A Publication
of Reliable Methods
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Annual Volume
Org. Synth. 2005, 82, 75
DOI: 10.15227/orgsyn.082.0075
[D-Ribonic acid, 2,3-O-(1-methylethylidene)-, γ-lactone]
Submitted by John D. Williams1, Vivekanand P. Kamath2, Philip E. Morris2, and Leroy B. Townsend1.
Checked by Anthony Cuzzupe and Peter Wipf.
1. Procedure
Caution! Bromine is volatile and corrosive, and causes severe burns upon contact with skin. Proper protective equipment and an efficient fume hood are required.
A. D-Ribonolactone. A 1-L three-necked, round-bottomed flask fitted with a mechanical stirrer, a 100-mL pressure-equalizing addition funnel and an internal thermometer is charged with D-ribose (100 g, 0.67 mol), sodium bicarbonate (112 g, 1.3 mol, 2 equiv) (Note 1) and water (600 mL). The mixture is stirred at room temperature for 15 min, during which time most of the solids dissolve (Note 2). The flask is then immersed in an ice-water bath. The addition funnel is filled with bromine (112 g, 0.70 mol, 1.04 equiv) (Note 1) and the bromine is added to the vigorously stirred aqueous solution at a rate of about 2 drops/sec such that the reaction temperature does not exceed 5°C. When the addition is complete (about 1 hr), the funnel is replaced with a stopper and the resulting orange solution is stirred for an additional 50 min. Sodium bisulfite (6.5 g, 62.5 mmol) is added in order to completely discharge the orange color (Note 3). The clear aqueous solution is transferred to a 2-L flask and evaporated on a rotary evaporator (bath temperature 60°C – 70°C, water aspirator pressure) until a wet slurry remains. Absolute EtOH (400 mL) and toluene (100 mL) are added to give a cloudy suspension and the solvent is removed by rotary evaporation (bath temperature 50°C, water aspirator pressure) to provide a damp solid. Absolute EtOH (400 mL) is added and the mixture is heated on a steam bath for 30 min. The hot ethanolic suspension is filtered and the solids are rinsed with hot absolute EtOH (100 mL). The filtrate is cooled to room temperature, and then refrigerated for 16 h. The crystalline product is filtered, rinsed first with cold absolute EtOH (100 mL) then with Et2O (100 mL), and dried under vacuum (room temperature, 0.25 mmHg) to yield 125 g of crude product (Note 4). The filtrate is concentrated (200 mL) and refrigerated to obtain additional product, which is filtered, washed with cold EtOH (25 mL) and Et2O (25 mL) and dried under vacuum (room temperature, 0.25 mmHg) to provide 35 g of additional crude product.
B. 2,3-Isopropylidene(D-ribonolactone). In a 2-L round-bottom flask, the crude ribonolactone (160 g) from above is suspended in dry acetone (700 mL), 2,2-dimethoxypropane (100 mL) and conc. H2SO4 (1 mL, 20 mmol) (Note 1). The solution is stirred vigorously at room temperature for 50 min, then silver carbonate (20 g, 73 mmol) is added (Notes 1 and 5). The resulting suspension is stirred at room temperature for 50 min, then the suspension is filtered through a 2 cm Celite pad. The solids are rinsed with acetone (100 mL), and the filtrate is evaporated to dryness. The crude acetonide is dissolved in EtOAc (250 mL) with heating on a steam bath. The resulting suspension is filtered through a 2 cm Celite pad, the solids are rinsed with hot EtOAc (50 mL), and the filtrate is allowed to cool to room temperature. Crystals of 2,3-isopropylidene(D-ribonolactone) form spontaneously as the solution cools. The resulting crystalline product is filtered and dried under vacuum (room temperature, 0.25 mmHg) to yield 68.7 g of product. The mother liquor is concentrated to 50 mL to yield 22.5 g of additional product after filtration and drying as above. The solids are combined to afford 91.2 g (73% overall yield from ribose) of white crystalline solid (Note 6, 7).
2. Notes
1. Ribose, bromine and silver carbonate were purchased from Acros Organics. Sodium bicarbonate was obtained from Mallinckrodt Baker, Inc. 2,2-Dimethoxypropane was obtained from Avocado Research Chemicals, Ltd. Deionized water was used as the solvent. All reagents were used as purchased.
2. Some of the sodium bicarbonate remains undissolved, but this does not affect the reaction yield, as the excess will be consumed during the course of the reaction.
3. If any orange color remains at this stage, the product will develop a pale brown color that cannot be removed by activated carbon.
4. The major contaminant is ~40-45% sodium bromide. The submitters recrystallized the crude product twice from hot n-BuOH (800 mL) to obtain 80 g of pure material. However, the crude material is of sufficient quality for the subsequent reaction. Pure ribonolactone has the following physical properties: mp 85-87°C; [α]25D + 11.9 (c 0.99, H2O); IR (KBr) cm−1: 3513, 3373, 3159, 1761, 1627, 1397, 1197, 1143; Rf 0.56 (30% v/v MeOH/CHCl3, p-anisaldehyde in ethanol stain); 1H NMR pdf (300 MHz, DMSO-d6) δ 5.73 (d, 1H, D2O exch, J = 7.7 Hz), 5.35 (d, 1H, D2O exch, J = 3.8 Hz), 5.15 (t, 1H, D2O exch, J = 5.4 Hz), 4.40 (dd, 1H, J = 7.7, 5.4 Hz), 4.21 (t, 1H, J = 3.5 Hz), 4.11 (app t, 1H, J = 4.9 Hz), 3.56 (dd, 2H, J = 5.4, 3.6 Hz); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 85.4, 69.3, 68.6, 60.5.
5. As an alternative to the expensive silver carbonate, the submitters also used 30 g of the weakly basic resin Amberlyst A-21. In this instance, additional acetone (200 mL total) is used to rinse the filtered solids, and care must be taken upon evaporation of the solvent to remove the residual water.
6. The recrystallized D-ribonolactone acetonide has the following physical properties: mp 134-137°C; [α]24D −66.7 (c 1.03, CHCl3); IR (KBr) cm−1: 3469, 2991, 2952, 2932, 1767, 1467, 1389, 1379, 1224; Rf 0.51 (1:3, hexane:EtOAc; p-anisaldehyde in ethanol stain); 1H NMR pdf (300 MHz, DMSO-d6) δ 5.30 (t, 1H, D2O exch, J = 5.0 Hz), 4.76 (s, 2H), 4.60 (t, 1H, J = 2.1 Hz), 3.67-3.55 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 174.3, 111.6, 82.3, 78.1, 75.0, 60.4, 26.6, 25.1; Anal. Calcd for C8H12O5: C, 51.06; H, 6.43. Found: C, 51.26; H, 6.46.
7. Extremely pure ribonolactone acetonide melts at >140°C, but material with a melting point >130°C is suitable for most reactions. Very pure material can be obtained by 1-2 additional recrystallizations from hot EtOAc.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The present procedure represents a modification of a previously published procedure for the bromine oxidation of ribose to ribonolactone.3 The improved procedure allows for the addition of a liquid reagent (bromine) instead of the solid reagent (sodium carbonate) used in the previous preparation, and thus requires neither a powder addition apparatus nor constant attention. Additionally, the present procedure does not require the careful monitoring of pH, the absence of which can lead to the complete failure of the previous preparation.
Industrial preparations of ribonolactone involve the epimerization of arabinonic acid salts under very caustic and harsh conditions, followed by fractional crystallization of the resulting ribonic acid salts from the arabinonic/ribonic acid salt mixture, and the cyclization of the resulting salts.4,5,6 An alternative rhenium-catalyzed oxidation procedure requires the preparation of an expensive catalyst and the removal of substantial amounts of benzalacetone (used as a terminal oxidant) and its reduction products.7
D-Ribonolactone is no longer commercially available in large quantities, and is very expensive. The acetonide is also very expensive. Although the above preparation of D-ribonolactone and D-ribonolactone acetonide is not high-yielding, the starting materials are inexpensive and the preparation is quite convenient. D-Ribonolactone and its derivatives have been used for the syntheses of many nucleoside analogs8,9 and natural products.10,11

