Regioselective radical ring-opening reaction of bicyclo[4.2.0]octan-2-ones promoted by samarium(II) iodide

Article abstract of DOI:10.1016/S0040-4039(03)00085-6

Radical ring-opening reactions of bicyclo[4.2.0]octanones, its C6 alkyl derivatives, and tricyclic ketones promoted by SmI₂ gave cyclohexanones via fission of the external cyclobutane bond. The CO₂Me, CN, and phenyl derivatives led t

Full text of DOI:10.1016/S0040-4039(03)00085-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1963–1966
Regioselective radical ring-opening reaction of
bicyclo[4.2.0]octan-2-ones promoted by samarium(II) iodide
Kiyomi Kakiuchi,a,* Koichi Minato,b Ken Tsutsumi,a Tsumoru Morimotoa and Hideo Kurosawab
aGraduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama, Ikoma, Nara 630-0101,
Japan
bDepartment of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 25 November 2002; revised 16 December 2002; accepted 20 December 2002
Abstract—Radical ring-opening reactions of bicyclo[4.2.0]octanones, its C6 alkyl derivatives, and tricyclic ketones promoted by
SmI2 gave cyclohexanones via fission of the external cyclobutane bond. The CO2Me, CN, and phenyl derivatives led to the
production of the eight-membered ring compounds through cleavage of the central cyclobutane bond. Using this regioselective
reaction, the synthesis of ( )-acorenone was achieved. © 2003 Elsevier Science Ltd. All rights reserved.
Samarium(II) iodide (SmI2) has become increasingly
important in organic synthesis because it can be used
under mild and neutral conditions and functions as a
one electron reductant.1 Although the radical ring-clo-
sure reactions promoted by SmI2 are well-documented,
detailed information on the chemistry of radical ring-
opening reactions promoted by SmI2 is not available.2
Recently we reported on the new and high-efficient
skeletal rearrangement of bicyclo[4.2.0]octan-2-ones to
bicyclo[4.2.1]nonanones and the use of this rearrange-
ment as a pivotal step in the total synthesis of ( )-tetra-
methylmediterraneol B.3 In an extension of these
studies, we now report a systematic study of the radical
ring opening of bicyclo[4.2.0]octan-2-ones 1a–n, as
promoted by SmI2. We disclose here a remarkable
effect of the C6 substituent on the regioselective
radical ring-opening of cyclobutyl ketones and the
application of this reaction to the synthesis of ( )-
acorenone (16).
obtained in high yields regardless of the nature of the
alkyl substituent. Moreover, reactions of tricyclic
ketones 1f–i, which have a cyclopentane ring fused on
the bicyclo[4.2.0] unit, gave different types of carbo-
cyclic compounds 2f–i, respectively, via the cleavage of
the external C1ꢀC8 bond.
In order to examine the substituent effect at C6, we
carried out reactions of ketones 1j and 1k having an
electron withdrawing group such as CO2Me and CN in
a similar manner. Interestingly, the reaction of the
ester-ketone 1j, using MeOH as a proton source instead
of t-BuOH, gave the cyclooctanols 4j (18%) and the
lactone 5 (55%), along with the recovered ketone 1j
(17%) (Scheme 2).5 The products 4j and 5 were derived
through fission of the central cyclobutane bond
(C1ꢀC6) followed by over-reduction and the subsequent
lactonization of 4j. In the case of the cyanoketone 1k,
the fission of the central bond was also observed. With
4 equiv. of SmI2, cyclooctanone 6k was obtained as a
minor product, along with bicyclo[3.3.1]nonanone 7 in
81% yield. The fact that the isolated cyanoketone 6k
was quantitatively converted to the a-hydroxyketone 7
under the same conditions, suggests that the hydroxy-
ketone 7 is produced by the reaction of 6k with another
SmI2 during the course of the reaction.5 Moreover, the
phenylketone 1l also gave cyclooctane derivatives 4l, 6l,
and 8, and bicyclo[3.3.0]octanol 9. As the amount of
SmI2 was increased and the reaction time prolonged,
the yields of ketone 6l and dimeric compound 8
decreased.
The reaction of bicyclo[4.2.0]octan-2-one 1a with SmI2,
t-BuOH, and HMPA in THF gave the cyclohexanone
2a and the over-reduced alcohol 3a via fission of the
external bond (C1ꢀC8) (Scheme 1).4 In the case of
ketones 1b–e, which contain an alkyl group at C6,
3,3-disubstituted cyclohexanones 2b–e were selectively
Keywords: bicyclo[4.2.0]octanones; radical ring opening; samarium-
(II) iodide; regioselectivity; acorenone.
* Corresponding author. E-mail: kakiuchi@ms.asit-nara.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00085-6

