Highly diastereoselective radical cyclizations on soluble ring opening metathesis supports

Article abstract of DOI:10.1021/ol016855d

equation presented This study represents the first examples of stereoselective radical cyclizations on soluble supports. A stereocontrol element consisting of a polymer-imbedded (+)-isosorbide chiral auxiliary was used in each monomer subunit. A survey of

Full text of DOI:10.1021/ol016855d

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3959-3962
Highly Diastereoselective Radical
Cyclizations on Soluble Ring Opening
Metathesis Supports
Eric J. Enholm* and Jennifer S. Cottone
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
enholm@chem.ufl.edu
Received October 4, 2001
ABSTRACT
This study represents the first examples of stereoselective radical cyclizations on soluble supports. A stereocontrol element consisting of a
polymer-imbedded (+)-isosorbide chiral auxiliary was used in each monomer subunit. A survey of various Lewis acids was also examined.
The best results gave very high distereoselectivites of >100:1 in a hepa-1,3-dienenyl radical cyclization using zinc chloride as a Lewis acid.
Considerable recent research efforts have enabled a much
better understanding of the transition metal catalyzed olefin
metathesis reaction.1 In particular, ring opening metathesis
polymerization (ROMP), commonly employing a Grubbs-
type ruthenium-based catalyst, has been used extensively in
organic materials and macromolecular applications but has
seen little use as a support for synthetic organic reactions.2
When properly constructed, such supports are soluble in a
variety of organic solvents and can be readily precipitated
as white crystalline-like solids from cold (-78 °C) methanol.
As an alternative to the drawbacks of commonly employed
cross-linked resin supports,3 interest has recently turned to
soluble polymers driven by a multitude of benefits, such as
direct NMR monitoring of the reaction, rapid product
purification, solution-phase reaction rates, and facile removal
of harmful solution organometallics by rapid filtration of the
precipitated solid support.4 Our investigations were further
motivated by the desire to abate physiologically and envi-
ronmentally toxic tin byproducts in tributyltin hydride
mediated radical reactions.4d,e The difficulty of tin removal
is considered by many to be the Achilles' heel of synthetic
radical methodology, which hinders it use and application
in pharmaceutical syntheses.5
An important recent goal in radical reactions is in control
of stereoselectivity and we recently began a new program
involving the attachment of chiral auxiliaries to soluble
polymer precursors.6 Polymer-bound chiral auxiliaries are
of particular importance as they can lead to asymmetric
radical reactions with concomitant facile recovery and
potential recycling of the supported chiral vehicle by simple
(1) (a) Novak, B. M.; Risse, W.; Grubbs, R. H. AdV. Polym. Sci. 1992,
102, 42. (b) Maughon, B. R.; Grubbs, R. H. Macromolecules 1997, 30,
3459.
(2) For examples of ROMP supports in synthesis, see: (a) Ball, C. P.;
Barrett A. G. M.: Poitout, L. F.; Smith, M. L.; Thorn, Z. E. Chem. Commun.
1998, 2453. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F.
J. Org. Lett. 1999, 1, 579. (c) Barrett, A. G. M.; Cramp, S. M.; Roberts, R.
S.; Zecri, F. J. Org. Lett. 2000, 2, 261.
(3) For examples of radical reactions on solid-phase resins, see: (a) Yim,
A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Lett. 1999, 40,
4535. (b) Caddick, S.; Hamza, D.; Wadman, S. N. Tetrahedron Lett. 1999,
40, 7285. (c) Zhu, X.; Ganesan, A. J. Comb. Chem. 1999, 1, 157.
(4) (a) Wentworth, P.; Janda, K. D. Chem. Commun. 1999, 1917. (b)
Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40, 6329. (c) Gravert, D.
J.; Janda, K. D. Curr. Opin. Chem. Biol. 1997, 1, 107. (d) Enholm, E. J.;
Gallagher, M. E.; Lombardi, J. S.; Moran, K. M.; Schulte, J. P. Org. Lett.
1999, 1, 689. (e) Enholm, E. J.; Schulte, J. P. Org. Lett. 1999, 1, 1275.
(5) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200. (b) Light, J.;
Breslow, R. Tetrahedron Lett. 1990, 31, 2965. (c) Clive, D. L.; Yang, W.
J. Org. Chem. 1995, 60, 2607. (d) Curran, D. P.; Hadida, S. J. Am. Chem.
Soc. 1996, 118, 2531. (e) Hays, D. S.; Fu, G. C. J. Org. Chem. 1996, 61,
4. (f) Enholm, E. J.; Schulte, J. P., II. Org. Lett. 1999, 1275. (g) Enholm,
E. J.; Gallagher, M.; Jiang, S.; Batson, W. S. Org. Lett. 2000, 2, 3355.
(6) Enholm, E. J.; Jiang, S. J. Org. Chem. 2000, 65, 4756-4758.
10.1021/ol016855d CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/07/2001