References and Notes
  1. Department of Medicinal Chemistry, University of Michigan, 428 Church St., Ann Arbor, MI 48105.
  2. BioCryst Pharmaceuticals, 2190 Parkway Lake Dr., Birmingham, AL 35244.
  3. Pudlo, J. S.; Townsend, L. B. In Nucleic Acid Chemistry: Improved and New Synthetic Procedures, Methods, and Techniques, Part 4.; Townsend, L. B., Tipson, R. S., Eds.; John Wiley & Sons: New York, 1991, p. 51–53.
  4. Flexser, L. A.; Hoffmann-La Roche, Inc.: US Patent 2,438,883, 1948.
  5. Sternbach, L. H.; Hoffmann-La Roche, Inc.: US Patent 2,438,881, 1948.
  6. Schmidt, W.; Paust, J.; BASF Aktiengesellschaft: US Patent 4,294,766, 1981.
  7. Isaac, I.; Stasik, I.; Beaupere, D.; Uzan, R. Tetrahedron Lett. 1995, 36, 383–386.
  8. Pankiewicz, K. W.; Sochacka, E.; Kabat, M. M.; Ciszewski, L. A.; Watanabe, K. A. J. Org. Chem. 1988, 53, 3473–3479.
  9. Cheng, J. C.-Y.; Hacksell, U.; Daves, G. D. J. J. Org. Chem. 1985, 50, 2778–2780.
  10. Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061–7069.
  11. Jiang, S.; Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1994, 35, 5505–5508.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

D-Ribose; (50-69-1)

Sodium bicarbonate:
Carbonic acid monosodium salt; (144-55-8)

Bromine; (7726-95-6)

Sodium bisulfite:
Sulfurous acid, monosodium salt; (7631-90-5)

D-Ribonic acid, g-lactone; (5336-08-3)

Propane, 2,2-dimethoxy-; (77-76-9)

Silver carbonate:
Carbonic acid, disilver(1 + ) salt; (534-16-7)