Regioselective cleavage of the cyclic ethereal bond of 7-oxabicyclo[2.2.1]heptane derivatives mediated by samarium(II) iodide

Article abstract of DOI:10.1016/S0040-4039(01)00423-3

It was established that exclusively high regioselective C-O bond cleavage of 7-oxabicyclo[2.2.1]heptane skeletons, which are unique Diels-Alder products of furans, under mild conditions using samarium(II) iodide and samarium powder yields cyclohexanol derivatives or aromatic compounds.

Full text of DOI:10.1016/S0040-4039(01)00423-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3603–3606
Regioselective cleavage of the cyclic ethereal bond of
7
-oxabicyclo[2.2.1]heptane derivatives mediated by
samarium(II) iodide
Akihiro Yoshida and Hiroaki Takayama*
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Received 31 January 2001; revised 26 February 2001; accepted 9 March 2001
Abstract—It was established that exclusively high regioselective CꢀO bond cleavage of 7-oxabicyclo[2.2.1]heptane skeletons, which
are unique Diels–Alder products of furans, under mild conditions using samarium(II) iodide and samarium powder yields
cyclohexanol derivatives or aromatic compounds. © 2001 Elsevier Science Ltd. All rights reserved.
7
-Oxabicyclo[2.2.1]heptane derivatives, which can be
synthesis of natural products such as vitamin D ana-
4e
readily prepared by Diels–Alder reactions with furans,
are very useful compounds for stereoselective synthesis
of natural products bearing multisubstituted cyclohex-
anol units after regioselective cleavage of the ethereal
CꢀO bond. However, in general, little or no regioselec-
tivity in the CꢀO bond cleavage reactions was observed
under nucleophilic conditions. Most of these exam-
ples utilize nucleophiles such as metal hydrides, alkyl-
lithiums, Grignard reagents and cuprates, which limit
application to non-multifunctional compounds.
logues (Scheme 1).
Diels–Alder adducts such as 3 bearing a carbonyl moi-
ety cannot be treated by DIBAL-H and Grignard
reagents for CꢀO bond cleavage reactions, and since
usual reductions with samarium(II) iodide proceed
under mild and neutral conditions, we considered
samarium(II) iodide to be a suitable reagent to open the
ethereal rings. It has been reported that the reductive
CꢀO bond cleavage can occur at the a-position to
carbonyls or the g-position to a,b-unsaturated car-
1,2
5
On the other hand, we have developed the chemistry of
furan-annulated sulfolene 1 and its derivatives. These
compounds behave as dienes in Diels–Alder reactions
and 3,4-dimethylenefuran synthons due to the smooth
cheletropic elimination of sulfur dioxide after cycload-
bonyls by samarium(II) iodide. It is worth noting that
3
not only alkoxycarbonyl groups but also alkoxy groups
can be eliminated by divalent samarium. Substrate 3
bearing an a,b-unsaturated ester moiety may be suit-
able for samarium(II)-mediated reductive elimination to
cleave CꢀO bond regiospecifically at the g-position.
However, it can be predicted that the ring opening of
bicyclic ether 3 is difficult because of stereoelectronic
effects described later. There have only been a few
4
ditions. Thus, we planned the regioselective cleavage of
the ethereal bond of Diels–Alder adduct 3 derived from
furan-annulated sulfolene 2, since the ring opening
product would be an important key compound for the
LiHMDS
EtO C
EtO2C
ClCO Et
2
MeO2C
CO2Me
O
2
DMPU
O S
2
O
O S
2
O
THF
toluene
CO Me
2
∆
CO Me
2
1
2
3
Scheme 1.
Keywords: samarium and compounds; cleavage reactions; regiocontrol; Diels–Alder reactions; furans; sulfur heterocycles.
*
Corresponding author. Tel.: +81-426-85-3713; fax: +81-426-85-3714; e-mail: hi-takay@pharm.teikyo-u.ac.jp
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00423-3

