Synthesis of a polymer-supported anthracene and its application as a dienophile scavenger

Article abstract of DOI:10.1021/ol036502+

A polymer-supported anthracene has been prepared and employed as a dienophile scavenger in Diels-Alder cycloadditions.

Full text of DOI:10.1021/ol036502+

ORGANIC
LETTERS
2004
Vol. 6, No. 5
795-798
Synthesis of a Polymer-Supported
Anthracene and Its Application as a
Dienophile Scavenger
Xiaoguang Lei and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@chem.bu.edu
Received December 24, 2003
ABSTRACT
A polymer-supported anthracene has been prepared and employed as a dienophile scavenger in Diels−Alder cycloadditions.
Polymer-supported reagents and scavengers have been in-
creasingly employed in solution-phase parallel synthesis for
the preparation of chemical libraries.1 Numerous polymer-
supported scavenger resins are currently available, most of
which are either nucleophilic or electrophilic.2 During the
course of a library synthesis project, we required a scavenger
for selective removal of maleimides and other dienophiles
in the presence of other electrophilic functionality on a tar-
get scaffold.3 On the basis of our work in the sequestration
of anthracene-tagged substrates with a polymer-supported
maleimide,4 we targeted a polymer-supported anthracene as
a chemoselective dienophile scavenger.5 Herein, we report
the synthesis of a polymer-supported anthracene and its
use as a scavenger for dienophiles in Diels-Alder cycload-
dition.6
Our initial synthesis of a polymer-supported anthracene 2
is shown in Scheme 1. Acylation of 9-anthracenemethanol
with succinic anhydride afforded anthracene acid 1,7 which
was coupled to commercially available aminomethyl poly-
styrene resin (PS-NH2, Argonaut Technologies, 1.52 mmol/
g) to provide polymer-bound anthracene 2. The scavenging
capacity of 2 was determined by thermolysis with N-(4-
bromophenyl)maleimide (3.0 equiv) in toluene at 70 °C (24
h). The loading of the resulting cycloadduct resin 3 was
calculated to be 0.84 mmol/g by elemental analysis (Br). The
loading of scavenger resin 2 was back-calculated to be 1.07
mmol/g, which was in agreement with the theoretical loading.
(1) (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-26.
(b) Parlow, J. J.; Devraj, R. V.; South, M. S. Curr. Opin. Chem. Biol. 1999,
3, 320-336. (c) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324-
337. (d) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195. (e) Guillier, F.; Orain,
D.; Bradley, M. Chem. ReV. 2000, 100, 2091-2157.
(5) Recently, interbead Diels-Alder reactions of a polymer-supported
anthracene and maleimide were reported; see: Thomas, I. P.; Ramsden, J.
A.; Kovacs, T. Z.; Brown, J. M. Chem. Commun. 1999, 1507-1508.
(6) For library synthesis employing Diels-Alder reactions, see: (a)
Boger, D. L. PCT Int. Appl. 1996, WO 9603424. (b) Wendeborn, S.;
Mesmaeker, A. D.; Brill, W. K.-D. Synlett. 1998, 8, 865-868. (c) Stavenger,
R. A.; Schreiber, S. L. Angew. Chem., Int. Ed. 2001, 40, 3417-3421. (d)
von Wangelin, A. J.; Neumann, H.; Goerdes, D.; Spannenberg, A.; Beller,
M. Org. Lett. 2001, 3, 2895-2898. (e) Graven, A.; St. Hilaire, P. M.;
Sanderson, S. J.; Mottram, J. C.; Coombs, G. H.; Meldal, M. J. Comb.
Chem. 2001, 3, 441-452. (f) Kwon, O.; Park, S. B.; Schreiber, S. L. J.
Am. Chem. Soc. 2002, 124, 13402-13404.
(2) For a review on polymer-supported scavenger resins, see: Eames,
J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213-1224.
(3) For recent studies on the use of fluorous dienophiles as diene
scavengers, see: Werner, S.; Curran, D. P. Org. Lett. 2003, 5, 3293-3296.
(4) (a) Wang, X.; Parlow, J. J.; Porco, J. A., Jr. Org. Lett. 2000, 2, 3509-
3512. (b) Lan, P.; Porco, J. A., Jr.; South, M. S.; Parlow, J. J. J. Comb.
Chem. 2003, 5, 660-669. (c) Lan, P.; Berta, D.; Porco, J. A., Jr.; South,
M. S.; Parlow, J. J. J. Org. Chem. 2003, 68, 9678-9686. For related studies,
see: (d) Li, X.; Abell, C.; Ladlow, M. J. Org. Chem. 2003, 68, 4189-
4194. (e) Andrews, S. P.; Ladlow, M. J. Org. Chem. 2003, 68, 5525-
5533.
(7) For ring-opening of glutaric anhydride with 9-anthracenemethanol,
see: Browning, J. L.; Nelson, D. L. J. Membr. Biol. 1979, 49, 75-103.
10.1021/ol036502+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/30/2004

