A novel safety-catch linker for the solid-phase synthesis of amides and esters

Article abstract of DOI:10.1021/ol990785h

(matrix presented) A new safety-catch linker for solid-phase organic synthesis is described. Synthesis and attachment of the linker to the solid phase was achieved via a simple and high-yielding strategy. The linker was exemplified by acylation to form unactivated amides, activation of the linker, and cleavage to release acyl moieties. Acids, amides, or esters were released under mild conditions and with exceptionally high purity. The reactivities of unactivated and activated amides are compared.

Full text of DOI:10.1021/ol990785h

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1149-1151
A Novel Safety-Catch Linker for the
Solid-Phase Synthesis of Amides and
Esters
Matthew H. Todd, Steven F. Oliver, and Chris Abell*
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ca26@cam.ac.uk
Received July 6, 1999
ABSTRACT
A new safety-catch linker for solid-phase organic synthesis is described. Synthesis and attachment of the linker to the solid phase was
achieved via a simple and high-yielding strategy. The linker was exemplified by acylation to form unactivated amides, activation of the linker,
and cleavage to release acyl moieties. Acids, amides, or esters were released under mild conditions and with exceptionally high purity. The
reactivities of unactivated and activated amides are compared.
Interest in combinatorial chemistry continues to grow, with
applications spreading beyond organic synthesis1 into areas
such as materials science2 and catalysis.3 This interest drives
the development of efficient and reliable chemistry for the
solid phase, which in turn requires new strategies of
attachment and release of molecules from the solid phase.
Safety-catch linkers are a particularly sophisticated form of
attachment, whereby a linker present throughout the library
assembly in a relatively inert form is activated and thereby
made labile at the end of the synthesis to release the products
from resin.4 This paper describes the development of a new
safety-catch linker (1) for attachment of carboxylic moieties
to the solid phase which allows their release as the parent
acid or as a simple derivative.
The principle of the linker is that amides such as 4 formed
on the aromatic amine will be relatively inert (Scheme 1).
However, after treatment with mild acid to remove the
dimethyl acetal group, the aldehyde intermediate will rapidly
Scheme 1
(1) (a) Bunin, B. A. The Combinatorial Index; Academic Press: San
Diego, 1998. (b) Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17-42. (c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
C. Tetrahedron 1997, 53, 5643-5678. (d) Thompson, L. A. Chem. ReV.
1996, 96, 555-600.
(2) Wang, J.; Yoo, Y.; Gao, C.; Takeuchi, I.; Sun, X.; Chang, H.; Xiang,
X.-D.; Schultz, P. G. Science 1998, 279, 1712-1714.
(3) (a) Gennari, C.; Nestler, H. P.; Piarulli, U.; Salom, B. Liebigs Ann.
Recl. 1997, 637-647. (c) Reddington, E.; Sapienza, A.; Gurau, B.;
Viswanathan, R.; Sarangapani, S.; Smotkin, E. S.; Mallouk, T. E. Science
1998, 280, 1735-1737.
10.1021/ol990785h CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

cyclize to form the corresponding acylindole. This amide
(5) is more reactive and can be cleaved in various ways to
yield acids, esters, or amides. Fukuyama et al. have previ-
ously reported the use of the dimethyl acetal 2 for the
solution-phase protection of acids and synthesis of amides
and esters.5 We have adapted the Fukuyama synthesis of 2
to make 1 where the inclusion of the 5-hydroxy group
provides a point of attachment to resin.
Scheme 3a
The synthesis of dimethyl acetal 1 (Scheme 2) began with
2-nitro-5-methoxytoluene 6. The first step was to make the
Scheme 2a
a (a) BnBr, Cs2CO3, DMF, rt, 16 h; (b) Me2NCH(OMe)2, DMF,
reflux; (c) CSA, MeOH, reflux, 16 h; (d) 10% Pd/C, H2, EtOH, rt,
2 h.
benzyl ether 7. The formation of the enamine 8 then
proceeded well6 and conversion of the enamine to dimethyl
acetal 9 was quantitative. If the 4-hydroxyl group was not
protected, 2-nitro-5-methoxytoluene was found to be a major
side product in the reaction to form the enamine. Catalytic
reduction of the nitro group of 9 also removed the benzyl
protecting group, to give the final linker 1 in an overall yield
of 47% over the four steps.
The linker 1 was then attached to the resin by treatment
with sodium methoxide in N,N-dimethylacetamide (DMA)
with tetrabutylammonium iodide at room temperature. This
gave quantitative loading as determined by the gel-phase 13C
NMR spectrum of the resin 3. The linker loading was further
confirmed by attachment and subsequent cleavage of an N-9-
fluorenylmethyloxycarbonyl group, and by the observation
of expected resin mass gain.
a (a) 4-iodobenzoyl chloride, pyridine, CH2Cl2, rt, 16 h; (b)
5-phenylvaleric acid, HATU, pyridine, DMA, rt, 16 h; (c) PPTS,
toluene, 50 °C, 16 h: (d) see Table 1.
appearance of two new sp2 carbon signals of the indole at
104 and 110 ppm, respectively (Figure 1). Quinoline, also
reported as a catalyst for this reaction in solution,5 was found
to give no conversion to the indolylamide.
The activated amides 12 and 13 were studied under a
variety of cleavage conditions. Treatment of resin 12 with
The support-bound linker 3, which is stable to storage at
ambient conditions, was then derivatized with 4-iodobenzoyl
chloride or 5-phenylvaleric acid to give resins 10 and 11,
respectively (Scheme 3). IR spectroscopy and the Kaiser test7
clearly indicated complete acylation of the aniline. The acid-
catalyzed closure of the indole ring to give 12 and 13,
respectively, was carried out using PPTS in toluene at 50
°C. This reaction resulted in complete disappearance of the
NH stretches and a significant shift of the carbonyl stretches
in the IR spectrum. The expected changes were also observed
by gel-phase 13C NMR spectroscopy: loss of the benzylic,
methoxy, and acetal carbons at 37, 55, and 107 ppm and
Figure 1. The gel-phase 13C NMR spectra of the linker in (a) its
unactivated form 10 and (b) the ring-closed, activated form 12.
Peaks marked with an asterisk in (a) are lost on ring closure and in
(b) are the newly formed indole peaks.
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Org. Lett., Vol. 1, No. 8, 1999

