SmI2-induced reductive cyclization of optically active β-alkoxyvinyl sulfoxides with aldehyde

Article abstract of DOI:10.1016/j.tetlet.2007.10.102

SmI₂-induced reductive cyclization of optically active (E)- and (Z)-β-alkoxyvinyl sulfoxides with aldehyde was developed for the construction of several stereoisomers of tetrahydropyran derivatives.

Full text of DOI:10.1016/j.tetlet.2007.10.102

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9171–9175
SmI2-induced reductive cyclization of optically active
b-alkoxyvinyl sulfoxides with aldehyde
Tomohiro Kimura, Mayumi Hagiwara and Tadashi Nakata*
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 19 September 2007; revised 16 October 2007; accepted 19 October 2007
Available online 24 October 2007
Dedicated to the memory of the late Professor Yoshihiko Ito
Abstract—SmI2-induced reductive cyclization of optically active (E)- and (Z)-b-alkoxyvinyl sulfoxides with aldehyde was developed
for the construction of several stereoisomers of tetrahydropyran derivatives.
Ó 2007 Elsevier Ltd. All rights reserved.
Marine polycyclic ethers exemplified by brevetoxin-B, a
red tide toxin, have a unique trans-fused polycyclic ether
ring system.1 Their synthetically challenging complex
structures and potent bioactivities have attracted the
attention of numerous synthetic organic chemists. Thus,
various methods for the synthesis of polycyclic ethers
have been extensively studied.2 We have already
developed an efficient method for the construction of
trans-fused polycyclic ether based on the SmI2-induced
reductive cyclization of b-alkoxyacrylate A with a
carbonyl group, affording 2,6-syn-2,3-trans-tetrahydro-
pyrans B with complete stereoselectivity (Fig. 1).3
Several groups have successfully applied this method
to the synthesis of polycyclic ethers.4 Recently, we have
also reported SmI2-induced reductive cyclization of (E)-
and (Z)-b-alkoxyvinyl sulfones with aldehyde to give
2,6-syn-2,3-trans- and 2,6-syn-2,3-cis-tetrahydropyrans,
respectively.5 We next turned our attention to the
SmI2-induced reaction of optically active b-alkoxyvinyl
sulfoxides with aldehyde. The chirality of sulfoxide
and the (E/Z)-stereochemistry of the olefin in the sub-
strates would be expected to influence the stereoselectiv-
ity in these reactions. Lee and co-workers recently
reported the same type of reaction using acyclic com-
pounds.6 Here, we present our results on SmI2-induced
intramolecular cyclization of b-alkoxyvinyl sulfoxide
with aldehyde.7
H
H
H
H
O
O
OH
SmI2
CHO
3
6
2
R
R
MeOH
THF
O
O
H
H
A
B
R = CO2Et, SO2Ph, or S(O)-p-Tol
Figure 1. SmI2-induced reductive cyclization.
First, we examined the SmI2-induced reductive cycliz-
ation with aldehydes 4b and 6b having (E)-b-alkoxyvinyl
(R)- or (S)-sulfoxide, respectively, as substrates (Scheme
1). Addition of alcohol 14f to (R)-ethynyl p-tolylsulfox-
ide 28 in the presence of N-methylmorpholine (NMM)
stereoselectively afforded (E)-b-alkoxyvinyl (R)-sulfox-
ide 4a in 96% yield,9 and this was reduced with DIBAH
to give aldehyde 4b in 85% yield. Treatment of (E)-(R)-
10
4b with 2.5 equiv of SmI2 in the presence of MeOH
(2.6 equiv) in THF effected reductive cyclization to give
2,6-anti-2,3-cis-tetrahydropyran 5a as a single product,
which, without purification, was acetylated with Ac2O
to give acetate 5b11 in 64% yield (two steps). Use of
CF3CH2OH instead of MeOH as a proton source
slightly improved the yield of 5b (71%).12 On the other
hand, the reaction of 1 and (S)-ethynyl p-tolylsulfoxide
3 in the presence of NMM, followed by DIBAH reduc-
tion, afforded aldehyde 6b. The SmI2-induced cycliz-
ation of (E)-(S)-6b in the presence of MeOH afforded
2,6-syn-2,3-trans-tetrahydropyran 7a, which was acetyl-
ated to give acetate 7b11 in 85% yield (two steps).
Keywords: Samarium diiodide; C–C bond formation; Polycyclic ethers;
Ethynyl p-tolylsulfoxide; Tetrahydropyranol.
*
Corresponding author. Tel.: +81 3 5228 8274; e-mail: nakata@
rs.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.102