filtration.7 The increasing demands of higher diastereo- and
enantioselectivity in the combinatorial/drug discovery area
are now just beginning to lead investigators to seek new
methods of incorporating asymmetry into polymer-supported
transformations.7b-d
enhanced as a result of the use of a combination of low
temperatures, Lewis acids, and appended chiral auxiliaries,
scaffolds, and templates.10 For example, radical cyclizations
with chiral auxiliaries such as oxazolidinones, sulfoxides,
and chiral esters have investigated.10d-f An important objec-
tive in our studies was to study radical cyclizations using a
removable carbohydrate on designer support as a stereocon-
trol element.11 Although carbohydrate auxiliaries not on
polymer support have been studied with many varieties of
reactions, they have not been systematically studied in radical
cyclizations or on support. In general, we hoped that this
would offer a well-documented and reliable means of radical
carbon-carbon bond formation.
In this study, 6-heptenyl radical cyclizations were exam-
ined on a new custom-synthesized designer support by
mounting each reaction on a soluble succinimide-derived
ROMP backbone, shown as 1 f 2 in Scheme 1.8
A
Scheme 1
Our studies on stereoselective and polymer-supported
radical cyclizations began with the construction of a meta-
thesis monomer. This would then be tethered to polymer-
supported norborene imide by a short series of four meth-
ylene units. All of the important structural features for the
6-heptenyl radical reaction were to be covalently secured
into the polymer backbone before polymerization of the
norborene ring system. This is done to ensure that each
monomer contains a cyclization precursor and, thus, increase
the loading on the polymer to an absolute maximum. In other
words, each monomer unit contains a reaction site integrated
into the backbone so that this designer polymer essentially
has 100% loading capacity. Standard solid-phase resins
cannot achieve this level of loading mainly because the
substrate is incompletely covalently attached to the polymer.
With the methodology discussed herein, the substrate is
always completely incorporated into each monomer and then
subsequently polymerized.
We decided to use norbornyl monomers in these studies
because they polymerize readily by ring-opening metathesis
with Grubbs’ well-defined ruthenium catalysts.12 The small
amount of strain inherent with norbornenes assists and
accelerates the metathesis.13 Moreover, a wide variety of
norbornenes are commercially available or readily prepared
by Diels-Alder reactions.
Diol 4 was constructed initially in 79% yield (two steps)
from 1,2-dihydronaphthalene (3) by ozonolysis and reductive
workup with sodium borohydride, as shown in Scheme 2.
stereocontrol element (R*) consisting of a polymer-imbedded
(+)-isosorbide chiral auxiliary was used in each monomer
subunit. Very high diastereoselectivites of >100:1 were
observed in the cyclization using zinc chloride as a Lewis
acid and >99% enantiomeric excess was achieved after
cleavage from the support. A survey of various solvent
systems, radical initiators, temperatures, and Lewis acids
resulted in highly diastereoselective cyclic products. It is
worth noting that this work contains the first examples of
asymmetric radical cyclizations on soluble support.8
Radical reactions offer synthetic benefits such as neutral
reaction conditions and tolerance of various functional groups
and protecting schemes.9 New studies have shown the
diastereoselectivity of free radical reactions is greatly
(9) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: New York, 1986. (b) Ramaiah, M.
Tetrahedron 1987, 43, 3541. (c) Curran, D. P. Synthesis 1988, 417, 489.
(d) Hart, D. J. Science 1984, 223, 883. (e) Motherwell, W. B.; Crich, D.
Free Radical Chain Reactions in Organic Synthesis; Academic Press: New
York, 1992.
(10) (a) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem.
Soc. 1997, 119, 11713. (b) Porter, N. A.; Giese, B.; Curran, D. P. Acc.
Chem. Res. 1991, 24, 296 and references therein. (c) Renaud, P.; Gerster,
M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2562. (d) Nishida, M.; Hayashi,
H.; Yamaura, Y.; Yanaginuma, E.; Yone-mitsu, O. Tetrahedron Lett. 1995,
36, 269. (e) 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. (f) Badone, D.; Bernassau, J.-M.; Cardamone,
R.; Guzzi, U. Angew. Chem., Int. Ed. Engl. 1996, 35, 535.
(11) Enholm, E. J.; Cottone, J. S.; Allais, F. Org. Lett. 2000, 3, 145.
(12) (a) Maughon, B. R.; Grubbs, R. H. Macromolecules 1997, 30, 3459-
3469. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 2000,
1, 953-956. Chang, S.; Jones, L.; Wang, C. M.; Henling, L. M.; Grubbs,
R. H. Organometallics 1998, 17, 3460-3465.
(13) Makovetsky, K. L.; Finkelshtein, E. S.; Ostrovskaya, I. Y.; Portnykh,
E. B.; Gorbacheva, L. I.; Goldberg, A. L.; Ushakov, N. V.; Yampolsky, Y.
P. J. Mol. Catal. 1992, 76, 107-121.
(7) (a) Lei, M.; Wang, Y. G.Chin. J. Org. Chem. 2001, 21, 436. (b)
Allin, S. M. Shuttleworth, S. J. Tetrahedron Lett. 1996, 8023. (c) Moon,
H.; Schore, N. E.; Kurth, M. J. Tetrahedron Lett. 1994, 8915. (d) Moon,
H. S.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1992, 57, 6088. (e) Wu,
W. X.; McPhail, A. T.; Porter, N. A. J. Org. Chem. 1994, 59, 1302.
(8) For examples of radical reactions on commercial resin supports,
see: (a) Sibi, M. P.; Chandramouli, S. V. Tetrahedron Lett. 1997 38, 8929-
8932. (b) Miyabe, H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443-
1445. (c) Jia, G. F.; Iida, H.; Lown, J. W. Synlett 2000, 603-606. (d)
Wendeborn, S.; De Mesmaeker, A.; Brill, W. K. D.; Berteina, S. Acc. Chem.
Res. 2000, 215-224. (e) Jeon, G. H.; Yoon, J. Y.; Kim, S.; Kim, S. S.
Synlett 2000, 128-130. (f) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa,
K.; Naito, T. Tetrahedron 2000, 56, 2413-2420. (g) Miyabe, H.; Tanaka,
H.; Naito, T. Tetrahedron Lett. 1999, 40, 8387-8390. (h) Caddick, S.;
Hamza, D.; Wadman, S. N. Tetrahedron Lett. 1999, 40, 7285-7288. (i)
Berteina, S.; De Mesmaeker, A.; Wendeborn, S.; Synlett 1999, 1121-1123.
(j) Zhu, X. W.; Ganesan, A. J. Comb. Chem. 1999, 1, 157-162. (k) Yim,
A. M.; Vidal, Y.; Viallefont, P.; Martinez, J.; Tetrahedron Lett. 1999, 40,
4535-4538. (l) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 2000,
64, 2174-2175. (m) Watanabe, Y.; Ishikawa, S.; Takao, G.; Toru, T.
Tetrahedron Lett. 1999, 40, 3411-3414. (n) Berteina, S.; Wendeborn, S.;
De Mesmaeker, A. Synlett 1998, 1231-1233.
3960
Org. Lett., Vol. 3, No. 24, 2001

