Immobilization of glyoxylic acid on Wang resin

Article abstract of DOI:10.1016/S0040-4039(00)00799-1

We report herein the simple preparation of immobilized glyoxylic acid, where the acid function is either linked through an amide or an ester bond to Wang resin. These compounds represent interesting aldehyde inputs for the generation of new libraries of s

Full text of DOI:10.1016/S0040-4039(00)00799-1

Tetrahedron Letters 41 (2000) 5147±5150
Immobilization of glyoxylic acid on Wang resin
Nathalie Schlienger,a Martin R. Bryceb and Thomas K. Hansena,*
aMedicinal Chemistry Research IV, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark
bDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Received 24 March 2000; accepted 10 May 2000
Abstract
We report herein the simple preparation of immobilized glyoxylic acid, where the acid function is either
linked through an amide or an ester bond to Wang resin. These compounds represent interesting aldehyde
inputs for the generation of new libraries of small molecules. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: aldehydes; solid-phase synthesis.
Resin-bound aldehydes have been used in combinatorial chemistry on solid support in a very
large range of di€erent types of reactions. In most cases, the preparation of the resin-bound
aldehyde is performed by linking a preformed aldehyde to the polymer or by generating the
aldehyde functionality from a resin-bound primary alcohol by various oxidation methods (e.g.
Swern oxidations or ozonolysis). In contrast, despite their versatility in solution phase chemistry,
resin-bound glyoxylic acid ester or amide derivatives have received only little attention. They
have been mostly used in combination with peptide synthesis, where glyoxylyl peptides provide an
important way for the assembly of large constructs from smaller fragments through ecient chemical
reactions, such as hydrazone, oxime and thiazolidine chemical ligations.1 To date, literature
methods for immobilizing glyoxylic acid have exclusively employed polymers compatible with
aqueous solvents, and the aldehyde function is usually generated via periodic oxidation of a
terminal serine.2
As part of our ongoing research in combinatorial chemistry we wished to employ a glyoxylic
entity bound on polystyrene resin, due to its high loading, its mechanical properties, its ability to
swell in a wide range of organic solvents, and its compatibility with lipophilic reagents. We decided
to prepare two types of glyoxylic linkers, one being anchored through an amide bond to the
polymeric support, the other via an ester functionality. To prepare the amide-based linker, we
tried to transfer directly the literature procedures based on serine mentioned above to a polystyrene-
bound amine, but no signi®cant amount of the expected compounds was obtained, probably due
* Corresponding author. E-mail: tkha@novo.dk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00799-1

5148
to the low solubility of sodium periodate in resin-compatible solvents. Concerning the ester-
linked immobilized glyoxylic acid, we anticipated severe problems during the coupling procedure.
The primary hydroxyl group of serine is likely to undergo an unwanted acylation reaction and
would hence require elaborate protection schemes. In order to avoid the solubility problems as
well as the undesired acylation reactions, we developed a procedure using a immobilized tartranilic
acid derivative combined with tetrabutylammonium periodate to perform the oxidation of the
diol. This method has led to the desired glyoxylyl resins, with both amide and ester anchors.
For the preparation of amide linked glyoxylic acid derivative 3 (Scheme 1), we ®rst coupled (^)-
4-methyltartranilic acid 2, to the previously prepared piperazine Wang resin 13 by the inter-
mediate preparation of an active ester. Compound 2 has good solubility in DMF, is commercially
available or easily accessible adapting literature procedures.4 No acylations of the hydroxyl
functions were observed and the coupling eciency has been determined5 to be 81% based on the
theoretical loading of the resin. The oxidative cleavage of the diol was smoothly carried out using
tetrabutylammonium periodate readily soluble in 1,2-dichloroethane. Reactions with sodium
periodate or lead tetraacetate did not lead to the desired product.
Scheme 1.
Following the same strategy, we tried to obtain derivative 6 (Scheme 2) where glyoxylic acid is
bound directly to Wang resin through an ester bond. However, several attempts to perform the
coupling reaction using various coupling agents [e.g. diisopropylcarbodiimide (DIC), benzo-
triazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexa¯uorophosphate (PyBOP)] did not lead to
1
signi®cant amounts of resin-bound tartranilic acid, as judged by H NMR analysis of the crude
product after cleavage from the resin.
Scheme 2.
We then explored the activated diazo linker 4 for the preparation of compound 6 (Scheme 2).
The synthesis of the highly reactive diazo linker 4 on Wang resin was performed according to
literature procedures6 starting from Wang aldehyde resin. The addition of 2 equivalents of the
tartranilic acid 2 to the diazo linker 4 in DMF gave the expected ester 5 cleanly and in high yields
(78%).5 Upon addition of the acid the colour of the diazo resin changed from dark red to yellow,

