A thermally-cleavable linker for solid-phase synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.12.067

Oxabicyclo[2.2.1]norbornenes constitute a convenient and readily cleaved linker for solid-phase organic synthesis. A simple and inexpensive furfuryl-substituted resin has been shown to capture and release maleimide dienophiles under conditions compatible with intermediate synthetic steps. The synthesis of β-amino, -thiophenoxy, and -hydrazino alcohols by epoxide ring opening, and maleimide-functionalized Leu-enkephalin by standard peptide coupling techniques, are described to illustrate the utility of the solid-phase synthesis methodology.

Full text of DOI:10.1016/j.tetlet.2004.12.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1181–1184
A thermally-cleavable linker for solid-phase synthesis
Keith A. Keller, Jianhua Guo, Sreenivas Punna and M. G. Finn*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA
Received 27 October 2004; revised 14 December 2004; accepted 15 December 2004
Available online 7 January 2005
Abstract—Oxabicyclo[2.2.1]norbornenes constitute a convenient and readily cleaved linker for solid-phase organic synthesis. A sim-
ple and inexpensive furfuryl-substituted resin has been shown to capture and release maleimide dienophiles under conditions com-
patible with intermediate synthetic steps. The synthesis of b-amino, -thiophenoxy, and -hydrazino alcohols by epoxide ring opening,
and maleimide-functionalized Leu-enkephalin by standard peptide coupling techniques, are described to illustrate the utility of the
solid-phase synthesis methodology.
Ó 2004 Elsevier Ltd. All rights reserved.
The utility of solid-phase organic synthetic methods de-
pends upon the ease with which tethered products can
be removed from the solid support. The development
of cleavable linkers for this purpose has been the subject
of much effort, and a wide variety of systems exist to
accommodate various reaction conditions.1 Cleavage is
most commonly accomplished by treatment with acid;
other methods include the use of base, fluoride, oxi-
dants, olefin metathesis, and irradiation. We report here
the development of a simple linker that is cleaved by
thermal promotion of retro-Diels–Alder (rDA) reac-
tions,2 and a demonstration of its use in solid-phase
organic synthesis.
cycloreversion processes have been used to modulate
the properties of a polymer.8 We describe here the prop-
erties of the linkage based on adduct 1, which incorpo-
rates a maleimide dienophile in its construction. This
system is particularly appropriate for the attachment
of amine-containing molecules to solid supports, succin-
imides, and phthalimides being widely used as amine
protecting groups.9
Furan Diels–Alder (DA) adducts have found extensive
use in organic synthesis;3 the resulting 7-oxanorbornene
is often elaborated and/or ring opened, providing routes
to a wealth of valuable synthetic targets. The relative
ease of formation and rDA cleavage of these systems
provides the basis for a set of linkers of varying thermal
stability for use in solid-phase organic synthesis. One
previous report has appeared on this topic,4 and other
thermally-cleaved linkers have also been developed.5 In
addition, the Diels–Alder reaction of a resin-bound
maleimide has been used as a scavenger for anthra-
cene-tagged molecules with subsequent release by ester
hydrolysis,6 furan-substituted resins have been used to
capture and release C60,7 and [4+2] cycloaddition and
To demonstrate the utility of maleimide–furan linker
1, epoxide-functionalized maleimides 5a and 5b were
prepared as shown in Scheme 1. N-(methoxycar-
bonyl)maleimide 2 (formed from maleimide and methyl
chloroformate)10 was a convenient starting material,
undergoing smooth exchange with amino alcohols to
give 3. The maleimide group was protected for further
manipulations as the exo furan DA adduct 4. Attach-
ment of an enantiomerically pure glycidyl fragment11
was then accomplished in good yield, followed by depro-
tection by rDA reaction to provide 5. The furan-substi-
tuted polystyrene resin 6 was prepared on 25 g scale
from furfuryl alcohol and standard Merrifield resin
under basic conditions (NaH, KI, N,N-dimethylacet-
amide solvent, 25 °C) and is therefore inexpensive and
easily accessed.
Keywords: Solid-phase; Linker; Cleavage; Peptides.
*
Corresponding author. Tel./fax: +1 8587848845; e-mail: mgfinn@
scripps.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.067

