Diastereoselective synthesis of 2,6-disubstituted 4-(Dimethoxymethyl)tetra- hydropyrans using TMSOTf-promoted prins-pinacol cyclization

Article abstract of DOI:10.1055/s-0033-1339709

We have described a highly diastereoselective synthesis of 2,6-disubstituted 4-(dimethoxymethyl)tetrahydropyrans via TMSOTf-promoted Prins-pinacol reaction of methylene diol with acetals. This reaction provides an efficient procedure to synthesize functionalized tetrahydropyrans containing an acetal group at the C4 position with all-cis 2,4,6 relative configuration.

Full text of DOI:10.1055/s-0033-1339709

2292▌
LETTER
lDettierastereoselective Synthesis of 2,6-Disubstituted 4-(Dimethoxymethyl)tetra-
hydropyrans Using TMSOTf-Promoted Prins–Pinacol Cyclization
2,6-Disubstituted 4-(Dimethoxymethyl)tetrahydropyrans
Young Seub Kim,a,b Jae Kyun Lee,a Ae Nim Pae,a,b Yong Seo Cho,*a,b Sun-Joon Min*a,b
a
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu,
Seoul 136-791, South Korea
Fax +822(958)5189; E-mail: sjmin@kist.re.kr; E-mail: ys4049@kist.re.kr
b
Department of Biological Chemistry, University of Science and Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon, 305-333, South
Korea
Received: 16.07.2013; Accepted after revision: 13.08.2013
in a single step through a stereoelectronically favored
Abstract: We have described a highly diastereoselective synthesis
transition state.6 4-Acetyl-2,6-disubstituted tetrahydropy-
of 2,6-disubstituted 4-(dimethoxymethyl)tetrahydropyrans via
rans 1 (R3 = Me) were obtained in useful yields and high
stereoselectivities by this Prins–pinacol sequences,
TMSOTf-promoted Prins–pinacol reaction of methylene diol with
acetals. This reaction provides an efficient procedure to synthesize
functionalized tetrahydropyrans containing an acetal group at the whereas application of this strategy to the preparation of
4-formyltetrahydropyrans 1 (R3 = H) turned out to be less
C4 position with all-cis 2,4,6 relative configuration.
successful due to considerably low yields and low selec-
tivities, which resulted from oligomerization and less
preferential hydride migration in the pinacol step. Thus,
we tried to find a new method for the preparation of such
tetrahydropyran derivatives with high stereoselectivities.
For this purpose, our current study has been focused on
the Prins–pinacol reactions based on the following ap-
proaches: 1) investigation of Lewis acid promoters and
additives and 2) utilization of acetals as electrophiles. We
herein report an efficient and stereocontrolled synthesis of
2,6-disubstituted 4-(dimethoxymethyl)tetrahydropyrans
through a TMSOTf-promoted Prins–pinacol reaction.
Key words: cyclization, Lewis acids, oxonium ion, diastereoselec-
tivity, 2,4,6-trisubstituted tetrahydropyrans
Tetrahydropyrans are important structural building blocks
for a number of biologically active natural products as
well as therapeutically useful agents.1 In particular, tetra-
hydropyran ring bearing various substituents in different
positions has attracted significant attention in recent
years, which drives the development of novel methodolo-
gies for stereoselective synthesis of substituted tetrahy-
dropyran ring system.2 Among several synthetic
strategies, Prins-type cyclizations have been used effec-
tively for the stereoselective synthesis of tetrahydropyran
ring structures.3 In general, the reaction involves the acid-
mediated formation of a homoallylic oxocarbenium inter-
mediate, which undergoes cyclization followed by effi-
cient termination process such as nucleophile trapping or
elimination to afford the tetrahydropyran ring. Our recent
studies have highlighted the opportunities in construction
of structurally complex tetrahydropyrans provided by uti-
lizing a silyl group to terminate a Prins cyclization.4
O
H
O
R3
N
N
N
R1
H
O
R1
O
R2
R2
Figure 1 Structures of T-type calcium channel blockers for SAR
study and their tetrahydropyran component
R3
OH
R3
O
Meanwhile, we were interested in the synthesis of substi-
tuted tetrahydropyrans during the course of lead optimiza-
tion of T-type calcium channel blockers (Figure 1).5 In
order to study the structure–activity relationship of di-
verse tetrahydropyran analogues, it is necessary to synthe-
size 2-substituted or 2,6-disubstituted tetrahydropyran 4-
carbaldehyde 1 diastereoselectively, which can be easily
used to construct tertiary amine structures via reductive
amination. As depicted in Scheme 1, it has been reported
that the Prins–pinacol-type cyclization of 2-methylene-
1,4-diol 2 with aldehydes in the presence of Lewis acid
can afford substituted tetrahydropyran 4-carbaldehydes 1
SnCl4 or TfOH
MeNO2, –25 °C
O
+
R2
H
R1
O
R2
R1
OH
R3 = Me, 81–51% (18:1 to 6:1)
3 = H, 65–34% (ca 7:3)
2
1
R
Scheme 1 Overman’s study on the synthesis of 2,6-disubstituted tet-
rahydropyran 4-carbaldehyde via Prins–pinacol reaction
To improve the selectivity of the Prins–pinacol protocol
developed by Overman,6a we first commenced with the re-
action of 3-hydroxymethylbut-3-en-1-ol (3)7 with benzal-
dehyde in the presence of various Lewis acids (Table 1).
