Radical fragmentation of ω-bromoalkyl cyclobutanones. A modular approach to eight-membered carbocycles

Article abstract of DOI:10.1021/ol026666a

(graph presented) An eight-membered ring was conveniently appended onto a cycloalkene carboxylate by employing a facile radical cyclization-fragmentation reaction of an ω-bromoalkyl spirocyclobutanone, which was readily accessible by the Kulinkovich cyclo

Full text of DOI:10.1021/ol026666a

ORGANIC
LETTERS
2
002
Vol. 4, No. 21
707-3709
Radical Fragmentation of ω-Bromoalkyl
Cyclobutanones. A Modular Approach to
Eight-Membered Carbocycles
3
,†
Heong-Sub Oh, Hyoung Ik Lee, and Jin Kun Cha*
Department of Chemistry, UniVersity of Alabama, Tuscaloosa, Alabama 35487
jcha@bama.ua.edu
Received August 3, 2002
ABSTRACT
An eight-membered ring was conveniently appended onto a cycloalkene carboxylate by employing a facile radical cyclization−fragmentation
reaction of an ω-bromoalkyl spirocyclobutanone, which was readily accessible by the Kulinkovich cyclopropanation and subsequent electrophilic
addition to a 3-bromoalkyl acetal.
In the past two decades, free radicals have emerged as
versatile reaction intermediates in the construction of the
Scheme 1
carbon-carbon bonds in the presence of other functional
1
groups. Particularly useful is a free radical fragmentation
(ring-opening) strategy of spiro- and fused-strained rings to
bring about ring expansion for preparing medium-sized
carbocycles. For example, sequential application of an inter-
or intramolecular [2 + 2] photocycloaddition and a radical
fragmentation reaction of the resulting, typically fused
cyclobutane derivative has provided a convenient method
2
for generating medium-sized rings. We herein report an
Our approach to the requisite ω-bromoalkyl-tethered
cyclobutanones was built upon the Kulinkovich reaction of
cycloalkene carboxylates and subsequent condensation of
expedient annulation of an eight-membered ring onto a
cycloalkene carboxylate by relying on facile radical frag-
mentation of a spiro-cyclobutanone (Scheme 1).
1-cycloalkenylcyclopropanols with ω-bromoalkyl acetals
-5
(
Scheme 2). The original Kulinkovich cyclopropanation3
†
Current address: Department of Chemistry, Wayne State University,
of methyl cyclohexenecarboxylate (1) and methyl cyclopen-
tenecarboxylate (2) with ethylmagnesium bromide in the
Detroit, MI 48202. E-mail: jcha@chem.wayne.edu.
(1) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, 1986. (b) Jasperse, C. P.; Curran,
D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237. (c) Motherwell, W. B.;
Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic
Press: San Diego, 1992. (d) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals
in Organic Chemistry; Wiley: Chichester, UK, 1995. (e) Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P. Eds.; Wiley-VCH: Weinheim,
Germany, 2001.
(3) (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789.
(b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835.
(4) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pri-
tytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh.
Org. Khim. 1991, 27, 294. (c) Kulinkovich, O. G.; Sviridov, S. V.;
Vasilevskii, D. A. Synthesis 1991, 234. (d) Kulinkovich, O. G.; Savchenko,
A. I.; Sviridov, S. V.; Vasilevskii, D. A. MendeleeV Commun. 1993, 230.
(5) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc.
1996, 118, 291. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198. See also: (c) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36,
6079. (d) Kasatkin, A.; Kobayashi, K.; Okamoto, S.; Sato, F. Tetrahedron
Lett. 1996, 37, 1849.
(
2) For representative examples, see: (a) Dowd, P.; Zhang, W. J. Org.
Chem. 1992, 57, 7163. (b) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93,
091. (c) Zhang, W.; Collins, M. R.; Mahmood, K.; Dowd, P. Tetrahedron
2
Lett. 1995, 36, 2729. (d) Rawal, V. H.; Dufour, C.; Iwasa, S. Tetrahedron
Lett. 1995, 36, 19. (e) Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E.
Tetrahedron Lett. 1996, 37, 6519. (f) Lange, G. L.; Gottardo, C. J. Org.
Chem. 1995, 60, 2183.
1
0.1021/ol026666a CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/20/2002

