Selective preparation of 6- and 7-(polyhydroxypropyl)-pterins from pentos-2-uloses

Article abstract of DOI:10.3987/COM-13-S(S)47

The Gabriel-Isay condensation of three types of pentos-2-uloses with 2,5,6-triaminopyrimidin-4(3H)-one (3) was examined under both acidic and basic conditions. The condensation of 5-deoxy- and 5-O-protected pentofuranos-2-uloses with 3 at pH 8 afforded 6-

Full text of DOI:10.3987/COM-13-S(S)47

HETEROCYCLES, Vol. 88, No. 2, 2014
1491
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1491 - 1499. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 25th June, 2013, Accepted, 7th August, 2013, Published online, 19th August, 2013
DOI: 10.3987/COM-13-S(S)47
SELECTIVE PREPARATION OF 6- AND 7-(POLYHYDROXYPROPYL)-
PTERINS FROM PENTOS-2-ULOSES
Tadashi Hanaya* and Kasumi Ito
Department of Chemistry, Faculty of Science, Okayama University, Tsushima-
naka, Kita-ku, Okayama 700-8530, Japan. E-mail: hanaya@cc.okayama-u.ac.jp
This paper is dedicated to Professor Victor Snieckus on celebration of his 77th
birthday.
Abstract – The Gabriel-Isay condensation of three types of pentos-2-uloses with
2
,5,6-triaminopyrimidin-4(3H)-one (3) was examined under both acidic and basic
conditions. The condensation of 5-deoxy- and 5-O-protected pentofuranos-
-uloses with 3 at pH 8 afforded 6-substituted pterins as major isomers, whereas
the same reaction at pH 3 yielded the 7-substituted pterins predominantly.
2
Various pterin derivatives having a polyhydroxyalkyl side-chain at C-6 or C-7 have been isolated from
1
many living organisms. Among them, biopterin (1a) is one of the most ubiquitous naturally occurring
2
pterins and was isolated for the first time from human urine. Its 5,6,7,8-tetrahydro derivative exhibits
3
4
enzyme cofactor activity in hydroxylation of aromatic amino acids and nitric oxide synthesis. In
5
5
addition to 1a, primapterin (7-biopterin) (1b), neopterin (2a), and anapterin (7-neopterin) (2b) have also
6
been isolated from the urine of patients with hyperphenylalaninemia. Neopterin (2a) has attracted
7
attention as a marker for activation of cellular immunity or an inducer of apoptosis.
8
The Gabriel-Isay reaction is one of the most effective methods to obtain the 6- and 7-substituted
pteridines directly from the condensation of 5,6-diaminopyrimidines and 2-ketoaldehyde. As the
condensation of the unsymmetrical diaminopyrimidines with unsymmetrical dicarbonyl compounds
generally leads to the formation of regioisomers, various means of controlling a preponderant formation