9172
T. Kimura et al. / Tetrahedron Letters 48 (2007) 9171–9175
H
H
H
H
H
R
R
S
p-Tol
Ph
O
O
Ph
O
O
a,b
c
S(O)-p-Tol
6
2
3
O
R
O
O
O
O
or d
O
O
OR
H
H
H
H
H
S
S
p-Tol
p-Tol
(R)-2
(S)-3
H
H
H
H
4a: R = CO2Et
4b: R = CHO
5a: R = H
5b: R = Ac
Ph
O
OH
CO2Et
O
O
H
H
H
H
H
S
S
S
p-Tol
Ph
O
O
Ph
O
O
a,b
c
S(O)-p-Tol
1
6
2
3
O
R
O
O
O
O
OR
H
H
H
H
H
7a: R = H
7b: R = Ac
6a: R = CO2Et
6b: R = CHO
Scheme 1. Reagents and conditions: (a) (R)-2 or (S)-3, NMM, CH2Cl2, rt, 96% for 4a, 96% for 6a; (b) DIBAH, CH2Cl2, À78 °C, 85% for 4b, 92% for
6b; (c) SmI2, MeOH, CH2Cl2, 0 °C; Ac2O, pyridine, rt, 64% for 5b (two steps), 85% for 7b (two steps); (d) SmI2, CF3CH2OH, THF, 0 °C; Ac2O,
pyridine, rt, 71% for 5b (two steps).
p-Tol
O
S
R
O
S(O)-p-Tol
R
H
H
H
H
H
H
H
H
H
H
H
H
R
R
Ph
O
O
Ph
O
O
Ph
O
c
a,b
a,b
S(O)-p-Tol
6
2
3
3
+
O
R
O
O
or d
O
O
OR
O
OR
H
H
H
8a: R = CO2Et
8b: R = CHO
9a: R = H
9b: R = Ac
10a: R = H
1
10b: R = Ac
p-Tol
O
R
S(O)-p-Tol
S
S
H
H
H
H
H
S
H
H
S
Ph
O
O
Ph
O
O
Ph
O
O
c
S(O)-p-Tol
6
2
3
+
7b
+
3
O
O
or d
O
R
O
OR
O
OR
O
H
H
H
H
H
H
H
H
11a: R = CO2Et
11b: R = CHO
12a: R = H
12b: R = Ac
13a: R = H
13b: R = Ac
Scheme 2. Reagents and conditions: (a) LHMDS, (R)-2 or (S)-3, THF, 0 °C, then 1, À78 to À20 °C, 88% for 8a, 91% for 11a; (b) DIBAH, CH2Cl2,
À78 °C, 45% for 8b, 73% for 11b; (c) SmI2, MeOH, CH2Cl2, 0 °C; Ac2O, pyridine, rt, 27% for 9b and 26% for 10b (two steps), 3% for 7b, 15% for 12b,
and 21% for 13b (two steps); (d) SmI2, CF3CH2OH, THF, 0 °C; Ac2O, pyridine, rt, 45% for 9b and 27% for 10b (two steps).
Next, aldehydes 8b and 11b, having (Z)-b-alkoxyvinyl
(R)- and (S)-sulfoxide, respectively, were examined
(Scheme 2). Treatment of alcohol 1 and (R)-sulfoxide
2 with LHMDS stereoselectively afforded (Z)-b-alkoxy-
vinyl (R)-sulfoxide 8a in 88% yield,9 and DIBAH reduc-
tion gave aldehyde 8b (45%). Treatment of (Z)-(R)-8b
with SmI2 in the presence of MeOH in THF followed
by acetylation afforded two products; 2,6-syn-2,3-cis-tet-
rahydropyran 9b11 (27%) and c-acetoxyvinyl sulfoxide
10b13 (26%). Use of CF3CH2OH instead of MeOH in
the present reaction afforded 9b (45%) and 10b (27%).
Moreover, addition of 1 and (S)-3 in the presence of
LHMDS, followed by DIBAH reduction, afforded alde-
hyde 11b. The same reaction of (Z)-(S)-11b with SmI2,
followed by acetylation, gave many products, which
contain 2,6-syn-2,3-trans-7b (3%), 2,6-syn-2,3-cis-12b11
(15%), c-acetoxyvinyl sulfoxide 13b13 (21%), etc. Use
of CF3CH2OH did not improve the yield of 7b and 12b.
4b with SmI2, cyclization would proceed through transi-
tion state ii chelated by Sm(III) and sulfoxide to give 5a,
because ii has an equatorial p-tolyl group in the chair-
like conformation, whereas i has an axial one.14 Simi-
larly, the reaction of (E)-(S)-6b would proceed through
the chelated transition state iii having an equatorial
p-tolyl group to give 7a. The reaction of (Z)-(R)-8b
would also proceed through the chelated transition state
v to give 9a. In the case of 11b, the corresponding
chelated transition state vi would be unfavorable
because of the axial p-tolyl group; thus, the reaction
would proceed via the non-chelated transition state vii
or viii to give 7a and 12a. The olefinic by-products 10a
and 13a might be produced by ring opening subsequent
to the cyclization; the axial-OSm(III) group of the inter-
mediate ix, generated through v or viii via C–C bond
formation followed by the second reduction with
SmI2, might participate in the ring opening together
with the ring-O atom.
These results can be explained as follows (Fig. 2). In the
SmI2-induced cyclization, the first single electron reduc-
tion of aldehyde with SmI2 gives a ketyl radical and then
C–C bond formation occurs in the chelated intermediate
to give the cyclized product.3,5 In the reaction of (E)-(R)-
The p-tolylsulfoxymethyl group of product 7a was trans-
formed to an aldehyde group for application to the syn-
thesis of polycyclic ethers (Scheme 3). SmI2-induced
reaction of 6b followed by TBS protection afforded the

