A new synthesis of ciliapterin and dictyopterin. Ene reactions of (alkenylamino)-nitroso-pyrimidines

Article abstract of DOI:10.1002/hlca.200890255

A comparison of the reactivity of (acylamino)-nitroso-pyrimidines 1 and the alkenylamino analogue 17 in intramolecular ene reactions showed the considerably lower reactivity of 17, leading to the pteridine 18. Pteridin-7-one 11 resulting from 1 (R¹

Full text of DOI:10.1002/hlca.200890255

Helvetica Chimica Acta – Vol. 91 (2008)
2351
A New Synthesis of Ciliapterin and Dictyopterin. Ene Reactions of
(Alkenylamino)-nitroso-pyrimidines
by Fang-Li Zhang and Andrea Vasella*
Laboratorium fꢀr Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, HCI, CH-8093 Zꢀrich
A comparison of the reactivity of (acylamino)-nitroso-pyrimidines 1 and the alkenylamino analogue
17 in intramolecular ene reactions showed the considerably lower reactivity of 17, leading to the pteridine
18. Pteridin-7-one 11 resulting from 1 (R1 ¼ OBn, R2 ¼ Me) was transformed into 4-(benzyloxy)-6-[(E)-
prop-1-enyl]pteridin-2-amine (13) by O-triflation, followed by reduction with LiBHEt3, while the 4-MeO
analogue 18 was prepared by spontaneous oxidation of the initial ene product of 17. The (alkenylamino)-
nitroso-pyrimidine 17 was synthesized by substitution of the dimethoxy-nitroso-pyrimidine 16 with the
allylamine 15. Ciliapterin (5) and dictyopterin (7) were synthesized from pteridine 18 by a Sharpless
asymmetric dihydroxylation.
Introduction. – We recently described a high-yielding synthesis of C(6)-alkenyl
pteridinones 2 by the nitroso-ene reaction of 6-(acylamino)-5-nitrosopyrimidines 1
(Scheme 1) [1]. Transforming the pteridinones 2 into pteridines 4, as required for the
synthesis of biopterin (8), ciliapterin (5), and dictyopterin (7) ([2]; Fig. 1, see below),
appears feasible by deoxygenating the lactam moiety. Pterins might, however, be
obtained in a more straightforward way via a nitroso-ene reaction of 6-(alkenylamino)-
5-nitrosopyrimidines 3. The expected weaker electrophilicity of 3 as compared to 1
may, however, disfavour the ene reaction, require harsher reaction conditions, and
perhaps result in unsatisfactory yields.
Scheme 1
ꢁ 2008 Verlag Helvetica Chimica Acta AG, Zꢀrich

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We wished to compare the reactivity of 6-(alkenylamino)-5-nitrosopyrimidines 3 in
the nitroso-ene reaction, ultimately providing pteridins 4, to the nitroso-ene reaction of
1, and the synthesis of 4 from 3 to the one from the acylamino analogues 1. The
practicality of the synthesis of 4 should be tested by transforming 4 into ciliapterin (5)
and dictyopterin (7).
The name ꢂciliapterinꢃ was given in 1968 by Kidder and Dewey [3] to the pterin they
isolated from the ciliate protozoan Tetrahymena pyriformis, and to which they had
assigned the structure of 6-(l-threo-1,2-dihydroxypropyl)pterin (5; Fig. 1), a known
compound that had been synthesized by Green and Rembold in 1966 [4]. The
constitution and absolute configuration of ciliapterin were revised by Klein et al. [5] to
6-(d-threo-1,2,3-trihydroxypropyl)pterin (6), a known compound that had already been
given the trivial name of umanopterin [6]. ꢂCiliapterinꢃ is still used as trivial name for 6-
(l-threo-1,2-dihydroxypropyl)pterin, and a natural compound possessing this structure
was isolated from human urine in 1992 by Ogiwara et al., and termed ꢂorinapterinꢃ
[6]1). Several glycosides of ciliapterin (6-(l-threo-1,2-dihydroxypropyl)pterin) were
then obtained from the cyanobacterium Alphanizomenon flos-aquae [11], and the 1-O-
b-l-N-acetylglucosaminide of ciliapterin was isolated from Chlorobium tepidum, a
thermophilic photosynthetic green sulphur bacterium [12].