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HETEROCYCLES, Vol. 88, No. 2, 2014
9
,10
of the 6- or 7-substituted pterins have been attempted.
For example, the pteridine ring formation of
2
,5,6-triaminopyrimidin-4(3H)-one (3) with phenyl glyoxal under acidic conditions affords the
-phenylpterin (4a), whereas the same condensation under basic conditions yields 7-phenylpterin (4b)
6
1
0
preferentially (Scheme 1).
Scheme 1. Preparation of 6- and 7-phenylpterins (4a,b)
The difference in the major product provided under these two conditions could be explained in terms of
the combination of basicity of the relevant two amino groups (5- and 6-) of pyrimidine 3 and the higher
electrophilicity of the aldehyde carbon (than that of the keto); under the basic conditions, the most
nucleophilic 5-amino group of 3 would attack the aldehyde carbon, while under the acidic conditions an
attack of the 6-amino group of 3 (owing to the protonation of the 5-amino group) to the aldehyde would
preferentially take place.
With regard to preparation of (polyhydroxyalkyl)pterins (such as 1a,b, 2a,b) and theirꢀderivatives, the
condensation of 3 and the appropriate sugar precursors (2-ketoaldoses) seems to be feasible. The
2
-ketoaldoses, however, exist in an equilibrium between cyclic hemiacetal and acyclic aldehyde forms
and therefore it is difficult to predict which carbonyl carbon reacts initially. Although the Gabriel-Isay
reaction has been used for preparation of simple 6- and 7-alkylpterins well, the application of it to
1
1
(polyhydroxyalkyl)pterin syntheses has scarcely been reported so far.
We now report a systematic
investigation of the regioselectivity and synthetic efficiency for the Gabriel-Isay condensation in the
preparation of biopterin (1a) and neopterin (2a) derivatives from 2-ketoaldoses.
With regard to the sugar precursors for pteridine-ring formation, we chose three types of pentos-2-ulose,
that is, 5-deoxy-pentofuranos-2-ulose, pentofuranos-2-ulose, and pentopyranos-2-ulose derivatives (6, 8,
1
0) (Scheme 2). 5-Deoxy-3-O-(p-methoxybenzyl)-L-erythro-pentofuranos-2-ulose (6) was prepared
1
2
from L-rhamnose in nine steps via the thioacetal (5) according to the reported procedures.
Glycosidation of D-ribose with benzyl alcohol, followed by protection with 1,1,3,3-tetraisopropyl-
1
3
disiloxan-1,3-diyl (TIPDS) group and Swern oxidation, afforded the benzyl pentofuranosid-2-ulose (7),
which was then hydrogenated with 10%-Pd-C to give 3,5-O-TIPDS-D-erythro-pentofuranos-2-ulose (8).

HETEROCYCLES, Vol. 88, No. 2, 2014
1493
Meanwhile, benzyl glycosidation of D-arabinose, followed by acetalization with acetone and then Swern
1
4
oxidation, provided the benzyl pentopyranosid-2-ulose (9), which was then hydrogenated to give
,4-O-isopropylidene-D-erythro-pentopyranos-2-ulose (10).
3
Scheme 2. Preparation of the pentos-2-uloses (6, 8, 10)
The Gabriel-Isay condensation of pentos-2-uloses (6, 8, 10) with monosulfate of 2,5,6-triamino-
pyrimidin-4(3H)-one (3) was examined on both a condition to add sodium bicarbonate (pH 8) and a
condition not to add (pH 3). The resulting mixture of the 6- and 7-substituted pterins was acetylated
1
with acetic anhydride-pyridine for purification of products and determination of their ratio by H NMR
spectra (Scheme 3, Table 1).
The pteridine ring formation of the 5-deoxy-pentofuranos-2-ulose (6) with 3 (1.2 mol equiv.) at pH 8 and
the following acetylation afforded an inseparable mixture (76:24) of the 6-substituted pterin (biopterin)
(11a) and its 7-substituted isomer (primapterin) (11b), whereas the same reaction at pH 3 resulted in a
predominant formation of 11b in a ratio of 20:80 (Table 1, Entries 1,2).
The condensation of the 3,5-O-protected pentofuranos-2-ulose (8) with 3 showed a tendency of the
regioselectivity similar to that of 6. Namely, the 6-substituted pterin (neopterin) (12a) was obtained as a
major isomer under the basic condition, while the 7-substituted pterin (anapterin) (13b) was obtained
selectively under the acidic condition accompanying with cleavage of the TIPDS group (Entries 3,4).
The condensation of the 3,4-O-protected pentopyranos-2-ulose (10) with 3, however, resulted in a

