.97,
81.43, 71.34, 66.83, 36.96, 34.94, 31.05 ppm; HRMS-EI: m/z: calcd for
C10H16O2: 168.1150 [M]+; found: 168.1147.
(Æ)-(3aS,5S,8aR)-8a-(Iodomethyl)-5-isopropyl-8-
methyleneoctahydrofuro
(iodomethyl)-5-isopropyl-8-methylene octahydrofuroACTHNUGRTENUNG[3,2-b]oxepine (38b)
G
(Æ)-2-[(2S,7S)-7-Isopropyl-3,4-dimethyleneoxepan-2-yl]ethanol (35)
By following the same procedure as that used for the preparation of 37a/
b, the reaction of the acetate 35 (90 mg, 0.43 mmol), NaHCO3 (720 mg,
8.57 mmol), and iodine (1.08 g, 4.27 mmol) in Et2O (8 mL)/H2O (2 mL)
gave a diastereomeric mixture of the iodides 38a/b (110 mg, 77%) as a
colorless oil after purification by column chromatography on silica gel
(EtOAc/n-hexane 1:20).
By following the same procedure as that used for the preparation of 34,
the reaction of the acetate 32 (240 mg, 0.95 mmol) and potassium carbon-
ate (263 mg, 1.90 mmol) in MeOH (8 mL)/H2O (2 mL) gave the alcohol
35 (190 mg, 95%) as a colorless oil after purification by column chroma-
tography on silica gel (EtOAc/n-hexane 1:4). IR (thin film): n˜ =2958,
2874, 1738, 1626, 1470, 1386, 1248, 1057 cmÀ1 1H NMR (400 MHz,
;
Product 38a (major)
CDCl3): d=5.09 (s, 1H), 4.94 (d, 1H, J=2.0 Hz), 4.85 (s, 1H), 4.79 (s,
1H), 4.34–4.31 (m, 1H), 3.85–3.81 (m, 2H), 3.26–3.21 (m, 1H), 2.66–2.64
(m, 1H), 2.58–2.52 (m, H), 2.20–2.19 (m, 1H), 2.00–1.97 (m, 1H), 1.85–
1.79 (m, 2H), 1.77–1.70 (m, 1H), 1.53–1.47 (m, 1H), 0.93 (d, 3H, J=
6.8 Hz), 0.91 ppm (d, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): d=
154.45, 150.04, 112.23, 110.79,85.54, 82.25, 61.11, 37.74, 35.12, 33.97, 32.98,
19.04, 18.20 ppm; HRMS-CI: m/z: calcd for C13H21O2: 209.1542 [MÀH]+;
found: 209.1539.
1H NMR (400 MHz, CDCl3): d=5.37 (m, 1H), 5.06 (m, 1H), 4.02–3.92
(m, 3H), 3.39 (d, 1H, J=10.6 Hz), 3.36 (d, 1H, J=10.6 Hz), 2.97 (ddd,
1H, J=11.2, 6.7, 2.2 Hz), 2.54 (ddd, 1H, J=13.7, 3.9, 3.9 Hz), 2.42–2.30
(m, 1H), 2.05–1.95 (m, 2H), 1.89–1.83 (m, 1H), 1.70–1.45 (m, 2H), 0.91
(d, 1H, J=6.7 Hz), 0.86 ppm (d, 1H, J=6.7 Hz).
Product 38b (minor)
1H NMR (400 MHz, CDCl3): d=5.13 (s, 1H), 5.05 (s, 1H), 4.32 (dd, 1H,
J=4.2, 2.3 Hz), 4.07 (ddd, 1H, J=11.8, 6.5, 6.5 Hz), 4.02–3.96 (m, 1H),
2098
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2092 – 2100

Synthesis of 3,4-Dimethylidene Oxacycles
3.67 (d, 1H, J=10.6 Hz), 3.61 (ddd, 1H, J=11.8, 6.4, 6.4 Hz), 3.52 (d,
1H, J=10.6 Hz), 3.30 (ddd, 1H, J=3.5, 5.6, 2.8 Hz), 2.35–2.28 (m, 1H),
2.10–2.00 (m, 2H), 1.85–1.80 (m, 1H), 1.70–1.35 (m, 3H), 0.90 (d, 1H,
J=6.7 Hz), 0.89 ppm (d, 1H, J=6.7 Hz).
