Facile Synthesis of the Chalcones and Dihydrochalcones from Naringin, Neohesperidin and Hesperidin

H. A. B. L i n k e and D. E . E v e l e i g h * Department of Microbiology, New York University Dental Center, New York

(Z. Naturforsch. 30 b, 606-608 [1975]; received April 1, 1975)

Dihydrochalcones, Sweeteners, Flavanone Glycosides, UV Spectra, Hydrogenation

The flavanone glycosides naringin, neohesperidin and hesperidin were converted chemically to the corresponding chalcones and dihydrochalcones; the one-step synthesis, performed at room temperature, required the presence of 25% KOH in the reaction mixture for the former and 10% KOH, a catalyst and molecular hydrogen at atmospheric pressure for the latter.

Results and Discussion flavanone glycosides (Fig. 1) can be converted The ban of cyclamate from the U.S. market of either in a single step after A (25% KOH) to the artificial sweeteners in 1969 was followed by a corresponding chalcones or in a single step after B dramatically increased effort to search for new (10% KOH, H2, catalyst) to the corresponding natural and artificial noncaloric sweeteners. Narin­ dihydrochalcones. The synthesis of the sweet gin dihydrochalcone (7) and neohesperidin dihydro- tasting dihydrochalcones proceeds without any chalcone ( 8) derived from the naturally occurring complications, and the yields are nearly theoretical. flavanone glycosides naringin ( 1 ) and neohesperidin Therefore, the economic character of this novel (2) are intensely sweet tasting compounds, and have synthesis is evident. In addition, this synthesis has a strong potential to serve as a substitute for the advantage over the other known methods 3 that sucrose, whereas hesperidin dihydrochalcone (9) there is no pressure required for the hydrogenation obtained from the flavanone glycoside hesperidin (3) has no sweet taste1. The chemical synthesis of 7, 8, and 9 from their corresponding flavanone glycosides is not very economical, since either a two-step synthesis, isola­ tion of the corresponding chalcones (4, 5, and 6) followed by hydrogenation2, or a more complicated hydrogenation procedure, utilizing high pressure is required3. During preliminary studies on this subject 4 we found a facile chemical synthesis using mild condi­ tions that yielded the chalcones as well as the dihydrochalcones from the corresponding flavanone 4, 5, 6 7, 8, 9 glycosides; depending on the alkalinity of the 1: R = /?-neohesperidosyl, Rx = OH, R2 = H, reaction mixture and the reaction conditions, the 2: R = /S-neohesperidosyl, Rx = OCH3, Ra = OH, 3: R = /?-rutinosyl, Rx = OCH3, R2 = OH, * Department of Biochemistry and Microbiology, 4: chalcone of 1, . Cook College, Rutgers University, New Brunswick, o: chalcone of 2, N.J. 08903, USA. 6: chalcone of 3, 7: dihydrochalcone of 1, 8: dihydrochalcone of 2, Requests for reprints should be sent to Dr. H. A. B. 9: dihydrochalcone of 3. L i n k e , Department of Microbiology, New York Uni­ versity Dental Center, 421 First Avenue, N ew York , Fig. 1. Synthesis of chalcones and dihydrochalcones N.Y. 10010, USA. from the flavanone glycosides.

Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung This work has been digitalized and published in 2013 by Verlag Zeitschrift in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der für Naturforschung in cooperation with the Max Planck Society for the Wissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht: Advancement of Science under a Creative Commons Attribution Creative Commons Namensnennung 4.0 Lizenz. 4.0 International License. H. A. B. LINKE-D. E. EVELEIGH • FACILE SYNTHESIS OF DIHYDROCHALCONES 607 procedure, utilizing a reusable catalyst. The purity was stirred magnetically at room temperature and of all compounds was secured by thin-layer chro­ atmospheric pressure. After 6 hours the catalyst was removed from the reaction mixture with the aid matography. The melting points and UV maxima of a Buchner funnel; the resulting clear and colorless of the described compounds 1 to 9 are summarized filtrate was acidified with 8 ml of conc. HC1 and in Table I. then placed in a refrigerator. After several hours the whitish precipitate was collected with the aid of a Experimental Section Buchner funnel, re crystallized from hot water, washed with ice cold water and finally dried in a UV spectra: UV maxima were obtained from the UV spectra as determined in a Cary 14 Recording desiccator. Spectrophotometer (Table I). The measurements Yield: 4.9 g of 7. were carried out in 1.0 cm quartz cuvettes con­ Anal, for C 27H 340Jl4 taining a solution of 1.0 mg compound /100 ml Calcd C 55.67 H 5.88, methanol. Found C 54.77 H 6.43.

Table I. Melting points (°C) and UV maxima (nm/log e) Neohesperidin (2): A crude sample obtained from of some flavanone glycosides, their chalcones and R. E. Leitz (Nutrilite Products, Inc., Lakeview, dihydrochalcones. Ca.) was re crystallized from boiling water.