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HETEROCYCLES, Vol. 88, No. 2, 2014
predominant formation of the 7-substituted isomers (14b and 13b) under both basic and acidic conditions
Entries 5,6).
(
Scheme 3. Preparation of the 6- and 7-(polyhydroxypropyl)pterin derivatives (11–14)
a
Table 1. Condensation of pentos-2-uloses (6, 8, 10) with 2,5,6-triaminopyrimidin-4(3H)-one (3) and
the following acetylation
b
c
Entry
Pentos-2-ulose
Condition
pH 8
Products (total yield)
11a, 11b (84%)
11a, 11b (76%)
12a, 12b (63%)
13a, 13b (59%)
14a, 14b (65%)
13a, 13b (53%)
Ratio of products
76:24
1
2
3
4
5
6
6
6
pH 3
20:80
8
pH 8
70:30
8
pH 3
7:93
10
10
pH 8
19:81
pH 3
17:83
a
Condensation of pentos-2-uloses with sulfate of 3 (1.2 mol equiv.) was carried out in refluxing MeOH-water (1:1)
b
c
1
for 3 h.
At pH 8: addition of NaHCO . At pH 3: no additive base.
Determined by H NMR spectroscopy.
3
From these results, the combination of the more reactive carbonyl group of the 2-uloses (6, 8, 10) and the
more reactive amino group of the pyrimidine (3) under each condition seems to be as follows. Plausible

HETEROCYCLES, Vol. 88, No. 2, 2014
1495
pathways for the formation of the major isomers (12a, 13b, 14b) from the pentos-2-uloses (8 and 10) are
illustrated in Scheme 4.
Under the basic condition (pH 8), the most nucleophilic 5-amino group of 3 would attack the 2-keto
group of 6 and 8 (existing mainly as cyclic hemiacetals rather than open-chain 2-ketoaldehydes like 8’)
and the following pteridine ring formation would preferentially yield the 6-substituted isomers 11a and
1
2a (Table 1, Entries 1,3). On the other hand, under the acidic condition (pH 3) an attack of the 6-amino
group of 3 (owing to the protonation of the 5-amino group) to the 2-keto groups of 6 and 15 (arising from
the TIPDS cleavage of 8) would predominantly take place to afford the 7-substituted isomers 11b and
1
3b (Entries 2,4).
i
SiPr
2
O
O
O
O
N
O
i
O SiPr2
5
NH2
i
Pr Si
OH
2
HN
H N
N
N
O
HN
AcHN
O
O
OH
i
O
N 6 NH2
Pr Si
2
O
OAc
2
i
Pr Si
2
CHO
O
3
(pH 8)
8
12a
i
O
Pr Si
2
O
+
H O
3
8'
O
O
N
+
O
NH
N
3
HN
H N
OH
HN
AcHN
OAc
HO
HO
OAc
N
NH2
N
2
O
OAc
3
(pH 3)
15
13b
+
H O
3
O
N
O
CHO
N
N
OAc
O
O
HN
AcHN
NH2
NH2
OH
HN
H N
OH
O
O
O
N
O
O
O
O
2
3
(pH 8)
10
10''
14b
OH
CHO
O
O
O
10'
Scheme 4. Plausible pathways for the formation of the major isomers (12a, 13b, 14b)
In contrast to the results of Entries 1 and 3, the predominant production of the 7-substituted isomer (14b)
from 10 in Entry 5 appears to ascribe to an initial attack of the 5-amino group of 3 to the C-1 of the
1
5
aldehyde form present in an equilibrated solution of 10. The pentos-2-ulo-2,5-furanose (10’’) having a
stable cis-fused bicyclic structure is considered as the most probable structure to afford 14b, rather than
the acyclic aldehyde (10’). As well as Entry 4, the preferential formation of 13b in Entry 6 seems to

