Radical cyclization of β-alkoxymethacrylates: Expedient synthesis of (+)-methyl nonactate

Article abstract of DOI:10.1021/ol9909536

(matrix presented) Radical cyclization of the β-alkoxymethacrylate obtained from 5-benzyloxy-1-iodohexan-3-ol led to the stereoselective preparation of the benzyl ether of (+)-methyl nonactate, demonstrating "2,5-cis" selectivity in the radical cyclizatio

Full text of DOI:10.1021/ol9909536

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1127-1128
Radical Cyclization of
â-Alkoxymethacrylates: Expedient
Synthesis of (+)-Methyl Nonactate
Eun Lee* and Seung Jib Choi
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity,
Seoul 151-742, Korea
eunlee@snu.ac.kr
Received August 17, 1999
ABSTRACT
Radical cyclization of the â-alkoxymethacrylate obtained from 5-benzyloxy-1-iodohexan-3-ol led to the stereoselective preparation of the benzyl
ether of (+)-methyl nonactate, demonstrating “2,5-cis” selectivity in the radical cyclization step in forming a tetrahydrofuran ring system and
“threo” selectivity in the hydrogen abstraction step.
Radical cyclization of â-alkoxyacrylates is a highly useful
method for stereoselective preparation of cis-2,5-substituted
Scheme 1
tetrahydrofurans and cis-2,6-substituted tetrahydropyrans.1
Radical cyclization reactions of different â-alkoxyacrylates
were employed as key steps in the total synthesis of
dactomelynes,2 kumausyne,3 and kumausallene,4 demonstrat-
ing the generality of these reactions.5
One of the more difficult problems concerning these types
of reactions would be the control of the stereoselectivity
outside of the oxacycle when R-substituted â-alkoxyacrylates
are employed in the radical cyclization (Scheme 1). In this
context, reported work6 by Guindon and co-workers on
radical-mediated reduction of R-halo carboxylates is highly
pertinent; it is reported that radical-mediated reduction of
R-substituted â-alkoxy-R-halo carboxylates resulted in high
threo selectivity. Theoretical studies6b indicate that the
stereoselectivity originates primarily from the preference for
“outside alkoxy” conformation of the intermediate radical
species. In this model, both allylic 1,3-strain and electrostatic
repulsions are minimized, and an early transition state for
hydrogen abstraction in which attack occurs from the least
hindered face of the radical is apparently operative.
(1) (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993,
34, 4831. (b) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C.; Yun, M.; Kim,
S. Tetrahedron Lett. 1994, 35, 129. (c) Lee, E.; Park, C. M. J. Chem. Soc.,
Chem. Commun. 1994, 293. (d) Lee, E.; Jeong, J.-w.; Yu, Y. Tetrahedron
Lett. 1997, 38, 7765.
(2) Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc. 1995, 117, 8017.
(3) Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong, Y. H.
Tetrahedron Lett. 1997, 38, 7757.
(4) Lee, E.; Yoo, S.-K.; Choo, H.; Song, H. Y. Tetrahedron Lett. 1998,
39, 317.
(5) More recently, the scope of radical cyclization reactions of â-alkoxy-
acrylates expanded considerably; see the following references: (a) Use of
acyl radicals: Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem.
1996, 61, 4880 and references therein. (b) Formation of oxepanes in the
presence of a Lewis acid: Yuasa, Y.; Sato, W.; Shibuya, S. Synth. Commun.
1997, 27, 573. (c) Photosensitized electron-transfer cyclization of alde-
hydes: Pandey, G.; Hajra, S.; Ghorai, M. K.; Kumar, R. J. Org. Chem.
1997, 62, 5966. (d) SmI2-induced cyclization of aldehydes: Hori, N.;
Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811.
(e) O-Linked oxepane synthesis: Sasaki, M.; Noguchi, T.; Tachibana, K.
Tetrahedron Lett. 1999, 40, 1337.
We were thus encouraged that the “2,5-cis” selectivity
encountered in the â-alkoxyacrylate radical cyclization
(6) (a) Guindon, Y.; Lavalle´e, J.-F.; Boisvert, L.; Chabot, C.; Delorme,
D.; Yoakim, C.; Hall, D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett.
1991, 32, 27. (b) Durkin, K.; Liotta, D.; Rancourt, J.; Lavalle´e, J.-F.;
Boisvert, L.; Guindon, Y. J. Am. Chem. Soc. 1992, 114, 4912.
10.1021/ol9909536 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/14/1999

