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Keywords:

  • pteridine;
  • pterin glycoside;
  • biopterin;
  • ciliapterin;
  • neopterin;
  • limipterin;
  • tepidopterin;
  • asperopterin-A;
  • protecting group;
  • glycosylation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Certain pterins having a hydroxyalkyl side chain at C-6 have been found as glycosidic forms in certain prokaryotes, such as 2′-O-(α-D-glucopyranosyl)biopterin from various kinds of cyanobacteria, and limipterin from a green sulfur photosynthetic bacterium. Synthetic studies on glycosides of biopterin and related pterins have been made in view of the structural proof as well as for closer examination of their biological activities and functions. The syntheses of these natural pterin glycosides have effectively been achieved, mostly through appropriately protected N2-(N,N-dimethylaminomethylene)-3-[2-(4-nitrophenyl)ethyl]pterin derivatives as glycosyl acceptors, and are reviewed here. © 2013 IUBMB Life 65(4):300–309, 2013.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Various pterin [2-aminopteridin-4(3H)-one] derivatives are biosynthesized from guanosine triphosphate in biological systems and have been isolated from many living organisms. Along with folic acid, biopterin (1a) can be regarded as one of the most important naturally occurring pterins, because its tetrahydro derivative of 1a plays a central role as crucial cofactor in oxidative hydroxylation of aromatic amino acids (1–3) and of 1-glyceryl ethers (4), and nitric oxide synthesis (5–7). Biopterin was isolated for the first time from human urine in 1955 (8) and later found in many living organisms including microorganisms (9), insects (10), crustaceans (11), fish (12), and amphibians (13).

Meanwhile, some glycosides of biopterin having a sugar attached to the side chain at C-6 of the pteridine ring have been found in nature (Fig. 1). For example, 2′-O-(α-D-glucopyranosyl)biopterin (1b) and its β-D-ribofuranosyl analog (1c) were isolated from cyanobacteria (14–18), whereas 2′-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)biopterin (limipterin) (1d) was obtained from a green sulfur photosynthetic bacterium (19). Similar congeners of other pterins having a hydroxyalkyl side chain at C-6, such as ciliapterin (2a), neopterin (3a), 6-hydroxymethylpterin (4a), and 6-(pentahydroxypentyl)pterin (5a), have also been obtained in certain prokaryotes (20–28). These natural pterin glycosides (1b–d, 2b–e, 3b,c, 4b,c, 5b, 6b) are listed in Table 1 together with their source. The anomeric structures of the side chain sugars and the positions of the pterin moiety, where the sugar is attached, still remains unsettled for some glycosides in this list. Distribution of these pterin glycosides seems to be restricted to a few classes of prokaryotes such as cyanobacteria, anaerobic photosynthetic bacteria, and chemoautotrophic archaebacteria. Above all, cyanobacteria contain relatively high levels of the pterin glycosides and contribute much to photosynthesis in aquatic ecosystems. The structures of pterin glycosides reveal some variations in their pterin and glycosyl moieties and also in the position and the anomeric structure of glycosidic linkage. Asperopterin-A (6b) isolated from Aspergillus oryzae (28) is a unique glycoside of compound 6a having an isoxanthopterin (7-xanthopterin) structure as a parent ring.

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Figure 1. Naturally occurring pterin glycosides.

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Table 1. Naturally occurring pterin glycosides and their source
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Biopterin α-D-glucoside (1b), the most noteworthy one among these pterin glycosides, has been found in various kinds of cyanobacteria, namely Anacystis nidulans (14), Oscillatoria sp. (15), Spirulina platensis (16), and Synechococcus sp. (17) since its first discovery in 1958. Although some inhibitory activities against tyrosinase (29) and photostabilization of photosynthetic pigments (17, 30) were reported for 1b, no systematic approach to investigate the physiological functions of pterin glycosides has been made so far. Attempts at preparation of pterin glycosides, however, have been made in recent years in view of structural proof of these reported natural products as well as their biological activities and functions. This review summarizes mainly synthetic explorations of various types of glycosides of biopterin and related pterins.