1496
HETEROCYCLES, Vol. 88, No. 2, 2014
result from the condensation of the 6-amino group of 3 with the C-2 of 15 derived from the acid
hydrolysis of 10.
The present work thus demonstrates the regioselectivity for the Gabriel-Isay condensation of some
pentos-2-uloses with 2,5,6-triaminopyrimidin-4(3H)-one (3). The condensation of 5-deoxy- and
5
-O-protected pentofuranos-2-uloses with 3 under basic conditions was found to be effective for
preparation of 6-substituted pterins such as biopterin (1a) and neopterin (2a), while the same reaction
under acidic conditions was found to be convenient for 7-substituted pterins. The same condensation of
the 3,4-O-protected pentopyranos-2-ulose, however, resulted in a predominant formation of 7-substituted
pterins regardless of the pH values. Extension of this work including applications of these findings in
synthesizing other 6- and 7-(polyhydroxyalkyl)pterins, as well as improvement of regioselectivity and
yield for the condensation, is expected.
EXPERIMENTAL
All reactions were monitored by TLC (Merck Silica gel 60 F254 or Merck Cellulose F) with an appropriate
solvent system. Column chromatography was performed with Daiso Silica Gel IR-60/210w.
Components were detected by exposing the plates to UV light and/or spraying them with 20%
1
H
2
SO
4
-EtOH (with subsequent heating). The H NMR spectra were measured in CDCl
3
with Varian
NMR System 600 (600 MHz) or 400-MR (400 MHz) at 23 °C. Chemical shifts are reported as ! values
3
relative to CHCl (7.26 ppm) as an internal standard.
2
Di-N :2’-O-acetyl-1’-O-(4-methoxybenzyl)biopterin (11a) and its 7-biopterin isomer (11b).
3
A. Condensation at pH 8. Monosulfate of 3 (90.0 mg, 0.376 mmol) and NaHCO (130 mg, 1.54
1
2
mmol) were dissolved in water (3 mL), and then a solution of compound 6 (79.0 mg, 0.313 mmol)
dissolved in MeOH (3 mL) was added. The mixture was refluxed for 3 h and then evaporated in vacuo.
The residue was dissolved in DMF and sodium sulfate was filtered off. The filtrate was concentrated in
vacuo. The residue was dissolved in dry pyridine (3 mL) and acetic anhydride (0.50 mL, 5.3 mmol) was
added at 0 °C. The mixture was stirred at rt for 16 h and then concentrated in vacuo. The residue was
3
purified by column chromatography with 1:19 MeOH-CHCl to give an inseparable mixture (76:24) of
the biopterin derivative (11a) and its 7-substituted isomer (11b) (116 mg, 84% yield from 6) as a pale
1
yellow foam: R
f
= 0.33 (1:19 MeOH-CHCl
3
): H-NMR (600 MHz) for 11a ! 1.24 (3H, d, J2’,3’ = 6.5 Hz,
H
3
-3’), 1.96 (3H, s, AcO-2’), 2.42 (3H, s, AcN), 3.79 (3H, s, MeO), 4.51 (2H, s, CH
2
O-1’), 4.76 (1H, d,
J
1’,2’ = 5.0 Hz, H-1’), 5.37 (1H, qd, H-2’), 6.83, 7.20 (2H each, 2d, Jo,m = 8.5 Hz, C H ), 9.09 (1H, s, H-7),
6 4
1
1
0.93 [1H, br s, H-N(3)], 12.60 (1H, br s, AcNH); H-NMR (600 MHz) for 11b ! 1.22 (3H, d, J2’, 3’ = 6.7