Fig. 1. Structure of ciliapterin (5), umanopterin (6), dictyopterin (7), and biopterin (8)
Dictyopterin (6-(d-threo-1,2-dihydroxypropyl)pterin (7); Fig. 1) was isolated as the
major pterin from extracts of vegetative cells of the myxobacterium Dictyostelium
discoideum after perchloric acid deproteinization and oxidation with I2 under acidic
conditions [13]. Dictyopterin and tetrahydrodictyopterin are thought to be involved in
the transition of this myxobacterium from the unicellular growing phase to the
multicellular developmental phase. A G-protein-linked signaling pathway was reported
to be involved in the regulation of GTP cyclohydrolase I activity and in the production
of tetrahydrodictyopterin during the early development of D. discoideum [14].
1
)
The separation of diastereoisomers of neopterin and biopterin [7] (8; Fig. 1) is based on reversed-
phase ligand-exchange chromatography [8], and a determination of individual pterins in the urine of
cancer patients is of diagnostic relevance [9][10].

Helvetica Chimica Acta – Vol. 91 (2008)
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Ciliapterin was synthesized in a yield of ca. 9% by condensing 2,5,6-triaminopyr-
imidin-4(3H)-one dihydrochloride with 5-deoxy-l-xylose phenylhydrazone, followed
by oxidation with K3[Fe(CN)6] and H2O2 in the presence of KI. Similarly, dictyopterin
was synthesized in a yield of ca. 4.5% from 5-deoxy-d-xylose phenylhydrazone [4][15].
Ciliapterin was also prepared from biopterin in a yield of ca. 32% [16].
Results and Discussion. – We already described the synthesis of pteridinone 11 [1].
It was obtained in almost quantitative yield by nitroso-ene reaction of the pent-2-
enamide 10 that was obtained in 60 to 65% yield from the known diamino-nitroso-
pyrimidine 9 and (E)-pent-2-enoyl chloride.
The pteridinone 11 was transformed into the triflate (trifluoromethylsulfonate; 12;
57%) by treatment with PhNTf2 and DBU (Scheme 2). Although this triflate was
slowly hydrolysed to 11 upon exposure to H2O and had to be stored under Ar, it could
be isolated by adding H2O to the reaction mixture and collecting the precipitate.
Reduction of the triflate 12 with LiBHEt3 led mostly to an over-reduced product that
was, however, readily aromatized in situ to yield 86% of 13 that is much better soluble
in organic solvents than the pteridinone 11.
Scheme 2
a) (E)-Pent-2-enoyl chloride, K2CO3, ꢀ 188, THF; 63%. b) Suspension in toluene, 11 mm, 1008, then
10% I2, reflux; ca. 98%. c) 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), PhNTf2 (Tf ¼ trifluoromethyl-
sulfonyl), 08, DMF; 57%. d) LiBHEt3, ꢀ 788, THF, then air; 86%.
The direct synthesis of pterins was studied by submitting the more readily available
O-methyl- (rather than O-benzyl-) protected 5-nitroso-4-(pent-2-enylamino) pyrimi-
dine 17 to the conditions of a nitroso-ene reaction. The starting blue-violet nitroso-
pyrimidine 17 was prepared in a yield of 89% by reaction of 2-amino-4,6-dimethoxy-5-
nitrosopyrimidine (16) [17] with the pent-2-enamine (15 [18]; Scheme 3). Heating 17 at
2008 in 1,2,3,5-tetramethylbenzene for 45 min resulted in a ca. 50% transformation of
17, yielding, besides 54% of starting material, 36% of 18 and some decomposition
products. Prolonged heating did not improve the yield, but led to more extensive
decomposition. No improvement resulted from adding Lewis acids or protic acids, or by
using microwaves. The nitroso-ene reaction of 17 required significantly harsher

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conditions than that of the (acylamino)-5-nitrosopyrimidine 10 which reacted
completely within 3 h at 1008.
Scheme 3
a) Ph3P, diisopropyl azodicarboxylate (DIAD), phthalimide, THF; 94% then H2NNH2 · H2O, MeOH;
70%. b) 16, DMSO; 89%. c) 2008, 1,2,3,5-Tetramethylbenzene; 54% of 17, 36% of 18. d) AD-Mix-a,
MeSO2NH2, 0 – 48, tBuOH/H2O; 48%, ee 96%. e) 1n NaOH, dioxane, then AcOH; 93%. f) AD-Mix-b,
t
MeSO2NH2, 0 – 48, BuOH/H2O; 46%, ee 97%. g) 1n NaOH, dioxane, then AcOH; 90%.