5149
which o€ers a practical visualization of the coupling step. The subsequent oxidation of the tartaric
acid derivative with tetrabutylammonium periodate led to the desired ester-bound glyoxylic acid 6.
The formation of the aldehyde function had to be proven unambiguously by its conversion into
a well-de®ned chemical moiety, to allow isolation, identi®cation and quanti®cation of the resulting
product. In this respect, we found that the conversion of the bound aldehyde into the correspond-
ing p-nitrophenylhydrazone derivative 7 (Scheme 3) was a practical and high-yielding method,
which allowed the characterization of the product after cleavage from the resin by LCMS and 1H
NMR.
Scheme 3.
The preparation of aldehydes 3 and 6 opens the way for their use as starting materials in very
di€erent types of reactions. For example, modifying literature procedures,7,8 we treated 6 with
benzylamine in trimethylorthoformate (TMOF) followed by the addition of mercaptosuccinic
acid. The mixture was kept at 60ꢀC for two days, leading to the thiazolidinone derivative 8 in
33% yield (unoptimized), after cleavage from the resin.
In conclusion, we report herein the ®rst synthesis of resin-bound glyoxylic acid, linked through
either an ester or an amide bond to polystyrene Wang resin. These immobilized aldehyde com-
pounds should provide valuable starting materials for a range of reaction types, e.g. reductive
aminations or Ugi reactions,9 allowing the preparation of new diverse libraries of small molecules.
Preparation of glyoxylic amide 3. To a solution of (^)-4-methyltartranilic acid 2 (3.39 g, 14.1
mmol) and 1-hydroxybenzotriazole (1.91 g, 14.1 mmol) in DMF (70 mL), N,N0-diisopro-
pylcarbodiimide (2.21 mL, 14.1 mmol) was added dropwise at 0ꢀC during 10 min. Stirring is
maintained for another 0.5 h at 0ꢀC, then for 0.5 h at rt. Resin 13 (1.77 g, ca. 1.8 mmol), swelled
in DMF, was added in several portions to the active ester solution and the reaction stirred for
another 1 h. The resin was ®ltered, washed with DMF, dichloromethane, methanol and 10%
acetic acid in dichloromethane, and then added to a solution of tetrabutylammonium periodate
(6.1 g, 14.1 mmol) in 1,2-dichloroethane (50 mL). The mixture was shaken overnight at rt, ®ltered,
the resin washed as described above and dried in vacuo. For yield determination, a sample of 3
(100 mg) was converted into a hydrazone by treatment with a solution of p-nitrophenylhydrazine
(154 mg, 1.0 mmol) in N-methyl-2-pyrrolidinone (1.9 mL) and acetic acid (0.1 mL). After stirring
overnight at rt, the resin was ®ltered and washed as previously. The product was cleaved o€ the
resin by treatment with TFA/dichloromethane (2 mL, 1:1 v:v) for 30 min and obtained after
evaporation of the solvents in 81% yield.
Preparation of glyoxalate 6. The activated diazo linker 4 was synthesized according to literature
procedures.6 A solution of 2 (1.15 g, 4.8 mmol) in DMF (20 mL) was added to a suspension of
the activated resin 4 (1.0 g, ca. 2.4 mmol) in DMF (15 mL). The mixture was shaken for 45 min
during which time the resin turned yellow and e€ervescence was observed. The resin was ®ltered,
washed with DMF, dichloromethane, methanol and 10% acetic acid in dichloromethane. The

5150
resin was subsequently added to a solution of tetrabutylammonium periodate (3.5 g, 8.08 mmol)
in 1,2-dichloroethane (15 mL). The mixture was shaken overnight at rt, ®ltered and the resin
washed as described above. A small sample of 6 was converted into the corresponding p-nitro-
phenylhydrazone as described above. The overall yield was determined to be 78% based on the
theoretical loading of the resin.
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