Parallel synthesis and purification using anthracene-tagged substrates.

Article abstract of DOI:10.1021/ol0065625

[reaction: see text] A new strategy for the synthesis and purification of synthetic intermediates is described using anthracene-tagged ester substrates in conjunction with an N-benzylmaleimide resin. Anthracene chemical tags permit use of standard solution-phase reaction conditions and reaction-monitoring techniques.

Full text of DOI:10.1021/ol0065625

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3509-3512
Parallel Synthesis and Purification
Using Anthracene-Tagged Substrates
,†
Xiang Wang,† John J. Parlow,‡ and John A. Porco, Jr.*
Department of Chemistry and Center for Streamlined Synthesis,
Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215,
and Pharmacia Corporation, 800 North Lindbergh BlVd., St. Louis, Missouri 63167
porco@chem.bu.edu
Received September 7, 2000
ABSTRACT
A new strategy for the synthesis and purification of synthetic intermediates is described using anthracene-tagged ester substrates in conjunction
with an N-benzylmaleimide resin. Anthracene chemical tags permit use of standard solution-phase reaction conditions and reaction-monitoring
techniques.
A variety of methods are currently available for parallel
synthesis of small organic molecules. Polymer-supported
synthesis1 is an attractive option because of the possibility
for product isolation by simple filtration. However, solid-
phase synthesis methods can suffer from practical disadvan-
tages such as the need for extensive reaction optimization
and inability to monitor chemical transformations using
routine analytical methods such as TLC. Not surprisingly,
recent applications of parallel synthesis have emphasized the
development of solution-phase protocols that may have the
overall advantages of solid-phase synthesis.2 A number of
these new methodologies involve the use of “chemically
tagged” reagents and substrates to enable their chemoselec-
tive removal from reaction mixtures.3 Such tag methodologies
are analogous to purification techniques commonly used in
molecular biology such as affinity chromatography of
hexahistidine-tagged proteins.4 For example, Curran and co-
workers have pioneered the development and use of fluorous
affinity tags for both reagents and reactants.5 Recently, a
number of other chemical tag systems have been reported,
including a quinoline tag which precipitates when protonated
by mineral acid,6 a 2-pyridylsilyl tag for acidic extraction
of synthetic intermediates,7 a crown ether tag utilized in
conjunction with a polymer affinity column,8 and hydropho-
Am. Chem. Soc. 1996, 118, 2567-2573. (d) Parlow, J. J.; Devraj, R. V.;
South, M. S. Curr. Opin. Chem. Biol. 1999, 3, 320-336. (e) Flynn, D. L.
Med. Res. ReV. 1999, 19, 408-431. (f) Brummer, O.; Clapham, B.; Janda,
K. D. Curr. Opin. Drug DiscoVery DeV. 2000, 3, 462-473.
(3) Porco, J. A., Jr. Comb. Chem. High Throughput Screening 2000, 3,
93-102.
† Boston University.
‡ Pharmacia Corporation.
(1) (a) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555-600.
(b) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1997,
53, 5643-5678.
(2) (a) Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 6419-6423. (b) Boger, D. L.; Tarby, C. M.;
Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109-10. (c)
Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D. L. J.
(4) Janknecht, R.; Nordheim, A.; Stunnenberg, H. G. Proc. Natl. Acad.
Sci. U.S.A. 1991, 88, 8972-8976.
(5) (a) Curran, D. P. Med. Res. ReV. 1999, 19, 432-438. (b) Curran, D.
P. Angew. Chem., Int. Ed. 1998, 37, 1175-1196.
(6) Perrier, H.; Labelle, M. J. Org. Chem. 1999, 64, 2110-2113.
10.1021/ol0065625 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

