Target alcohol/phenol release by cyclative cleavage using glycine as a
safety catch linker†‡
Sadagopan Raghavan* and A. Rajender
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received (in Cambridge, UK) 4th April 2002, Accepted 10th June 2002
First published as an Advance Article on the web 20th June 2002
The utility of glycine as a safety catch linker for the
immobilization of alcohols and phenols to the solid-support
is demonstrated by performing a variety of synthetic
transformations.
The synthesis of small organic molecules on solid-support has
received widespread attention.1 The repertoire of organic
reactions developed on the solid-phase is considerable and
Scheme 1
paramount to the synthesis of compound libraries on solid-
support is the availability of suitable linkers for attachment of
7
2
demonstrates the utility of the linker to release alcohols under
mild conditions and in high yield.
The suitability of the linker for application in a variety of
synthetic transformations was then investigated. Towards this
end, tert-butyl glycine·HCl was coupled to Merrifield resin in
the desired compounds to the polymeric carrier. Linkers that
are broadly applicable, stable under the variety of reaction
conditions used for elaborating the substrate and yet allow
release of the synthesized products under mild conditions are
highly desirable. The key challenge in the design of new linkers
is to utilize cleavage reagents which can be easily removed from
the released products and thus facilitate automation.
7
the presence of NaI at 65 °C for 36 h using Hunig’s base and
DMF as the solvent to afford 3b. Deprotection with 1+1 TFA–
3
DCM and rinsing with 5% Et N–DCM afforded acid 6, which
Not surprisingly, given the range of reaction conditions a
linker may have to survive, the different types of molecules and
functional groups that may have to survive the cleavage
conditions and the wide variety of functional groups through
which a substrate may be attached to the solid-phase, a wide
variety of linkers have been designed and synthesized. Safety
was esterified with p-iodobenzyl alcohol. The polymer bound
8
aryl iodide 3c was then transformed by Suzuki and Sonoga-
shira9 reactions (Scheme 3). The products 8 and 10, re-
spectively, were released from the solid-support under mild
conditions employing the two step activation and cyclization
7
catch linkers rely on a two step cleavage process.2a,3 The first
protocol. In another experiment, the polymer bound glycine 6
was esterified with methyl-3-OH-cinnamate. The unsaturated
step involves activation of the linker and the second step
involves the actual cleavage. The main advantage of safety
catch linkers is that conditions similar to the cleavage
conditions can be accommodated during the synthesis, as the
linker is stable until activated. Cyclative cleavage occurs when
reagent treatment induces a pendant functionality to attack the
product resulting in cleavage from the solid-support. Cyclative
cleavage is highly desirable especially for preparing libraries
since products can be isolated in high purity avoiding the need
for purification. Only those molecules containing the nucleo-
phile would undergo cleavage, hence if synthetic steps which
introduced the nucleophile went in poor conversion, the desired
product would be mainly obtained after cleavage although in
ester 3d so obtained was subjected to nitrile oxide cycloaddi-
10
tion to afford a 4+1 mixture of regioisomeric products 13 and
7
1
(
4 in high yield and purity after cleavage from solid support
Scheme 3). Furthermore, glycine 6 was esterified with
hydroquinone and the resulting product, 3e was subsequently
reacted with p-iodobenzyl alcohol employing the Mitsunobu
protocol to afford the ether 15. Cleavage from solid-support
7
afforded product 16 in 60% yield (Scheme 3). It is important to
note that the presence of the free amino group in the linker
imposes restrictions on the reactions that can be performed. For
instance, acylation of the hydroxy group in the product, or use
of oxidants like peroxides and peracids. By virtue of the alcohol
being attached to the linker by an ester linkage, reducing agents
need to be avoided. Acidic conditions would quaternise the
amine, however treatment with a tertiary amine would re-
generate the linker. The protection of the amino group as a
carbamate (Fmoc) would however remedy these deficiencies.
To conclude, a new safety catch linker for immobilizing
alcohols and phenols that is stable under a wide variety of
reaction conditions and yet cleaved under mild conditions has
been developed. The alcohol that is to be immobilized can either
be reacted directly with the glycine linker 6 using DCC or be
4
poorer yields. We now report on the development of glycine as
5
a new safety catch linker, that permits anchoring and release of
alcohols and phenols from the polymeric support in high yield
under mild conditions. The key mechanistic feature of the safety
catch linker is product release by cyclative cleavage via
hydantoin formation on the solid-support. Activation of the
linker, involves reaction with an isocyanate to afford a urea,
which upon treatment with a base undergoes cyclization
releasing the target alcohol (Scheme 1).
The glycine ester 3a was prepared by coupling commercially
available aminomethyl polystyrene 1 with iodoacetate 2,
elaborated by esterification of chloroacetic acid with piperonyl
alcohol followed by the Finkelstein reaction. Activation of 3a
with benzyl isocyanate and subsequent treatment of the
6
resulting urea 4 with neat diisopropylamine releases piperonyl
alcohol in 80% yield (Scheme 2). This experiment clearly
†
‡
IICT Communication No. 011207.
Electronic supplementary information (ESI) available: experimental data.
2 2
Scheme 2 Reagents: (a) iPr NEt, DMF, rt, 16 h; (b) PhCH NCO, toluene–
See http://www.rsc.org/suppdata/cc/b2/b203270h/
2
DMF (1+1), rt, 8 h; (c) iPr NH, rt, 1 h 80%.
1
572
CHEM. COMMUN., 2002, 1572–1573
This journal is © The Royal Society of Chemistry 2002
Raghavan, Sadagopan