1964
K. Kakiuchi et al. / Tetrahedron Letters 44 (2003) 1963–1966
Scheme 2.
urated side chain, a cyclization via the radical 11 or 12
Scheme 1.
would be feasible as a secondary step. A favored pro-
cess could be the well-known 5-exo cyclization of 5-hex-
enyl radicals.7 Treatment of the ketone 1m bearing an
allyl group at C6 with SmI2 as described above gave the
expected spiro[4.5]decanone 15 in 95% yield as a 62:38
mixture of C2 methyl epimers, suggesting the intermedi-
acy of the radical 11m (Scheme 4).
A plausible reaction path is shown in Scheme 3. A one
electron transfer from SmI2 to ketone 1 generates the
cyclobutylcarbinyl radical 10. There are two pathways
available for the radical 10 to react. In the case of
R=H, alkyl, and tricyclic ketones 1a–i, fission of the
external cyclobutane bond (path a) produces the radical
intermediate 11. The over-reduction of the ketone 2
leads to the alcohol 3. On the other hand, car-
bomethoxy-, cyano-, and phenyl-ketones 1j–l gave the
radical 12 via cleavage of the central cyclobutane bond
(path b). In a similar manner, another one electron
transfer followed by protonation of the organosamar-
ium 13 leads to the cyclooctanone 6. Radical dimeriza-
tion of 12 gives the product 8. Transannular cyclization
of 13 (path c) yields the alcohol 9. The over-reduction
of 6 also leads to the alcohol 4 via the radical 14. In the
case of carbomethoxy-ketone 1j, an intramolecular
esterexchange reaction proceeds to give the lactone 5.
In the case of RꢁCN, the radical 14 undergoes an
intramolecular ketyl-nitrile cyclization predominantly
(path d) followed by protonation and subsequent
hydrolysis to give the a-hydroxyketone 7.6
Finally, we demonstrate that the ring-opening reaction
shown above is applicable to the synthesis of the
sesquiterpene, ( )-acorenone (16). A similar reaction of
the cyclobutane derivative 1n8 with SmI2 gave the
ketone 2n in 99% yield (Scheme 5). Since the transfor-
mation of 2n to 16 has been established previously,9 a
formal total synthesis of ( )-acorenone (16) was
accomplished.
In summary, we found that the regioselective radical
ring-opening reactions of bicyclo[4.2.0]octanones are
promoted by SmI2, and the selectivity of the reaction is
controlled by the C6 substituent, while the reason gov-
erning the regioselectivity is not clear at present. The
radical reaction was applied to the selective synthesis of
( )-acorenone (16). The elucidation of factors that con-
trol the regioselectivity is currently in progress in our
laboratory.
Linking the bicyclo[4.2.0] unit to an appropriate unsat-

K. Kakiuchi et al. / Tetrahedron Letters 44 (2003) 1963–1966
1965
Scheme 3.
Scheme 4.
Scheme 5.
Lee, I. S. Heteroatom Chem. 1992, 3, 509; (d) Lee, P. H.;
Lee, J. Tetrahedron Lett. 1998, 39, 7889; (e) Kusama, H.;
Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.;
Nakamura, N.; Morihira, K.; Kuwajima, I. J. Am. Chem.
Soc. 2000, 122, 3811. Epoxy ketones and esters: (f)
Mukaiyama, T.; Arai, H.; Shiina, I. Chem. Lett. 2000, 580;
(g) Molander, G. A.; La Belle, B. E.; Hahn, G. J. Org.
Chem. 1986, 51, 5259 and the preceding paper; (h) Otsubo,
K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1987,
28, 4437. Aziridine ketone: (i) Molander, G. A.; Stengel, P.
J. J. Org. Chem. 1995, 60, 6660. Cyclobutyl ketones: (j)
Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett.
2002, 4, 1611 and the preceding papers; (k) Shipe, W. D.;
Sorensen, E. J. Org. Lett. 2002, 4, 2063. Cyclopentyl-
chloromethane: (l) Honda, T.; Ishikawa, F. J. Org. Chem.
1999, 64, 5542 and the preceding papers. Tetra-
hydropyranyl ketones: (m) Enholm, E. J.; Schreier, J. A. J.
Org. Chem. 1995, 60, 1110.
3. (a) Kakiuchi, K.; Fukunaga, K.; Matsuo, F.; Ohnishi, Y.;
Tobe, Y. J. Org. Chem. 1991, 56, 6742; (b) Kakiuchi, K.;
Nakamura, I.; Matsuo, F.; Nakata, M.; Ogura, M.; Tobe,
Y.; Kurosawa, H. J. Org. Chem. 1995, 60, 3318.
Acknowledgements
This work was supported in part by a Grant-in-Aid
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan. Thanks are also given
to the Instrumental Analysis Center, Faculty of Engi-
neering, Osaka University, for assistance in MS, NMR,
and HRMS analyses.
4. All new compounds gave satisfactory spectral data and
high-resolution mass spectra. General experimental proce-
dure is as follows: under an atmosphere of argon, Sm
metal (99.9%, 423 mg, 1.66 mmol) and a magnetic stirring
bar were placed in a two-necked 50 mL flask and equipped
with a septum inlet. After the flask was flame-dried in
vacuo, 1,2-diiodoethane (423 mg, 1.50 mmol) was placed
in the flask, which was then purged with argon. THF (15
mL) was added via a syringe through the rubber septum
with stirring. The mixture was stirred at room temperature
for 3–5 h until a dark blue 0.1 M THF solution of SmI2
was formed. The SmI2–THF solution was added by cannu-
lar transfer at room temperature to a mixture of ketone 1
(0.5 mmol), t-BuOH or MeOH (2.0 mmol), and HMPA
(1.78 mL, 10 mmol) in dry THF (20 mL) with stirring.
Once the addition was complete, the deep purple color
faded to an opaque gray. After 30 min, the reaction
mixture was quenched with MeOH. 1N HCl was added to
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K. Kakiuchi et al. / Tetrahedron Letters 44 (2003) 1963–1966
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