Screening conventional Lewis acids for Prins–pinacol cy-
clizations, we found that BF3·OEt2, TfOH, and TMSOTf
SYNLETT 2013, 24, 2292–2296
Advanced online publication: 13.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339709; Art ID: ST-2013-U0662-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,6-Disubstituted 4-(Dimethoxymethyl)tetrahydropyrans
2293
effectively provided the desired aldehyde 4a in reasonable diastereoselectivity. It should be pointed out that the addi-
yields although the diastereoselectivities were consider- tion of TMSOTf in both cases rapidly led to formation of
ably moderate in all cases (Table 1, entries 6–8). The yield 5a within 30 minutes at –78 °C, and longer reaction time
of the product 4a increased when we applied collidine as did not change the cis/trans selectivity, which indicated
an additive base (Table 1, entry 9). Finally, we observed that this reaction presumably proceeded via a kinetic tran-
that the reaction yield was significantly improved up to sition state. The structure and stereochemistry of 5a was
75% in the presence of i-Pr2NEt (Table 1, entry 10).8,9 confirmed by assigning all protons based on their proton
However, the 3:1 diastereomeric ratio was not changed coupling constants and 1H-COSY, indicating a 2,4-cis re-
under these conditions. This low selectivity is presumably lationship on the tetrahydropyran ring.
due to the lack of facial preference of hydride migration.
OTMS
or
OH
TMSOTf (2.0 equiv)
DIPEA (2.0 equiv)
Table 1 Screening of Lewis Acids for Improving the Stereoselectiv-
ity of the Prins–Pinacol Reaction
OMe
OMe
+
Ph
O
4 Å MS, CH2Cl2, –78 °C
O
OH
CHO
CHO
OTMS
6a
OH
Lewis acid, additive
Ph
+
3
6b
4 Å MS, CH2Cl2 (0.05 M),
–78 °C, 2 h
MeO
OMe
O
Ph
TMSOTf (2.5 equiv)
DIPEA (2.5 equiv)
OH
OMe
OMe
3
4a
3
+
+
4a
4 Å MS, CH2Cl2, –78 °C
then
TMSOTf (1.0 equiv)
7%
Ph
Entry
Conditions (equiv)
Yield (%) (cis/trans)a
(cis/trans = 3:1)
O
Ph
68%
(cis/trans = 12:1)
5a
b
1
2
Me2AlCl (1.5)
–
b
MeO
OMe
Ti(Oi-Pr)4 (1.5)
InBr3 (1.5)
–
TMSOTf (1.0 equiv)
OMe
b
3
–
+
4a
6a +
Ph
4 Å MS, CH2Cl2, –78 °C
7%
OMe
b
4
Sc(OTf)3 (1.5)
–
63%
(cis/trans = 12:1)
(cis/trans = 3:1)
O
Ph
b
5
TiCl4 (1.5)
–
5a
6
BF3·OEt2 (1.5)
14 (3:1)
34 (3:1)
49 (3:1)
60 (3:1)
75 (3:1)
Scheme 2 Prins–pinacol reactions of 3 and 6a with benzaldehyde di-
methyl acetal
7
TfOH (1.5)
8
TMSOTf (2.0)
Mechanistically, high stereoselectivity for the formation
of acetal 5a is rationalized as shown in Scheme 3. We
speculated that an oxocarbenium ion I is generated from
the condensation of diol 3 with either aldehyde or acetal.