Synthesis of Limipterin (1d)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Because of the efficiently stabilized intramolecular hydrogen bondings in the solid state (31), many pterin derivatives including biopterin (1a) are scarcely soluble in nonpolar aprotic solvents such as dichloromethane in which glycosylation reactions proceed smoothly. This problem has been effectively overcome by introducing an N,N-dimethylaminomethylene group for protection of the 2-amino group, 2-(4-nitrophenyl)ethyl (NPE) group for N(3) of the pteridine ring and a trimethylsilyl group for hydroxy groups of the side chain as shown in the five-step conversion of the starting material 1a into the suitably protected and sufficiently solubilized derivative (7) in 87% overall yield (18, 32, 33) (Scheme 1). Then, glycosylation of 7 with 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide (8) (34) in the presence of tin(IV) chloride has resulted in the formation of a mixture of 2′-O-(β-D-glucopyranosyl) 9a (41% yield), 1′-O-glycosyl isomer 9b (15% yield), and the 1′,2′-di-O-glycoside 9c (14% yield) (33).

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Scheme 1. A synthetic approach to biopterin D-glucosides.

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A marked improvement has been made to establish an efficient synthetic protocol to achieve completely regioselective 2′-O-glycosylation using a suitably 1′-O-protected (with p-methoxybenzyl (PMB)) biopterin derivative (10) as a key glycosyl acceptor (35, 36) (Scheme 2a). From a retrosynthetic analysis outlined in Scheme 2a compound 10 was thought best to be prepared by the condensation of 2,5,6-triamino-4-hydroxypyrimidine (11) with 3-O-protected L-erythro-pentos-2-ulose (12), which in turn would be derived from D-xylose via 3-O-protected 5-deoxy-L-arabinose 13 involving C-4 inversion and then C-5 deoxygenation. This has been achieved as follows.

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Scheme 2. Retrosynthetic analyses of the biopterin derivative 10 (a) and the ciliapterin derivative 21 (b).

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The successful nine-step synthetic sequence for the 5-deoxy-L-erythro-pentos-2-ulose (12) from D-xylose is shown in Scheme 3. The 5-deoxy-4-enofuranose derivative (14), prepared from D-xylose in four steps (37) was stereoselectively hydrogenated, followed by introduction of the PMB group to give the 5-deoxy-L-arabinose derivative (15), which was then converted into 13. Selective oxidation of the 2-hydroxy group of 13 with cupric acetate provided the 3-O-PMB-L-erythro- pentos-2-ulose (12) (36).

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Scheme 3. Preparation of the glycosyl acceptor (10) from D-xylose.

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Condensation of 12 with the sulfate of 11 in an aqueous sodium bicarbonate solution afforded a 78:22 mixture of the 6-substituted (biopterin) derivative 16a and its 7-substituted (primapterin) isomer 16b. Successive treatment of the mixture with N,N-dimethylformamide dimethyl acetal in dimethylformamide (DMF), with acetic anhydride in pyridine, and then with NPE alcohol in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD), yielded the fully protected derivatives 17a,b, which were then separated by column chromatography into the desired biopterin derivative 17a (53% overall yield from 12) and the primapterin derivative 17b (15% yield). Methanolysis of 17a in the presence of sodium methoxide provided the 1′-O-PMB derivative 10 quantitatively, an ideal precursor for 2′-O-monoglycosylation.

An efficient glycosylation is shown in Scheme 4 for the condensation of 10 with tetra-O-benzoyl-α-D-glucopyranosyl bromide (8) in the presence of silver triflate and tetramethylurea (TMU) in dichloromethane, affording the 2′-O-β-D-glucopyranosyl derivative 18 as sole product in 75% yield. Removal of the protecting groups of 18 was carried out by the successive treatment with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (to cleave the PMB group), sodium methoxide (to cleave the benzoyl groups), aqueous ammonia (to cleave the N,N-dimethylaminomethylene group), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (to cleave the NPE group) to give 2′-O-(β-D-glucopyranosyl)biopterin (1e), the anomeric isomer of natural pterin glycoside 1b (34, 35).