reactions in forming tetrahydrofuranyl ring systems may be
coupled with the “threo” selectivity at the exocyclic R sites,
which will offer easy access to a number of oxacyclic natural
products on the condition that appropriately R-substituted
â-alkoxyacrylates are prepared with relative ease. Herein,
we wish to describe results of our recent efforts along these
directions, which resulted in a short synthesis of (+)-methyl
nonactate.7
(R)-3-Benzyloxybutanal(1)8 was treated with allyltri-
methylsilane in the presence of titanium tetrachloride ac-
cording to Reetz’s procedure9 to give the alcohol 2. It was
converted into the tosylate 3 of 5-benzyloxyhexane-1,3-diol
by ozonolysis, NaBH4 reduction, and selective tosylation of
the primary hydroxy group. When the tosylate 3 was reacted
with excess methyl 3,3-dimethoxy-2-methylpropanoate(4)10
in benzene under reflux in the presence of pyridinium
p-toluenesulfonate, conversion to the corresponding â-alkoxy-
methacrylate was reasonably efficient. The radical cyclization
precursor 5 was then obtained via routine iodide substitution
(Scheme 2).
the threo product 6 and the erythro product 7 was obtained
when the substrate 5 was allowed to react with tributylstan-
nane in the presence of triethylborane and air in toluene at
-20 °C. At -78 °C, the hydride abstraction became a little
more selective, producing an 11:1 mixture of 6 and 7. The
best result was obtained when tris(trimethylsilyl)silane was
employed as the hydride source as the reaction in toluene at
-20 °C resulting in an almost exclusive formation of the
product 6. The reaction of 5 with tributylstannane in
dichloromethane at -20 °C proceeded to yield a 4:1 mixture
of 6 and 7. Addition of magnesium bromide did not alter
the ratio of the products.11 Finally, hydrogenolysis of the
benzyloxy group in 6 proceeded uneventfully to yield (+)-
methyl nonactate(8)12 in high yield (Scheme 3).
Scheme 3
Scheme 2
The stereoselectivity observed in the key step may be
rationalized by invoking the conformational preference of
the intermediate radical as discussed above. Future investiga-
tions from these laboratories will focus on further develop-
ments in stereoselective radical reactions as applied in natural
product synthesis.
Acknowledgment. This research was supported by the
Ministry of Education (BSRI-98-3416) and S.N.U. Research
Fund.
Cyclization of 5 was studied under different reaction
conditions. A chromatographically separable 9:1 mixture of
OL9909536
(11) “Erythro” selectivity was reported for chelation-controlled reductions
of R-substituted â-alkoxy-R-iodo carboxylates in the presence of Lewis
acids: Guindon, Y.; Lavalle´e, J.-F.; Llinas-Brunet, M.; Horner, G.; Rancourt,
J. J. Am. Chem. Soc. 1991, 113, 9701. This selectivity originates from
reactions of chelated forms of the substrate R-iodo carboxylates. Obviously,
the R-carbonyl radicals obtained from the cyclization step engage in
hydrogen abstraction oblivious to the Lewis acid in our case.
(7) A large number of reports concern the synthesis of nonactic acid
derivatives. Three of the more recent ones are as follows: (a) Lee, J. Y.;
Kim, B. H. Tetrahedron 1996, 52, 571. (b) Mandville, G.; Girad, C.; Bloch,
R. Tetrahedron 1997, 53, 17079. (c) Meiners, U.; Cramer, E.; Fro¨lich, R.;
Wibbeling, B.; Metz, P. Eur. J. Org. Chem. 1998, 2073.
(8) (a) Mahler, U.; Devant, R. M.; Braun, M. Chem. Ber. 1988, 121,
2035. (b) Widmer, U. Synthesis 1987, 568.
(12) The synthetic sample exhibited spectroscopic characteristics identical
(9) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729.
(10) Walkup, R. D.; Obeyesekere, N. U. Synlett 1987, 607.
to those reported in the literature: [R]22 ) +22.2 (c 0.11, CHCl3) (lit.7b
D
[R]20 ) +21.8 (c 1.04, CHCl3)).
D
1128
Org. Lett., Vol. 1, No. 7, 1999