33.25, 30.63, 22.05, 19.14, 18.60 ppm; HRMS-CI: m/z: calcd for C12H21O3:
212.1412 [M+H]+; found: 213.1490.
(Æ)-(3aS,5S,7aR,101R)-5-Isopropyloctahydro-2H-difuro[3,2-b:3’,4’-
c]oxepin-7a-ol (42)
(Æ)-(3aS,8aR)-8a-(Iodomethyl)hexahydrofuro
(39)
ACHTUNGERTN[NUNG 3,2-b]oxepin-8(2H)one
NMO (21 mg, 0.18 mmol) and osmium tetroxide (1.5 mg, 0.004 mmol)
were added to a solution of the alkene 38a (30 mg, 0.089 mmol) in ace-
tone (8 mL) and water (2 mL). The resulting mixture was stirred for 36 h
at room temperature. After the addition of aqueous sodium hydrogen
sulfite (5 mL), the mixture was stirred for another 24 h and extracted
with ethyl acetate (3ꢁ10 mL). The organic extract was washed with
brine, dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (EtOAc/n-
hexane 1:10) to give the tricyclic compound 42 (18 mg, 85%) as a clear
oil. IR (thin film): n˜ =2963, 2943, 2884, 1726, 1145, 1326, 1276, 1194,
The alkene 37a (40 mg, 0.14 mmol) in CH2Cl2 (10 mL) was cooled to
À788C and then ozone was passed into the reaction mixture until a light-
blue color persisted (45 min to 1 h). Argon gas was then bubbled through
the solution to remove excess ozone. Dimethyl sulfide (17 mg,
0.27 mmol) was added and the dry ice/acetone bath was replaced by an
ice bath. The reaction mixture was allowed to warm to 238C and stirred
for an additional 18 h. The solvent was removed under reduced pressure
and the residue was purified by column chromatography on silica gel
(EtOAc/n-hexane 1:20) to give the ketone 39 (34 mg, 85%) as an oil. IR
1108, 1072, 1013 cmÀ1 1H NMR (400 MHz,CDCl3): d=4.16–4.10 (m,
;
(thin film): n˜ =2957, 2876, 1721, 1438, 1319, 1199, 1103, 1062, 946 cmÀ1
;
2H), 4.01 (d, 1H, J=4.0 Hz), 3.99–3.94 (m, 1H), 3.92 (d, 1H, J=8.8 Hz),
3.86 (d, 1H, J=8.4 Hz), 3.71–3.65 (m, 1H), 3.58 (dd, 2H, J=3.6 Hz),
2.19–2.06 (m, 2H), 1.88–1.80 (m, 2H), 1.64–1.50 (m, 4H), 0.94 (d, 3H,
J=6.8 Hz), 0.87 ppm (d, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3):
d=94.54, 83.74, 81.98, 80.00, 78.25, 72.81, 65.50, 34.84, 33.66, 27.83, 21.49,
18.98, 18.84 ppm; HRMS-CI: m/z: calcd for C13H23O4: 243.1596 [M+H]+;
found: 243.1593.
1H NMR (400 MHz, CDCl3): d=4.11–4.06 (m, 1H), 4.03–3.83 (m, 2H),
3.68–3.60 (m, 1H), 3.54 (d, 1H, J=10.8 Hz), 3.43 (d, 1H, J=10.8 Hz),
2.66–2.63 (m, 2H), 2.30–2.28 (m, 1H), 2.27–2.18 (m, 1H), 2.05–1.90 ppm
(m, 3H); 13C NMR (100 MHz, CDCl3): d=204.28, 93.04, 84.83, 71.20,
67.85, 38.14, 35.17, 26.63, 6.78 ppm; HRMS-CI: m/z: calcd for C9H14IO3:
296.9988 [M+H]+; found: 296.9985.