The route from the nitrosopyrimidine 9 to pterin 13 (Scheme 2), requiring four
steps, viz., acylation, ene reaction, triflation, and reduction, resulted in a total yield of
30%. It also required preparing the acyl chloride, and rather expensive reagents for
triflation and reduction. The route from the nitroso-pyrimidine 16 to pteridine 18
(Scheme 3) involved two steps, viz., substitution and ene reaction, and resulted in a
total yield of 32%. It also required the synthesis of the allylamine 15 from the allyl
alcohol 14, but no expensive reagents.
Slow concentration of a solution of 17 in 1,1,1,3,3,3-hexafluoropropan-2-ol/THF
1:1 provided crystals suitable for X-ray analysis (Fig. 2). There are two molecules of 17
with a highly disordered pentenyl group, and two molecules of hexafluoropropan-2-ol
in the unit cell. The intramolecular H-bond between C(5)ꢀNO and C(4)ꢀNH is
characterized by a N¼O ··· HꢀN distance of 1.907/1.937 ꢄ, and the intermolecular H-
bond between C(5)ꢀNO and the OH group of hexafluoropropan-2-ol by a N¼O ···
HꢀO distance of 1.711/1.689 ꢄ.
The reactivity of 17 in the nitroso-ene reaction is much lower than that of 10, most
probably due to the stronger donor– acceptor interactions between the amino and NO
groups of 17. The stronger interaction could be reflected in the relative bond lengths,
and the N¼O, CꢀNO, C¼C, and CꢀNH bond lengths of the crystalline (acylamino)-

Helvetica Chimica Acta – Vol. 91 (2008)
2355
Fig. 2. Crystal structure of 17 showing the inter- and intramolecular H-bonds
nitroso-pyrimidines I [19], II [20], and III [1] that are similar to 10 were compared to
those of 17, as listed in the Table2).
Table. Comparison of Bond Lengths of I, II, III, and 17 (in ꢄ)2)
I
II
III
17
N¼O
1.263
1.361
1.437
1.366
0.017
1.275
1.353
1.445
1.368
0.001
1.226 – 1.297
1.352 – 1.371
1.409 – 1.478
1.340 – 1.406
0.095
1.302/1.295
1.352/1.304
1.416/1.511
1.338/1.318
0.020
CꢀNO
C¼C
CꢀNH
D/smax
As shown by the data in the Table, there is a slight, but hardly significant tendency
for an elongation of the N¼O and C¼C bonds, and a shortening of the CꢀNO and
CꢀNH bonds of 17, as compared to those of I, II, and III, resulting from a combination
of the stronger donor– acceptor interaction and the relative strength of the H-bonds, as
determined by the less acidic HꢀN group of 17.
2
)
There are eight molecules in the unit cell of III, and two molecules in the unit cell of 17. The
crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-696734 for II, CCDC-696735 for 17, and CCDC-667942 for 18. Copies of the
data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge
CB21EZ (fax: þ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

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Large amber crystals were obtained by slow evaporation of a solution of 18 in
CH2Cl2/MeOH 1:1. The crystal-structure analysis showed that, in the unit cell, one
molecule of 18 forms two H-bonds with another two molecules between C(2)ꢀNH2
and the ring N(1) and N(3), with N ··· H distances of 2.31 and 2.35 ꢄ, respectively, as
shown in Fig. 3.
Fig. 3. Crystal structure of 18 showing the intermolecular H-bonds
The Sharpless asymmetric dihydroxylation [21] of a C(6)-[(E)-alkenyl]-pteridine
was reported by Guiney et al., but without determining its enantioselectivity [22], and
Torigoe et al. dihydroxylated C(6)- and C(7)-[(E)-alkenyl]-lumazines, but without
assigning the absolute configuration of the product [23].
The pteridine 18 was dihydroxylated with ca. 0.9 mol-% OsO4 and 2 mol-% ligand
at 0 – 48 for 2 d, providing, in the presence of AD-mix-a, the (1S,2S)-diol 19 (48%, ee3)
96%) and, in the presence of AD-mix-b, the (1R,2R)-enantiomer 20 (46%, ee 97%).
The unsatisfactory yields of the diols 19 and 20 are due to their poor solubility in
organic solvents and good solubility in H2O, requiring a diol-phased silica-gel
chromatography [24] for their separation from organic and inorganic impurities. The
imino ethers 19 and 20 were smoothly deprotected by boiling them in 1n NaOH/
dioxane [25] to afford ciliapterin (5; 93%) and dictyopterin (7; 90%), respectively, as
off-white precipitates upon neutralization by AcOH. The structure of the products was
confirmed by NMR spectroscopy and HR-EI mass spectrometry, by elemental analysis,
and by the UV spectra and specific rotation of 5 and 7, all data being in complete
agreement with the published data [4]. The overall yield of ciliapterin (5) from the
nitrosopyrimidine 16 amounts to 14%, and that of dictyopterin to 13%, while the
highest yield of known syntheses (disregarding the preparation of 5-deoxy-l-xylose
phenylhydrazone) is 9% [15].