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Scheme 4. Preparation of biopterin β-D-glucoside (1e) and limipterin (1d).

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Similarly, glycosylation of 10 with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl bromide (19) (38) provided the 2′-O-glucopyranosyl derivative (20) in 82% yield. After treatment of 20 with DDQ, removal of the phthaloyl group and N,N-dimethylaminomethylene group with methylamine, followed by the action of acetic anhydride, afforded the fully acetylated derivative, which was then treated with aqueous ammonia and then with DBU to give limipterin (1d) in 74% (overall yield from 20) (35, 36).

Synthesis of Tepidopterin (2e)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Based on the successful strategy for the regioselective synthesis of biopterin 2′-O-glycosides (1b,d) using the 1′-O-protected precursor (10) in Scheme 4, preparation of 2′-O-glycosides of ciliapterin (2a) has also been accomplished (36). Tepidopterin (2e) is the 2′-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl) derivative of ciliapterin (2a), corresponding to the 1′-epimer of limipterin (1d). Similar to the retrosynthesis of the 1′-O-PMB-biopterin precursor (10) demonstrated in Scheme 2a, the 1′-O-PMB-ciliapterin derivative (21), a versatile precursor for 2e, was expected to become available by condensation of the pyrimidine derivative (11) with 3′-O-PMB-L-threo-pentos-2-ulose (22) derived from L-xylose via 5-deoxy-3-O-PMB-L-xylose (23) as shown in Scheme 2b. This was achieved as follows.

5-O-Tosyl-1,2-O-isopropylidene-α-L-xylofuranose (24) readily prepared from L-xylose was efficiently converted into 5-deoxy-1,2-O-isopropylidene-3-O-PMB-α-L-lyxose (25) on hydride reduction and then p-methoxybenzylation (Scheme 5). Acetal cleavage of 25 to afford 23, followed by oxidation with cupric acetate, yielded the pentos-2-ulose 22.

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Scheme 5. Synthetic route to tepidopterin (2e).

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The condensation of 22 with the sulfate of 11 in an aqueous sodium bicarbonate solution gave a 75:25 mixture of the 6-substituted pterin (ciliapterin) derivative (26a) and its 7-substituted isomer (26b). These products were, as in the cases of 17a,b from 16a,b (Scheme 3), converted into the chromatographically separable 2′-O-acetyl-N2-(N,N-dimethylaminomethylene)-3-NPE-1′-O-PMB derivative (27a) (52% overall yield from 22) and the 7-substituted derivative (27b) (17% yield).

Methanolysis of 27a with sodium methoxide provided the 1′-O-PMB derivative (21), a versatile precursor for the 2′-O-monoglycosylation. Efficient glycosylation of 21 was attained with 2-deoxy-2-phthalimido-D-glucopyranosyl bromide (19) in the presence of silver triflate and TMU, affording the 2′-O-(β-D-glucopyranosyl)ciliapterin derivative (28). Successive removal of the protecting groups of 28 (using the same procedures described for 1d from 20 in Scheme 4) has enabled the first synthesis of tepidopterin (2e) (36). Similarly, 2′-O-(α-D-mannopyranosyl)ciliapterin (2c) has been prepared from the 1′-O-PMB-ciliapterin derivative (21) (39).

Synthesis of Biopterin α-D-Glucoside (1b)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

