Scheme 1. Plan for Application of R-Alkoxy Bridgehead Radi-
cal to Construct a Linkage between Two Oxygenated Carbo-
cycles
Scheme 2. Generation and Subsequent CꢀC bond Formation of
R-Alkoxy Bridgehead Radical
reactive species with minimum steric interactions. The key
reactive intermediate selected for this purpose is R-alkoxy
bridgehead radical 3 (Scheme 1).6 Homolytic cleavage
of the C-X bond of 2,4,10-trioxadamantane orthoester 1
would generate radical 3, which subsequently adds to
cyclic R,β-unsaturated ketone 4, resulting in the carbon-
chain attached bicycle 2 after introduction of the R group
to 5. Bridgehead radical 3 was considered to be advanta-
geous over the corresponding acyclic R-alkoxy radical due
to its high reactivity and predestined stereochemical out-
come. Namely, the radical of 3 is spacially more exposed
and thus more reactive, and the O-based stereocenter
is fixed by the cage structure throughout the reaction.
Despite these potentially useful properties, bridgehead radi-
cals with R-oxygen atoms have not been systematically
studied7 in comparison to their carbocyclic counterparts
(e.g., adamantyl radical8).9
were first investigated (Scheme 2). Two radical precursors 7
and 8 were prepared from carboxylic acid 6.10 Conversion
of 6 into the acid chloride using (COCl)2 and a polymer-
bound amine11,12 was followed by addition of the sodium
salt of N-hydroxypyridine-2-thione to yield Barton ester
7.13 Photoirradiation of 7 in turn induced generation of
radical 3 at room temperature, which was immediately
trapped by (PhSe)2 to afford O,Se-acetal 8 in 61% yield.14
In contrast to this successful SePh introduction, the photo-
induced carbon extension from 7 in the presence of methyl
acrylate and n-Bu3SnH resulted in decomposition of 7 and
low yielding formation of 9 (15%).15 On the other hand, O,
Se-acetal 8 gave 9 in much higher yield (66%) when treated
(11) Dong, C.-G.; Henderson, J. A.; Kaburagi, Y.; Sasaki, T.; Kim,
D.-S.; Kim, J.-T.; Urabe, D.; Guo, H.; Kishi, Y. J. Am. Chem. Soc. 2009,
131, 15642–15646.
(12) Acid chloride formation using Et3N was unsuccessful due to
lability of 7 to aqueous workup.
To evaluate the synthetic potential of R-alkoxy bridge-
head radicals, generation of 3 and subsequent addition
(13) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun 1983, 939–941. For reviews on Barton ester, see: (b)
Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675–684. (c)
Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413–1432. (d) Saraiva,
M. F.; Couri, M. R. C.; Hyaric, M. L.; de Almeida, M. V. Tetrahedron
2009, 65, 3563–3572.
(14) Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron Lett. 1984,
25, 5777–5780.
(15) The low yield appeared to originate from chemical instability of
the activated ester moiety of 7 upon the radical reaction with methyl
acrylate.
(16) For application of O,Se-acetals for intermolecular radical reac-
tions, see: (a) Abel, S.; Linker, T.; Giese, B. Synlett 1991, 171–172. (b)
Nishiyama, Y.; Yamamoto, H.; Nakata, S.; Ishii, Y. Chem. Lett. 1993,
841–844. (c) SanMartin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.;
Gallagher, T. Org. Lett. 2000, 2, 4051–4054. (d) Abe, H.; Shuto, S.;
Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882. (e) Liu, Y.;
Gallagher, T. Org. Lett. 2004, 6, 2445–2448. (f) Woodward, H.; Smith,
N.; Gallagher, T. Synlett 2010, 869–872. For a review, see: (g) Togo, H.;
He, W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700–717.
(6) For a review on bridgehead radicals, see: Walton, J. C. Chem. Soc.
Rev. 1992, 105–112.
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(7) (a) Buch, G.; Wuest, H. J. Org. Chem. 1979, 44, 546–549. (b)
Hatakeyama, S.; Kawamura, M.; Takano, S. J. Am. Chem. Soc. 1994,
116, 4081–4082.
(8) Ohno, M.; Ishizaki, K.; Eguchi, S. J. Org. Chem. 1988, 53, 1285–
1288 and references cited therein.
(9) For representative examples on application of carbocyclic bridge-
head radicals to synthetic studies on natural products, see: (a) Kraus,
G. A.; Andersh, B.; Su, Q.; Shi, J. Tetrahedron Lett. 1993, 34, 1741–1744.
(b) Kraus, G. A.; Su, Q. Synlett 1994, 237–237. (c) Kraus, G. A.;
Siclovan, T. M.; Watson, B. Synlett 1995, 201–202. (d) Chatgilialoglu,
C.; Ferreri, C.; Ballestri, M. Tetrahedron Lett. 1996, 37, 6387–6390. (e)
Kim, S.; Cheong, J. H. Synlett 1997, 947–949.
(10) Compound 6 was synthesized in six steps from the literature
known (1r,3R,5S)-3,5-bis((tert-butyldimethylsilyl)oxy)cyclohexanol.
Carda, M.; Van der Eycken, J.; Vanderwalle, M. Tetrahedron: Asym-
metry 1990, 1, 17–20. See Supporting Information for details.
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