We thank the ETH Zꢀrich and F. Hoffmann-La Roche AG, Basel, for generous support, Dr. Bruno
Bernet for checking the analytical data, and Dr. W. Bernd Schweizer for the X-ray analysis.
3
)
The ee values were determined by HPLC, as detailed in the Exper. Part.

Helvetica Chimica Acta – Vol. 91 (2008)
2357
Experimental Part
General. See [26]. Flash chromatography (FC): Merck silica gel 60 (0.063 – 0.200 mm). FT-IR
Spectra: neat (ATR), absorption in cmꢀ1. UV Spectra (MeOH): lmax (log e). HR-MALDI-MS: in 3-
hydroxypicolinic acid (3-HPA) matrix.
2-Amino-4-(benzyloxy)-6-[(E)-prop-1-enyl]pteridin-7-yl Trifluoromethanesulfonate (12). Method
A. A suspension of 11 (2.03 g, 6.56 mmol) in DMF (250 ml) was cooled to 08 and treated with DBU
(2.95 ml, 19.68 mmol). The mixture was stirred for 15 min and treated slowly (syringe pump) with a soln.
of PhNTf2 (6.66 g, 18.37 mmol) in DMF (20 ml) over 2 h. The resulting mixture was stirred for 1.5 h at 08
and filtered. Evaporation of the filtrate (308, 0.5 – 1 mbar) yielded a brown solid (7.2 g) that was filtered
through silica gel (elution with CH2Cl2). Evaporation at 308 gave a yellow solid (3.19 g; mixture of 12 and
DBU). Recrystallization in AcOEt (dissolved at 358 and precipitated upon stepwise cooling to 258 and
then ꢀ 208) afforded pure 12 (950 mg, 33%). The yellow residue of the mother liquor (2.02 g) contained
ca. 40% of 12.
Method B. A suspension of 11 (90 mg, 0.29 mmol) in DMF (25 ml) was cooled to 08 and treated with
DBU (48 ml, 0.32 mmol). The mixture was stirred for 1 h, treated with PhNTf2 (127 mg, 0.35 mmol),
stirred for 6 h at 08, and filtered. The filtrate was cooled to 08, H2O (15 ml) was added, and the resulting
bright-yellow precipitation was filtered off and dried to afford pure 12 (77 mg, 57%). M.p. 1758 (dec.). Rf
(CH2Cl2/MeOH 20 :1) 0.63. UV: 251 (4.17), 293 (4.27), 391 (4.09). IR (ATR): 3486m, 3267w, 3200w,
3162w, 3055m, 2964m, 2912m, 2851m, 1631s, 1599s, 1519s, 1467s, 1430m, 1407s, 1396s, 1364s, 1343s, 1322m,
1309s, 1277s, 1262s, 1247s, 1198w, 1143m, 1125m, 1082m, 1070m, 975m, 940m, 911m, 897m, 841w, 822m,
1
809m. H-NMR (300 MHz, (D6)DMSO): 7.91 (br. s, NH2); 7.50 – 7.53 (m, 2 arom. H); 7.36 – 7.44 (m, 3
arom. H); 6.95 (dq, J ¼ 15.7, 6.9, HꢀC(2’)); 6.64 (dq, J ¼ 15.7, 1.7, HꢀC(1’)); 5.49 (s, PhCH2); 1.87 (dd,
J ¼ 6.9, 1.7, Me). 13C-NMR (100 MHz, (D6)DMSO): serious decomposition during measurement. 19F-
NMR (282 MHz, (D6)DMSO): ꢀ 71.69 (s, CF3). HR-MALDI-MS: 442.0784 (100, [M þ H]þ,
C17H15F3N5O4Sþ; calc. 442.0791), 464.0615 (10, [M þ Na]þ, C17H14F3N5NaO4Sþ; calc. 464.0611).
4-(Benzyloxy)-6-[(E)-prop-1-enyl]pteridin-2-amine (13). A soln. of 12 (662 mg, 1.5 mmol) in THF
(60 ml) was cooled to ꢀ 788, treated dropwise with 1.0m LiEt3BH (3.2 ml, 3.2 mmol) over a period of 1 h,
and stirred for 0.5 h. Air was slowly bubbled through the soln. during warming to r.t. within 3 h. The
mixture was diluted with H2O (100 ml) and extracted with CH2Cl2 (150 ml ꢁ 2). The combined org. layers
were washed with sat. NH4Cl (50 ml), dried (Na2SO4), and evaporated. FC (CH2Cl2/MeOH 100 :1 !