3
604
A. Yoshida, H. Takayama / Tetrahedron Letters 42 (2001) 3603–3606
reports on the samarium(II)-mediated ring opening
reaction of cyclic ethers, and there have been no
protonation at the a-position of the resultant trienolate
intermediate, though in a low yield. Starting material 6
was recovered in a relatively high percentage. Other
entries gave phenylacetate 8 via dehydration (aroma-
tization) after the formation of 7 along with the recov-
ery of 6. The addition of 1,3-dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone (DMPU), which was often
used as a Lewis base instead of HMPA, to the reaction
system was inefficient (entry 3).
6
reports on the CꢀO bond cleavage of the substrates
such as 3 with a rigid conformation. In this study, we
first investigated the ring opening reactions of 7-oxabi-
7
cyclo[2.2.1]hept-5-en-2-one (4), which is more reactive
than 3, using a combination of samarium(II) iodide and
various proton sources as preliminary experiments.
The reaction was carried out by adding a SmI (2.2
equiv.) solution in THF to a THF solution of 4 in the
2
8
To prevent the ring opening product from aromatiza-
tion, we prepared the bicyclic saturated substrate 9 by
hydrogenation of 4 followed by carboxyolefination, and
then carried out the samarium(II)-mediated reactions
under various conditions (Table 2). All entries gave
b,g-unsaturated ester 10 through regiospecific ring
opening followed by kinetic protonation at the a-posi-
tion of dienolate intermediate. Using weak acid such as
methanol and ethylene glycol, 10 was obtained in low
yields along with recovery of the starting 9 (entries
1–3). Although strong acid such as trifluoroacetic acid
presence of a proton source (2.2 equiv.) such as
methanol. Surprisingly, phenol (5) was obtained exclu-
sively (Scheme 2). We speculated that this compound 5
was produced through a dehydration–aromatization
process after cleavage of the CꢀO bond at the a-posi-
tion of ketone 4. No opposite CꢀO bond cleavage
product 5% was observed. Pivalic acid as a proton source
gave 5 in a higher yield than methanol. This can be an
efficient synthetic method of multisubstituted phenols,
when multisubstituted substrates, prepared by Diels–
Alder reactions of multisubstituted furans with ketene
equivalents, are used instead of 4.
9
(TFA) or trifluoromethanesulfonic acid (TfOH) was
used to achieve higher yields, the isolated yields were up
to 33% (in entries 4–6). A strong Lewis base DMPU as
an additive was also ineffective (entry 5). The addition
of Sm(OTf)3 as a Lewis acid, which could activate
ethereal oxygen, was ineffective (entry 7). However,
zero valent samarium powder was extremely effective to
Next, we investigated the reductive ring opening of
a,b-unsaturated ester 6 (E/Z=4:6) prepared from
ketone 4 via a Horner–Wadsworth–Emmons reaction.
The results are summarized in Table 1. In entry 1, the
ring opening product 7 was obtained through CꢀO
bond cleavage at the g-position followed by kinetic
1
0
give 10 in a higher yield (entry 8). A SmI –Sm system
2
was effective because it had a stronger reducing ability
OH
OSmIII Ln
O
SmI2
proton source
O
OH
O
O
proton source
4
5
THF
OSmIII Ln
OH
4
5
5'
proton source : PvOH 85% yield
MeOH 31% yield
mechanism
Scheme 2.
Table 1. Ring opening-aromatization reactions by samarium(II) iodide
SmI (2.2 eq.)
proton source
2
CO Et
CO2Et
O
2
CO Et
2
+
THF
rt
OH
6
(E / Z = 4 : 6)
7
8
Entry
Proton source
Yield (%)
a
a
7
8
6 (recovery)
1
2
MeOH (2.2 equiv.)
PvOH (2.2 equiv.)
MeOH (2.2 equiv.)
MeOH (2.2 equiv.)
MeOH (4.4 equiv.)
MeOH (4.4 equiv.)
(CH OH) (2.2 equiv.)
16 (63)
(Trace)
6 (21)
(Trace)
37 (69)
14 (17)
6 (12)
74
76
81
46
17
47
59
–
–
–
–
–
–
b
3
4
c
5
6
7
27 (65)
2
2
a
Values in parentheses were conversion yields (%).
DMPU (8.8 equiv.) was added.
SmI2 (4.4 equiv.) was used.
b
c