Scheme 2
Scheme 4
ring in 12, as shown in Scheme 5. Because soluble polymers
behave much like normal solution-phase organic reactions,
the reactions discussed here behaved similarly to liquid-phase
radical cyclization reactions.11 After the tin-mediated radical
cyclization to 12, the precipitated polymer was subjected to
immediate saponification conditions with LiOH so that
enantiomeric excess of the resultant acid derivative could
be studied by chiral HPLC using a (S)-tert-leucine-(R)-1-
(R-naphthyl)ethylamine column.
Next, diol 4 was selectively oxidized in the benzylic position
with manganese dioxide, followed by a Wittig reaction,
providing R,â-unsaturated ester 5 in 59% yield. The ester
was saponified with lithium hydroxide and converted to the
corresponding bromide 6.
Starting tricyclic norborene adduct 7, constructed by the
Diels-Alder reaction of maleimide and cyclopentadiene, is
shown in Scheme 3. Bromide 8 was obtained in 85% yield
Scheme 3
Scheme 5
by treatment with base in the presence of 1,4-dibromobutane.
The remaining halide was next displaced with (+)-isosorbide
in a Williamson ether synthesis, constructing 9 in 76% yield.
Scheme 4 illustrates the final construction of the monomer
units and metathesis polymerization. DCC esterification of
carboxylic acid derivative 6 with succinimide alcohol 9 gave
succinimide ester 10 in 86% yield. Subsequent polymeriza-
tion of the succinimide ester 10 with Grubbs' ruthenium
catalyst yielded modest molecular weight polymers of 11
after a span of 2-3.5 days, as shown in Scheme 4. The
brown polymer was precipitated in methanol at ambient
temperature and was washed several times with excess
solvent to remove unwanted byproducts. Because of the
Several Lewis acids, such as magnesium bromide etherate,
zinc chloride, and ytterbium(III) triflate, were employed in
the reaction and are shown in Table 1. As predicted, the (+)-
isosorbide sugar gave excellent diastereomeric ratios using
zinc chloride in the 6-heptenyl radical closure.11 More than
Table 1
temp
(°C)
yield
(%)
entry
Lewis acid
solvent
CH2Cl2
ee
1
2
3
4
5
none
none
0
-78
87
84
84
80
72
0
40
86
>90
75
CH2Cl2
1
solubility of the polymers generated, H NMR techniques
MgBr2(OEt2) -78
CH2Cl2/Et2O(1:1)
CH2Cl2/THF (1:1)
CH2Cl2/Et2O (1:1)
were employed to observe reaction completion and success.
The radical cyclization precursor 11 was next subjected
to standard tin hydride conditions to prepare the cyclohexane
ZnCl2
Yb(OTf)3
-78
-78
Org. Lett., Vol. 3, No. 24, 2001
3961