T. Kimura et al. / Tetrahedron Letters 48 (2007) 9171–9175
9173
Ph
H
O
O
O
H
Ph
H
H
O
O
O
O
O
H
H
O
O
R
S
I2Sm
R
S
5a
Sm
I2
O
<<
O
axial
i
ii
Me
equatorial
Me
Ph
H
O
O
H
H
Ph
O
O
O
H
H
O
O
O
H
O
O
Me
S
S
>>
7a
I2Sm
Sm
I2
S
O
O
equatorial
S
Me
iv
iii
axial
Me
axial
Me
I2
Sm
I2
Sm
Ph
Ph
H
H
O
O
O
O
O
O
H
O
H
S
S
O
O
R
S
equatorial
O
H
O
H
O
9a
vi
v
Me
Me
O
O
Ph
Ph
I2Sm
H
H
O
O
O
O
O
O
S
S
H
H
H
O
S
S
O
O
H
7a
12a
OSmI2
viii
vii
I2
Ph
H
O
O
Sm
H
O
Me
O
H
10a, 13a
v or viii
O
S
O
R
or S
ix
Figure 2. Plausible transition states of SmI2-induced cyclization of 4b, 6b, 8b, and 11b.
H
H
H
H
H
H
H
H
H
H
H
S
Ph
O
O
Ph
O
O
CHO
S(O)-p-Tol
a,b
c
6b
O
O
O
OTBS
O
OTBS
H
14
15
Scheme 3. Reagents and conditions: (a) SmI2, MeOH, THF, 0 °C; (b) TBSCl, imidazole, DMF, rt, 90% (two steps); (c) (CF3CO)2O, pyridine,
MeCN, 0 °C; H2O, K2CO3, 0 °C, 72%.

