RU2793707C2 - Method for production of 2-deoxy-d-ribolactone - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, in particular to a method for the production of 2-deoxy-D-ribolactone used in chemistry, biology, and medicine. A method for the production of 2-deoxy-D-ribolactone is disclosed, including hydration of [(1S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one] levoglucosenone in water, oxidation of the resulting [(1R,2S,5R)-2-hydroxy-6,8-dioxabicyclo[3.2.1]-octane-4-one] ketol, and lactonization of resulting intermediate products of ketol oxidation into a target product by acidic treatment. The method differs in that hydration of levoglucosenone in water is carried out at a temperature of 20-60°C for 2-6 days, oxidation of ketol is carried out with hydrogen peroxide at a temperature of 50-90°C.

EFFECT: invention provides simplification and price reduction of the production of 2-deoxy-D-ribolactone.

4 cl, 3 ex

Description

The invention relates to organic chemistry, specifically to a method for producing 2-deoxy-D-ribolactone [synonyms: 2-deoxy-D-ribo-1,4-lactone, (4S,5R)-4-hydroxy-5-(hydroxymethyl)- dihydrofuran-2(3H)-one, (4S,5R)-4-hydroxy-5-(hydroxymethyl)-4-butanolide, (4S,5R)-3,4,5-trihydroxypentanoic acid 1,4-lactone] ( 1).

The results of the invention can be used in chemistry, biology and medicine.

2-Deoxy-D-ribolactone 1, a carbohydrate-derived compound, has versatile biological activity and, despite its inaccessibility, is widely used for the synthesis of various natural objects.

2-Deoxy-D-ribolactone 1 exhibits antioxidant, antimicrobial activity against Escherichia coli, Micrococcus luteus, Pseudomonas agarici and Staphylococcus warneri, as well as the ability to inhibit acetylcholinesterase [F. Kaaniche, A. Hamed, AS Abdel-Razek, D. Wibberg, N. Abdissa, IZ El Euch, N. Allouche, L. Mellouli, M. Shaaban, N. Sewald. Bioactive secondary metabolites from new endophytic fungus Curvularia. sp isolated from Rauwolfia macrophylla II PLoS ONE, 2019, v. 14, Art. No: E0217627]. 2-Deoxy-D-ribolactone 1 in cells competes with PGE ₂ in binding to EP receptors [PO Miranda, F. Estevez, J. Quintana, CI Garcia, I. Brouard, JI Padron, JP Pivel, J. Bermejo. Enantioselective synthesis and biological activity of (3S,4R)- and (3S,4S)-3-hydroxy-4-hydroxymethyl-4-butanolides in relation to PGE ₂ // J. Med. Chem., 2004, v.47, p. 292]. It inhibits the formation of superoxide anions and the release of neutrophil elastase [ML Yang, R.C. Kuo, TL Hwang, TS Wu. Anti-inflammatory principles from Cordyceps sinensis II J. Nat. Prod., 2011, v.74, p. 1996].

