Spiranes synthesis based on samarium diiodide-mediated reductive cyclization

Article abstract of DOI:10.1016/j.tetlet.2012.02.068

A general and efficient method for the preparation of spiro compounds is described. Enone-aldehydes were exposed to samarium diiodide under mild conditions and various spirocyclic γ-hydroxyketones were obtained in good yields.

Full text of DOI:10.1016/j.tetlet.2012.02.068

Tetrahedron Letters 53 (2012) 2185–2188
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Tetrahedron Letters
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Spiranes synthesis based on samarium diiodide-mediated reductive cyclization
⇑
Day-Shin Hsu , Chi-Wei Hsu
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung 621, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient method for the preparation of spiro compounds is described. Enone–aldehydes
Received 29 December 2011
Revised 7 February 2012
Accepted 14 February 2012
Available online 20 February 2012
were exposed to samarium diiodide under mild conditions and various spirocyclic
were obtained in good yields.
c-hydroxyketones
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spiranes
Enone–aldehydes
Samarium diiodide
Reductive cyclization
Many natural products having the spiro core and exhibiting sig-
nificant biological activities are known to exist (Fig. 1). Further,
owing to the biological importance of the spiro core in nature,
the development of new and efficient strategies for constructing
it has become a major focal point of synthetic chemistry.1 There-
fore, our aim was to develop a general and efficient method for pre-
paring spiro compounds.
Samarium (II) diiodide (SmI2) is a powerful one-electron reduc-
ing agent that has found widespread use in organic synthesis.2 One
of the widely applied processes involving the use of SmI2 includes
the intramolecular ketyl olefin radical coupling reaction to achieve
carbon–carbon bond formation between aldehydes or ketones and
olefins.3 Recently, cyclization reactions involving the use of SmI2
have been proved to be valuable tools for the synthesis of natural
products.4 Therefore, our developed method for preparing spiranes
focuses on the intramolecular cyclization reactions of aldehydes
chromate (PCC) to give enones 12. Hydrolysis of the acetal moiety
under acidic conditions gave the desired enone–aldehydes 9 in
good overall yields.
Having obtained the enone–aldehydes, we first used 6a to
examine the reaction conditions. SmI2 (0.1 M in THF, 4 equiv)
was added to a solution of 6a in THF in the presence of MeOH at
room temperature. We found that 6a was completely consumed
within 1 min and gave cyclized product 13 in 72% yield (Table 2,
entry 1). However, under these conditions, the ketone was also re-
duced to alcohol owing to an excess of the reducing agent.
Then, we reduced the 4 equiv of SmI2 to 2 equiv. In this case, the
desired spirocyclic c
-hydroxyketones 14a and 14a0 were obtained
in 60% yield as a 1:1 mixture of inseparable diastereoisomers (en-
try 2). When an attempt was made to improve the diastereoselec-
tivity by decreasing the reaction temperature to 0 °C, 14a and 14a0
were obtained in 75% yield in a ratio of 3:2 (entry 3). A similar dia-
stereoselectivity was observed when the reaction was carried out
at ꢀ20 °C or at lower temperatures; however, at these tempera-
tures, the yield decreased and the required reaction time increased
onto cyclic a,b-unsaturated ketones.
Spirane precursors, enone–aldehydes 6–9, were prepared from
3-alkoxyenones 1–4, which were either purchased from commer-
cial suppliers or obtained from corresponding cyclic 1,3-diones
using a method reported in the literature.5 The 1,2-addition of
Grignard reagents 5a–c6 to 1–4 and subsequent treatment of the
resulting addition products with an acidic aqueous solution gave
enone–aldehydes 6–8 in good yields, with an exception of 9a (Ta-
ble 1). Thus, enone–aldehydes 9 were prepared from another sub-
strate, 2-cyclohepten-1-one (10), as shown in Scheme 1. Similarly,
the 1,2-addition of 5a–b generated the tertiary allylic alcohols 11.
This addition was followed by the oxidation of pyridinium chloro-
H
O
N
O
Cl
HO
Br
elatol
Figure 1. Natural products containing the spiro core structures.
Cl
OH
halichlorine
⇑
Corresponding author. Tel.: +886 5 2720411x66417; fax: +886 5 272 1040.
E-mail address: chedsh@ccu.edu.tw (D.-S. Hsu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.068