50 :1) gave 13 (380 mg, 86%). M.p. 1728 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.49. UV: 206 (4.25), 244
(4.20), 290 (4.27), 387 (3.98). IR (ATR): 3431w, 3325w, 3224w, 3132w, 2960w, 2847w, 1653s, 1627s, 1593m,
1564m, 1516m, 1430w, 1373m, 1353s, 1317s, 1299m, 1284m, 1273m, 1259m, 1234s, 1208s, 1195m, 1165s,
1
1121m, 1097w, 1073m, 1028m, 968w, 942w, 898m, 851m, 827s, 804m. H-NMR (300 MHz, (D6)DMSO):
8.98 (s, HꢀC(7)); 7.54 – 7.59 (m, 2 arom. H); 7.37 – 7.45 (m, 3 arom. H); 7.20 (br. s, NH2); 6.79 (dq, J ¼
16.0, 6.6, HꢀC(2’)); 6.58 (dq, J ¼ 16.0, 1.6, HꢀC(1’)); 5.75 (s, PhCH2); 1.90 (dd, J ¼ 6.6, 1.6, Me).
13C-NMR (75 MHz, (D6)DMSO, assignment based on a HMBC spectrum): 166.32 (s, C(4)); 160.92 (s,
C(2)); 156.00 (s, C(8a)); 149.29 (d, C(7)); 145.69 (s, C(6)); 135.89 (s); 132.04 (d, C(2’)); 128.72 (2d);
128.43 (2d); 128.23 (d); 128.23 (d, C(1’)); 121.68 (s, C(4a)); 68.25 (t, PhCH2); 18.32 (q, C(3’)). HR-
MALDI-MS: 294.1346 (100, [M þ H]þ, C16H16N5Oþ; calc. 294.1349), 316.1172 (4, [M þ Na]þ,
C16H15N5NaOþ; calc. 316.1169).
(E)-Pent-2-enamine (15). A soln. of 14 (2.29 ml, 22.5 mmol), phthalimide (4.3 g, 29 mmol), and
Ph3P (7.65 g, 29.0 mmol) in THF (200 ml) was dropwise treated with DIAD (5.75 ml, 29.25 mmol) in the
dark at r.t., and stirred for 4 h. The mixture was concentrated to ca. 50 ml, diluted with H2O (400 ml), and
extracted with cyclohexane (3 ꢁ 300 ml). The combined org. layers were washed with brine, dried
(MgSO4), and filtered. The filtrate was evaporated (Ph3PO was filtered off after concentrating the soln.).
FC (cyclohexane/AcOEt 100 :1) provided N-(pent-2-enyl)phthalimide (4.55 g, 94%) as a white solid.
A soln. of N-(pent-2-enyl)phthalimide (5.0 g, 23.2 mmol) in MeOH (100 ml) was treated with
NH2NH2 · H2O (1.4 ml, 27.8 mmol) and stirred at r.t. for 12 h. After the addition of 37.5% HCl (5 ml) and
H2O (100 ml), the mixture was stirred for 12 h. The precipitate was filtered off, and the filtrate was
diluted with an equal amount of H2O, acidified (pH < 2), and washed with Et2O. The aq. layer was
basified with solid KOH (pH > 10) and extracted with Et2O (4 ꢁ 200 ml). The combined Et2O layers

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Helvetica Chimica Acta – Vol. 91 (2008)
were washed with brine, dried (MgSO4), and concentrated to a 22% soln. of 15 in Et2O (6.2 g;
1
1
corresponding to 70% 15; concentration determined by H-NMR). H-NMR (300 MHz, CDCl3): 5.62
(dt, J ¼ 15.6, 5.4, HꢀC(3)); 5.53 (dt, J ¼ 15.6, 5.4, HꢀC(2)); 5.30 (br. s, NH2); 3.26 (d, J ¼ 5.1, 2 HꢀC(1));
2.03 (quint., J ꢂ 7.2, 2 HꢀC(4)); 0.98 (td, J ¼ 7.5, 2.4, Me). 13C-NMR (75 MHz, CDCl3): 133.24, 129.43
(2d, CH¼CH); 44.03 (t, C(1)); 25.46 (t, C(4)); 13.77 (q, Me).
