Convenient annulation of bicyclo[6.3.0]undecanes

Article abstract of DOI:10.1016/S0040-4039(01)01184-4

A facile, albeit nonstereoselective, method for the construction of a bicyclo[6.3.0]undecane skeleton has been developed by sequential application of the Suárez cleavage and 5-exo radical cyclization on the readily available [4+3] cycloadducts of cyclic oxyallyls.

Full text of DOI:10.1016/S0040-4039(01)01184-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6019–6021
Convenient annulation of bicyclo[6.3.0]undecanes†
Kwangho Lee and Jin Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487, USA
Received 30 May 2001; accepted 26 June 2001
Abstract—A facile, albeit nonstereoselective, method for the construction of a bicyclo[6.3.0]undecane skeleton has been developed
by sequential application of the Sua´rez cleavage and 5-exo radical cyclization on the readily available [4+3] cycloadducts of cyclic
oxyallyls. © 2001 Elsevier Science Ltd. All rights reserved.
The presence of bicyclo[5.3.0]decane and bicyclo[6.3.0]-
undecane skeletons characterizes many naturally occur-
ring terpenes and presents considerable synthetic chal-
lenges due to unfavorable entropic and enthalpic
factors.2 Development of efficient annulation methods
for the medium-sized carbocycles has been an active
area of research. We previously reported the prepara-
tion of functionalized seven- and eight-membered car-
bocycles and heterocycles by means of the [4+3]
cycloaddition of cyclic oxyallyls (and related amino-
allyls) and subsequent Sua´rez cleavage (2“3) of the
ketone bridge.3 Radical cyclization of the resulting
iodide 3 to a suitably tethered olefin presented itself as
a potentially convenient entry to 5,7- or 5,8-fused tri-
cyclic rings 4 (Eq. (1)). As a preliminary synthetic study
toward structurally complex natural products, we
herein report a convenient construction of fused 5,8-
bicyclic rings by sequential application of the Sua´rez
cleavage and 5-exo radical cyclization starting from the
[4+3] cycloadducts 1 (n=1).
Of particular interest is the little known diastereoselec-
tivity of the transformations 3“4; in contrast to a large
body of data available on venerable 5-hexenyl cycliza-
tions of five- and six-membered ring radicals, as well as
acyclic radicals, there remains a paucity of examples
concerning those of radicals embedded in the larger,
conformationally flexible medium-sized rings.4
Our synthesis started from the [4+3] cycloadducts 1a,b,
which were converted to the alcohols 5a,b by standard
methods (Scheme 1).3,5 At the outset, we chose to
introduce a stereocenter in the butenyl side chain by
addition of an allylmetal reagent to the aldehyde
derived from 5a,b so as to evaluate the substituent
effects on diastereoselectivity of 5-exo radical cycliza-
tions. Thus, Swern oxidation of 5a, followed by addi-
tion of the allylindium reagent, gave a 4:5 mixture of 6
and 7 in 90% yield.7 In any event, separation8 and
standard functional group manipulation of 6 and 7 then
furnished 8 and 9, the requisite substrates for Sua´rez
X
O
X
steps
n
[4 + 3] cycloaddition
X
HO
O
1
n
n = 0, 1
n
Y
(1)
X
O
PhI(OAc)2
I2
2
*
n
*
n-Bu3Sn
O
O
n
I
X
O
O
3
4
* Corresponding author. E-mail: jcha@bama.ua.edu
† See Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01184-4

6020
K. Lee, J. K. Cha / Tetrahedron Letters 42 (2001) 6019–6021
1. LAH
1. Swern oxid
2. CH2=CHCH2Br
In, H2O
2. BOMCl
3. O3; NaBH4
4. PivCl
X
X
PivO
HO
PivO
*
81-90%
HO
BOMO
H
O
H
O
BOM
5a: X = CH2
5b: X = O
1a: X = CH2
1b: X = O
6: β-OH
7: α-OH
43-54%
PhI(OAc)2
I2
cyclohexane
1. NaH; Me2SO4
2. PPTS
HO
3. TPAP
4. n-Bu4NOH
*
*
O
I
MeO
MeO
O
O
8: β-OMe
9: α-OMe
10: β-OMe (49%)
11: α-OMe (42%)
Scheme 1.
cleavage, respectively. Their unequivocal stereochemical
determination was secured later by X-ray crystallo-
graphic analysis of the resulting cyclization products
(vide infra).
ring junction stereochemistry was observed for the mis-
matched cyclization of 11. The disappointing lack of
diastereocontrol in these radical cyclizations is in sharp
contrast to the exclusive preference for the trans fused
ring junction and the chair-like transition structure
exhibited for a b-keto radical embedded in the unsub-
stituted cyclooctane ring (carried out at room tempera-
ture).12–14 The possibility of several local conformations
of similar energies for the central eight-membered ring,
especially in the presence of the lactone ring and also at
elevated temperatures (i.e. refluxing benzene), may
account for the observed poor stereoselectivities.14
Irradiation (100 W lamp, 40°C, cyclohexane) of a reac-
tion mixture of 8 and PhI(OAc)2ꢀI2 afforded the iodo-
lactone 10 as a diastereomeric mixture in 49% yield.9,10a
Under identical conditions, Sua´rez cleavage of the
epimer 9 also gave 11 (42%).
Tin hydride-mediated radical cyclizations of 10 and 11
proceeded in excellent yields, but with modest
diastereoselectivities (Scheme 2).10b,11 The relative stereo-
chemistry of 12 was unequivocally determined by X-
ray analysis; structures for the remaining products were
In summary, we have developed a facile method for the
construction of a bicyclo[6.3.0]undecane skeleton by the
readily available [4+3] cycloadducts, followed by
sequential application of the Sua´rez cleavage and 5-exo
radical cyclization. Studies are underway to achieve
diastereoselective 5-exo cyclization by inducing a local
conformational bias of the central eight-membered ring
with a judicious choice of substituents and/or at low
1
tentatively assigned by analysis of the H NMR spectra
and consideration of the anticipated geometry of 5-exo
cyclization.10c The radical cyclization of 10 thus exhib-
ited modest diastereoselectivity in favor of the trans-
ring fused stereochemistry, whereas no preference in the
Me
Me
H
H
H
n-Bu3SnH
AIBN
PhH, reflux
+
+
O
O
O
10
H
H
H
OMe
OMe
OMe
O
O
O
12 (47%)
13 (31%)
14 (15%)
R
R
H
H
H
H
H
H
n-Bu3SnH
AIBN
PhH, reflux
+
+
O
O
O
11
OMe
OMe
O
O
OMe
O
15: R = β-Me (31%)
16: R = α-Me (26%)
17: R = β-Me (11%)
18: R = α-Me (21%)
19: α-H (10%)
20: β-H (5%)
Scheme 2.