Then, cyclization proceeds through a chairlike transition
state to afford the tetrahydropyranyl carbocation species
II. According to the literature,12 the trapping of the tertiary
carbocation with an external nucleophile is kinetically fa-
vorable at the equatorial position. In our cases, TMSOMe
or TMSOH may act as a nucleophile to interact with the
carbocation intermediate to generate IIa or IIb temporar-
ily, which induces hydride migration to the axial position
giving 2,4-cis-tetrahydropyran as the major isomer. In this
event, we thought that the formation of IIb is more selec-
tive than that of IIa due to the preferential complexation
with TMSOMe over TMSOH at the C4 equatorial posi-
tion. In addition, further acetalization of III with
TMSOMe under anhydrous conditions is responsible for
the formation of 5. Therefore, acetal substrates in our
Prins–pinacol sequences showed a high diastereoselectiv-
ity providing tetrahydropyranyl acetal 5 as a major prod-
uct.
9
TMSOTf (2.0), collidine (1.2)
TMSOTf (2.0), i-Pr2NEt (1.2)
10
a The ratio was determined by NMR spectroscopy.
b The starting material was recovered.
Next, we turned our attention to the Prins–pinacol reac-
tions of 3 with acetals (Scheme 2). It has been reported
that acetals prove to be excellent substrates for Lewis acid
mediated C–C bond-forming reactions through oxocarbe-
nium intermediate.10 Initially, we attempted the cycliza-
tion reaction under the same conditions as previously
optimized, but it did not proceed to give the desired tetra-
hydropyrans. We suspected that two equivalents of
TMSOTf may be insufficient for promoting the cycliza-
tion reaction due to formation of the bissilyl ether 6a or
cyclic acetal 6b. Accordingly, diol 3 was completely con-
verted into the corresponding bissilyl ether 6a, which was
subsequently subjected to an additional one equivalent of
TMSOTf. Interestingly, we obtained dimethyl acetal 5a as
the major product (not aldehyde 4a) in 68% yield with
high diastereoselectivity.11 Alternatively, bissilyl ether
6a, isolated by column chromatography, was also treated
with one equivalent of TMSOTf, which dominantly pro-
duce the same dimethyl acetal 5a in good yield and high
With this successful formation of acetal 5a, we then ex-
amined the scope of the cyclization process with various
acetals as summarized in Table 2. In general, a wide range
of aromatic acetals were tolerated under these reaction
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2292–2296

2294
Y. S. Kim et al.
LETTER
X, Y = H or OTMS
H
Table 2 Scope of the Prins–Pinacol Reaction of 3 with Various Ac-
etals
Y
X
SiMe3
OR2
OH
MeO
OMe
OMe
TMSOTf (2.5 equiv)
DIPEA (2.5 equiv)
O
O
O
R1
R1
R1
R2
R2
+
OMe
4 Å MS, CH2Cl2, –78 °C
then TMSOTf (1.0 equiv)
I
stabilized by TMSOR
IIa, R = H (from aldehyde)
IIb, R = Me (from acetal)
O
R1
OH
3
R2
‡
5
TMSOH
H
O
4
SiMe3
R1
Entry
R1
R2
Yield of 5 (%) Yield of 4 (%)
(cis/trans)a
(cis/trans)a
TMSOMe
1
2
3
4
5
6
7
8
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-O2NC6H4
naphthyl
Bn
H
H
H
H
H
H
H
61 (>20:1)
51b
16 (3:1)
28 (3:1)
21 (3:1)
O
5
III
Scheme 3 Proposed mechanism for the formation of 4 and 5
60 (19:1)
n.r.c
conditions. The Prins–pinacol reactions of 3 with elec-
tron-rich benzaldehyde dimethyl acetals gave the corre-
sponding 2,4-cis-disubstituted tetrahydropyrans 5 in good
yield and high diastereoselectivity, although a small
amount of aldehydes 4 were also formed as 3:1 mixtures
of diastereomers (Table 2, entries 1 and 2).13 We found
that chlorobenzaldehyde was still a valid substrate for our
reaction process, whereas no desired product was ob-
served in the case of nitrobenzaldehyde dimethyl acetal
(Table 2, entries 3 and 4). The reactions of 3 with aliphatic
acetals such 1,4-dimethoxyheptane or (2,2-dimethoxyeth-
yl)benzene also proceeded to afford acetals 5 with high
stereoselectivity (Table 2, entries 6 and 7). It is notewor-
thy that we could obtain the 2,2-disubstituted tetrahydro-
pyran derivative effectively in 57% yield (Table 2, entry
8).
