Synthesis of trilobatin from naringin via prunin as the key intermediate: acidic hydrolysis of the α-rhamnosidic linkage in naringin under improved conditions

Abstract

Trilobatin [4'-(β-D-glucopyranosyloxy)-2',4",6'-trihydroxydihydrochalcone] was synthesized from commercially available naringin in three steps with an overall yield of 30%. The key step was the acid-catalyzed site-selective hydrolysis of terminal α-rhamnopyranosidic linkage in neohesperidose involved in naringin under controlled conditions, by applying a high-pressure steam sterilizer.

Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance

“…Hydrolytic cleavage of the diglycoside was achieved by acidic hydrolysis at 121 °C in a high‐pressure steam sterilizer . Hydrolysis was slower than that of naringin, a similar flavanone diglycoside, under the same conditions, probably as a result of the low solubility of 9 .…”

“…Hydrolytic cleavage of the diglycoside was achieved by acidic hydrolysis at 121 °C in a high‐pressure steam sterilizer . Hydrolysis was slower than that of naringin, a similar flavanone diglycoside, under the same conditions, probably as a result of the low solubility of 9 . Complete hydrolysis of 9 to the aglycone hesperetin ( 10 ) required an increase in the reaction time from 2 h to 4 h and stronger dilution of 9 (from 7 %, w / v , to 3.5 %, w / v ) with 2 % sulfuric acid.…”

“…Diglycosylated 7 was obtained in 60 % yield by removal of the remaining acetate groups under mild conditions with triethylamine in methanol . Next, partial hydrolysis of the α‐rhamnosyl group at the nonreducing end was attempted with dilute sulfuric acid at high temperature for a shorter reaction time than the exhaustive hydrolysis of the diglycoside unit in 9 to afford 10 (Scheme ). The desired monoglycosylated 6 was obtained in 36 % yield, together with the over‐hydrolysed aglycone 5,7‐dihydroxy‐3′,4‐dimethoxyflavone (DHDMF, 16 ) in 19 % yield.…”

“…[26,27] Hydrolysis was slower than that of naringin, as imilar flavanoned iglycoside, under the same conditions, [27] probably as ar esult of the low solubility of 9. [31] Complete hydrolysis of 9 to the aglyconeh esperetin (10)r equired an increasei nt he reactiont ime from 2h [27] to 4h and stronger dilution of 9 (from 7%, [27] w/v,t o3 .5 %, w/v)w ith 2% sulfuric acid. Hesperetin (10)w as dehydrogenated to diosmetin (11)a ccording to a literaturep rocedure.…”

“…We are currently investigating site‐selective synthetic approaches to bioactive flavonoids from naturally abundant and easily available glycosylated forms . We therefore became interested in the derivatives 6 – 8 (Scheme ) in which the hydroxy group at C‐7 is capped with a mono‐, di‐ or triglycoside, respectively, rather than the methoxy group in 4 and 5 .…”