Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

Article abstract of DOI:10.3762/bjoc.16.46

The synthetic utility of pterins is often hampered by the notorious insolubility of this heterocycle, slowing the development of medicinally relevant pteridine derivatives. Reactions which expedite the development of new pterins are thus of great importance. Through a dual role of diazabicycloundecene (DBU), 7-carboxymethylpterin is converted to the soluble DBU salt, with additional DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural features in the amines which significantly affect success, monitored the reaction kinetics using a pseudo-first order kinetics model, and further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often >80%.

Full text of DOI:10.3762/bjoc.16.46

Exploring the scope of DBU-promoted amidations of
7-methoxycarbonylpterin
Anna R. Bockman and Jeffrey M. Pruet*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 509–514.
Department of Chemistry, Valparaiso University, 1710 Chapel Dr,
Valparaiso, IN 46383, USA
doi:10.3762/bjoc.16.46
Received: 04 February 2020
Accepted: 19 March 2020
Published: 26 March 2020
Email:
Jeffrey M. Pruet* - Jeffrey.pruet@valpo.edu
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
amidation; DBU; folate; pterin
© 2020 Bockman and Pruet; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The synthetic utility of pterins is often hampered by the notorious insolubility of this heterocycle, slowing the development of me-
dicinally relevant pteridine derivatives. Reactions which expedite the development of new pterins are thus of great importance.
Through a dual role of diazabicycloundecene (DBU), 7-carboxymethylpterin is converted to the soluble DBU salt, with additional
DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural fea-
tures in the amines which significantly affect success, monitored the reaction kinetics using a pseudo-first order kinetics model, and
further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often >80%.
Introduction
Pteridines are a class of fused bicyclic heterocycles with signifi- iosis [9]. In addition to their therapeutic potential, pterin deriva-
cant biological relevance. The 2-amino-4-pteridinone core, tives have been an attractive scaffold in the field of supramolec-
simply referred to as “pterin”, is present in various biological ular chemistry, due to their well-defined donor/acceptor hydro-
cofactors like folates, biopterin, and molybdopterin [1]. Owing gen-bonding arrays [10,11].
to this biological relevance, pterins are an attractive building
block in the development of various pharmaceuticals, with One limitation often encountered with the synthesis of struc-
methotrexate being the most well-known [2]. In addition to turally diverse pterins is the notorious insolubility in most sol-
pteridine derivatives being used as inhibitors of dihydrofolate vents. This can be dealt with by preemptive modifications to the
reductase and dihydropteroate synthase, pterins have been a pteridine core which disrupt the hydrogen-bond assembly, such
useful scaffold in the development of inhibitors of ricin [3,4], as benzylation of the lactam oxygen or conversion of the
methionine synthase [5], nitric oxide synthase [6], shigella [7], exocyclic amine to the pivalic amide [12,13]. The installation
and aldose reductase [8], as well as for treatment of leishman- and subsequent removal of these groups naturally affects the
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Beilstein J. Org. Chem. 2020, 16, 509–514.
overall yield and time necessary to generate new pterins. As monitoring the reaction by employing a pseudo-first order
such, any reaction which expedites the synthesis of pterin deriv- kinetics model. Furthermore, we adapted the reaction to allow
atives, especially those which bypass the insolubility, is of great for reaction times as little as 5 minutes, with yields reaching up
importance to both medicinal and supramolecular chemists.
to 99%.
We first reported the application of DBU as a crucial additive in Results and Discussion
the synthesis of pterins used for ricin toxin A (RTA) inhibitors The general procedure for the DBU-promoted amidation
[14]. By deprotonation of the lactam NH, and conversion to the involved the initial suspension of 7-CMP (1) in a small quanti-
DBU salt, the pterin easily dissolves in methanol at high con- ty of anhydrous methanol, followed by the addition of 2 equiv
centrations, unprecedented for unfunctionalized pterins. This DBU resulting in the full dissolution of the pterin ester, where-
greatly accelerated the development of a library of bioactive upon 2 equiv of the amine of interest were added and the reac-
pterins, as it bypassed the problematic insolubility and assisted tion was stirred until complete (Scheme 1). The isolation of the
in derivatization [14-16]. In addition to this improvement in amide products 2–16 was achieved by careful acidification with
solubility, we can further take advantage of a mechanistic role dilute aqueous HCl. By reversing the DBU-salt formation, the
of DBU, as it catalyzes the ester-to-amide transformation, pterin turns again insoluble and cleanly precipitates, allowing
allowing for 7-methoxycarbonylpterin (7-CMP, 1) to smoothly for an isolation by simple filtration.
generate new pterin amides (Figure 1) [14,17]. The same
process used in generating RTA inhibitors was later used as a Initially, the reaction was allowed to proceed at room tempera-
key step in the development of new aldolase reductase inhibi- ture overnight to ensure adequate times for all amines screened
tors [8]. The benefit of DBU as an additive in these previous to react. This preliminary screen of amines gave acceptable
reports was largely empirical, and reaction times were still in yields for a range of substituted amines, with primary amines
the order of several hours.
often giving the best results, as expected. To streamline the
amine screening and allow for better comparisons of reactivity,
Viewing this reaction as an essential tool for pteridine chemists a variety of times and temperatures were screened with benzyl-