bic tags such as the tetrabenzo[a,c,g,i]fluorine (Tbf) moiety.9
As part of our interest in developing new methods for the
rapid synthesis and purification of functionalized intermedi-
ates, we have undertaken studies to develop affinity tags to
facilitate product sequestration and overall purification by
Diels-Alder resin capture/release10 processes. Utilization of
“cycloaddition-removable tags” (CRT’s) is highly under-
developed, and two examples have been documented in the
literature. Keana reported a 1,3-diene-containing phase-
transfer catalyst and its removal from reactions using a silica-
based triazolinedione (TAD) dienophile.11 Pieken and co-
workers have described a related method for solution-phase
synthesis of oligonucleotides using di-hexadienoxytrityl
protected nucleosides.12 A major benefit of CRT’s is the
possibility for highly orthogonal and chemoselective removal
of the tagged molecule. In this Letter, we wish to report our
initial studies on the use of anthracene-tagged13 protecting
groups in conjunction with a polymeric maleimide dienophile
(Figure 1).
Scheme 1. Synthesis and Reactivity of Benzylmaleimide
Resin 2
ation16 of unfunctionalized polystyrene resin (Scheme 1) for
more flexible control of maleimide loading. Treatment of
1% cross-linked polystyrene with N-chloromethylmaleimide
(1)17 and FeCl3 as catalyst18 led to the production of
N-benzylmaleimide resin (2) in loadings of 1.0-1.6 mmol/
g.19 Resin loadings were determined by elemental analysis
(N) and the active maleimide content further confirmed by
elemental analysis (Br) of resin 3 derived from cycloaddition
with anthracene derivative 4a.
Figure 1. Anthracenes as cycloaddition-removable tags (CRT’s).
To demonstrate transformations using anthracene tags, we
conducted Stille coupling20 reactions using 9-anthrylmethyl
esters13a,b (Table 1). Anthracene-tagged benzoates 4a-c were
In planning our studies, we required a suitable resin-bound
dienophile to facilitate sequestration of anthracene-tagged
compounds. Since maleimides are reactive dienophiles in
Diels-Alder cycloaddition,14 we focused on developing a
practical synthesis of a polystyrene-based maleimide. Al-
though benzylmaleimide resin has been prepared from
aminomethylpolystyrene,15 we employed maleimidomethyl-
Table 1. Parallel Stille Reactions Using 9-Anthrymethyl Ester
Tags
(7) Yoshida, J-i.; Itami, K.; Mitsudo, K.; Suga, S. Tetrahedron Lett. 1999,
40, 3403-3406.
(8) Zhang, S.-Q.; Fukase, K.; Kusumoto, S. Tetrahedron Lett. 1999, 40,
7479-7483.
(9) Ramage, R.; Swenson, H. R.; Shaw, K. T. Tetrahedron Lett. 1998,
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(10) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
2574-2583. (b) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.;
Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360.
(c) Kulkarni, B. A.; Ganesan, A. Angew. Chem., Int. Ed. Engl. 1997, 36,
2454-2455. (d) Liu, Y.; Zhao, C.; Bergbreiter, D. E.; Romo, D. J. Org.
Chem. 1998, 63, 3471-3473. (e) Hu, Y.; Baudart, S.; Porco, J. A., Jr. J.
Org. Chem. 1999, 64, 1049-1051.
(11) (a) Keana, J. F. W.; Ward, D. D. Synth. Commun. 1983, 13, 729-
735. (b) Keana, J. F. W.; Guzikowski, A. P.; Ward, D. D.; Morat, C.; Van
Nice, F. L. J. Org. Chem. 1983, 48, 2654-2660.
(12) Pieken, W.; McGee, D.; Settle, A.; Zhai, Y.; Huang, J.; Hill, K.
WO 98/47910.
(13) (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.
(14) (a) Fleischhauer, J.; Asaad, A. N.; Schleker, W.; Scharf, H.-D.
Liebigs Ann. Chem. 1981, 306-311. (b) Chung, Y.; Duerr, B. F.; McKelvey,
T. A.; Nanjappan, P.; Czarnik, A. W. J. Org. Chem. 1989, 54, 1018-1032.
(c) Thomas, I. P.; Ramsden, J. A.; Kovacs, T. Z.; Brown, J. M. Chem.
Commun. 1999, 1507-1508.
reacted in parallel with 2 equiv of aryl- or alkenylstannane
(5 mol % of Pd(PPh3)4, toluene, 100 °C, 12 h) using a
3510
Org. Lett., Vol. 2, No. 22, 2000