These successive syntheses of the 2′-O-β-glucosides (1d, 1e, and 2e) of biopterin and ciliapterin have led to execute the preparation of biopterin 2′-O-α-glucoside (1b). The stereoselective synthesis of the β-glycosides (1d, 1e, 2e) from 10 and 21 is apparently caused by participation of the 2-O-benzoyl and 2-N-phthaloyl groups of the glycosyl donors (8, 19) through the formation of an acyloxonium ion intermediate (40). Accordingly, to avoid such neighboring group participation in the synthesis of the α-D-glucopyranoside (1b), the PMB group has been chosen for the protection of 2-OH of the glycosyl donor. Then, methyl penta-O-acetyl-1-thio-β-D-glucopyranoside (29) serves as the starting material for the preparation of 4,6-di-O-acetyl-2,3-di-O-PMB-α-D-glucopyranosyl bromide (32), the novel potential glycosyl donor for pterin α-glycosides (Scheme 6). Indeed methanolysis of 29 and subsequent acetalization and p-methoxybenzylation afforded the 2,3-di-O-PMB derivative (30). Hydrolysis of 30, followed by acetylation, provided the 4,6-di-O-acetyl derivative (31), which was converted into the glycosyl bromide (32) by the action of bromine (41).

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Scheme 6. Synthetic route to biopterin α-D-glucoside (1b).

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Glycosylation of 10 with 4.0 molecular equivalents of 32 in dichloromethane in the presence of silver triflate (2.0 mol equiv.) and TMU (1.0 mol equiv) afforded an inseparable anomeric mixture (85:15) of the 2′-O-(α-D-glucopyranosyl)biopterin derivative (33a) and its β-anomer (33b) in 66% yield, along with some recovery of 10 (24%). Removal of PMB groups from these isomers with DDQ and the subsequent acetylation and chromatographic separation afforded the desired 34a in 51% (total yield from 10) and its β-anomer (34b) in 9% yield. The α-anomeric structure of 34a was deduced from its J1,2 value (3.9 Hz) in the proton-nuclear magnetic resonance (1H NMR) spectra, while the larger J1,2 value (8.1 Hz) confirmed the β-form of 34b. Removal of the protecting groups of 34a by the usual procedures has led to the first synthesis of 2′-O-(α-D-glucopyranosyl)biopterin (1b) (41).

Synthesis of Neopterin β-D-Glucuronide (3b)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Subsequent to the syntheses of biopterin and ciliapterin glycosides, the preparation of 3′-O-(β-D-glucopyranosyluronic acid)neopterin (3b) was attempted as the first synthetic example of a natural neopterin glycoside (42). The glycosyl donor (36) was prepared from D-glucofuranurono-6,3-lactone via the methyl D-glucopyranosyluronate derivative (35) in three steps (43) (Scheme 7), while the glycosyl acceptor (39), whose pyrimidine moiety and 1′,2′-hydroxy groups of the side chain were protected, was made from neopterin (3a) (available from D-arabinose and 11).

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Scheme 7. Synthetic route to neopterin β-D-glucuronide (3b).

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Treatment of 3a with N,N-dimethylformamide dimethyl acetal in DMF, followed by the selective 3′-O-protection with tert-butyldimethylsilyl (TBS) group and then 1′,2′-di-O-acetylation afforded the N2-(N,N-dimethylaminomethylene)neopterin derivative (37), whose N-3 position was then protected with the NPE group by a Mitsunobu reaction, to provide 38. Although deprotection of the 3′-O-TBS group of 38 with tetrabutylammonium fluoride resulted in the formation of a mixture of 1′,3′-di-O- and 2′,3′-di-O-acetates instead of the desired 1′,2′-di-O-acetate (39), the cleavage of 3′-O-TBS group of 38 under acidic conditions (60% acetic acid) provided predominantly the desired 39 (84% yield).

Treatment of 39 with the methyl D-glucopyranosyluronate bromide (36) in the presence of silver triflate and TMU afforded 3′-O-(β-D-glucopyranosyluronate)neopterin derivative (40) in 64% yield, along with the recovery of 39 (26%). Selective cleavage of methyl ester of the neopterin glycoside (40) by lithium iodide in pyridine, followed by deacetylation with sodium methoxide, afforded the β-D-glucopyranosiduronic acid derivative (41). Treatment of 41 with aqueous ammonia–methanol and then with DBU, followed by acidification using an ion-exchange resin, has provided the target compound 3′-O-(β-D-glucopyranosyluronic acid)neopterin (3b).