seeking to rapidly generate diverse pterin structures, we sought amine chosen as a representative example (i.e., formation of
to explore the scope of amines which can be easily appended to product 4) in the method optimization (Table 1). It quickly be-
the pterin core. Trends in reactivity were further probed by came apparent that simple amines easily gave rise to the amide
Figure 1: The dual role of DBU in the amidation of 7-CMP.
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Beilstein J. Org. Chem. 2020, 16, 509–514.
Scheme 1: DBU-promoted amidation of 7-CMP (1).
Table 1: Optimizing the conditions with benzylamine.
under mild reaction conditions (5 min at 60 °C). Using this
modified method allowed for all screened amines to be
adequately reassessed on their ease of amidation (Table 2).
Temp (°C)
Time (min)
Yield (%)
110
110
80
80
60
60
60
40
30
20
30
10
10
5
78
90
89
90
91
91
44
46
It was found that the reaction was most affected by an α-substi-
tution on the amine (Table 2; products 11–13). This is in agree-
ment with known Taft parameters which show steric effects are
more pronounced for an isopropyl group compared to a benzyl
substituent [18]. The deleterious effect of a substituent α to the
amine was most pronounced in the case of alanine (product 13),
as compared to glycine (product 2). However, this steric
constraint could be largely overcome by the presence of a
1
5
Table 2: Summary of amines screened for amidation of 7-CMP.
Product
Amine tested
Conditionsa
Yield (%)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
glycine
4-nitrophenethylamine
benzylamine
serine
1-propylamine
1-amino-2-propanol
4-(2-aminoethyl)aniline
2-(methylamino)ethanol
2-(2-aminoethyl)pyridine
isopropylamine
α-methylbenzylamine
alanine
methyl 2-(aminomethyl)-5-furanoate
morpholine
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
60 °C, 5 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
60 °C, 5 min
80 °C, 20 min
130 °C, 3 h
99
96
91
88
87
85
76
71
66
66
60
49
47b
44
63c
N-methylbenzylamine
aTypical conditions: 2 equiv amine, 2 equiv DBU, sealed reaction vessel. bThe low yield for this amine was due to a side reaction. cNo reaction under
typical conditions. 10 equiv amine were used.
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Beilstein J. Org. Chem. 2020, 16, 509–514.
β-hydroxy group, as seen with serine (product 5). For Another noteworthy entry from Table 2 was methyl 2-amino-
β-hydroxyamines it is expected the hydroxy group expedites the methyl-5-furanoate (for 14). As the DBU amidation relies on an
amidation via hydrogen bonding to the 7-CMP carbonyl group, activation of the methyl ester of 7-CMP (1), the use of an amine
to assist in bringing the amine nucleophile into place (Figure 2). with an additional ester functionality can therefore pose a limi-
Quite unsurprisingly, secondary amines were less reactive, with tation in what this reaction may tolerate. Yields were dimin-
N-methylbenzylamine (for 16) being entirely unreactive under ished for this reaction, owing to a side reaction whereby the
the typical reaction conditions. In this case the reaction re- amine effectively polymerizes. However, the desired product
quired 3 h at 130 °C before product formation was observed. was still accessible within a short reaction time, and easily puri-
Interestingly, much like the improved results for serine, a fied [20]. This highlighted a limitation of the reaction, but
β-hydroxy group dramatically overcame this issue for second- nevertheless showed the reaction may be used in tethering addi-
ary amines, as 2-(methylamino)ethanol smoothly reacted tional reactive functionality to the pterin for future diversifica-
affording product 9 in good yield under reaction conditions tion.
identical to those for the unhindered primary amines (5 min,
60 °C). Consistent with previous NMR studies of secondary In an effort to better understand the relative reactivity of the
amides, each of these were observed as a resolved mixture of various amines, a pseudo-first order kinetics of the amidation
the s-cis and s-trans rotamers [19]. Product 16 obtained from reaction was probed. The reaction was followed by 1H NMR
N-methylbenzylamine was found to be a near 1-to-1 mixture of spectroscopy at room temperature, following the disappearance
rotamers, while product 9 from 2-(methylamino)ethanol of 7-CMP and appearance of the amide product (Figure 3). By
appeared as a 2-to-1 mixture favoring the s-cis form.
monitoring the reaction within the NMR tube with a large
excess of the amine, the relative rate constants were determined
for a representative set of amines (Table 3). These results
further highlight the dramatic rate enhancement brought on by
substituent effects. Glycine reacted most swiftly, as the carbox-
ylate anion likely ion pairs with the cationic DBU-activated
acyl intermediate (see Figure 1). However, the α-substitution in
alanine clearly abolishes any rate acceleration driven by ionic
interactions, and most α-substituted amines had similar rates.
Rate acceleration is recovered in serine, owing to the effect of
the β-hydroxy group discussed previously. The 1-amino-2-
propanol reacted faster than serine, likely due to a lack of
Figure 2: Role of a β-hydroxy group in aiding the amidation reaction.
Figure 3: Pseudo-first order kinetics for representative amines.
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Beilstein J. Org. Chem. 2020, 16, 509–514.
Table 3: Rate constants determined by 1H NMR kinetics.a
Amine
k @ 22 °C
(M−1 s−1)
Amine
k @ 22 °C
(M−1 s−1)
glycine
1-amino-2-propanol
serine
3.4 × 10−3
2.3 × 10−3
1.5 × 10−3
1.1 × 10−3
2-(methylamino)ethanol
isopropylamine
α-methylbenzylamine
alanine
0.78 × 10−3
0.61 × 10−3
0.57 × 10−3
0.45 × 10−3
benzylamine
aValues determined by first finding kobs from pseudo-first order kinetic plot.
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ORCID® iDs
Anna R. Bockman - https://orcid.org/0000-0003-2248-0634
Jeffrey M. Pruet - https://orcid.org/0000-0002-6100-4633
doi:10.1016/j.bmcl.2013.10.017
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