excess n-butylamine in THF at room temperature resulted
in release of butyl-p-iodobenzamide 15. After shaking the
resin overnight, this product was obtained in 70% yield. Most
encouragingly, however, the released product was greater
than 98% pure by HPLC and by proton NMR spectroscopy.
Conditions were optimized for the production of amides,
esters, and acids (Table 1). In all of the amide releases
respectively, only traces of product were observed. Under
such conditions, resin 12 was shown to be around 400 times
more labile than 10.8
A Suzuki cross coupling reaction was carried out on resin
10 to exemplify the utility of this linker (Scheme 4). Reaction
Scheme 4a
Table 1. Yields and Purities of Cleaved Products
product
% yield (time)
% purityd
14a
15a
16a
17a
18b
19c
20b
21c
24a
25b
96 (72 h)
90 (72 h)
89 (0.5 h)
91 (16 h)
92 (72 h)
89 (72 h)
94 (0.5 h)
58 (16 h)
84 (72 h)
92 (0.5 h)
>95
>95
>95
>95
>98
>98
>98
93
>95
>98
a 15 equiv of amine, THF, rt, wash cleavage mixture with 1 N HCl.
b 5% MeOH in THF, catalytic NaNH2, wash cleavage mixture with saturated
NH4Cl. c 1:1:3 1 N NaOH:MeOH:1,4-dioxane. d All cleaved products except
21 were >99% pure by HPLC with UV detection (254 nm); >95% indicates
1
trace impurities by H NMR spectroscopy; >98% indicates no impurities
a (a) PhB(OH)2, Na2CO3, Pd(PPh3)4, DMF, 50 °C, 16 h; (b)
PPTS, toluene, 50 °C, 16 h; (c) see Table 1.
1
by H NMR spectroscopy.
undertaken, around 50% of product was liberated after 3 h,
70% after 16 h, and 90% after 72 h. Yields are quoted for
the four-step procedure on the basis of the initial loading of
the Merrifield resin. The reaction was found to be solvent
sensitive, product release in toluene was more sluggish than
in THF, and the reaction required elevated temperatures.
Methyl ester production was carried out with 5% methanol
in THF with a catalytic amount of sodium amide. By
employing this system, a wider range of ester products should
be accessible from this linker since one is not limited to
alcohols which swell Merrifield resin.
In all cases purities and yields were excellent. No
purification of the product was required beyond aqueous
washing of the cleaved material. When the unactivated
dimethyl acetal resins 10 and 11 were treated under the
optimized conditions for amide release from 12 and 13,
with phenylboronic acid in the presence of palladium(0) gave
the biaryl resin 22. No decomposition of the linker or indole
formation was observed by gel-phase 13C NMR spectroscopy
during this step. Dimethyl acetal 22 was then ring-closed to
23 prior to cleavage with pyrrolidine or methanol to yield
biaryls 24 and 25, respectively. Again, yields and purities
were excellent (Table 1), with no need for chromatographic
purification.
In summary, we have shown the facile attachment to the
solid phase of the novel safety-catch linker element 1 which
may be used in the generation of carboxylic acids, esters,
and amides. Release is effective under extremely mild
conditions, and purities and yields are exceptional in all cases
studied. It is envisaged that this linker will have wide utility
in solid-phase organic synthesis.
Acknowledgment. We thank Zeneca Pharmaceuticals for
studentships (to M.H.T. and S.F.O.).
(4) (a) Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. J. Chem. Soc.,
Chem. Commun. 1971, 636-637. (b) Routledge, A.; Abell, C.; Balasubra-
manian, S. Tetrahedron Lett. 1997, 38, 1227-1230. (c) Backes, B. J.;
Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1996, 118, 3055-3056.
(5) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 71-74.
Supporting Information Available: Experimental details
of resin preparations and cleavages. This material is available
free of charge via the Internet at http://pubs.acs.org.
(6) (a) Batcho, A. D.; Leimgruber, W.; Hoffman La Roche Inc.: United
States, 1973. (b) Batcho, A. D.; Leimgruber, W. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VIII, pp 34-41.
OL990785H
(8) Determined using an internal standard in the 1H NMR spectra of
two identically trreated batches of 12 and 10.
(7) NoVabiochem Catalog & Peptide Synthesis Handbook; 1999, p S43.
Org. Lett., Vol. 1, No. 8, 1999
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