Syntheses of Asperopterin-A (6b)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

Synthetic methodology for pterin glycosides described above has also been applied to preparation of asperopterin-A (6b) known as the sole example of a natural isoxanthopterin glycoside (44). As for the early work for preparation of asperopterin-B (6a), the aglycone of asperopterin-A (6b), two synthetic pathways starting with 2,5-diamino-6-methylamino-3H-pyrimidin-4-one (42) have been reported (Scheme 8). One is the condensation of the hydrochloride of 42 with ethyl glyoxalate and the subsequent hydoxymethylation of the resulting 9-methylisoxanthopterin (43) with methanol and ammonium peroxydisulfate (45, 46), and another is the condensation of 42 with methyl pyruvate and the subsequent bromination and hydroxylation of the resulting 6,8-dimethylisoxanthopterin (44) (45, 47).

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Scheme 8. Preparation of asperopterin-B (6a).

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A novel alternative way to prepare 6a and its derivatives in better overall yield has been attained by direct condensation of 42 with the 2-oxopropinonate derivative (46) (Scheme 9).

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Scheme 9. Synthetic route to asperopterin-A (6b).

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Ethyl 3-(tert-butyldimethylsilyloxy)-2-oxopropionate (46) was prepared from ethyl acrylate in three steps via 45. The pteridine ring formation of the pyrimidine derivative (42) with 46 and the following introduction of N,N-dimethylaminomethylene group afforded the isoxanthopterin derivative (47) in 48% overall yield. Protection of 47 with NPE group and the subsequent removal of TBS group provided 6-hydroxymethyl compound (48), which was then temporarily silylated to afford the trimethylsilyl derivative (49).

Glycosylation of 49 with 2.0 mol equiv of the glycosyl donor 50 in the presence of boron trifluoride etherate in chloroform did not proceed due to precipitation of desilylated 48, whereas the similar treatment of 49 with 50 in the presence of tin(IV) chloride (2.0 mol equiv) afforded the β-D-ribofuranosyl derivative (51) in 43% yield, along with some recovery of 48 (45%). The successive three-step deprotection of 51 according to well established procedures has led to the first synthesis of the natural isoxanthopterin glycoside asperopterin-A (6b), although yields of the ring formation, protection, and glycosylation of isoxanthopterin derivatives have remained relatively low when compared with those of other pterin derivatives such as 1b, d, and 2e.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References

The synthetic strategy using N2-(N,N-dimethylaminomethylene)-3-NPE-protected pterin derivatives demonstrates a useful method applicable to the preparation of natural pterin glycosides having various pterin and sugar moieties. Using the key glycosyl acceptor 1′-O-PMB-biopterin and ciliapterin derivatives (10, 21), a novel, effective way for selective preparation of both pterin 2′-O-β- and 2′-O-α-glycosides has been developed, as exemplified by the first synthesis of biopterin α-D-glucoside (1b) (from 10 with the novel glycosyl donor 32) and limipterin (1d) (from 10 with the glycosyl donor 19). Besides biopterin glycosides, these synthetic methodologies have been applied to glycoside syntheses of other pterins such as ciliapterin (2a), neopterin (3a), 6-hydroxymethylpterin (4a) (48), and 6-hydroxymethylisoxanthopterin (6a). The NMR data of the synthetic pterin glycosides have proved to be essentially identical with those reported for the natural products, thus validating their proposed structures. However, as noted in the introduction, detailed studies of biological activities and functions of a series of natural pterin glycosides using these synthesized specimens will need to be performed systematically. Their reduced derivatives, tetrahydrobiopterin glycosides, (49,50) that can effectively deliver the important pterin cofactor (tetrahydrobiopterin) into the brain by overcoming the blood-brain barrier will also draw interest in view of development into potential drug candidates.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Synthesis of Limipterin (1d)
  5. Synthesis of Tepidopterin (2e)
  6. Synthesis of Biopterin α-D-Glucoside (1b)
  7. Synthesis of Neopterin β-D-Glucuronide (3b)
  8. Syntheses of Asperopterin-A (6b)
  9. Conclusion
  10. References
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