Bioorganic & Medicinal Chemistry Letters 19 (2009) 6706–6708
Bioorganic & Medicinal Chemistry Letters
Solid phase synthesis of acylglycine human metabolites
a
a,b,
Rolando Perez-Pineiro a, , Ying Wei Dong , David S. Wishart
*
*
a Department of Biological Sciences, University of Alberta, Edmonton AB, Canada T6G 2E9
b Department of Computing Science, University of Alberta, Edmonton AB, Canada T6G 2E9
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Revised 26 September 2009
Accepted 30 September 2009
Available online 3 October 2009
Acylglycines represents a large and important class of human metabolites. They are often used in med-
icine to identify fatty acid oxidation disorders. A highly efficient solid phase synthesis approach to obtain
these clinically important compounds is developed via coupling reaction between glycine-preloaded
Wang resin and a set of carboxylic acids. The developed methodology facilitates the preparation of sev-
eral structurally-diverse acylglycines with high yields and purity.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Acylglycines
Human metabolome database
Solid phase synthesis
Metabolomics is a newly emerging field of ‘omics’ science that
uses NMR and mass spectrometry to rapidly identify and quantify
large numbers of metabolites from biological materials.1 One of the
continuing challenges in metabolomics is having sufficient quanti-
ties of authentic reference compounds to identify or confirm the
identity of a putative metabolite. A similar problem also exists in
the field of clinical chemistry where the lack of authentic standards
for key metabolites often prevents routine testing for certain met-
abolic disorders. Acylglycines represent an important class of dis-
ease-associated metabolites for which a relatively small number
of authentic standards are commercially available. Given their
importance in both clinical chemistry and in metabolomic studies
we have developed an efficient general solid phase synthetic strat-
egy that should greatly enhance the yield, synthetic diversity and
ease-of-purification of acylglycines.
Acylglycines 1 possess a common amidoacetic acid moiety and
are normally minor metabolites of fatty acids. Elevated levels of cer-
tain acylglycines appear in the urine and blood of patients with var-
ious fatty acid oxidation disorders. They are normally produced
through the action of glycine N-acyltransferase which is an enzyme
that catalyzes the chemical reaction: acyl-CoA + glycine M CoA + N-
acylglycine.2
desired compounds by reaction with acyl chlorides follow by basic
hydrolysis, Scheme 1B.5 Similarly glycine methyl ester hydrochlo-
ride can react with acids and acyl chlorides under different
coupling conditions, Scheme 1C.6,7 In an alternate approach
several
a,b-unsaturated acylglycines have been recently obtained
by acylation of unprotected aminoacids with N-(a,b-unsaturated
acyl) benzotriazole, Scheme 1D.8
Many of the solution phase methodologies described above pos-
sess important drawbacks such as long reaction times, poor yields
and exhaustive purification protocols. In this context we have fore-
seen that the use of solid phase strategies9 to obtain acylglycines
could overcome some of the deficiencies observed in previous syn-
thetic protocols.
Surprisingly, despite the enormous advancements in the field of
solid phase organic synthesis over the past decades the only report
about the formation of an amidoacetic functionality on polymeric
supports describes the preparation of a series of resin-bound
N-substituted-N-acylglycines as intermediates in the synthesis of
ketoimidazoles.10 In this case the amidoacetic moiety is generated
via nucleophilic substitution reaction between previously obtained
Wang bromoacetate resin and several amines. With the aim to
expand the limited synthetic repertoire of acylglycines currently
available we report herein an alternate approach to synthesize this
class of compounds. This novel procedure possesses the inherent
advantages of solid phase organic synthesis, including simplicity,
highyieldsandeasypurification.Thisstrategyhasalsobeensuccess-
fully implemented to obtain a series of structurally-diverse amido-
acetic derivatives.
Several solution phase synthetic protocols have been described
for the synthesis of acylglycines. According to Scheme 1 the amido-
acetic functionality could be generated by reaction of acid deriva-
tives with glycine in basic aqueous or organic medium, Scheme
1A.3,4 Glycine methyl esters have also been reported to afford the
Our solid phase strategy and the results of the synthesis of the
acylglycines are depicted in Scheme 2 and Table 1, respectively.
In the first step Fmoc-Gly-OH is readily attached to Wang
resin (1.1 mmol/g) using the symmetrical anhydride protocol.
* Corresponding authors. Tel.: +1 780 492 8574; fax: +1 780 492 9234 (R.P.-P.),
tel.: +1 780 492 0383; fax: +1 780 492 1071 (D.S.W.).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.