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K. A. Keller et al. / Tetrahedron Letters 46 (2005) 1181–1184
Scheme 1.
Attachment of maleimides such as 5 is accomplished by
heating an excess of the dienophile with the resin in
refluxing benzene. While a safety-catch scheme has been
described in which the Diels–Alder adduct is modified to
give 8 and then cleaved at low temperature,4 we have
found it convenient to rely upon mass action to load
the resin and simple heating to remove the group when
desired. The process may be conveniently monitored by
IR spectroscopy to detect the attached imide group
(mC@O = 1770 cmÀ1). The density of functional groups
on the resin can be diluted by mixing 5 with an unfunc-
tionalized dienophile such as N-methylmaleimide
(NMM) in the desired ratio, since we find that 5 and
NMM react at equal rates. This allows for precise con-
trol of resin loading from a single starting chloromethyl-
ated polymer.
bound compound unchanged for solid-phase use. Cleav-
age of 7a and 7b in refluxing toluene (110 °C) required
6 h to reach completion, with compounds 5a and
5b being isolated directly in pure form without
chromatography.
We have found maleimide adducts of furfuryl alcohol to
be sensitive to Lewis acids; thus, compound 9a was
cleaved at room temperature in the presence of AlCl3
or Ti(OiPr)4, whereas benzyl ether 9b was stable to these
conditions (Scheme 2). The chelating interaction in 10 is
presumed to be responsible for activating the carbonyl
group for rDA reaction. Similarly, the attempted ring
opening of resin-bound epoxide 7a with diethylamine
in the presence of lithium perchlorate12 gave rise to
rDA reaction faster than epoxide ring opening, again
presumably because of a chelating interaction with the
Lewis acidic metal as shown. The chain-extended ana-
logue 7b (Scheme 1) does not undergo rDA cleavage
under these conditions and is also stable to 5 M LiClO4
in diethyl ether, which has been demonstrated to cata-
lyze the cycloreversion of some furan cycloadducts.13
A preliminary investigation of the stability of such DA
adducts was performed using compound 4, which was
found to have a half-life toward cycloreversion of
approximately 36 h at 80 °C. This provides ample
opportunity to perform chemistry on the attached
groups without cleavage from the solid-phase. Partial
cleavage for analytical purposes is easily accomplished
by heating for a few hours, leaving most of the resin-
Nucleophilic ring opening of resin-bound epoxide 7b
provided convenient access to a series of enantiomeri-
Scheme 2.

K. A. Keller et al. / Tetrahedron Letters 46 (2005) 1181–1184
1183
tagged pentapeptide 15. While not traceless, this meth-
odology is attractive if one wishes to attach the com-
pounds produced to a biological target by means of
ligation to a thiol residue. Accordingly, methylthioace-
tate was used to trap the released maleimide to give
16; HPLC analysis showed the material to be >85%
pure.
We have shown here that the simple furfuryl-substituted
resin 6 can capture and release dienophiles such as
maleimides to facilitate the synthetic elaboration of
these useful compounds. The relatively mild conditions
necessary for cleavage have also prompted us to develop
two other linkers (17 and 18), which are cleaved at high-
er temperatures (P150 °C). Their construction and
application will be described separately.
Figure 1. Synthesis of chiral alcohol maleimides. Reagents and
conditions: (a) PhSH, K2CO3, acetone, 25 °C; (b) amine, LiClO4 or
Mg(ClO4)2, 9:1 CH2Cl2–MeCN, 25 °C; (c) MeNHNH2, LiClO4, 9:1
CH2Cl2–MeCN, 25 °C; (d) toluene, 110 °C, 8 h.
cally pure compounds, as shown in Figure 1.14 The ter-
tiary amino alcohols 12 are useful as chiral catalysts of
dialkylzinc addition to carbonyl compounds. In all
cases, the removal of functionalized maleimides from
the polystyrene support was accomplished by heating
the resin to reflux in toluene for 8 h. Infrared spectra
of the recovered polymer showed no sign of the imide
carbonyls after this treatment, and the resultant polymer
6 could be recycled without difficulty. The released com-
pounds 11–13 were isolated in >70% yield without the
need for further purification.
Acknowledgements
Part of this work was performed at the University of
Virginia. We thank the ARCS Foundation for a fellow-
ship (K.A.K.), the National Science Foundation, the
University of Virginia, and The Skaggs Institute for
Chemical Biology for funding; S.P. is a Skaggs Post-
doctoral Fellow. We are also grateful to Professor Philip
Dawson for assistance with peptide synthesis.
Resin 6 was also employed in solid-phase peptide syn-
thesis; for demonstration purposes, the neuropeptide
Leu-enkephalin (YGGFL),15 was chosen. The amino-
terminated adduct 14 was generated and standard Fmoc
steps were used to install the proper residues (Fig. 2).
Thermal cleavage gave the appropriate maleimide-
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2004.12.067.
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Typical method for the ring opening of resin-bound epox-
ides: resin 7b (100 mg) and magnesium perchlorate
(110 mg, 0.5 mmol) were stirred in 9:1 CH2Cl2–CH3CN,
10 min, after which time the amine (20 equiv) was added.
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48–96 h. The polymer was filtered and washed with
CH2Cl2, CH3CN, MeOH, water, and MeOH, and then
dried under vacuum.
General method for the cleavage of resin-bound species: the
substituted resin was taken up in approximately 100 mL of
toluene and heated to reflux for 12 h. After cooling to
room temperature the solvent was filtered away from the
polymer and evaporated yielding the free maleimide.
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