6-Methoxy-5-nitroso-4-[(E)-(pent-2-enylamino]pyrimidin-2-amine (17). A soln. of 16 (968 mg,
5.25 mmol) in DMSO (12 ml) was treated slowly (syringe pump) over 20 h with a 22% soln. of 15 in Et2O
(1.9 g, 5.52 mmol). The mixture was cooled to 08 and treated with H2O (25 ml). The resulting violet
precipitate was filtered off, dissolved in CH2Cl2 (200 ml), and washed with H2O (2 ꢁ 50 ml). Evaporation
gave 17 (1.11 g, 89%). M.p. 121 – 1238. Rf (CH2Cl2/MeOH 20 :1) 0.43. UV: 203 (4.54), 236 (4.13), 330
(4.35). IR (ATR): 3482w, 3316m, 3108m, 2961m, 2933w, 2873w, 1670m, 1649m, 1565s, 1527s, 1448s,
1398m, 1379s, 1352s, 1331s, 1299s, 1207s, 1188m, 1150s, 1079s, 1055s, 993m, 970m, 886w, 835w. 1H-NMR
(300 MHz, (D6)DMSO): 11.33 (t, J ¼ 5.4, HNꢀC(4)); 8.02 (br. s, NH2); 5.64 (dt, J ¼ 15.3, 6.0, HꢀC(3’));
5.49 (dt, J ¼ 15.3, 5.4, HꢀC(2’)); 4.04 (s, MeO); 3.97 (t, J ¼ 5.4, 2 HꢀC(1’)); 2.01 (quint., J ꢂ 7.5,
2 HꢀC(4’)); 0.93 (t, J ¼ 7.5, Me). 13C-NMR (75 MHz, (D6)DMSO): 170.84, 163.21, 150.05, 138.43 (4s,
4 C of pyrimidine); 134.14, 124.04 (2d, CH¼CH); 54.09 (q, MeO); 40.43 (t, C(1’)); 24.48 (t, C(4’)); 13.09
(q, Me). HR-EI-MS: 237.1221 (30, Mþ, C10H15N5O2þ ; calc. 237.1220).
X-Ray Analysis of 17. Slow evaporation of a soln. of 17 in (CF3)2CHOH/THF 1:1 gave suitable
crystals. Dimensions: cube 0.4 ꢁ 0.16 ꢁ 0.08 mm; color: amber. C10H15N5O2 · C3H2F6O, Mr 405.299,
monoclinic P21/c, a ¼ 33.183 (2), b ¼ 14.6867 (6), c ¼ 7.3473 (3) ꢄ, a ¼ 90.008, b ¼ 91.7848 (14)8, g ¼
90.008, V¼ 3579.0 (3) ꢄ3, Z ¼ 8, Dx ¼ 1.504 Mg/m3, F(000) ¼ 1664.0, fine-focus sealed tube. Intensities
were measured on a Nonius Kappa CCD diffractometer, with MoKa radiation l ¼ 0.71073 ꢄ, Cell
parameters from 32263 refl. q ¼ 2.425 – 27.485 8, m ¼ 0.149 mmꢀ1, T¼ 223 K, 13221 measured reflections,
6841 independent reflections, 2598 observed reflections. Refinement on F2: full-matrix least-squares
refinement, R(all) ¼ 0.2417, R(gt) ¼ 0.1212. D/smax ¼ 0.020. Heavily disordered pentenyl groups. Some
constraints on bond lengths. All calculations were performed using maXus (Bruker Nonius, Delft &
MacScience, Japan). Programme used to solve structure: SIR97. Programme used to refine structure:
SHELXL-97.
(E)-4-Methoxy-6-(prop-1-enyl)pteridin-2-amine (18). A stirred suspension of 17 (1 g, 4.21 mmol) in
1,2,3,5-tetramethylbenzene (200 ml) was kept in an oil bath at 2008 for 45 min. The mixture was passed
through a column with dry silica gel (100 g), and 1,2,3,5-tetramethylbenzene was recovered by washing
the column first with cyclohexane, then eluting with CH2Cl2/MeOH (100 :1 ! 50 :1) to give 17 (540 mg,
54%) and 18 (278 mg, 36% based on starting material, 66% based on recovered starting material).
Yellow powder. M.p. > 1708 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.50. UV: 201 (4.22), 242 (4.27), 289
(4.30), 387 (3.95). IR (ATR): 3367m, 3330m, 3153m, 2966w, 1654s, 1582s, 1567s, 1517s, 1481m, 1427s,
1403s, 1356s, 1308m, 1274m, 1232m, 1201m, 1167s, 1134m, 1097s, 1050m, 991w, 958s, 923w, 875w, 826m.
