Soluble polymer bound cleavage reagents: A multipolymer strategy for the cleavage of tertiary amines from REM resin

Article abstract of DOI:10.1021/ol0059403

(equation presented) Soluble polymer bound reagent 1 has been prepared to cleave tertiary amines from REM resin. Normally, amines cleaved from REM resin require extraction or chromatography to remove excess cleavage reagent and its byproducts. The solubility profile of non-crosslinked polystyrene (NCPS) based reagent 1 eliminates the need for such purification and allows for the direct isolation of a library of pure tertiary amines through simple filtration and concentration operations.

Full text of DOI:10.1021/ol0059403

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2205-2207
Soluble Polymer Bound Cleavage
Reagents: A Multipolymer Strategy for
the Cleavage of Tertiary Amines from
REM Resin
Patrick H. Toy, Thomas S. Reger, and Kim D. Janda*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
kdjanda@scripps.edu
Received April 12, 2000
ABSTRACT
Soluble polymer bound reagent 1 has been prepared to cleave tertiary amines from REM resin. Normally, amines cleaved from REM resin
require extraction or chromatography to remove excess cleavage reagent and its byproducts. The solubility profile of non-crosslinked polystyrene
(NCPS) based reagent 1 eliminates the need for such purification and allows for the direct isolation of a library of pure tertiary amines through
simple filtration and concentration operations.
The past decade has witnessed a renewal of interest in
polymer-supported organic chemistry. Much of the current
research has utilized insoluble polymer resins as platforms
for organic synthesis.1 Such resins offer many advantages
with regard to compound isolation and handling. However,
the insoluble nature of the resins can complicate character-
ization of compounds attached to them and lead to reagent
accessibility problems. Such deficiencies have prompted the
evaluation of soluble polymers as supports for organic
chemistry,2 and this field has been a major area of focus for
our research group.2c Recently our group has begun to
examine new solid-phase organic chemistry supports with
the goal of identifying materials which maintain the advan-
tages of both types of polymers in an attempt to bridge the
gap between solution- and solid-phase organic chemistry.3
One successful merging of solid- and solution-phase
chemistry is the use of resin-immobilized reagents that
selectively remove excess reaction reagents and byproducts.4
They have found wide application in solution-phase com-
pound library production and allow for isolation of pure
compounds after filtration and concentration. A solid-phase
analogue of this purification strategy would be to use soluble
polymer based reagents to cleave compounds from resins
and subsequent removal of the reagents and byproducts
through precipitation of the polymers and filtration. Cur-
rently, one of the more common methods for cleavage of
product compounds from resins is to use volatile reagents
such as trifluoroacetic acid in conjunction with linker groups
that do not produce byproducts. In situations where such
conditions are not possible, a soluble polymer bound cleavage
(1) (a) Brown, A. R.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees,
D. C. Synlett 1998, 6, 817-827. (b) Dolle, R. E.; Nelson, K. H., Jr. J.
Comb. Chem. 1999, 1, 235-282. (c) Brown, R. C. D. J. Chem. Soc., Perkin
Trans. 1 1998, 3293-3320.
(2) (a) Harwig, C. W.; Gravert, D. J.; Janda, K. D. Chemtracts 1999,
12, 1-26. (b) Wentworth Jr., P.; Janda, K. D. Chem. Commun. 1999, 1917-
1924. (c) Toy, P. H.; Janda, K. D. Acc. Chem. Res. In press.
(3) (a) Hori, M.; Gravert, D. J.; Wentworth Jr., P.; Janda, K. D. Bioorg.
Med. Chem. Lett. 1998, 8, 2363-2368. (b) Toy, P. H.; Janda, K. D.
Tetrahedron Lett. 1999, 40, 6329-6332. (c) Garibay, P.; Toy, P. H.; Hoeg-
Jensen, T.; Janda, K. D. Synlett 1999, 7, 1438-1440.
(4) (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-26.
(b) Flynn, D. L. Med. Res. ReV. 1999, 19, 408-431. (c) Parlow, J. J.; Devraj,
R. V.; South, M. S. Curr. Opin. Chem. Biol. 1999, 3, 320-336.
10.1021/ol0059403 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/27/2000