Table 1. Dienophile Sequestration Using Anthracene Resin 5a,b
Scheme 1. Synthesis of a First-Generation Polymer-Supported
Anthracene 2
Although resin 2 can efficiently scavenge N-phenylmale-
imide using microwave irradiation (150 °C, 20 min),8
9-anthracenemethanol was also observed as a byproduct. The
thermal instability of this resin may be derived from the
properties of the 9-anthrylmethyl system9 or intramolecular
participation by the amide nitrogen in ester hydrolysis.10 In
an effort to develop a more stable resin attachment, we
prepared a scavenger resin lacking both the 9-anthrylmethyl
ester and succinate spacer (Scheme 2). Second-generation
Scheme 2. Synthesis of a Second-Generation
Polymer-Supported Anthracene 5
resin 5 was prepared by treatment of aminomethyl polysty-
rene with readily available isopropylidene malonate 44e in
toluene (100 °C, 12 h).11 The dienophile scavenging capacity
of resin 5 was determined to be 1.09 mmol/g by HPLC
analysis using N-phenylmaleimide as a dienophile and
4-biphenylmethanol as an internal standard.
(8) For recent reviews of reactions accelerated by microwave-assisted
heating, see: (a) Lidstrom, P.; Westman, J.; Anthony, L. Combin. Chem.
High Throughput Screen. 2002, 5, 441-458. (b) Lew, A.; Krutzik, P. O.;
Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105. (c)
Blackwell, H. E. Org. Biomol. Chem. 2003, 1, 1251-1255. For recent
examples of [4 + 2] Diels-Alder reactions accelerated by microwave-
assisted heating, see: (d) Sridhar, M.; Krishna, K. L.; Srinivas, K.; Rao, J.
M. Tetrahedron Lett. 1998, 39, 6529-6532. (e) Jankowski, C. K.; LeClair,
G.; Belanger, J. M. R.; Pare, J. R. J.; Van Calsteren, M. Can. J. Chem.
2001, 79, 1906-1909. (f) Diaz-Ortiz, A.l; De la Hoz, A.; Moreno, A.; Prieto,
P.; Leon, R.; Herrero, M. A. Synlett 2002, 12, 2037-2038.
(9) (a) Stewart, F. H. C. Aust. J. Chem. 1965, 18, 1699-1703. (b)
Kornblum, N.; Scott, A. J. Am. Chem. Soc. 1974, 96, 590-591. (c)
Kornblum, N.; Scott, A. J. Org. Chem. 1977, 42, 399-400.
(10) Hibbert, F.; Sellens, R. J. J. Chem. Soc., Perkin Trans. 2 1988, 3,
399-402.
a Conditions: 2.0 equiv of resin 5 (0.1 M in dienophile). (A) Thermal
reactions were conducted using the MiniBlock XT parallel solution-phase
synthesizer, toluene, 100 °C. (B) Microwave-mediated reactions were
conducted using the CEM Discover Microwave System, 1,2-dichloroethane
(DCE), 150 °C, 150W. b Performed with 3.0 equiv of resin 5 (0.07 M in
dienophile).
We next examined the reactivity of 5 as a scavenger for
a series of dienophiles (Table 1). Resin 5 (2-3 equiv.) was
incubated with a number of dienophiles12 using both thermal
and microwave heating. TLC and NMR analysis showed that
reactive dienophiles, including maleimides and N-phenyl-
(11) For acylation of Wang resin with Meldrum’s acid, see: (a) Hamper,
B. C.; Kolodziej, S. A.; Scates, A. M. Tetrahedron Lett. 1998, 39, 2047-
2050. (b) For reaction of isopropylidenemalonates with O- and N-
nucleophiles, see: Zitsane, D. R.; Ravinya, I. T.; Riikure, I. A.; Tetere, Z.
F.; Gudrinietse, E. Y.; Kalei, U. O. Russ. J. Org. Chem. 2000, 36, 496-
501.
796
Org. Lett., Vol. 6, No. 5, 2004