1H-NMR (300 MHz, (D6)DMSO): 8.95 (s, HꢀC(7)); 7.25 (br. s, NH2); 6.83 (dq, J ¼ 16.0, 6.9, HꢀC(2’));
6.60 (dq, J ¼ 16.0, 1.5, HꢀC(1’)); 4.05 (s, MeO); 1.93 (dd, J ¼ 6.9, 1.5, Me). 13C-NMR (75 MHz,
(D6)DMSO; assignment based on a HMBC spectrum): 166.73 (s, C(4)); 160.80 (s, C(2)); 155.60 (s,
C(8a)); 149.13 (d, C(7)); 145.37 (s, C(6)); 131.81 (d, C(2’)); 127.96 (d, C(1’)); 121.59 (s, C(4a)); 54.34 (q,
MeO); 18.43 (q, C(3’)). HR-EI-MS: 216.0881 (100, [M ꢀ H]þ, C10H10N5Oþ; calc. 216.0880). Anal. calc.
for C10H11N5O · 0.25 CH3OH (225.24): C 54.66, H 5.37, N 31.09; found: C 54.68, H 5.16, N 30.53.
X-Ray Analysis of 18. Slow evaporation of a soln. of 18 in CH2Cl2/MeOH 1:1 gave suitable crystals.
Dimensions: cube 0.5 ꢁ 0.4 ꢁ 0.3 mm; color: yellow. C10H11N5O, Mr 217.232, monoclinic P2/c, a ¼ 9.8207
(2), b ¼ 7.2210 (2), c ¼ 14.9754 (4) ꢄ, a ¼ 90.008, b ¼ 105.5742 (11)8, g ¼ 90.008, V¼ 1022.99 (4) ꢄ3, Z ¼ 4,
Dx ¼ 1.410 Mg/m3, F(000) ¼ 456.0, fine-focus sealed tube. Intensities were measured on a Nonius Kappa
CCD diffractometer, with MoKa radiation l ¼ 0.71073 ꢄ, Cell parameters from 6979 refl. q ¼ 2.167 –
27.4858, m ¼ 0.099 mmꢀ1, T¼ 243 K, 4399 measured reflections, 2322 independent reflections, 2064
observed reflections. Refinement on F2: full-matrix least-squares refinement, R(all) ¼ 0.0489, R(gt) ¼
0.0446. All calculations were performed using maXus (Bruker Nonius, Delft & MacScience, Japan).
Programme used to solve structure: SIR97. Programme used to refine structure: SHELXL-97.
(1S,2S)-1-(2-Amino-4-methoxypteridin-6-yl)propane-1,2-diol (19). A soln. of AD-mix-a (18.37 g) in
t-BuOH (50 ml) and H2O (50 ml) was stirred at r.t. for 5 min, treated with MeSO2NH2 (500 mg,

Helvetica Chimica Acta – Vol. 91 (2008)
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5.25 mmol), stirred for 5 min, and cooled to 08, whereupon 18 (1.14 g, 5.25 mmol) was added at once. The
heterogeneous slurry was stirred vigorously at 48 for 2 d, treated with solid sodium sulfite (20 g), and
stirred at r.t. for 60 min. After evaporation of the solvent, the residue was thoroughly washed with MeOH
(3 ꢁ 100 ml). The combined MeOH extract was evaporated. FC (diol-phased silica gel, CH2Cl2/MeOH
50 :1 ! 10 :1) gave 19 (634 mg, 48%). Off-white powder. [a]2D5 ¼ þ83.2 (c ¼ 0.5, H2O). M.p. 219 – 2228
(dec.). Rf (CH2Cl2/MeOH 10 :1) 0.20. Rf (CH2Cl2/MeOH 20 :1; diol-phased TLC) 0.36. ee 96% (Anal.