2-deoxy-D-ribolactone 1 is most widely used as a starting or intermediate compound in the synthesis of practically important compounds. For example, due to the fact that the glycosidic part of nucleic acids contains 2-deoxy-D-ribose, 2-deoxy-D-ribolactone 1 has found application in the synthesis of antiviral and anticancer nucleosides [(1) US 0175648 A1, 06/25/2015; (2) WO 164812 A1, October 29, 2015; (3) WO 041877 A1, March 24, 2016; (4) WO 069975 A1, May 6, 2016; (5) WO 140615 A1, 09/09/2016; (6) J. H. Rothman. Direct and facile syntheses of heterocyclic vinyl-C-nucleosides for recognition of inverted base pairs by DNA triple helix formation: First report by direct wittig route // J. Org. Chem., 2007, v. 72, p. 3945; (7) S. Zhou, S. Mahmoud, P. Liu, L. Zhou, M. Ehteshami, L. Bassit, S. Tao, R.A. Domaoal, O. Sari, C. De Schutter, S. Amiralaei, A. Khalil, O.O. Russell, T. McBrayer, T. Whitaker, N. Abou-Taleb, F. Amblard, S.J. Coats, R.F. Chinaz. 2'-Chloro,2'-fluoro ribonucleotide prodrugs with potent pan-genotypic activity against hepatitis C virus replication in culture // J. Med. Chem., 2017, v. 60, p. 5424]. Based on 2-deoxy-D-ribolactone 1, various biologically active lactones of synthetic and natural origin were synthesized [(1) US 0220251 A1, 04.11.2004; (2) EP 0460413 A1, 12/11/1991; (3) J.C. Briggs, A.P. Dawson, I. Gibson, A.H. Haines, J. Hook, R.J.K. Taylora. The synthesis of conformationally-restricted diacyl glycerol analogues // Bioorg. Med. Chem. Lett., 1992, v.2, 131], alkaloids [P. Cao, Z.J. Li, W.W. Sun, S. Malhotra, Y.L. Ma, B. Wu, V.S. Parmar. Cascade N-alkylation/hemiacetalization for facile construction of the spiroketal skeleton of acortatarin alkaloids with therapeutic potentiality in diabetic nephropathy // Nat. Prod. Bioprospect., 2015, v. 5 p. 3] and cyclic a-amino acids [D. Scarpi, L. Bartali, A. Casini, E.G. Occhiato. Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams // Eur. J. Org. Chem., 2013, p. 1306].

2-Deoxy-D-ribolactone 1 is increasingly attracting the attention of synthetic scientists for solving their problems; therefore, effective methods for its preparation are needed.

2-Deoxy-D-ribolactone 1 occurs in various natural objects. It can be isolated from the aerial part of Mentha haplocalyx Briq [L. Su, Y. Wang, K. Zhong, G. Tu, Y. Jiang, B. Liu. Chemical constituents of mentha haplocalyx II Chem. Nat. Compd., 2019, v.55, p.351, from the roots and rhizomes of Clematis hexapetala Pall and Clematis mandshurica Rupr. [(1) C.X. Dong, S.P. Shi, K.S. Wu, P.F. Tu Chemical constituents from the roots and rhizomes of Clematis hexapetala Pall. // Z. Naturforsch., B: J. Chem. Sc., 2007, v. 62, p. 854; (2) S.P. Shi, D. Jiang, C.X. Dong, P.F. Tu. New phenolic glycosides from Clematis mandshurica II Helv. Chim. Acta., 2006, v. 89, p. 1023], from plant fruits: Pimpinella anisum L [E. Fujimatu, T. Ishikawa, J. Kitajima. Aromatic compound glucosides, alkyl glucoside and glucose from the fruit of anise // Phytochemistry, 2003, v. 63, p. 609], Anethum graveolens L. [T. Ishikawa, M. Kudo, J. Kitajima. Water-soluble constituents of dill, Chem. Pharm. Bull., 2002, v. 50, p. 501], Cnidium monnieri [J. Kitajima, T. Ishikawa, Y. Aoki. Glucides of Cnidium monnieri fruit // Phytochemistry, 2001, v. 58, p. 641], Carum ajowan (Umbelliferae) [T. Ishikawa, Y. Sega, J. Kitajima. Water-soluble constituents of ajowan // Chem. Pharm. Bull., 2001, v. 49, p. 840], Foeniculum vulgare Miller (Umbelliferae) [J. Kitajima, T. Ishikawa, Y. Tanaka, Y. Ida. Water-soluble constituents of fennel. IX. Glucides and Nucleosides // Chem. Pharm. Bull., 1999, v. 47, p. 988]. 2-Deoxy-D-ribolactone 1 can be isolated from an extract of the endophytic fungus Curvularia sp. living on Rauwolfia macrophylla [F. Kaaniche, A. Hamed, A.S. Abdel-Razek, D. Wibberg, N. Abdissa, I.Z. El Euch, N. Allouche, L. Mellouli, M. Shaaban, N. Sewald. Bioactive secondary metabolites from new endophytic fungus Curvularia. sp isolated from Rauwolfia macrophylla II PLoS ONE, 2019, v. 14, Art. No: E0217627], from the mycelium of the fungus Cordyceps sinensis [M.L Yang, P.C. Kuo, T.L. Hwang, T.S. wu. Anti-inflammatory principles from Cordyceps sinensis II J. Nat. Prod., 2011, v. 74, p. 1996]. However, isolation of 2-deoxy-D-ribolactone 1 from natural objects is ineffective due to its low content.