K. Lee, J. K. Cha / Tetrahedron Letters 42 (2001) 6019–6021
6021
temperatures. Also included is the application of this
annulation approach to a total synthesis of natural
products.
precursor could be accomplished by the action of an
appropriate lipase or esterase.1a,3c,6
6. Lee, K.; Cha, J. K. Unpublished results.
7. Similarly, a 16:1 mixture of the corresponding homoallyl
alcohols were obtained in 81% yield from 5b. The con-
spicuous difference in diastereoselectivity in the allylation
reaction of 5a and 5b can be attributed to the bridged
oxygen atom in the latter compound.
Acknowledgements
We thank the National Institutes of Health (GM
35956) for generous financial support. We are indebted
to Professor Robin D. Rogers for the X-ray structure
determination of 12.
8. Deprotection of the pivaloyl group was found to greatly
facilitate the separation of the two diastereomers by
column chromatography.
9. (a) Freire, R.; Marrero, J. J.; Rodr´ıguez, M. S.; Sua´rez,
E. Tetrahedron Lett. 1986, 27, 383; (b) de Armas, P.;
Francisco, C. G.; Sua´rez, E. J. Am. Chem. Soc. 1993, 115,
8865 and references cited therein; (c) See also: Ref. 3b.
10. (a) Unoptimized yield; (b) Diastereoselectivities were
References
1
1. Part 15 in the series of synthetic studies on [4+3] cycload-
ditions of oxyallyls. See also: (a) Part 14: Lee, K.; Cha, J.
K. J. Am. Chem. Soc. 2001, 123, 5590; (b) Part 13: Lee,
J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243; (c)
Part 12: Lee, J. C.; Cha, J. K. Tetrahedron 2000, 56,
10175; (d) Part 11: Sung, M. J.; Lee, H. I.; Chong, Y.;
Cha, J. K. Org. Lett. 1999, 1, 2017.
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3. For previous work, see: (a) Oh, J.; Choi, J.-R.; Cha, J. K.
J. Org. Chem. 1992, 57, 6664; (b) Lee, J.; Oh, J.; Jin, S.-j.;
Choi, J.-R.; Atwood, J. L.; Cha, J. K. J. Org. Chem.
1994, 59, 6955; (c) Kim, H.; Ziani-Cherif, C.; Oh, J.; Cha,
J. K. J. Org. Chem. 1995, 60, 792; (d) Jin, S.-j.; Choi,
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4. For an excellent review, see: Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions: Concepts,
Guidelines, and Synthetic Applications; VCH: New York,
1996.
determined by isolation yields and/or analysis of the H
NMR spectra; (c) The products 17–20 were obtained as
an inseparable mixture, and their stereochemistry was
tentatively assigned on the basis of the 1H NMR
spectrum.
11. Comparable results were also obtained for the corre-
sponding oxocanes which were prepared from 5b.6
12. (a) Booker-Milburn, K. I. Synlett 1992, 809; (b) Booker-
Milburn, K. I.; Thompson, D. F. J. Chem. Soc., Perkin
Trans. 1 1995, 2315.
13. (a) Iwasawa, N.; Funahashi, M.; Hayakawa, S.;
Narasaka, K. Chem. Lett. 1993, 545; (b) Iwasawa, N.;
Hayakawa, S.; Funahashi, M.; Isobe, K.; Narasaka, K.
Bull. Chem. Soc. Jpn. 1993, 66, 819.
14. As the size of the existing ring becomes larger, an increas-
ing amount of the trans ring fused products has been
observed, while five- or six-membered ring systems pre-
dominantly lead to the cis-fused bicyclic products. See,
for example: (a) Winkler, J. D.; Sridar, V. Tetrahedron
Lett. 1988, 29, 6219 and references cited therein; (b)
Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1990, 55,
5442; (c) The orientation of the alkenyl side-chain on the
existing ring, in particular cyclohexyl rings, is also known
to influence the level of diastereoselectivity: RajanBabu,
T. V.; Fukunaga, T. J. Am. Chem. Soc. 1989, 111, 296.
5. In the present study we chose to work with racemic
compounds as a matter of convenience. However, we
note that enzymatic asymmetrization of the meso diol
.