9174
T. Kimura et al. / Tetrahedron Letters 48 (2007) 9171–9175
H
H
H
S
S
S
p-Tol
O
O
O
S(O)-p-Tol
OH
OR
a,b
c,d
CHO
O
OR
H
16
17a: R = H
18a: R = TBS
18b: R = H
17b: R = TBS
p-Tol
O
S
H
S
S
O
O
e
S(O)-p-Tol
CHO
OH
H
19
20
Scheme 4. Reagents and conditions: (a) SmI2, MeOH, THF, 0 °C, 87% for 17a; (b) TBSCl, imidazole, DMF, rt, 88% for 17b; (c) (CF3CO)2O,
pyridine, MeCN, 0 °C, then H2O, K2CO3, NaBH4, 97% for 18a; (d) n-Bu4NF, THF, rt, 100% for 18b; (e) SmI2, CF3CH2OH, THF, 0 °C, 68%.
H
I2
Sm
O
O
H
O
Me
O
O
S
S
S
17a
S
>>
H
Sm
I2
O
equatorial
axial
xi
x
Me
Figure 3. Plausible transition state of SmI2-induced cyclization of 17.
TBS–ether 14 in 90% yield. Sulfoxide 14 was subjected
to the Pummerer rearrangement to give aldehyde 15 in
72% yield.
appropriate combination of substrate and reagent, (R)-
2 or (S)-3. Thus, asymmetric synthesis of 3-tetrahydro-
pyranols was efficiently accomplished.
The stereospecific cyclization in the present reactions
apparently proceeded via a chelated transition state
involving strong coordination with sulfoxide and
Sm(III). Therefore, we expected that reductive cycliz-
ation using acyclic aldehyde having an optically active
b-alkoxyvinyl sulfoxide would be an effective approach
for the asymmetric synthesis of tetrahydropyran deriva-
tives. Treatment of aldehyde 1615 having (E)-(S)-vinyl-
sulfoxide with SmI2 in the presence of MeOH effected
reductive cyclization to give the trans-tetrahydropyran
17a in 87% yield as a single product with >99% ee
(Scheme 4).6 This result means that the reaction pro-
ceeds through the completely chelated transition state
x (Fig. 3). Alcohol 17a was converted into (À)-3-tetra-
hydropyranol derivatives 18a16 and 18b16 in excellent
yield via TBS protection, Pummerer rearrangement–
NaBH4 reduction, and removal of the TBS group. This
method for the synthesis of (À)-18a and (À)-18b is
expected to be useful, because these compounds were
previously prepared from L-glucose.17 On the other
hand, the reaction of aldehyde 1915 having (Z)-(S)-vinyl-
sulfoxide with SmI2 in the presence of CF3CH2OH gave
cis-tetrahydropyran 20 in 68% yield. The same reaction
using the corresponding enantiomers of 16 and 19
having (R)-vinylsulfoxide gave the enantiomers of 17a
and 20, respectively.
Acknowledgement
This work was financially supported by the Uehara
Memorial Foundation and by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and notes
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´
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´
(a) Alvarez, E.; Candenas, M.-L.; Perez, R.; Ravelo, J.;
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Commun. 2006, 3571.
In summary, the SmI2-induced stereospecific cyclization
of b-alkoxyvinyl sulfoxide with aldehyde was developed
for the construction of several stereoisomers of tetra-
hydropyran derivatives. The desired stereoisomers of
tetrahydropyrans could be obtained by selecting the
3. (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T.
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H.; Nakata, T. Org. Lett. 1999, 1, 1099; (c) Matsuo, G.;
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9.8, 4.6 Hz, 1H); 9b: d 5.11 (broad, W1/2 = 5.6 Hz, 1H);
12b: d 5.05 (broad, W1/2 = 7.0 Hz, 1H). NOEs between
C2–H and C6–H in 9b and 12b were observed.
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1
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13. Selected H NMR data. 10b: d 6.53 (dd, J = 15.3, 5.5 Hz,
1H), 6.38 (dd, J = 15.3, 1.2 Hz, 1H), 5.67 (m, 1H), 4.69
(ddd, J = 11.0, 9.8, 4.9 Hz, 1H); 13b: d 6.49 (dd, J = 15.2,
5.8 Hz, 1H), 6.41 (d, J = 15.2 Hz, 1H), 5.65 (m, 1H), 4.66
(ddd, J = 10.9, 10.9, 4.8 Hz, 1H). Alkaline hydrolysis of
the diacetate 10b followed by acetylation afforded a 2:3
mixture of 2,6-syn-2,3-cis-tetrahydropyran 9b and 2,6-
anti-2,3-trans-isomer via an intramolecular cyclization,
and the same reaction of 13b predominantly afforded 2,6-
anti-2,3-trans-tetrahydropyran. These results confirmed
the b-configuration of the 3-acetoxy group in 10b and 13b.
14. Lee et al. reported the same type of reaction using acyclic
stereoisomers, including 21.6 They proposed similar tran-
sition states through sulfoxide and Sm(III) coordination
to those shown here. However, they noted that it is
difficult to propose
a transition state structure for
conversion of 21 to 22; a possible transition state structure
xii does not adopt the familiar chair-like conformation.
Their result would be well explained by our proposed
transition state, i.e., the cyclization of 21 should proceed
through the transition state xiii to give 22.
H
R
H
H
R
SmI2
MeOH
p-Tol
O
O
BnO
S
BnO
S(O)-p-Tol
CHO
O
OH
THF, 0 ºC
80%
H
21
22
I2
Sm
H
BnO
O
O
H
Me
O
R
H
O
O
I2Sm
H
S
R
S
O
H
BnO
xiii
equatorial
xii
Me
Hagiwara, M.; Nakata, T. Abstract of Papers, Part 4, p
20, 127th Annual Meeting of the Pharmaceutical Society
of Japan, Toyama, Japan, March 28–30, 2007.
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dithiol, CH2Cl2, rt;18 (2a) (S)-3, NMM, CH2Cl2, rt, 85%
(two steps) or (2b) (S)-3, LHMDS, THF, À20 °C, 92%
(two steps); (3) MeI, CaCO3, MeCN, H2O, 60 °C, 88% for
16, 79% for 19.
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(ddd, J = 11.3, 5.5, 5.5 Hz, 1H); 7b: d 4.67 (ddd, J = 11.0,
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acetyl-D-glucal: Nicolaou, K. C.; Hwang, C.-K.; Marron,
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