(Æ)-(2S,7S)-2-(2-Hydroxyethyl)-7-isopropyl-3-methyleneoxepan-4-one
(43)
(Æ)-(3aS,5S,8aR)-8a-(Iodomethyl)-5-isopropylhexahydrofuro
b]oxepin-8(2H)one (40a) and (Æ)-(3aS,5S,8aS)-8a-(iodomethyl)-5-
isopropylhexahydrofuro[3,2-b]oxepin-8(2H)one (40b)
ACHTUNGTNER[NUNG 3,2-
ACHTUNGTRENNUNG
HMPA (0.5 mL) and SmI2 (0.89 mL, 0.5m solution in THF, prepared
from samarium and CH2I2 by following the literature procedure)[15] were
added to a solution of the iodide 40a (50 mg, 0.15 mmol) in THF (5 mL)
at room temperature. After having been stirred for 12 h, the reaction
mixture was quenched with 1.0n HCl (10 mL) and extracted with EtOAc
(3ꢁ10 mL). The organic extracts were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (EtOAc/n-hexane
1:6) to give the enone 43 (19 mg, 60%) as an oil. IR (thin film): n˜ =2960,
By following the same procedure as that used for the preparation of 39,
the reaction of the alkene 38a/b (110 mg, 0.33 mmol), ozone, and dime-
thylsulfide (41 mg, 0.66 mmol) in CH2Cl2 (30 mL) gave the ketones 40a
(74 mg, 67%) and 40b (25 mg, 23%) as colorless oils after purification
by column chromatography on silica gel (EtOAc/n-hexane 1:20).
Product 40a
IR (thin film): n˜ =2974, 2912, 2880, 1720, 1343, 1263, 1192, 1078, 1025,
2867, 1695, 1435, 1345, 1260, 1123, 1056 cmÀ1 1H NMR (400 MHz,
;
936 cmÀ1 1H NMR (400 MHz, CDCl3): d=4.12–4.09 (m, 2H), 4.04–3.97
;
CDCl3): d=6.03 (s, 2H), 5.32 (s, 1H), 4.50 (t, 1H, J=6.4 Hz), 3.90–3.86
(m, 2H), 3.47–3.41 (m, 1H), 2.77–2.68 (m, 2H), 1.99–1.89 (m, 4H), 1.78–
1.70 (m, 2H), 0.97 (d, 3H, J=6.8 Hz), 0.94 ppm (d, 3H, J=6.8 Hz);
13C NMR (100 MHz, CDCl3): d=202.79, 149.83, 120.69, 87.48, 76.71,
58.93, 40.83, 36.26, 33.63, 29.62, 18.98, 18.66 ppm; HRMS-EI: m/z: calcd
for C12H20O3: 212.1412 [M]+; found: 212.1410.
(m, 1H), 3.52 (d, 1H, J=10.4 Hz), 3.37 (d, 1H, J=10.8 Hz), 3.19–3.14
(m, 1H), 2.64–2.61 (m, 2H), 2.26–2.61 (m, 2H), 2.05–2.01 (m, 1H), 1.94–
1.90 (m, 1H), 1.71–1.60 (m, 2H), 0.89 (d, 3H, J=6.7 Hz), 0.86 ppm (d,
3H, J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=205.11, 93.54, 88.93,
86.23, 68.54, 37.34, 35.14, 33.04, 30.04, 19.13, 10.57, 7.28 ppm; HRMS-EI:
m/z: calcd for C12H19IO3: 338.0379 [M]+; found: 338.0374.