52b
20 (3:1)
10 (3:1)
22 (3:1)
6
50b
n-C6H13
39 (20:1)
57
–(CH2)5–
a The ratio was determined by NMR spectroscopy.
b The ratio could not be determined by NMR analysis.
c n.r. = no reaction.
phatic acetal and ketal substrates (Table 3, entries 7 and
8). The stereochemistry of 10 was established based on
the analysis of NMR spectra.
1) PPh3CH3Br
KOt-Bu
2) p-TsOH, acetone
O
OH
1) p-TsOH, 74%
2) NaIO4, 78%
Finally, we attempted the synthesis of 2,6-disubstituted 4-
(dimethoxymethyl)tetrahydropyrans 10 using diol 9 bear-
ing secondary alcohol as a substrate. We expected that all
substituents on the tetrahydropyran 10 would occupy
equatorial positions due to the cyclization of an (E)-oxo-
carbenium ion in a chairlike conformation I as suggested
in Scheme 3 above. In order to prepare diol 9, we planned
to use Masuyama’s protocol14 involving allylation of
benzaldehyde with 2-methylene-1,3-diol (8) in the pres-
ence of palladium catalyst (Scheme 4). Thus, diol 8 was
first synthesized starting from Trizma® HCl using the fol-
lowing reaction sequences: ketal formation, oxidative
cleavage of alkene,15 Wittig olefination, and hydrolysis of
ketal. Next, a mixture of benzaldehyde and diol 8 was
smoothly transformed into the desired diol 9 by treatment
of tin(II) chloride in the presence of PdCl2(PhCN)2. With
this substrate 9 in hand, we performed the reaction of 9
with various acetals under the previously optimized con-
ditions (Table 3). As anticipated, the desired tetrahydro-
pyrans 10 were obtained as acetal forms in good yield and
high selectivity along with the formation of a small
amount of aldehyde products.16 Only the use of 4-nitro-
benzaldehyde dimethyl acetal (Table 3, entry 5) led to the
formation of 10 in low yield, presumably caused by insta-
bility of an oxocarbenium intermediate. On the other
hand, the reactions were also effective in the case of ali-
NH3Cl
O
O
OH OH
75% (2 steps)
OH OH
8
7
R1R2C(OMe)2
TMSOTf (2.5 equiv)
DIPEA (2.5 equiv)
OH
R3
PhCHO
SnCl2⋅2H2O
PdCl2(PhCN)2
DMF, r.t.
83%
4 Å MS, MeCN, –78 °C
then
TMSOTf (1.0 equiv)
Ph
O
R1
Ph
OH
R2
9
10 R3 = CH(OMe)2
11 R3 = CHO
(see Table 3)
Scheme 4 Synthesis of 2,6-disubstituted 4-dimethoxymethyl tetra-
hydropyrans
In conclusion, we here described the diastereoselective
synthesis of highly substituted tetrahydropyrans via
TMOTf-promoted Prins–pinacol reactions of methylene
diol with various acetals. We can easily operate this pro-
tocol in a single process to selectively construct all-cis
2,4,6-trisubstituted tetrahydropyran derivatives contain-
ing acetal functionality at the C4 position. Thus, the high
efficiency and stereoselectivity achieved in this method
provide its synthetic utility for the construction of diverse
compounds, which will be rapidly available for medicinal
Synlett 2013, 24, 2292–2296
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,6-Disubstituted 4-(Dimethoxymethyl)tetrahydropyrans
2295
Kim, Y.; Chang, M. H.; Cho, Y. S. Angew. Chem. Int. Ed.