reagent would allow for the isolation of pure compounds
through simple liquid transfer and filtration operations. Our
experience with soluble polymer assisted organic chemistry
prompted us to develop the first such reagent, and its use is
described herein. To our knowledge the use of soluble
polymers in conjunction with insoluble polymers has only
been described in the synthesis of polypeptides5 and in our
Sharpless asymmetric olefin dihydroxylation system.6
Rees and co-workers have introduced a recyclable acrylate
derivatized solid-phase synthesis support that they named
REM (REgenerated Michael acceptor) resin.7 It was devel-
oped for the preparation of tertiary amines by a sequential
process of Michael addition, quaternization, and cleavage
(Scheme 1). In addition to the preparation of amines, this
either extraction or chromatography for product purification.
While the use of an insoluble polymer based cleavage reagent
eliminated the need for product purification, it complicated
the reusability of the REM resin since at the end of the
sequence the resins were mixed together. We felt that using
non-crosslinked polystyrene (NCPS) based basic reagent 1
would still allow for direct isolation of pure compounds but
also have the advantage of easy reuse of the REM resin.
The removal of 1 from the other two components of the
reaction mixture would be based on its insolubility in
methanol (Scheme 1).
Reagent 1 was prepared according to the method outlined
in Scheme 2. Amine-containing monomer 2 was prepared
Scheme 2. Synthesis of NCPS-Based Cleavage Reagent 1 and
JandaJel-REM Resin (3)a
Scheme 1. Synthesis of Tertiary Amines Using REM Resina
a (a) AIBN, PhMe, 85 °C; (b) acryloyl chloride, iPr2EtN, CH2Cl2,
rt (two times).
a (a) R1R2NH, DMF, rt; (b) R3X (X ) Br or I), DMF, rt; (c)
iPr2EtN or 1, CH2Cl2, rt.
by the procedure of Itsuno from 4-vinylbenzyl chloride and
diethylamine.12 Radical copolymerization of 2 with styrene
in a 1:10 ratio was initiated by AIBN to afford 1.13
We have recently introduced a new class of resins
(JandaJels14) that contain flexible tetrahydrofuran derived
crosslinkers and exhibit superior swelling in common organic
solvents.3b To use this polymer matrix in the present study,
a hydroxymethyl functionalized version of our resin15 was
acylated with acryloyl chloride according to the procedure
of Morphy7c (Scheme 2) to form 3 (JandaJel-REM).16
resin has been used in the synthesis of 5,6-dihydropyrimi-
8
dine-2,4-diones and â-peptoids9 and in Baylis-Hillman10
and Heck11 reactions. We chose to use this resin in our study
because of the report by Armstrong in which a basic ion-
exchange resin was used in the product cleavage step.7d
Normally, the use of REM resin for amine synthesis requires
(5) (a) Frank, H.; Hagenmaier, H. Experientia 1975, 31, 131-133. (b)
Frank, H.; Meyer, H.; Hagenmaier, H. Chem. Ztg. 1977, 101, 188-193.
(c) Heusel, G.; Bovermann, G.; Gohring, W.; Jung, G. Angew, Chem., Int.
Ed. Engl. 1977, 16, 642-643.
(6) Han, H.; Janda, K. D. Angew. Chem., Int. Ed. Engl. 1997, 36, 6,
1731-1733.
(7) (a) Morphy, J. R.; Rankovic, Z.; Rees, D. Tetrahedron Lett. 1996,
37, 3209-3212. (b) Kroll, F. E. K.; Morphy, R.; Rees, D.; Gani, D.
Tetrahedron Lett. 1997, 38, 8573-8576. (c) Brown, A. R.; Rees, D. C.;
Rankovic, Z.; Morphy, J. R. J. Am. Chem. Soc. 1997, 119, 3288-3295. (d)
Ouyang, X.; Armstrong, R. W.; Murphy, M. M. J. Org. Chem. 1998, 63,
1027-1032. (e) Luo, Y.; Ouyang, X.; Armstrong, R. W.; Murphy, M. M.
J. Org. Chem. 1998, 63, 8719-8722. (f) Brown, A. J. Comb. Chem. 1999,
1, 283-285. (g) Cottney, J.; Rankovic, Z.; Morphy, J. R. Biorg. Med. Chem.
Lett. 1999, 9, 1323-1328. (h) Yamamoto, Y.; Tanabe, K.; Okonogi, T.
Chem. Lett. 1999, 103-104.
(8) Kolodziej, S. A.; Hamper, B. C. Tetrahedron Lett. 1996, 37, 5277-
5280.
(9) Hamper, B. C.; Kolodziej, S. A.; Scates, A. M.; Smith, R. G.; Cortez,
E. J. Org. Chem. 1998, 63, 708-718.
(10) (a) Prien, O.; Rolfing, K.; Thiel, M.; Kunzer, H. Synlett 1997, 5,
325-326. (b) Richter, H.; Walk, T.; Holtzel, A.; Jung, G. J. Org. Chem.
1999, 64, 1362-1365. (c) Kulkarni, B. A.; Ganesan, A. J. Comb. Chem.
1999, 1, 373-378.
(11) Kondo, Y.; Inamoto, K.; Sakamoto, T. J. Comb. Chem. 2000, 2,
Articles ASAP.
(12) Itsuno, S.; Sawada, T.; Hayashi, T.; Ito, K. J. Inorg. Organomet.
Polym. 1994, 4, 403-414.
(13) Preparation of NCPS-NEt2 (1). A stirred solution containing 200
g (1.9 mol) of styrene, 36 g (0.19 mol) of diethylaminomethylstyrene (2),
and 600 mL of toluene was purged with N2 for 30 min. After addition of
1.5 g of AIBN, the mixture was heated at 90 °C for 24 h. The solution was
concentrated, and the residue was taken up in 200 mL of THF. This solution
was added dropwise to a cold, stirring solution of methanol (2 L). The
white precipitate was filtered and then stirred in methanol at 50 °C for 2 h
to remove traces of unreacted monomers. The suspension was filtered, and
the white solid was dried under vacuum at 50 °C to afford 150 g (64%) of
NCPS-NEt2 (1) as a white powder. A nitrogen loading level of 0.85 mmol/g
was determined by 1H NMR spectroscopy: 1H NMR (CDCl3, 400 MHz) δ
1.00-1.10 (6H), 1.30-1.60 (21H), 1.60-2.00 (11H), 3.40-3.60 (2H),
6.30-6.70 (21H), and 6.90-7.20 (31H). The ratio of monomer incorporation
into the product polymer 1 was determined by 1H NMR to be 9.5:1 (styrene:
2). This corresponds to a loading of 0.85 mmol N/g of 1. It was found that
higher loaded versions of 1 were slightly soluble in methanol and the use
of these polymers for amine cleavage afforded impure products.
(14) JandaJel is a registered trademark of the Aldrich Chemical Co.
(15) Reger, T. S.; Janda, K. D. J. Am. Chem. Soc. In press.
2206
Org. Lett., Vol. 2, No. 15, 2000