Product 40b
IR (thin film): n˜ =2959, 2930, 2875, 1728, 1470, 1435, 1368, 1256, 1192,
Acknowledgements
1107, 1059 cmÀ1 1H NMR (400 MHz, CDCl3): d=4.23–4.17 (m, 1H),
;
4.12 (t, 1H, J=3.2 Hz), 3.78–3.72 (m, 1H), 3.67 (d, 1H, J=11.2 Hz), 3.39
(d, 2H, J=10.8 Hz), 3.04–3.00 (m, 1H), 2.44–2.40 (m, 1H), 2.28–2.22 (m,
1H), 2.13–2.09 (m, 1H), 1.91–1.89 (m, 1H), 1.71–1.63 (m, 2H), 1.47–1.40
(m, 1H), 0.91 (d, 3H, J=6.7 Hz), 0.90 ppm (d, 3H, J=6.7 Hz); 13C NMR
(100 MHz, CDCl3): d=210.17, 83.50, 82.13, 78.19, 58.92, 35.41, 34.05,
33.51, 28.40, 18.72, 17.48, 11.79 ppm; HRMS-CI: m/z: calcd for
C12H20IO3: 339.0457 [M+H]+; found: 339.0452.
This research project was financially supported by the Korea Institute of
Science and Technology (KIST), Seoul, South Korea.
[1] a) E. Arundale, L. A. Mikeska, Chem. Rev. 1952, 51, 505; b) D. R.
Adams, S. P. Bhatnagar, Synthesis 1977, 661; c) B. B. Snider, In Com-
prehensive Organic Synthesis, Vol. 2 (Eds.: B. Trost, I. Fleming, C. H.
Heathcook), Pergamon, New Yok, NY, 1991, pp. 527–561.
[2] For recent reviews of Prins-type cyclizations, see: a) I. M. Pastor, M.
Yus, Curr. Org. Chem. 2007, 11, 925; b) C. Olier, M. Kaafarani, S.
Gastaldi, M. P. Bertrand, Tetrahedron 2010, 66, 413.
[3] a) G. S. Viswanathan, J. Yang, C. J. Li, Org. Lett. 1999, 1, 993; b) Y.
Lian, R. J. Hinkle, J. Org. Chem. 2006, 71, 7071; c) L. E. Overman,
A. Castaneda, T. A. Blumenkopf, J. Am. Chem. Soc. 1986, 108,
1303; d) C. Semeyn, R. H. Blaauw, H. Hiemstra, W. N. Speckamp, J.
Org. Chem. 1997, 62, 3426; e) A. P. Dobbs, S. Martinovic, Tetrahe-
dron Lett. 2002, 43, 7055; f) K. Meilert, M. A. Brimble, Org. Lett.
2005, 7, 3497.
[4] a) H. Huang, J. S. Panek, J. Am. Chem. Soc. 2000, 122, 9836; b) I. E.
Markꢂ, R. Dumeunier, C. Leclercq, B. Leroy, J.-M. Plancher, A.
Mekhalfia, D. J. Bayston, Synthesis 2002, 958; c) B. Leroy, I. E.
Markꢂ, J. Org. Chem. 2002, 67, 8744; d) C. M. Yu, J. Y. Lee, B, So,
(Æ)-(3aS,5S,8aR)-5-Isopropyl-8a-methylhexahydrofuro
8(2H)one (41)
ACHTUNGTREN[NGNU 3,2-b]oxepin-
nBu3SnH (39 mg, 0.13 mmol) was added to a solution of the iodide 40a
(15 mg, 0.044 mmol) and AIBN (7.3 mg, 0.044 mmol) in benzene (5 mL)
at room temperature. The reaction mixture was stirred at 908C for 2 h.
The solvent was removed under reduced pressure and the residue was
purified by column chromatography on silica gel (EtOAc/n-hexane 1:25)
to give the title compound 41 (7.5 mg, 80%) as a clear oil. IR (thin film):
n˜ =2957, 2929, 2858, 1724, 1459, 1379, 1276, 1113, 1077 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=4.06–3.99 (m, 2H), 3.96 (d, 1H, J=5.6 Hz), 3.17–
3.12 (m, 1H), 2.72–2.65 (m, 1H), 2.61–2.55 (m, 1H), 2.19–2.16 (m, 1H),
2.05–2.00 (m, 1H), 1.91–1.87 (m, 1H), 1.70–1.58 (m, 2H), 1.36 (s, 3H),
0.90 (d, 3H, J=6.7 Hz), 0.87 ppm (d, 3H, J=6.7 Hz); 13C NMR
(100 MHz, CDCl3): d=209.36, 92.74, 88.97, 86.93, 67.80, 37.76, 34.01,
Chem. Asian J. 2011, 6, 2092 – 2100
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2099

S.-J. Min, Y. S. Cho et al.