2009, 48, 2196. (c) Chavre, S. N.; Ullapu, P. R.; Min, S.-J.;
Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. Org. Lett. 2009,
11, 3834.
Table 3 Scope of the Prins–Pinacol Annulation of 9 with Various
Acetals
Entry
R1
R2
Yield of 10 (%) Yield of 11 (%)
(cis/trans)a
(cis/trans)a
(5) (a) Gu, S. J.; Lee, J. K.; Pae, A. N.; Chung, H. J.; Rhim, H.;
Han, S. Y.; Min, S.-J.; Cho, Y. S. Bioorg. Med. Chem. Lett.
2010, 20, 2705. (b) Shipe, W. D.; Barrow, J. C.; Yang, Z. Q.;
Lindsley, C. W.; Yang, F. V. J. Med. Chem. 2008, 51, 3692.
(6) (a) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc.
1999, 121, 1092. (b) For a recent review of semipinacol
rearragement, see: Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem.
Rev. 2011, 111, 7523.
(7) 3-Hydroxymethylbut-3-en-1-ol (3) was easily synthesized
from reduction of dimethyl itaconate with
diisopropylaluminum hydride in THF at 0 °C for 2.5 h.
(8) The reaction in the presence of a 1:1 ratio of TMSOTf and i-
Pr2NEt gave only the mixture of mono- or bistrimethylsilyl
ethers.
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
75 (12:1)
63 (8:1)
61b
trace
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-O2NC6H4
naphthyl
Bn
18 (2:1)
21b
52 (10:1)
17b
21 (2:1)
trace
59 (10:1)
44 (9:1)b
68 (3:1)b
7 (1.3:1)
10 (3:1)
trace
(9) Experimental Procedure for the Synthesis of 4 (Table 1,
Entry 10)
–(CH2)5–
a The ratio was determined by NMR spectroscopy.
To a solution of diol 3 (30 mg, 0.29 mmol), benzaldehyde
(60 μL, 0.58 mmol), and DIPEA (60 μL, 0.35 mmol) in
anhydrous CH2Cl2 (6.0 mL) was added TMSOTf (0.11 mL,
0.58 mmol) at –78 °C. The mixture was stirred at –78 °C for
2 h, quenched with sat. aq NaHCO3 and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure. The crude residue was
purified by column chromatography on silica gel (EtOAc–
n-hexane, 1:8) to afford cis-4a (42 mg, 56%) and trans-4a
(14 mg, 18%) as a colorless oil.
b The ratio could not be determined by NMR analysis.
chemistry to explore small molecule–protein interaction.
We are currently expanding this methodology to the for-
mation of highly substituted tetrahydropyrans in an enan-
tioselective manner. The results of these studies will be
reported in due course.
Compound cis-4a: 1H NMR (300 MHz, CDCl3): δ = 9.65 (s,
1 H), 7.36–7.26 (m, 5 H), 4.38 (dd, J = 11.3, 2.1 Hz, 1 H),
4.27 (dd, J = 11.7, 4.5 Hz, 1 H), 3.66 (td, J = 10.9, 2.1 Hz, 1
H), 2.69 (m, 1 H), 2.13 (m, 1 H), 1.91 (m, 1 H), 1.70 (m, 1
H), 1.58 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 202.2,
142.0, 128.4, 127.7, 125.8, 79.3, 78.9, 67.4, 48.2, 33.2, 29.7,
25.4. HRMS (EI+): m/z calcd for C12H14O2: 190.0994 [M]+;
found: 190.0996.
Acknowledgment
We are grateful to the Korea Institute of Science and Technology
(2E24183, 2E23770, 2E23870) and the National Research Founda-
tion (NRF-2010-0022531) for financial support of this research.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
Compound trans-4a: 1H NMR (300 MHz, CDCl3): δ = 9.90
(s, 1 H), 7.36–7.24 (m, 5 H), 4.37 (dd, J = 11.3, 2.4 Hz, 1 H),
4.03 (m, 1 H), 3.60 (td, J = 12.0, 2.9 Hz, 1 H), 2.79 (m, 1 H),
2.34 (m, 1 H), 2.10 (m, 1 H), 2.04 (m, 1 H), 1.95 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 203.8, 142.2, 128.4, 127.5,
125.7, 76.3, 65.3, 44.7, 31.8, 24.3.