2186
D.-S. Hsu, C.-W. Hsu / Tetrahedron Letters 53 (2012) 2185–2188
Table 1
Preparation of enone–aldehydes 6–9 from 3-alkoxyenones 1–4
O
O
O
BrMg
1.
O
O
n
THF, rt, 5 h
R
R
R
R
n
OR'
m
m
2.10% HCl, THF, rt, 5 h
6−9
1−4
5a, n = 1
5b, n = 2
5c, n = 0
Entry
3-Alkoxyenone
Grignard
Product
Yield (%)
1
2
3
5a
5b
5c
6a, n = 1
6b, n = 2
6c, n = 0
75
80
47
O
O
O
1
n
OEt
O
4
5
5a
5b
7a, n = 1
7b, n = 2
63
57
O
O
n
OMe
2
6
7
5a
5b
8a, n = 1
8b, n = 2
65
68
O
O
O
n
3
OMe
O
O
O
8
5a
9a, n = 1
20
4
OEt
Table 2
O
O
O
Intramolecular reductive cyclization of 6a with SmI2
n
HO
BrMg
O
O
PCC
CH Cl , rt, 2 h
OH
O
O
n
O
OH
OH
OH
THF, rt, 4 h
O
2
2
SmI2, MeOH
+
+
5a, n = 1
5b, n = 2
THF, T, t
10
11a, n = 1 (72%)
11b, n = 2 (70%)
13
6a
Entry
14a
14a'
O
O
O
a
SmI2 (equiv)
T (°C)
t (min)
Product/yield (%)
14a:14a0
O
10% HCl
O
1
2
3
4
5
6
7
4
2
2
2
2
2
2
rt
rt
0
ꢀ20
ꢀ30
ꢀ40
ꢀ50
1
5
10
20
40
13/72
—
1:1
THF, rt, 4 h
n
n
14a + 14a0/60
14a + 14a0/75
14a + 14a0/65
14a + 14a0/60
14a + 14a0/50
14a + 14a0/56
1.5:1
1.5:1
1.7:1
1.5:1
1.5:1
9a, n = 1 (92%)
9b, n = 2 (85%)
12a, n = 1
12b, n = 2
100
200
Scheme 1. Preparation of enone–aldehydes 9 from 2-cyclohepten-1-one (10).
a
The ratios were determined by 1H NMR.
(entries 4–7). Thus, in the reductive cyclization of 6a, the best yield
and the optimum diastereoselectivity were observed when the
reaction was carried out at 0 °C with 2 equiv of SmI2.
Other enone–aldehydes 6–9 were examined to the optimized
single diastereomer 17b was obtained (entry 9) but its yield was
considerably low (25%). Fortunately, its yield increased to 58%
when the reaction was carried out at ꢀ20 °C. In order to confirm
conditions, and the desired spirocyclic
c-hydroxyketones 14–17
were obtained as inseparable diastereoisomers in moderate to
good yields in various diastereomeric ratios (Table 3). With a
three-carbon side chain in the substrate, the desired spiro[3.5]non-
ane skeleton could not be observed, and this resulted in a complex
mixture (entry 3). The spiro[3.5]nonane skeleton could not be ob-
served probably because of the ring strain. Formation of a cyclobu-
tane ring under these conditions was difficult. Surprisingly,
cycloheptenone substrates 9 showed different results (entries 8
and 9). One of the spirocyclic diastereomers spontaneously cy-
clized and formed a tricyclic hemiketal 17a0 (entry 8). Further, a
that the obtained inseparable spirocyclic
c-hydroxyketones are
diastereomers, the mixture of diastereomers 14–16 was oxidized
by PCC to give a single 1,4-dione in each case (Table 3).
The structures of 14–17 were satisfactorily characterized by IR,
1H, 13C NMR, and low- and high-resolution MS analyses. The ste-
reostructures of 14–17 were determined by NOESY experiments
(Fig. 2). The NOESY spectra of 14a–17b showed a cross-peak be-
tween C1H and the
a-hydrogen of the ketone, whereas those of
14a0–16b0 did not show a cross-peak.