There are several ways to obtain 2-deoxy-D-ribolactone 1. The most accessible method for obtaining 2-deoxy-D-ribolactone 1 is the oxidation of 2-deoxy-D-ribose to 1,4-lactone in water with the help of bromine. Oxidation of 2-deoxy-D-ribose proceeds from 2 to 5 days with a product yield of up to 73% [(1) J.C. Briggs, A.R. Dawson, I. Gibson, A. H. Haines, J. Hook, R.J.K. Taylora. The synthesis of conformationally-restricted diacyl glycerol analogues // Bioorg. Med. Chem. Lett., 1992, v. 2, p. 131; (2) R.E. Deriaz, W.G. Overend, M. Stacey, E.G. Teece, L.F. Wiggins, Deoxy-sugars. Part V. A reinvestigation of the glycal method for the synthesis of 2-deoxy-D- and -L-ribose.// J. Chem. Soc, 1949, p. 1879-1883].

A known method of obtaining 2-deoxy-D-ribolactone 1 in one stage through the deoxygenation of D-arabino- and D-ribolactone using the SmI ₂ -THF/H ₂ O system, where the product yield was 56 and 44%, respectively [S. Hanessian, C. Girard. One step α-deoxygenation of unprotected aldonolactones using samarium diiodide-THF/H ₂ O system - A new synthesis of 2-deoxy-D-ribose // Synlett, 1994, p. 861-862]. Deoxygenation of D-arabinopyranose to 2-deoxy-D-ribolactone 1 can be realized through sulfonates in the presence of lead hydroxide [P.A. Gakhokidze, N.N. Sidamonidze. A convenient method for obtaining 2-deoxyerythropetose// Journal of General Chemistry, 1987, v. 57, p. 2399]. 2-Deoxy-D-ribolactone 1 can be obtained from 2,3-O-isopropylidene-D-glyceraldehyde [(1) K. Mikami, M. Terada, T. Nakai. Lanthanide (III) catalyzed aldol reactions of glyceraldehyde acetonide with ketene silyl acetals: catalytic asymmetric route to monosaccharides // Tetrahedron: Asymmetry, 1991, v. 2, p. 993; (2) Y, Kita, O. Tamura, F. Itoh, H. Yasuda, H. Kishino, YY Ke, Y. Tamura. Chemistry of O-silylated ketene acetals: stereocontrolled synthesis of 2-deoxy- and 2-deoxy-2-C-alkyl-erythro-pentoses // J. Org. Chem., 1988, v. 53, p. 554], but the disadvantage of these methods of synthesis is their multistage nature. In addition, all the above methods of synthesis are similar in that to obtain 2-deoxy-D-ribolactone 1, close carbohydrate precursors are used, which themselves can be extremely rare compounds or the use of expensive reagents is necessary.

The closest way to obtain 2-deoxy-D-ribolactone 1 in relation to the proposed method for its production is the use of levoglucosenone [(1S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one] 2 This method includes several stages of synthesis. The first stage consists in the hydration of levoglucosenone 2 in water in the presence of triethylamine to the ketoalcohol [(1R,2S,5R)-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-4-one] 3 and its isolation from the reaction mass . Next, the ketoalcohol 3 is oxidized with peracetic acid in acetic acid according to the Baeyer-Villiger reaction. The final stage consists in the hydrolysis of the intermediate formates formed as a result of the oxidation of intermediate formates with hydrochloric acid in methanol to obtain 2-deoxy-D-ribolactone 1 in a total yield of 64.3%. [K. Matsumoto, T. Ebata, K. Koseki, K. Okano, H. Kawakami, H. Matsushita. Short synthesis of (3S,4R)- and (3R,4R)-3-hydroxy-4-hydroxymethyl-4-butanolides, two lactones from levoglucosenone // Bull. Chem. soc. Jpn., 1995, v. 68, p. 670]. The disadvantages of this method are the need to isolate the intermediate, namely the product of hydration of levoglucosenone ketoalcohol 3, the use of peracetic acid in the Baeyer-Villiger reaction, which complicates the oxidation process, and the need to replace solvents at each stage of the synthesis.

