Tetrahedron Letters 51 (2010) 2539–2540
Tetrahedron Letters
Acyl radical insertion for the direct formation of new seven-substituted
pterin analogs
*
Jeff M. Pruet, Jon D. Robertus, Eric V. Anslyn
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of pterin molecules were synthesized via an under-utilized acyl radical insertion, using alde-
hydes and a-keto esters as the acyl source. These reactions gave complete regiospecificity for the 7-iso-
mer, with reaction times ranging in minutes, often with instantaneous product precipitation. This
approach led to the construction of new pterin analogs unaccessible via traditional Friedel–Crafts acyla-
tion. The compounds were characterized by NMR spectroscopy and high-resolution mass spectroscopy.
Published by Elsevier Ltd.
Received 19 February 2010
Accepted 1 March 2010
Available online 4 March 2010
Pterins have been shown to be a noteworthy lead in the search
for Ricin A chain inhibitors.1 In this context, we have explored dif-
ferent routes to pterin libraries, particularly those which remove
extraneous steps often needed to circumvent pterins’ insolubility
and poor reactivity. As with other diazoaromatic compounds, such
as pyrazines, direct substitution by electrophiles is not a viable
modifications and all required post-reaction substituent conver-
sion to arrive at the pterin.12–14 It thus follows that the overall yield
of the desired pterins would suffer from these additional steps.
We report here the use of peroxide and iron sulfate for the di-
rect one-step formation of a variety of pterins, starting simply from
pterin (1). As shown, aldehydes gave rise to acylpterins (2–5), and
reaction for pterins, as a result of these being so
p-electron defi-
a-keto esters gave rise to pterin esters (6–7).
cient.2,3 For this reason, the formation of acylpterins is typically
done through oxidation of alkyl side-chains to carboxylates or
alcohols.4,5 Taylor developed a method for forming isomerically
pure alkyl pterins, though it requires a multi-step construction of
the ring.6 Methods exist for the formation of isomerically enriched
alkyl pterins through a traditional one-step condensation, but the
formation of the undesirable isomer is still observed.5 Further-
more, due to the poor solubility of pterins, isolation of the desired
isomer can be difficult, often requiring further modifications.5,7
Direct acylation of heteroaromatic bases was first shown by
Caronna, whereby an aldehyde is allowed to react with a peroxide
in the presence of iron sulfate, generating an acyl radical which can
insert onto the protonated heterocyclic species.8 This reaction has
been performed on a variety of simple heterocycles, and has also
The general procedure for the reaction depicted in Scheme 1 in-
volves suspending pterin (1) in 50–60 mL water, and adding
5–6 mL concentrated sulfuric acid along with 2 equiv iron sulfate.
t
Separately, 5 equiv of the aldehyde and 2 equiv of butylperoxide
were mixed together, with cooling, and then added dropwise to
the reaction. In the cases where esters or amides inserted onto
the pterin, the product precipitated out instantaneously. In in-
stances where precipitation was not observed, the addition of a
small amount of ammonium hydroxide afforded the desired prod-
uct as a precipitate. The results are summarized in Table 1. The
been shown to proceed with a
-keto esters as the acyl source.2,9,10
Substituent-directing effects have been studied, and it was found
that groups which are electron withdrawing by resonance and
inductive effects direct to the para position.11 As related to pterins,
these directing effects would regiospecifically provide the 7-iso-
mer. This reaction has previously been utilized on molecules con-
taining the general pteridine substructure, and it was indeed
found that when both heteroaromatic positions are available, only
the 7-isomer is formed, while placement of electron-donating sub-
stituents on the 7-position allowed access to the 6-isomer.12–14
However, these pteridine analogs often had several preemptive
Scheme 1. Acyl radical addition to pterin.
Table 1
Entry
Acyl source
Time (min)
Product
% Yield
2
3
4
5
6
7
Acetaldehyde
Propionaldehyde
Formamide
10
10
3
R = CH3
R = CH2CH3
R = NH2
42
37
31
22
48
39
Anisaldehyde
Methyl pyruvate
Ethyl pyruvate
10
2
3
R = C6H4OCH3
R = OCH3
R = OCH2CH3
* Corresponding author. Tel.: +1 512 471 0068; fax: +1 512 471 7791.
0040-4039/$ - see front matter Published by Elsevier Ltd.
Pruet, Jeff M.