With the requisite polymeric materials in hand, a library
of tertiary amines (Table 1) was prepared in parallel via the
the cleavage reaction, the resin was filtered off and the filtrate
was concentrated to afford a white paste. This paste (a
mixture of 1 and product amines C) was washed with cold
methanol to separate insoluble 1 from soluble C. The
methanolic solution was concentrated to afford compounds
Table 1. Tertiary Amine Library
1
C that were essentially pure as determined by H NMR in
acceptable yields (Table 1). It should be noted that for
unknown reasons a few combinations of the secondary
amines and alkylating agents afforded only trace amounts
of impure desired product C. Perhaps steric hindrance by
the bulky ester group prevented alkylation of tert-butylproline
by allyl bromide and 4-nitrobenzyl bromide.
To demonstrate that the use of polymeric reagent 1 did
not become entrapped in resin 3 and interfere with the
recycling of it, we prepared one library member repeatedly
using the same sample of 3 (Table 2). No decrease in yield
Table 2. Recycling of REM Resin in the Synthesis of 4
run
yield (%)
1
2
3
4
5
71
79
70
67
68
reaction sequence described vide supra.17 Conjugate addition
of a set of five secondary amines to 3 afforded resins A.
These resins were quaternized with three alkylating agents
to afford resins B. The tertiary amines were cleaved by
reaction of B with a 3-fold excess of 1. After completion of
or purity of 4 was observed even after five synthesis cycles.
Attempts to recycle 1 by washing the triturated paste with
strong mineral base resulted in material that did not afford
pure cleavage products.
In summary, we have prepared a soluble polymer bound
amine base for use in solid-phase organic chemistry and
applied it in a mutipolymer system for the cleavage of tertiary
amines from REM resin. The simple liquid handling opera-
tions that are required to obtain pure products are amenable
to automation, and therefore 1 should find utility in the
preparation of large compound arrays.
(16) Preparation of JandaJel-REM (3). To a suspension of 20 g (16.8
mmol) of JandaJel-OH (loading ) 0.84 mmol/g) in 200 mL of CH2Cl2
was added 29 mL (168 mmol) of diisopropylethylamine followed by 13.6
mL (168 mmol) of acryloyl chloride. After stirring for 4 h at rt, the
suspension was filtered and the resin was washed (CH2Cl2, methanol,
hexane) and dried under vacuum. This procedure was repeated to ensure
complete derivatization of the hydroxyl functional groups.
(17) Procedure for library synthesis: To five separate 20 mL vials were
added 1 g of JandaJel-REM (3, loading ) 0.8 mmol/g) and 15 mL of
dimethylformamide. The different secondary amines (10 equiv, 8 mmol)
were added to each vial, and the suspensions were shaken for 24 h at rt.
The five resins A were recovered, washed (CH2Cl2, methanol, hexane),
and dried. Each resin A was divided into three ∼300 mg portions which
were placed in separate 20 mL vials. Dimethylformamide (10 mL) was
added to each vial followed by 10 equiv of the alkylating agent. The
suspensions were shaken for 24 h at rt, filtered, washed (CH2Cl2, methanol,
hexane), and dried to afford resins B. Each of the 15 resins B were placed
in separate 20 mL vials and suspended in 10 mL of CH2Cl2, and 3 equiv
of NCPS-NEt2 (1) was added. The suspensions were shaken for 24 h at rt,
filtered, and washed (CH2Cl2, hexane). The filtrate was concentrated to
afford a white foam which was dried in vacuo. The foam was triturated
with cold methanol, and the resulting slurry was filtered. The filtrate was
concentrated to dryness, and a small amount (∼5-10 mL) of cold methanol
was added. The solution was filtered through a pipet containing a glass
wool plug, concentrated, and dried to afford tertiary amines C in high purity.
Acknowledgment. Funding for this research was pro-
vided by The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, and the National Institutes of
Health (GM56154).
Supporting Information Available: Library member
structure characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0059403
Org. Lett., Vol. 2, No. 15, 2000
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