Compound m.p. a) Neohesperidin chalcone (5): 1 g of 2, dissolved Amax in 20 ml KOH (25%), was treated as described for

Naringin (1) 170-171 283/4.20 4. Since 5 did not crystallize in the cold, the column Neohesperidin (2) 239-240 283/4.27 eluate was evaporated to dryness in a rotary Hesperidin (3) 261-262 283/4.21 vacuum evaporator at 40 °C; yield of the red-orange Naringin chalcone (4) 201-202 364/4.48 compound was 875 mg. Crude 5 (100 mg) was Neohesperidin chalcone (5) 232-233 369/4.19 dissolved in 5 ml H 20-saturated n-butanol and Hesperidin chalcone (6) 204-205 368/4.07 placed on top of a silica gel (Woelm, particle size Naringin dihydrochalcone (7) 169-170 281/4.26 Neohesperidin dihydro­ <0.03 mm) column (25 X 160 mm) equilibrated chalcone (8) 152-153 282/4.25 with H 20-saturated n-butanol. The column was Hesperidin dihydrochalcone (9) 194-195 282/4.19 eluted with H 20-saturated n-butanol under pressure (4 atm .); the first yellow eluate was collected (30 ml) and evaporated to dryness in a rotary vacuum Melting points: m.p. were determined in a Thiele evaporator. m.p. apparatus and are not corrected (Table I). Yield: 80 mg of 5. The chalcones and dihydrochalcones start to soften b) Neohesperidin dihydrochalcone ( 8): 5 g of 2, far below their m. p. dissolved in 25 ml KOH (10%), were treated as Thin-layer chromatography: TLC was performed described for 7, and the resulting whitish substance on silica gel plates (Merck, 60F-254, 0.25 mm) was recrystallized from hot water. developed with H 20-saturated w-butanol; the com­ Yield: 4.7 g of 8. pounds were visualized under UV light (375 nm)5. Anal, for C 28H 360 15 • 2 H 20 Naringin (1): The commercially available product (Sigma, Grade 2) was recrystallized from boiling Calcd C 51.85 H 6.23, water. Found C 51.91 H 6.07. a) Naringin chalcone (4): 1 g of 1, dissolved in Hesperidin (3): The commercially available 20 ml KOH (25%), was magnetically stirred at product (Sigma, Grade 1) was re crystallized from room temperature for 2 hours. The yellow-orange boiling water. reaction mixture was diluted with water to 100 ml a) Hesperidin chalcone ( 6): 1 g of 3, dissolved in and passed through an Amberlite 200 (Rohm & 20 ml KOH (25%), was treated as described for 4. Haas, Philadelphia, Pa.) column (25 x 200 mm). Since 6 did not crystallize in the cold, the column The neutral yellow eluate (125 ml) was collected eluate was evaporated to dryness in a rotary and placed over night in a refrigerator. The vacuum evaporator. Yield of the crude red-brown, crystallized yellow substance was collected with the resin-like material was 660 mg. 100 mg of crude 6 aid of a Buchner funnel, washed twice with ice cold were dissolved in 8 ml of H 20-saturated n-butanol water and finally dried in a desiccator. and placed on top of a DEAE-cellulose (Serva) Yield: 640 mg of 4. column (25 x 200 mm) equilibrated with H ,0- b) Naringin dihydrochalcone (7): To 5 g of 1, saturated n-butanol. The column was eluted with dissolved in 25 ml KOH (10%), 500 mg palladium H 20-saturated n-butanol; the first yellow eluate black were added. The reaction vessel was flushed was collected (100 ml) and evaporated to dryness in with H 2 and finally connected to a small gasometer a rotary vacuum evaporator. containing H2. The orange-yellow reaction mixture Yield: 86 mg of 6. 608 H. A. B. LINKE-D. E. EVELEIGH • FACILE SYNTHESIS OF DIHYDROCHALCONES

b) Hesperidin dihydrochalcone (9): To 1 g of 3, Yield: 45 mg yellow-amber crystals of 9. dissolved in 5 ml KOH (10%), 100 mg palladium black were added and the reaction vessel flushed Anal, for C 28H 360 15 • 2 1/2 H 20 with H 2 at atmospheric pressure and finally Calcd C 51.14 H 6.28, connected to a small gasometer containing H2. The Found C 50.90 H 5.84. dark reaction mixture was stirred magnetically at room temperature and after 6 hours the obtained product was diluted with water to 50 ml, the catalyst removed with the aid of a Buchner funnel, and the We thank Mr. R. E. L e it z (Nutrilite Products, resulting amber solution was passed through an Inc., Lake view, Ca.) for the generous sample of Amberlite 200 (Rohm & Haas, Philadelphia, Pa.) neohesperidin, and we are grateful to Dr. C. P. column (25 X 180 mm). The column was flushed Schaffner for use of the Cary 14 Recording with a total of 300 ml water. The neutral eluate was Spectrophotometer and to Dr. W. Mechlinski for evaporated to dryness in a rotary vacuum evapora­ his valuable suggestions concerning HPLC. We tor and yielded 950 mg of a crude resinous amber appreciate the careful preparation of the manuscript compound. 100 mg of crude 9 were dissolved in 5 ml by Ms. Sherry Johanas. This work was supported of H 20-saturated %-butanol and the supernatant in part by the National Science Foundation (grant placed on top of a DEAE-cellulose (Serva) column number GI 34287 C). Paper of the Journal Series, (25 X 200 mm) equilibrated with H 20-saturated n- New Jersey Agricultural Experiment Station, Rut­ butanol. The column was eluted with H 20-saturated gers University - The State University of New Jer­ n-butanol, and the first yellow-amber eluate was sey, New Brunswick, N. J. 08903. C,H-determina- collected (100 ml) and evaporated to dryness in a tions were carried out by Schwarzkopf Microanaly- rotary vacuum evaporator. tical Laboratory, Woodside, N. Y.

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