References and Notes
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(10) (a) Lee, H. G.; Lysenko, I. L.; Cha, J. K. Angew. Chem. Int.
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(11) Experimental Procedure for the Synthesis of 5 (Scheme
2)
(3) For recent reviews of Prins-type cyclizations, see: (a) Pastor,
I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925. (b) Olier, C.;
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To a round-bottom flask equipped with a magnetic stir bar
and charged with CH2Cl2 (6 mL) was added 2-methylene-
butane-1,4-diol (3, 30 mg, 0.29 mmol), which was cooled to
–78 °C. DIPEA (125 μL, 0.35 mmol) and TMSOTf (130 μL,
0.73 mmol) were added slowly. After diol 3 was completely
converted into bistrimethylsilyl ether (monitored by TLC),
benzaldehyde dimethoxy acetal (130 μL, 0.88 mmol) and
TMSOTf (53 μL, 0.29 mmol) were successively added. The
reaction mixture was stirred at –78 °C for 5 min and
quenched with sat. aq NaHCO3. The resulting solution was
extracted with CH2Cl2 (3 × 10 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude residue was
purified by column chromatography on silica gel (EtOAc–n-
hexane, 1:12) to afford the title compound 5a (47 mg, 68%,
cis/trans = 8:1) as a colorless oil along with 4a (4 mg, 7%,
(4) (a) Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.;
Cho, Y. S. J. Org. Chem. 2008, 73, 7467. (b) Ullapu, P. R.;
Min, S.-J.; Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.;
© Georg Thieme Verlag Stuttgart · New York
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2296
Y. S. Kim et al.
cis/trans = 3:1).
LETTER
responsible for this cis/trans selectivity. However, we
believed that the kinetic process is still dominant because
epimerization did not take place when the isolated cis- or
trans-4a was treated with TMSOTf at –78 °C for 2 h.
(14) Masuyama, Y.; Kagawa, M.; Kurusu, Y. Chem. Commun.
1996, 1585.
Compound cis-5a: 1H NMR (300 MHz, CDCl3): δ = 7.38–
7.24 (m, 5 H), 4.33 (dd, J = 11.3, 1.7 Hz, 1 H), 4.22 (dd, J =
11.5, 3.9 Hz, 1 H), 4.07 (d, J = 7.2 Hz, 1 H), 3.61 (ddd, J =
12.2, 12.2, 1.8 Hz, 1 H), 3.39 (s, 3 H), 3.37 (s, 3 H), 2.00 (m,
1 H), 1.95 (m, 1 H), 1.73 (m, 1 H), 1.50–1.29 (m, 2 H). 13
C
NMR (75 MHz, CDCl3): δ = 143.2, 128.4, 127.5, 125.9,
(15) Forbes, D. C.; Ene, D. G.; Doyle, M. P. Synthesis 1998, 879.
(16) Compound cis-10 (Table 3, entry 1): 1H NMR (300 MHz,
CDCl3): δ = 7.48 (d, J = 9.0 Hz, 4 H), 7.37 (m, 4 H), 7.27–
7.31 (m, 2 H), 4.61 (dd, J = 10.8, 1.0 Hz, 2 H), 4.10 (d, J =
7.2 Hz, 1 H), 3.40 (s, 6 H), 2.32 (m, 1 H), 2.08 (dt, J = 12.7,
1.7 Hz, 2 H), 1.41 (q, J = 12.4 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): δ = 143.0, 128.2, 127.5, 127.3, 125.8, 108.0, 79.2,
54.1, 53.1, 39.1, 35.6, 33.7. HRMS (EI+): m/z calcd for
C20H24O3: 312.1725 [M]+; found: 312.1722.
108.0, 79.3, 68.0, 54.2, 53.7, 38.5, 35.9, 27.6. HRMS (EI+):
m/z calcd for C14H20O3: 236.1412 [M]+; found: 236.1406.
(12) (a) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem.
Soc. 2002, 124, 4960. (b) Jasti, R.; Vitale, J.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2002, 126, 9904.
(13) Based on our observation that the cis/trans ratio of aldehydes
4 is constant in Table 2, the isomerization via rapid
enolization under the acidic reaction conditions may be
Synlett 2013, 24, 2292–2296
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