99% enantiomeric excess was achieved with zinc chloride.
Ytterbium triflate and magnesium bromide etherate were less
successful in enhancing the diastereoselectivity of the cy-
clization, with enantiomeric excesses of 75% and 86%,
respectively.
In related reactions off-support, we achieved diastereo-
meric excesses of >100:1 for both ZnCl2 and MgBr2 for
radical cyclizations.11 These reactions lacked the imide
polymer backbone and four-carbon linker but were otherwise
the same. It appears that the polymer backbone here provides
a new microenvironment for the reaction that is not
conducive to high diastereomeric ratios with MgBr2.
The diastereoselectivity for the cyclization on soluble
support is particularly high when (+)-isosorbide is used with
zinc chloride, and thus this moiety possesses a high affinity
for certain Lewis acids.11 One explanation for this behavior
is that the high selectivity may result from the cup-like highly
oxygenated endo-surface of the sugar, providing several sites
for chelation for the Lewis acid (see Figure 1). Avidity rather
than affinity for a single pair of electrons from a Lewis acid
are likely a contributing factor for this efficient asymmetric
radical cyclization. A minor disfavored geometry has been
proposed for a transition state for the cyclization, leading to
the (R)-enantiomer. It is characterized by important non-
bonded interactions between the ring methylene and the
phenyl ring. A major favored transition state showing a much
reduced steric interaction between the cyclizing radical center
and the tetrahydrofuran oxygen is much better and the
reaction likely proceeds via this intermediate. The favored
transition state leads to the (S)-antipode as shown in Scheme
5.
Figure 1. Radical cyclization transition states.
soluble supports. A stereocontrol element (R*) consisting
of a polymer-imbedded (+)-isosorbide chiral auxiliary was
used in each monomer subunit. A survey of various Lewis
acids was also examined. The best results gave very high
distereoselectivites of >100:1 in a 6-heptenyl radical cy-
clization using zinc chloride as a Lewis acid. Each step using
the soluble support gave crystallinelike intermediates readily
separated by filtration from toxic tin compounds.
Acknowledgment. We gratefully acknowledge support
by the National Science Foundation (grant CHE-0111210)
for this work.
Supporting Information Available: Spectral information
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, a new study was discussed that represents
the first examples of stereoselective radical cyclizations on
OL016855D
3962
Org. Lett., Vol. 3, No. 24, 2001