HPLC-Chiral AD – H; 1.0 ml/min, UV, 254 nm; hexane/i-PrOH 85 :15; tR ¼ 33.45 min). UV: 202 (4.39),
236 (4.43), 265 (4.07), 365 (3.84). IR (ATR): 3391m, 3316m, 3199m, 2968w, 2916w, 1660m, 1644m, 1605s,
1566m, 1525s, 1479m, 1437s, 1414m, 1363s, 1313s, 1277m, 1255m, 1183s, 1130s, 1094m, 1075m, 1062m,
1
1041m, 1012m, 986m, 941w, 917w, 881w, 862w, 833m, 823w. H-NMR (300 MHz, (D6)DMSO): 8.86 (s,
HꢀC(7)); 7.22 (br. s, NH2); 5.56 (d, J ¼ 5.4, HOꢀC(1)); 4.62 (d, J ¼ 5.7, HOꢀC(2)); 4.47 (t, J ꢂ 4.8,
HꢀC(1)); 4.05 (s, MeO); 3.92 – 3.81 (m, HꢀC(2)); 1.06 (d, J ¼ 6.3, Me). 13C-NMR (75 MHz,
(D6)DMSO): 166.96 (s, C(4’)); 161.23 (s, C(2’)); 156.28 (s, C(8’a)); 152.34 (s, C(6’)); 150.17 (d, C(7’));
120.93 (s, C(4’a)); 76.62 (d, C(1)); 69.19 (d, C(2)); 54.29 (q, MeO); 19.40 (q, Me). HR-ESI-MS: 274.0910
(10, [M þ Na]þ, C10H13N5NaO3þ ; calc. 274.0911). Anal. calc. for C10H13N5O3 · 0.25 MeOH (259.25): C
47.49, H 5.44, N 27.01; found: C 47.65, H 5.32, N 26.85.
2-Amino-6-[(1S,2S)-1,2-dihydroxypropyl]pteridin-4(3H)-one (5) [4]. A suspension of 19 (50 mg,
0.2 mmol) in dioxane (1.2 ml) was treated with 1n NaOH (6 ml) and heated at 1008 for 20 min, leading to
a dissolution. The mixture was cooled to 708, treated with AcOH (1 ml), stirred for 5 min, and cooled to
08. The resulting off-white precipitate was filtered off, providing off-white solid 5 (44 mg, 93%). [a]D25
¼
þ99.7 (c ¼ 0.22, 0.1n HCl); [4]: þ 95 (c ¼ 0.2, 0.1n HCl). M.p. > 2708 (dec.). UV (H2O): 221 (3.88), 275
(4.14), 345 (3.74). IR (ATR): 3243m (br.), 3061m, 2794m, 2718m, 1722m, 1673s, 1641s, 1581m, 1537s,
1514m, 1488m, 1415m, 1360m, 1299m, 1279m, 1248m, 1175m, 1126s, 1065m, 1045m, 1001m, 973w, 957w,
924w, 881m, 867m, 846w, 822m. 1H-NMR (300 MHz, (D6)DMSO): 11.56 (br. s, NH); 8.70 (s, HꢀC(7));
6.90 (br. s, NH2); 5.49 (d, J ¼ 5.4, HOꢀC(1’)); 4.59 (d, J ¼ 5.4, HOꢀC(2’)); 4.44 (t, J ꢂ 4.5, HꢀC(1’));
3.90 – 3.80 (m, HꢀC(2’)); 1.05 (d, J ¼ 6.0, Me). 13C-NMR (125 MHz, (D6)DMSO): 161.17 (s, C(4));
156.05 (br. s, C(2)); 153.67 (s, C(8a)); 151.72 (s, C(6)); 148.35 (d, C(7)); 127.03 (s, C(4a)); 76.31 (d, C(1’));
69.09 (d, C(2’)); 19.22 (q, Me). HR-ESI-MS: 238.0936 (15, [M þ H]þ, C9H12N5O3þ ; calc. 238.0935);
229.1410 (100). Anal. calc. for C9H11N5O3 · 0.25 H2O (241.72): C 44.72, H 4.80, N 28.97; found: C 44.95, H
4.82, N 28.60.
(1R,2R)-1-(2-Amino-4-methoxypteridin-6-yl)propane-1,2-diol (20). Prepared, similarly to 19, from
18 (114 mg), with AD-mix-b. Yield: 61 mg (46%). Off-white powder. [a]2D5 ¼ ꢀ86.4 (c ¼ 0.5, H2O). ee
97% (Anal. HPLC-Chiral AD – H; 1.0 ml/min; UV, 254 nm, hexane/i-PrOH 85 :15, tR ¼ 25.85 min). IR
and NMR spectra identical to those of 19.
2-Amino-6-[(1R,2R)-1,2-dihydroxypropyl]pteridin-4(3H)-one (7) [4]. Prepared, similarly to 5, from
20 (50 mg). Yield: 42 mg (90%). Off-white to light-brown powder. [a]2D5 ¼ ꢀ101.6 (c ¼ 0.22, 0.1n HCl);
[4]: ꢀ 94 (c ¼ 0.2, 0.1n HCl). IR and NMR spectra identical to those of 5.
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Received August 7, 2008