triazolinedione (cf. entries 1-5), were efficiently scavenged
1
(>99% conversion by H NMR analysis) in less than 8 h
Scheme 3. Preparation of Model Flavonoid Dienes
(thermolysis) or 30 min (microwave heating). Other dieno-
philes (entries 6 to 9) were also scavenged with comparable
efficiency. 1,4-Naphthoquinone (entry 10) was also evaluated
as a representive unreactive dienophile. HPLC analysis
showed that the conversion was 60% using thermal heating
(16 h, 100 °C, toluene) and 71% using microwave heating
(40 min, 150 °C, DCE). Longer reaction times or use of
Lewis acids (e.g., Sc(OTf)3)13 led to the production of
byproducts from the resin.
With dienophile scavenger resin 5 in hand, we initiated
the preparation of natural product-like compounds using
Diels-Alder cycloaddition. A number of prenylflavonoid
Diels-Alder natural products have been isolated from the
mulberry tree and related plants.14 For example, kuwanon
G (8)15 and multicaulisin (9)16 are [4 + 2] Diels-Alder
cycloaddition products between prenylflavonoid dienes and
hydroxychalcones (Figure 1). The interesting structural
and 11 with N-(4-bromophenyl)maleimide (2.0 equiv) in
CDCl3 (65 °C, 4 h) cleanly afforded [4 + 2] Diels-Alder
cycloaddition products 15 and 16 (Scheme 4). Interestingly,
Scheme 4. [4 + 2] Diels-Alder Cycloaddition and Relative
Stereochemistry Assignment
Figure 1. Prenylflavonoid Diels-Alder natural products.
cycloadduct 15 exhibits restricted rotation about the aryl-
cyclohexenyl bond as evidenced by severe broadening of
the 1H NMR signals at room temperature.20 When the sample
was heated to 80 °C in DMSO-d6, sharp peaks were obtained.
NOE studies (cf. Scheme 4) indicated that both 15 and 16
were endo cycloaddition products.
diversity of these compounds prompted us to prepare the
corresponding flavonoid dienes for use in [4 + 2] Diels-
Alder cycloaddition with reactive dienophiles.17
Model flavonoid dienes 10 and 11 were efficiently pre-
pared using modified Suzuki coupling18 of iodides 12 and
13 with dienyl boronate 14 (Scheme 3).19 Treatment of 10
Finally, we prepared a number of flavonoid cycloadducts
by treatment of dienes 10 and 11 with four additional
dienophiles (Table 2). Due to observed retro Diels-Alder
reactions of N-phenyltriazolinedione cycloadducts using
microwave conditions,21 compounds 17 and 21 (entries 1 and
5) were synthesized by [4 + 2] cycloaddition and dienophile
sequestration with resin 5 using thermal heating (DCE, 80
°C). Other compounds were prepared using microwave
heating (150 °C, 150 W, DCE). For both steps, yields and
HPLC purities were determined from the crude reaction
mixtures without further purification.22
(12) Preparation of 6: (a) Corrie, J. E. T.; Moore, M. H.; Wilson, G. D.
J. Chem. Soc., Perkin Trans. 1 1996, 8, 777-781. Preparation of 7: (b)
Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997, 62, 2652-
2654.
(13) For Diels-Alder cycloaddition of anthracene with p-benzoquinone
using Sc(OTf)3 as catalyst, see: Fukuzumi, S.; Ohkubo, K.; Okamoto, T.
J. Am. Chem. Soc. 2002, 124, 14147-14155.
(14) Nomura, T. Pure Appl. Chem. 1999, 71, 1115-1118.
(15) (a) Nomura, T.; Fukai, T. Chem. Pharm. Bull. 1980, 28, 2548-
2552. (b) Nomura, T.; Fukai, T.; Narita, T. Heterocycles 1980, 14, 1493-
1951.
(16) Ferrari, F.; Delle Monache, F.; Suarez, A. I.; Compagnone, R. S.
Fitoterapia 2000, 71, 213-215.
(17) For model Diels-Alder reactions of trans-chalcone and 3-methyl-
1-phenyl-1,3-butadiene, see: Nomura, T.; Fukai, T.; Narita, T.; Terada, S.;
Uzawa, J.; Iitaka, Y. Tetrahedron Lett. 1981, 22, 2195-2198.
(18) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(19) Preparation of 12: (a) Chen, F. C.; Chang, C. T.; Chen, T. S. J.
Org. Chem. 1962, 27, 85-87. (b) Zhang, F. J.; Huang, Q. C.; Lin, G. Q. J.
Org. Chem. 1995, 60, 6427-6430. Preparation of 13: (c) Zembower, D.
E.; Zhang, H. J. Org. Chem. 1998, 63, 9300-9305. Preparation of 14: (d)
Matsumoto, Y.; Naito, M.; Hayashi, T. Organometallics 1992, 11, 2732-
2734.
(20) Fletcher, A. C.; Porter, L. J.; Haslam, E.; Gupta, R. K. J. Chem.
Soc., Perkin. Trans. 1 1977, 1628-1637.
(21) For retro-Diels-Alder reactions of triazolinedione cycloadducts,
see: Ashkenazi, P.; Ginsburg, D.; Macfarlane, R. D.; Oertling, W. A.;
McNeal, C. J.; Wamhoff, H.; Wald, K. M. NouV. J. Chim. 1983, 7, 213-
218.
(22) For cycloadduct 17, a slightly reduced purity was likely due to
addition of a second equivalent of N-phenyltriazolinedione as evidenced
by HPLC-MS analysis. See Supporting Information for details.
Org. Lett., Vol. 6, No. 5, 2004
797