D.-S. Hsu, C.-W. Hsu / Tetrahedron Letters 53 (2012) 2185–2188
2187
Table 3
Intramolecular reductive cyclization and oxidation
O
O
O
O
OH
O
SmI2 (2 eq.), MeOH
PCC
R
R
THF, 0 oC, t1
R
R
R
n
n
n
CH2Cl2, rt, t2
m
m
m
R
18−21
14−17
6−9
Entry
1
Enone–aldehyde
t1 (min)
Products
d.r.a
Yieldb (%)
t2 (h)
Product
Yieldb (%)
O
O
O
O
O
O
OH
OH
OH
O
10
1:5:1
75
1
90
93
—
+
+
6a
O
18a
14a
14a'
O
O
O
O
OH
2
3
4
25
30
25
5:1
—
70
2
6b
14b'
18b
14b
—
O
O
c
—
—
2
—
6c
O
O
O
O
O
O
OH
OH
OH
OH
O
16:1
57
96
+
15a'
15a
19a
7a
O
O
O
O
O
5
6
7
30
30
30
5:1
53
62
70
2
4
4
98
90
90
+
7b
O
19b
15b'
15b
O
O
O
OH
O
O
OH
3:1
+
8a
O
20a
16a
16a'
O
O
O
O
O
OH
OH
1:5:1
+
8b
20b
16b'
16b
O
O
O
OH
OH
O
H
8
9
10
10
—
—
33 + 52
25(58)d
—
5
—
—
+
17a
17a'
9a
O
O
O
O
OH
O
94
17b
21b
9b
a
b
c
The ratios were determined by 1H NMR.
Isolated yield.
Complex mixture.
d
The reaction was carried out at ꢀ20 °C.

2188
D.-S. Hsu, C.-W. Hsu / Tetrahedron Letters 53 (2012) 2185–2188
no NOESY
References and notes
NOESY
O
O
1. (a) Krapcho, A. P. Synthesis 1974, 383; (b) Pradhan, R.; Patra, M.; Behera, A. K.;
Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62, 779.
H
H
H
OH
H
OH
2. (a) Molander, G. A. Chem. Rev. 1992, 92, 29; (b) Molander, G. A.; Harris, C. R.
Chem. Rev. 1996, 96, 307; (c) Molander, G. A. Acc. Chem. Res. 1998, 31, 603; (d)
Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321; (e) Kagan, H. B.
Tetrahedron 2003, 59, 10351; (f) Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019; (g)
Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis using Samarium
Diiodide: A Practical Guide; Royal Society of Chemistry Publishing: UK, 2010; (h)
Harb, H. Y.; Procter, D. J. Synlett 2012, 23, 6.
1
1
1
R
1
n
R
n
2
2
m
m
R
R
14a−17b
14a'−16b'
Figure 2. NOESY investigations of 14–17.
3. (a) Fukuzawa, S.; Iida, M.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc., Chem.
Commun. 1987, 920; (b) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J.
Chem. Soc., Perkin Trans. 1 1988, 1669; (c) Enholm, E. J.; Trivellas, A. Tetrahedron
Lett. 1989, 30, 1063; (d) Kito, M.; Sakai, T.; Yamada, K.; Matsuda, F.; Shirahama,
H. Synlett 1993, 158; (e) Kan, T.; Nara, S.; Ito, S.; Matsuda, F.; Shirahama, H. J. Org.
Chem. 1994, 59, 5111; (f) Kan, T.; Hosokawa, S.; Nara, S.; Oikawa, M.; Ito, S.;
Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59, 5532; (g) Sakai, H.; Hagiwara,
H.; Ito, Y.; Hoshi, T.; Suzuki, T.; Ando, M. Tetrahedron Lett. 1999, 40, 2965; (h)
Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett. 1999, 40, 4913; (i)
Sono, M.; Nakashiba, Y.; Nakashima, K.; Tori, M. J. Org. Chem. 2000, 65, 3099; (j)
Sono, M.; Onishi, S.; Tori, M. Tetrahedron 2003, 59, 3385.
In conclusion, we have developed a general method for prepar-
ing various spirocyclic -hydroxyketones under mild conditions.
The ring size of the spiro compounds can be controlled easily either
by using different cyclic enones or by altering the length of the side
chain. The application of this efficient method to natural product
synthesis is currently under investigation.
c
4. (a) Johnston, D.; Couché, E.; Edmonds, D. J.; Muir, K. W.; Procter, D. J. Org. Biomol.
Chem. 2003, 1, 328; (b) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev.
2004, 104, 3371; (c) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed.
2009, 48, 7140; (d) Nakata, T. Chem. Soc. Rev. 2010, 39, 1955; (e) Nakata, T. Chem.
Rec. 2010, 10, 159; (f) Beemelmanns, C.; Reissig, H-U. Pure Appl. Chem. 2011, 83,
507.
Acknowledgment
We thank the National Science Council (NSC) of the Republic of
China for financial support (NSC 97-2113-M-194-011-MY2).
5. (a) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217; (b) Rajesh, S.;
Sidhanath, V.; Sheshanath, V.; Wang, T.; Zubaidha, P. K. Tetrahedron Lett. 2004,
45, 7187.
Supplementary data
6. (a) Keinan, E.; Sahai, M.; Shvily, R. Synthesis 1991, 641; (b) Varseev, G. N.; Maier,
M. E. Org. Lett. 2005, 7, 3881.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.068.