Highly diastereoselective 5-hexenyl radical cyclizations with Lewis acids and carbohydrate scaffolds.

Article abstract of DOI:10.1021/ol006651h

[figure: see text] Carbohydrates as removable chiral scaffolds for free radical cyclizations were examined for the first time. This investigation illustrates the utility of two inexpensive carbohydrate derivatives as sources of asymmetry for 5-hexenyl rad

Full text of DOI:10.1021/ol006651h

ORGANIC
LETTERS
2001
Vol. 3, No. 2
145-147
Highly Diastereoselective 5-Hexenyl
Radical Cyclizations with Lewis Acids
and Carbohydrate Scaffolds
Eric J. Enholm,* Jennifer S. Cottone, and Florent Allais
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
enholm@chem.ufl.edu
Received September 25, 2000
ABSTRACT
Carbohydrates as removable chiral scaffolds for free radical cyclizations were examined for the first time. This investigation illustrates the
utility of two inexpensive carbohydrate derivatives as sources of asymmetry for 5-hexenyl radical cyclizations. Diastereomeric ratios as high
as 100:1 were achieved with an ester-appended (+)-isosorbide hexose and 70:1 for a diol-protected D-xylose pentose. Temperature dependence,
Lewis acids, and solvents were all examined. By correlation with known compounds, the newly generated chiral centers were of the (S)-
configuration.
Radical cyclizations with activated olefins offer synthetic
chemists a well-documented and reliable means of carbon-
carbon bond formation.1 Synthetic benefits include neutral
reaction conditions and tolerance of various functional groups
and protecting schemes. All of these advantages render this
methodology attractive for a wide variety of synthetic
sequences.2 Recently, the diastereoselectivity of free radical
reactions has been greatly enhanced due to the use of a
combination of Lewis acids and appended chiral auxiliaries,
scaffolds, and templates.3-5 Although radical additions to
activated olefins have been studied extensively,2,6 5-hexenyl
cyclizations with chiral auxiliaries such as oxazolidinones,
sulfoxides, and chiral esters have been far less investigated.7
Interestingly, carbohydrates as removable chiral auxiliaries
for 5-hexenyl free radical cyclizations have not been studied.
This investigation examined the utility of two inexpensive
carbohydrate derivatives as sources of asymmetry for a
5-hexenyl radical cyclization of 1 at low temperatures (-78
°C) with tributyltin hydride, BEt3, and O2 (Scheme 1). Very
Scheme 1
(1) Leonard, J.; Diez-Barra, E.; Merino, S. Eur. J. Org. Chem. 1998,
2051.
(2) Sibi, M.; Ji, J.; Sausker, J.; Jasperse, C. J. Am. Chem. Soc. 1999,
121, 7517.
(3) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem. Soc.
1997, 119, 11713.
(4) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24,
296 and references therein.
(5) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562.
(6) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403. (b) Stack, J. G.; Curran, D. P.; Geib, S. V.; Rebek, J., Jr.; Ballester,
P. J. Am. Chem. Soc. 1992, 114, 7007. (c) Ruck, K.; Kunz, H. Synthesis
1993, 1018. (d) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc. 1995,
117, 10779.
10.1021/ol006651h CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/28/2000