The problem to be solved by the claimed invention is to simplify and reduce the cost of the process of obtaining 2-deoxy-D-ribolactone 1.

In the claimed method for obtaining 2-deoxy-D-ribolactone 1, levoglucosenone 2 is used as the starting compound. At the first stage, levoglucosenone 2 undergoes hydration by keeping in water for 2-6 days at a temperature of 20-60°C. This temperature range for the hydration of levoglucosenone 2 is optimal, since under these conditions it is quantitatively hydrated to ketoalcohol 3. The resulting ketoalcohol 3 is oxidized with hydrogen peroxide at a temperature of 50-90°C. Oxidation is carried out at any molar ratio of H ₂ O ₂ with respect to ketoalcohol 3. As a result of the oxidation of ketoalcohol 3 with hydrogen peroxide, a mixture of intermediate acids 4 [2-deoxy-D-ribonic acid] and 5 [2-deoxy-5-O-formyl -D-ribonic acid], which, in the case of an excess of H ₂ O ₂ , are lactonized by acid treatment to the target 2-deoxy-D-ribolactone 1 with a total yield of 92%. When this residual amount of H ₂ O ₂ can be neutralized by any available method. When using 1 equivalent of H ₂ O ₂ with respect to ketoalcohol 3, the intermediate acids 4 and 5 formed after the oxidation of ketoalcohol 3 are safely lactonized into the target product by boiling the resulting mixture with a yield of 86%. The use of 1 equivalent of H ₂ O ₂ with respect to ketoalcohol 3 is the most effective in practical terms, since there is no need to remove excess peroxide from the reaction mass. It should be noted that all stages of the proposed method for the preparation of 2-deoxy-D-ribolactone 1 are carried out in one reactor in an aqueous medium, intermediate products are not separated from the reaction mass, and all necessary reagents are added as needed.

Thus, a highly efficient method for the preparation of 2-deoxy-D-ribolactone 1 with a total yield of more than 86% has been proposed, the principal feature of which is that all stages of synthesis are carried out in one reactor in an aqueous medium. In addition, the proposed method is as close as possible to the principles of green chemistry, the practicality and efficiency of the synthesis is achieved through the use of inexpensive and non-toxic reagents, and the absence of the need to isolate intermediate products.

The essence of the invention is confirmed by the following examples:

Example 1 Synthesis of 2-deoxy-D-ribolactone using excess H ₂ O ₂ at room temperature. A solution of 10.0 g (0.079 mol) of levoglucosenone 2 in 100 ml of water was kept at room temperature for 6 days. Next, 16.1 _ml (0.158 mol) of 30% H ₂ O ₂ was slowly added to the solution, and the reaction mixture was stirred at 50°C for 1 h. the mass was evaporated under reduced pressure. The resulting thick mass was dissolved in 25 ml of MeCN, 1 ml of conc. HCl and the solution were stirred for 24 hours After the solution was evaporated, the residue was chromatographed on SiO ₂ . Yield 9.6 g (92%) 2-deoxy-D-ribolactone 1, transparent thick liquid, [α] _D ²² +21.5° (c 1.0, H ₂ O); after 2 days of keeping 2-deoxy-D-ribolactone 1 in water [α] _D ²² +18.0° (from 1.0, H ₂ O). [Tetrahedron, 1993, v. 49, p. 349: [α] _D ²² +19.9° (c 0.71, H ₂ O)]. R _f 0.4 (EtOAc). IR spectrum, ν, cm ^-1 : 3336, 1766, 1192, 1056. ¹ H NMR spectrum (500 MHz, CDCl ₃ ) δ, ppm (J, Hz): 2.38 (1H, dd, J= 18.0, J=2.4, H-2), 2.92 (1H, d.d, J=18.0, J=6.7, H-2), 3.68 (1H, d.d, J=12.5, J=3.7, CH ₂ OH), 3.76 (1H, d.d, J=12.5, J=3.3, CH ₂ OH), 4.35-4.40 (1H, m, H-4), 4.38 (1H, d.t, J=6.7, J =2.4, H-3), 4.70-4.90 (2H, m, OH). ^13C NMR spectrum (125 MHz, CDCl ₃ ) δ, ppm: 37.79 (C-2), 61.17 (CH ₂ OH), 68.33 (C-3), 88.78 (C-4), 177.41 (C- 1). Mass spectrum, m/z: 174.1 [M+MeCN+H] ⁺ . Found, %: С 45.73; H 6.01. C ₅ H ₈ O ₄ . Calculated, %: С 45.46; H 6.10.