A. Yoshida, H. Takayama / Tetrahedron Letters 42 (2001) 3603–3606
Table 2. Ring opening reactions by samarium(II) iodide
3605
SmI (4.0 eq.)
2
CO Et
proton source
additive
O
2
CO Et
2
THF
rt
OH
9
(E / Z = 3 : 7)
10
Entry
Proton source
Additive
Yield (%)
9 (recovery)
a
1
0
1
2
MeOH (4.4 equiv.)
–
–
–
–
11 (100)
11 (100)
22 (100)
89
89
78
71
78
64
69
–
(CH OH) (2.2 equiv.)
2
2
b
3
4
(CH OH) (4.4 equiv.)
2
2
b
c
TFA (4.4 equiv.)
TFA (4.4 equiv.)
TfOH (4.4 equiv.)
TfOH (4.4 equiv.)
TfOH (4.0 equiv.)
24 (81)
15 (67)
33 (90)
c
5
6
7
8
DMPU (16 equiv.)
–
Sm(OTf)3 (0.5 equiv.)
Sm (4.0 equiv.)
c
c
31 (100)
c
65
a
Values in parentheses were conversion yields (%).
The reaction was performed at 40°C.
THF-polymerization product was also obtained as a by-product.
b
c
than SmI and because of the regeneration of low valent
samarium from Sm(III) reduced by Sm(0).
Finally, we investigated the ring opening of multifunc-
tional substrate 3 derived from furan-annulated sulfo-
lene 1. As expected, multisubstituted cyclohexanol
derivatives 11 was obtained as a single diastereomer
(Scheme 4). An application of stereoselective synthesis
for an A-ring moiety of vitamin D analogues is cur-
rently underway in our laboratory.
2
1
0
The reason for the low yields except for entry 8 is due
to the stereoelectronic effect (Scheme 3). CꢀO bond
cleavage is considered to readily occur if the direction of
the CꢀO bond is fixed perpendicularly to the olefinic
plane because of the resulting new CꢀC p-bond forma-
tion. However, according to MM2 calculations, the
dihedral angle of bicyclic substrate 9 was estimated to be
between 150 and 160°. Thus, the ring opening of the
11
In summary, we have developed an efficient synthetic
route to multisubstituted cyclohexanols and aromatic
compounds by samarium(II)-mediated ring opening
reactions of 7-oxabicyclo[2.2.1]heptane derivatives. This
is the first example of regiospecific cleavage of the CꢀO
bond of 7-oxabicyclo[2.2.1]heptane derivatives bearing
the carbonyl function.
7
-oxabicyclo[2.2.1]heptane derivative is difficult to
achieve and it is an important point that our SmI –Sm
2
system overcomes this problem. The reaction was consid-
ered to proceed mainly through a stepwise mechanism.
EtO
III
LnSm
EtO
O
O
H
CO Et
SmIII Ln
SmIII Ln
O
2
O
O
O
H+
2
Sm(II)
CO Et
2
9
A
B
10
• kinetic protonation of dienolate
•
two electrons reduction by Sm(II)
favored
dihedral angle
disfavored
dihedral angle
150-160 °
CO Et
90 °
O
R
O
2
O
RO
B
–
RO–
most cleavable C-O bond
dihedral angle = 90 °)
inefficient cleavage due to
the larger dihedral angle
(
Scheme 3.

3
606
A. Yoshida, H. Takayama / Tetrahedron Letters 42 (2001) 3603–3606
EtO C
5. Reviews: (a) Kagan, H. B.; Namy, J. L. Tetrahedron
2
O
SmI2
CO2Me
EtO C
2
1986, 42, 6573–6614; (b) Inanaga, J. J. Synth. Org. Chem.
Jpn. 1989, 47, 200–211; (c) Molander, G. A. In Compre-
hensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, pp. 251–282; (d) Molan-
der, G. A. Org. React. 1994, 46, 211–367; Related to our
reports: (e) Mikami, K.; Yoshida, A. Angew. Chem., Int.
Ed. Engl. 1997, 109, 892–894; (f) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.;
Mikami, K. Tetrahedron Lett. 1997, 38, 2709–2712; (g)
Yoshida, A.; Mikami, K. Synlett 1997, 1375–1376; (h)
Yoshida, A.; Hanamoto, T.; Inanaga, J.; Mikami, K.
Tetrahedron Lett. 1998, 39, 1777–1780; (i) Mikami, K.;
Yamaoka, M.; Yoshida, A.; Nakamura, Y.; Takeuchi, S.;
Ohgo, Y. Synlett 1998, 607–608; (j) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.;
Mikami, K. Tetrahedron 1999, 55, 4595–4620.
Sm, TfOH
CO Me
CO Me
THF
(60%)
2
2
CO Me
OH
11
single diastereomer!
2
3
Scheme 4.
Acknowledgements
This work was partially supported by a Grant-in-Aid
for Young Scientists No. 11740342 from the Ministry
of Education, Culture, Sports, Science and Technology
of Japan. We are also grateful to Miss J. Shimode and
Miss M. Kitsukawa of the Instrument Analysis Center,
Teikyo University, for spectroscopic measurements.
6. Ring opening of tetrahydrofuranones is quite hard, see:
(
a) Linderman, R. J.; Cusack, K. P.; Kwochka, W. R.
Tetrahedron Lett. 1994, 35, 1477–1480; ring opening of
tetrahydropyrans bearing ketones on the side chain: (b)
Enholm, E. J.; Schreier, J. A. J. Org. Chem. 1995, 60,
1110–1111.
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2
8
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2
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3
1
865–1866.
mg, 60%).
.
.