high diastereomeric ratios were achieved while the effects
of temperature dependence, Lewis acids, and solvents were
all studied. By correlation with known compounds, the newly
generated chiral center in 2 in both carbohydrate-mediated
cyclizations is of the (S)-configuration. With these high
diastereomeric ratios, we believe these 5-hexenyl radical
cyclizations are some of the most highly diastereoselective
radical closures to date resulting from any removable
appended chiral molecule.
Scheme 3
Earlier investigations of auxiliaries used in various radical
reactions have relied on a chiral oxazolidinone ring;5,8
however, these investigations examined the commercially
available and less expensive sugar auxiliaries (+)-isosorbide
and (-)-D-xylose acetonide. Both carbohydrates are highly
oxygenated and provide multiple sites for metal chelation.
Thus, additional affinity that strongly attracts the Lewis acid
was a key and desirable trait in selecting these auxiliaries.
Precursor 1 was to be constructed via a Wittig reaction;
the main framework was to be assembled via an unsaturated
chiral ester and an aromatic aldehyde. Carbohydrate-derived
Wittig reagents 4a and 4b were synthesized from monoben-
zyl ethers 3a and 3b, respectively, in two steps, as illustrated
in Scheme 2. Monobenzylation of (+)-isosorbide and 1,2-
its acyclic form as an aldehyde with the bulky silylating agent
tert-butylchlorodiphenylsilane. The desired aldehyde was
achieved in three steps with an overall yield of 50%. Wittig
reagents 4a and 4b and aldehyde 6 were reacted in methylene
chloride, providing unsaturated chiral esters 7a and 7b.
Further manipulations included deprotection of the silyl ether
with HF followed by conversion to bromides 8a and 8b in
73% (isosorbide) and 77% (xylose), respectively.
Scheme 2
Once the unsaturated bromoester of each carbohydrate
derivative had been synthesized, various reaction conditions
for a 5-hexenyl radical cyclization were explored. It was
disquieting that the distance of the new cyclopentane center
was a lengthy fiVe atoms from the nearest controlling chiral
alkoxy carbon on the tetrahydrofuran rings in 8a and 8b.
Diastereomeric ratios of the isosorbide adduct 9a, obtained
via GC and HPLC, are shown in Table 1.
Table 1. Free Radical Cyclizations of 8a
O-isopropylidene-D-xylofuranose was achieved by etherifi-
cation with benzyl bromide, affording 3a and 3b, respec-
tively.9 The remaining hydroxyl functionality was converted
to a chloromethylene ester using chloroacetic anhydride in
pyridine.10 The corresponding ylides 4a and 4b were obtained
from triphenylphosphine followed with base treatment.
The Wittig reagents were then coupled with aromatic
aldehyde 6 synthesized from commercially available iso-
chroman (Scheme 3). Isochroman (5) was first oxidized with
PCC to isochroman-1-one and then reduced using Dibal to
isochroman-1-ol.11 The aromatic lactol was then trapped in
(7) (a) Nishida, M.; Hayashi, H.; Yamaura, Y.; Yanaginuma, E.;
Yonemitsu, O. Tetrahedron Lett. 1995, 36, 269. (b) Nishida, M.; Ueyama,
E.; Hayashi, H.; Ohtake, Y.; Yamaura, Y.; Yanaginuma, E.; Yonemutsu,
O.; Nishida, A.; Kawahara, N. J. Am. Chem. Soc. 1994, 116, 6455. (c)
Badone, D.; Bernassau, J.-M.; Cardamone, R.; Guzzi, U. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 535.
(8) Sibi, M.; Ji, J. J. Org. Chem. 1996, 61, 6090.
(9) Loupy, A.; Monteux, D. Tetrahedron Lett. 1996, 37, 7023.
(10) Bonadies, F.; Di Fabio, R. J. Org. Chem. 1984, 49, 1647.
At 80 °C, AIBN was used as a radical initiator; however,
triethylborane and oxygen were utilized for the lower
146
Org. Lett., Vol. 3, No. 2, 2001

temperature studies. As expected, the radical cyclization of
the (+)-isosorbide moiety 8a proved to be more selective at
lower temperatures. Without a Lewis acid, the diastereomer
ratios were low, ranging from 1.6:1 to 2.9:1. When a Lewis
acid was employed, diastereomeric ratios increased substan-
tially, suggesting the formation of an activated metal chelate
with the appended isosorbide auxiliary. Among the best of
the Lewis acids studied, zinc chloride and magnesium
bromide etherate proVed to be the most effectiVe for the
isosorbide chiral scaffold with diastereomeric Values of
>100:1 for each.
as high as 60:1 and 70:1, respectiVely. For both sugars,
lanthanides such as Eu(III) and Yb(III) were uniformly less
effective in enhancing the diastereoselectivity of the cycliza-
tion. In some cases the lanthanide Lewis acids gave ratios
that were similar to those reactions lacking any added Lewis
acids. This was unexpected because lanthanide Lewis acids
have demonstrated excellent results in recent radical stud-
ies.2,12
Once the diastereomeric ratios of each reaction parameter
set had been determined, elucidation of the absolute stereo-
chemistry of the newly formed chiral center was investigated.
Both cyclized products 9a and 9b were subjected to
saponification conditions using lithium hydroxide in water/
THF. Carboxylic acid 10, the major product in both
saponifications, was then isolated. This compound was
identical to (S)-(+)-indan acid as previously reported.13
In conclusion, the highly oxygenated nature of carbohy-
drate derivatives is extremely advantageous, offering ease
in functionalization, multiple sites for Lewis acid chelation,
and inexpensive ready availability. As chiral templates for
free radical 5-hexenyl cyclizations, both (+)-isosorbide and
(-)-D-xylose gave very high diastereomeric ratios. This high
selectivity can be attributed to the multiple sites of chelation,
firmly anchoring the Lewis acid to the polyoxygenated sugar.
The radical cyclization of D-xylose adduct 8b proved
successful as well, as shown in Table 2. Similar to Table 1,
Table 2. Free Radical Cyclizations of 8b
Acknowledgment. We gratefully acknowledge support
by the National Science Foundation (Grant CHE-9708139)
for this work.
Supporting Information Available: Experimental and
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL006651H
a temperature dependence and an improvement in diastereo-
meric ratios with Lewis acids were observed for these
cyclizations. Lewis acids, such as diethylaluminum chloride
and titanium tetrachloride, proVided diastereomeric ratios
(11) Stoss, P.; Merrath, P.; Schluter, G. Synthesis 1987, 2, 174.
(12) Mero, C. L.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 5155.
(13) Jones, J. B.; Marr, P. W.; Wu, W. S.; Schwartz, H. M. J. Am. Chem.
Soc. 1978, 16, 5199.
Org. Lett., Vol. 3, No. 2, 2001
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