HETEROCYCLES, Vol. 88, No. 2, 2014
1497
2
Hz, H
3
-3’), 1.98 (3H, s, AcO-2’), 2.42 (3H, s, AcN), 3.795 (3H, s, MeO), 4.52, 4.56 (1H each, 2d, J =
1
1.7 Hz, CH O-1’), 4.68 (1H, d, J1’,2’ = 4.1 Hz, H-1’), 5.37 (1H, qd, H-2’), 6.85, 7.22 (2H each, 2d, Jo,m =
2
8
.5 Hz, C H ), 8.89 (1H, s, H-6), 10.37 [1H, br s, H-N(3)], 12.60 (1H, br s, AcNH). Anal. Calcd for
6
4
C
21
H
23
N
5
O
6
: C, 57.14; H, 5.25. Found: C, 57.29; H, 5.14.
B. Condensation at pH 3. Monosulfate of 3 (86.0 mg, 0.360 mmol) was dissolved in water (3 mL), and
then a solution of compound 6 (76.0 mg, 0.301 mmol) dissolved in MeOH (3 mL) was added. The
mixture was refluxed for 3 h and then evaporated in vacuo. The residue was acetylated in the same
manner described above to give an inseparable mixture (20:80) of the biopterin derivative (11a) and its
7
-substituted isomer (11b) (101 mg, 76% yield from 6).
2
Di-N :2’-O-acetyl-1’,3’-O-(1,1,3,3-tetraisopropyldisilosan-1,3-diyl)neopterin (12a) and its 7-
neopterin isomer (12b).
1
3
Compound 7 (75.0 mg, 0.156 mmol) was dissolved in EtOAc (2 mL) and hydrogenated in the presence
of 10% Pd-C (34.0 mg, 0.032 mmol) at rt under an atmospheric pressure of H . After 20 h, the catalyst
was filtered off and the filtrate was evaporated in vacuo to give 3,5-O-TIPDS-D-erythro-
pentofuranos-2-ulose (8) (61.0 mg, quant.) in a colorless syrup: R = 0.50–0.38 (1:2 AcOEt-hexane).
Compound 8 was dissolved in MeOH (3 mL) and then added to a solution of 3 (monosulfate, 45.0 mg,
.188 mmol) and NaHCO (53.0 mg, 0.629 mmol) dissolved in water (3 mL). The mixture was refluxed
2
f
0
3
for 3 h and then evaporated in vacuo. The residue was dissolved in dry pyridine (2 mL) and acetic
anhydride (0.40 mL, 4.2 mmol) was added at 0 °C. The mixture was stirred at rt for 16 h and then
3
concentrated in vacuo. The residue was purified by column chromatography with 1:19 MeOH-CHCl to
give an inseparable mixture (70:30) of the neopterin derivative (12a) and its 7-substituted isomer (12b)
1
(
57.1 mg, 63% yield from 8) as a pale yellow syrup: R
for 12a ! 0.94–1.12 [28H, m, (Me CH)
-3’), 4.10 (1H, dd, J2’,3’a = 1.5 Hz, H
f
= 0.68 (1:9 MeOH-CHCl
3
): H-NMR (600 MHz)
2
2
Si], 2.14 (3H, s, AcO-2’), 2.35 (3H, s, AcN), 3.70 (1H, dd, J3’a,3’b
=
12.3, J2’,3’b = 8.2 Hz, H
b
a
-3’), 4.52 (1H, ddd, H-2’), 5.77 (1H, d,
1
J
1’,2’ = 6.5 Hz, H-1’), 8.90 (1H, s, H-7), 10.95 [1H, br s, H-N(3)], 12.45 (1H, br s, AcNH); H-NMR (600
MHz) for 12b ! 0.94–1.12 [28H, m, (Me
-3’), 4.16 (1H, dd, J2’,3’a = 1.5 Hz, H
d, J1’,2’ = 6.5 Hz, H-1’), 8.75 (1H, s, H-6), 10.85 [1H, br s, H-N(3)], 12.45 (1H, br s, AcNH). Anal.
2
CH)
2
Si], 1.98 (3H, s, AcO-2’), 2.35 (3H, s, AcN), 3.74 (1H, dd,
J3’a,3’b = 12.3, J2’,3’b = 7.9 Hz, H
b
a
-3’), 4.42 (1H, ddd, H-2’), 5.69 (1H,
41 5 7 2
Calcd for C25H N O Si : C, 51.79; H, 7.13. Found: C, 51.62; H, 7.21.
2
Tetra-N :1’,2’,3’-O-acetylneopterin (13a) and its 7-neopterin isomer (13b).
A. From 8. By employing the same procedures as those for preparation for 11a,b (by condensation at
pH 3), compound 8 gave an inseparable mixture (7:93) of the neopterin derivative (13a) and its