FirstMate synthesizer (Argonaut Technologies). A key
advantage of anthracene tags is their intense fluorescence
and ease of reaction monitoring by TLC. Incubation of the
crude reaction mixture with 1.6 equiv of N-benzylmaleimide
resin 2 (90 °C, 8 h) followed by resin washing and product
cleavage (NaOMe/THF-MeOH) led to the production of
products in 84-98% yield (92-99% HPLC purity, Table
1). Notably, compounds 5a-h were devoid of tin-containing
impurities (1H NMR), illustrating effective use of this system
to eliminate difficult to remove tributyltin byproducts.
In an effort to develop more reactive anthracene tags,
we compared the reactivity of 9,10-disubstituted and 9-
substituted derivatives 4b, 6, and 7 (Figure 2). Potential for
Table 2. Parallel Stille Reactions Using 9,10-Disubstituted
Tags
relative to that of 6 (approximately 3-fold) but also doubles
the amount of substrate loaded per anthracene template.
Finally, we demonstrated the use of 9-anthrylmethyl ester
tagged substrates in a multistep synthesis sequence (Scheme
2). Anthracene-tagged benzoate 4b was reacted in a Stille
Figure 2. Anthracene derivatives employed for kinetic studies.
Scheme 2. Multistep Synthesis Using a 9-Anthrylmethyl Ester
Tag
9,10-substituted anthracene derivatives as reactive CRT’s is
based on kinetic studies which demonstrate that Diels-Alder
cycloadditions of 9,10-dimethylanthracene with maleic an-
hydride are approximately 15 times faster than that of
9-methylanthracene.21 Comparison of the kinetic reactivity
for sequestration of tagged compounds 4b, 6, and 7 using
resin 2 (toluene, 90 °C) was determined by monitoring the
concentration of anthracene derivative using UV spectros-
copy.19 Second-order rate constants determined from kinetic
data demonstrate the increased reactivity of 6 (k2 ) 146 M-1
h-1) relative to ester 4b (k2 ) 10.8 M-1 h-1) and bis-ester 7
(k2 ) 48 M-1 h-1). These results are also in good agreement
with kinetic data reported for Diels-Alder addition of
substituted anthracene derivatives with maleic anhydride.21
9,10-Substituted anthracenes 6-8 were also employed in
parallel Stille couplings (Table 2) to afford ester products
(77-90% yield, 93-97% HPLC purity), in which case the
time for cycloaddition removal was reduced to 3 h on the
basis of the increased reactivity of 9,10-substituted tags. Use
of bivalent tags such as 7 reduces Diels-Alder reactivity
(15) Rebek, J., Jr.; Gavina, F. J. Am. Chem. Soc. 1975, 97, 3453-3456.
(16) Stevens, M. P.; Jenkins, A. D. J. Polym. Sci.: Polym. Chem. Ed.
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Stiteler, C. H.; Williams, A. R. J. Org. Chem. 1961, 26, 15-21.
(18) Cf. Zikos, C. C.; Ferderigos, N. G. Tetrahedron Lett. 1995, 36,
3741-3744.
(19) Full experimental details can be found in the Supporting Information.
(20) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(21) Mielert, A.; Braig, C.; Sauer, J.; Martelli, J.; Sustmann, R. Liebigs
Ann. Chem. 1980, 954-970.
coupling with (E)-tributyl-1-heptenyl stannane22 to afford 9.
After concentration, the crude product was dihydroxylated
to afford 10 which was incubated with excess maleimide
resin 2 to provide resin-captured diol 11. After resin washing,
the product was cleaved to benzoate 12 (64% yield, 93%
(22) Prepared according to: Eisch J. J.; Galle J. E. J. Organomet. Chem.
1988, 341, 293-313.
Org. Lett., Vol. 2, No. 22, 2000
3511

purity). It is noteworthy that osmylation of the resin-captured
form of 9 using similar conditions led to 40-50% conversion
(1H NMR) to a diol product after base-catalyzed cleavage,
demonstrating the compatibility of anthracene tags with
standard solution-phase conditions which may not translate
directly to solid-phase synthesis.23
In conclusion, we have demonstrated a new strategy for
synthesis and purification of synthetic intermediates using
anthracene-tagged substrates in conjunction with an N-
benzylmaleimide resin. Anthracene tags also permit use of
standard solution-phase reaction conditions and reaction-
monitoring techniques. Further studies utilizing CRT’s for
both protecting groups and reagents are in progress and will
be reported in due course.
Acknowledgment. We thank Wendy Miller (Argonaut
Technologies) for assistance with IR spectra and the Panek
lab for use of HPLC equipment. Work at the Boston
University Center for Streamlined Synthesis is supported by
Argonaut Technologies, Boehringer-Ingelheim, Glaxo-
Wellcome, and Savant Instruments.
Supporting Information Available: Experimental de-
1
tails, full characterization and kinetic data, and H NMR
spectra for 5a-h. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) For a discussion of solid-phase resins and analogy to reaction
solvents, see: Czarnik, A. W. Biotechnol. Bioeng. 1998, 61, 77-79.
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