above-mentioned results, 10a and 10b were obtained in 51%
yield in a 1.3:1 ratio from condensation of 8 with 3-bromo-
propionaldehyde dimethylacetal. Again, free radical-mediated
cyclization-fragmentation of 10a and 10b took place
smoothly to afford 4a and 4b (84∼93% yield), respectively,
as the sole product in each case.
Scheme 2
As outlined in Scheme 3, the reaction sequence is likely
to involve 6-exo-cyclization of the initially formed primary
radical A to the cyclobutanone functionality to generate the
Scheme 3
presence of titanium isopropoxide afforded the corresponding
6
cyclopropanols 5 and 6 in 95 and 86% yields, respectively.
Vinyl cyclopropanols and silyl ethers can be viewed as
vinylogous enols and enol silyl ethers, and their synthetic
utility in electrophilic addition reactions was first demon-
strated by the Wasserman and Trost groups and, more
recently, in our laboratory.7-9 Following standard silylation
(
88% yield), a vinylogous Mukaiyama condensation10 of 7
with 3-bromopropionaldehyde dimethylacetal by the action
of TiCl gave a 5:3 mixture of 9a and 9b (71% yield) that
4
were epimeric at the methoxy stereocenter. The ring junction
alkoxy radical B. Ring opening, which is driven by the relief
of strain in the four-membered ring, affords the fused bicyclic
radical C. The ring-annulated radical C is anticipated to
suffer 1,5-hydrogen transfer leading to the stabilized R-acyl
radical D, which finally undergoes hydrogen abstraction from
tributyltin hydride to furnish the bicyclic ketone products
stereochemistry of 9a and 9b was assigned on the basis of
8
the stereoelectronic requirements for electrophilic addition,
whereas the relative configuration of the methoxy substituent
could not be ascertained. Other Lewis acids such as TM-
3 2 2
SOTf, BF ‚Et O, and Et AlCl were ineffective in effecting
coupling with an acetal.
3
a,b and 4a,b. By analogy to a related system examined by
Slow addition of n-tributyltin hydride and AIBN to a
solution (14 M) of 9a in refluxing benzene afforded
cyclooctenone 3a as a single isomer in 99% yield. Similarly,
free radical-mediated cyclization-fragmentation of 9b also
proceeded efficiently to provide 3b in 91% yield. The
identical annulation sequence was also evaluated by starting
with 6, especially because the resultant bicyclo[6.3.0]-
undecane skeleton is commonly found in an increasing
2c
Dowd, the preferential formation of the trans isomers would
seem more favorable than the alternate cis ring junction
a b
isomers, arising from 1,5-hydrogen transfer of H (vs H )
(i.e., C over C′). Apparently, the methoxy configuration
exerted negligible influences on the stereochemical course,
which might be attributable to its small A value.
To confirm the presumed reaction mechanism involving
11
number of bioactive natural products. In parallel to the
1
,5-hydrogen transfer, the deuterium labeling experiment
using tributyltin deuteride and also the radical allylation
reaction by allyltributyltin were undertaken next (Scheme
(
6) For a previous synthesis of 5 and 6, see: Salaun, J.; Garnier, B.;
Conia, J. M. Tetrahedron 1974, 30, 1413.
(
(
7) Wasserman, H. H.; Keehn, P. M. J. Am. Chem. Soc. 1969, 91, 2375.
8) (a) Trost, B. M.; Brandi, A. J. Am. Chem. Soc. 1984, 106, 5041. (b)
4
). Reduction of 9a with tributyltin deuteride afforded 11
having the deuterium R to the carbonyl group as a 4:1
diastereomeric mixture (94%). Similarly, separate treatment
of 9a and 9b with allyltributyltin resulted in grafting an allyl
group adjacent to the carbonyl group to give 12 and 13 in
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556. For an excellent
review, see: (c) Trost, B. M. Top. Curr. Chem. 1986, 133, 3.
(
9) Youn, J.-H.; Lee, J.; Cha, J. K. Org. Lett. 2001, 3, 2935.
(10) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Murata, S.; Suzuki,
M.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248. See also: (c) Casiraghi,
G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929.
9
6 and 95% yields, respectively; in both cases, two diaster-
(11) (a) For recent reviews, see: Mehta, G.; Vishwakarma, S. Chem.
ReV. 1999, 99, 881. (b) Yet, L. Tetrahedron 1999, 55, 9349. For recent
examples, see: (c) Aloise, A. D.; Layton, M. E.; Shair, M. D. J. Am. Chem.
Soc. 2000, 122, 12610. (d) Mainetti, E.; Mouri e` s, V.; Fensterbank, L.;
Malacria, M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132.
eomers were obtained in a ∼6:1 ratio. The stereochemistry
of 9a,b and 11-13 was tentatively assigned as shown in
Scheme 4 primarily by analogy to 10a,b and 14-16 (vide
3708
Org. Lett., Vol. 4, No. 21, 2002

From individual radical allylation of 10a and 10b with
allyltributyltin, 14 (as a 5:1 diastereomeric mixture) and 16
Scheme 4
(as a 7:1 diastereomeric mixture) were obtained in 52 and
7
0% yields, respectively. The full stereochemistry of 10a,b
and 16 was unequivocally determined by single-crystal X-ray
analysis of carbamate 17 that was prepared from the major
diastereomer of 16 having the allyl group in the â-config-
4
uration by reduction with NaBH , followed by acylation of
the major alcohol with p-bromophenylisocyanate. The X-ray
structure of 17 is depicted in ORTEP presentation (Figure
1
2
1
).
Figure 1.
In summary, a convenient method for appending an eight-
membered ring to cycloalkene carboxylates has been devel-
oped by employing a facile radical cyclization-fragmentation
reaction of bromoalkyl-tethered spirocyclobutanones. The
requisite substrates for ring expansion were readily accessible
by a modular approach involving the Kulinkovich cyclo-
propanation of cycloalkene carboxylates and subsequent
electrophilic addition of the resulting alkenyl cyclopropanols
to a 3-bromoalkyl acetal.
Acknowledgment. We thank the National Institutes of
Health (GM35956) and the National Science Foundation
(CHE-0209321) for generous financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
1
infra), along with the H- H COSY, difference NOE
10b
measurements, and mechanistic considerations.
OL026666A
In the same fashion, treatment of 10b with tributyltin
deuteride furnished 15 as a 2:1 diastereomeric mixture (69%).
(
12) We thank Dr. Fook Tham (University of California, Riverside) for
X-ray analysis.
Org. Lett., Vol. 4, No. 21, 2002
3709