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HETEROCYCLES, Vol. 88, No. 2, 2014
1
7
-substituted isomer (13b) (59% yield) as a pale yellow syrup: R
f 3
= 0.53 (1:9 MeOH-CHCl ); H-NMR
(600 MHz) for 13a ! 1.98, 2.05, 2.16 (3H each, 3s, AcO-1’,2’,3’), 2.38 (3H, s, AcN), 4.30 (1H, dd, J3’a,3’b
=
12.3, J2’,3’b = 5.6 Hz, H -3’), 4.42 (1H, dd, J
= 3.2 Hz, H -3’), 5.63 (1H, ddd, H-2’), 6.14 (1H, d,
b
2’,3’a
a
1
J
1’,2’ = 6.5 Hz, H-1’), 8.91 (1H, s, H-7), 10.90 [1H, br s, H-N(3)], 12.50 (1H, br s, AcNH); H-NMR (600
MHz) for 13b ! 2.00, 2.01, 2.20 (3H each, 3s, AcO-1’,2’,3’), 2.37 (3H, s, AcN), 4.26 (1H, dd, J3’a,3’b
=
1
2.3, J2’,3’b = 6.3 Hz, H -3’), 4.38 (1H, dd, J
2’,3’a a 1’,2’
= 3.7 Hz, H -3’), 5.63 (1H, ddd, H-2’), 6.11 (1H, d, J
b
=
C
5.3 Hz, H-1’), 8.72 (1H, s, H-6), 10.90 [1H, br s, H-N(3)], 12.50 (1H, br s, AcNH). Anal. Calcd for
: C, 48.46; H, 4.54. Found: C, 48.33; H, 4.61.
17
19 5 8
H N O
B. From 10. By the same procedures described above, compound 10 gave an inseparable mixture
(17:83) of 13a and 13b in 53% yield.
2
Di-N :3’-O-acetyl-1’,2’-O-isopropylideneneopterin (14a) and its 7-neopterin isomer (14b).
1
3
Compound 9 (124 mg, 0.446 mol) was dissolved in EtOH (2.5 mL) and hydrogenated in the presence of
0% Pd(OH) -C (63.0 mg, 0.089 mmol) at rt under an atmospheric pressure of H . After 20 h, the
catalyst was filtered off and the filtrate was evaporated in vacuo to give 3,4-O-isopropylidene-
D-erythro-pentopyranos-2-ulose (10) (84.0 mg, quant.) in a colorless syrup: R = 0.62–0.50 (AcOEt).
Compound 10 was treated with the same procedures as those described for 11a,b (by condensation at pH
2
2
2
f
8
) to give an inseparable mixture (19:81) of the neopterin derivative (14a) and its 7-substituted isomer
1
(14b) (110 mg, 65% yield from 10) as a pale yellow syrup: R
f
= 0.58 (1:9 MeOH-CHCl
3
); H-NMR (400
MHz) for 14a ! 1.52, 1.71 (3H each, 2s, CMe ), 1.89 (3H, s, AcO-3’), 2.39 (3H, s, AcN), 3.67 (1H, dd,
2
J3’a,3’b = 11.9, J2’,3’b = 5.9 Hz, H
b
-3’), 3.98 (1H, dd, J2’,3’a = 3.9 Hz, H
a
-3’), 4.83 (1H, ddd, H-2’), 5.62 (1H,
1
d, J1’,2’ = 7.4 Hz, H-1’), 9.11 (1H, s, H-7), 10.90 [1H, br s, H-N(3)], 12.50 (1H, br s, AcNH); H-NMR
(
400 MHz) for 14b ! 1.52, 1.70 (3H each, 2s, CMe ), 1.86 (3H, s, AcO-3’), 2.36 (3H, s, AcN), 3.69 (1H,
2
dd, J3’a,3’b = 12.1, J2’,3’b = 5.7 Hz, H
b
-3’), 4.10 (1H, dd, J2’,3’a = 3.3 Hz, H
1H, d, J1’,2’ = 7.6 Hz, H-1’), 8.92 (1H, s, H-6), 10.90 [1H, br s, H-N(3)], 12.50 (1H, br s, AcNH). Anal.
Calcd for C16 : C, 50.93; H, 5.08. Found: C, 50.84; H, 5.10.
a
-3’), 4.82 (1H, ddd, H-2’), 5.46
(
19 5 6
H N O
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
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1
.
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