Example 2 Synthesis of 2-deoxy-D-ribolactone using excess H ₂ O ₂ at 50°C. A solution of 10 g (0.079 mol) of levoglucosenone 2 in 100 ml of water was kept at 50°С for 48 h. Next, 16.1 ml (0.158 mol) of 30% H ₂ O ₂ was slowly added to the solution, and the reaction mixture was stirred at 50°С for 1 h. To neutralize excess hydrogen peroxide, the solution was cooled to room temperature, 6 ml of Me ₂ S was added and stirred for 1 h. The reaction mass was evaporated under reduced pressure. For lactonization, the resulting thick mass was dissolved in 25 ml of MeCN, 1 ml of conc. HCl and the solution were stirred for 24 hours After the solution was evaporated, the residue was chromatographed on SiO ₂ . Yield 8.7 g (83%) of 2-deoxy-D-ribolactone 1.

Example 3 Synthesis of 2-deoxy-D-ribolactone using 1 equivalent of H ₂ O ₂ . A solution of 10.0 g (0.079 mol) of levoglucosenone 2 in 100 ml of water was kept at room temperature for 6 days. Next, 8.1 ml (0.079 mol) of 30% H ₂ O ₂ was slowly added to the solution. The reaction mass was stirred at 50°C for 1 h, then boiled for 2 h. To remove impurities from the reaction mass, the solution was cooled to room temperature, extracted once with 50 ml of CH ₂ Cl ₂ . The aqueous phase was evaporated, the resulting thick mass was kept for 2 hours at 90°C at a pressure of 1-2 mm Hg. Yield 10.5 g (100%) of 2-deoxy-D-ribolactone 1, transparent or slightly yellowish thick liquid, product purity 86%.

Claims (4)

1. Method for obtaining 2-deoxy-D-ribolactone, including hydration of [(1S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one] levoglucosenone in water, oxidation of the obtained [(1R ,2S,5R)-2-hydroxy-6,8-dioxabicyclo[3.2.1]-octan-4-one] ketoalcohol and lactonization of the resulting intermediate products of ketoalcohol oxidation into the target product by acid treatment, characterized in that the hydration of levoglucosenone in water carried out at a temperature of 20-60°C for 2-6 days, the oxidation of ketoalcohol lead to hydrogen peroxide at a temperature of 50-90°C. 2. The method according to claim 1, characterized in that the mixture of intermediate acids formed after the oxidation of the ketoalcohol [2-deoxy-D-ribonic acid and 2-deoxy-5-O-formyl-D-ribonic acid] is not isolated from the reaction mass. 3. The method according to p. 1, characterized in that when using 1 equivalent of hydrogen peroxide in relation to ketoalcohol, the resulting mixture of intermediate acids is lactonized into the target product by boiling the reaction mass. 4. The method according to p. 1, characterized in that all stages of the synthesis of 2-deoxy-D-ribolactone are carried out in one reactor.