FULL PAPERS
J. Hong, Angew. Chem. 2002, 114, 169; Angew. Chem. Int. Ed. 2002,
41, 161; e) D. L. Aubele, C. A. Lee, P. E. Floreancig, Org. Lett. 2003,
5, 4521; f) K. P. Chan, T. P. Loh, Tetrahedron Lett. 2004, 45, 8387;
g) C. Pꢃrez-Balado, I. E. Markꢂ, Tetrahedron Lett. 2005, 46, 4887;
h) M. Pham, A. Allatabakhsh, T. G. Minehan, J. Org. Chem. 2008,
73, 741; i) W. R. Roush, G. J. Dilley, Synlett 2001, 955.
[9] Propionaldehydes 20 were easily prepared from addition of the cor-
responding lithium acetylide (generated from alkyne and nBuLi) to
dimethylformamide.
[10] a) T. Shimizu, R. Kobayashi, K. Osako, H. Osada, T. Nakata, Tetra-
hedron Lett. 1996, 37, 6755; b) M.-P. Heitz, A. Wagner, C. Mioskow-
ski, J. Org. Chem. 1989, 54, 500.
[5] a) Y. S. Cho, K. Karupaiyan, H. J. Kung, A. N. Pae, J. H. Cha, H. Y.
Koh, M. H. Chang, Chem. Commun. 2003, 2346; b) H. J. Kang, S. H.
Kim, A. N. Pae, H. Y. Koh, M. H. Chang, K. I. Choi, S.-Y. Han, Y. S.
Cho, Synlett 2004, 2545.
[6] P. R. Ullapu, S.-J. Min, S. N. Chavre, H. Choo, J. K. Lee, A. N. Pae,
Y. Kim, M. H. Chang, Y. S. Cho, Angew. Chem. 2009, 121, 2230;
Angew. Chem. Int. Ed. 2009, 48, 2196.
[7] For synthesis of 2-aryl-4-methylenetetrahydrofurans from allyltrime-
thylsilane, see: a) B. M. Trost, S. A. King, Tetrahedron Lett. 1986, 27,
5971; b) T. Oriyama, A. Ishiwata, T. Sano, T. Matsuda, M. Takaha-
shi, G. Koga, Tetrahedron Lett. 1995, 36, 5581.
[8] a) B. M. Trost, H. Urabe, J. Am. Chem. Soc. 1990, 112, 4982; b) P. H.
Lee, K. Bang, H. Ahn, K. Lee, Bull. Korean Chem. Soc. 2001, 22,
1385.
[11] Allenylmethylsilane 24 was prepared by the same procedure as re-
ported in reference [8b].
[12] For examples of various oxacycles in natural products, see:
a) T. L. B. Boivin, Tetrahedron 1987, 43, 3309; b) P. A. Clarke, S.
Santos, Eur. J. Org. Chem. 2006, 2045; c) M. L. A. A. Luiz, L. S, M.
Vasconcellos, Quim. Nova 2006, 29, 834.
[13] C.-G. Yang, N. W. Reich, Z. Shi, C. He, Org. Lett. 2005, 7, 4553.
[14] L. Coulombel, I. Favier, E. DuÇach, Chem. Commun. 2005, 2286.
[15] T. Nishiyama, K. Kitano, H. Kishi, F. Yamada, Bull. Chem. Soc. Jpn.
1993, 66, 3822.
[16] P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,
2693.
Received: February 15, 2011
Published online: June 9, 2011
2100
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2092 – 2100