Table 2. Syntheses of Flavonoid Diels-Alder Cycloadducts
a Conditions: (A) 2.0 equiv of dienophile, 80 °C, DCE, 3 h. (B) 2.0 equiv of resin 5, 80 °C, DCE, 3 h. b Conditions: (A) 150 °C, microwave heating,
DCE, 150W, 10 min. (B) 2.0 equiv of resin 5, 150 °C, microwave heating, DCE, 150W, 20 min. c HPLC analysis: CH3CN/H2O 10-95% (10 min). Purities
are reported using ELS detection (UV detection, 214 nm in parentheses). d HPLC analysis before the scavenging step: CH3CN/H2O 10-95% (10 min).
Purity reported using UV detection, 214 nm (see Supporting Information for details).
In summary, we have developed a thermally stable poly-
mer-supported anthracene for use as a dienophile scavenger.
The scavenger resin has been employed to sequester reactive
dienophiles (e.g., maleimides) in Diels-Alder cycloadditions
to prepare natural product-like compounds. Further studies
on the use of dienophile scavengers to produce complex
chemical libraries are in progress and will be reported in
due course.
edged. We thank Prof. John Snyder, Dr. Aaron Beeler, and
Mr. Ruichao Shen (Boston University) for helpful discus-
sions, CEM Corporation (Matthews, NC) for assistance with
microwave equipment, and Metter-Toledo AutoChem (Mill-
ersville, MD) for assistance with reaction blocks.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
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Org. Lett., Vol. 6, No. 5, 2004