General Papers ARKIVOC 2008 (ii) 19-24
Simple and efficient synthesis of arbutin Ivica Cepanec* and Mladen Litvic
BELUPO Pharmaceuticals Inc., Research Department, Danica 5, 48000 Koprivnica, Croatia E-mail:
[email protected]
Abstract An efficient synthesis of arbutin, 4-hydroxyphenyl-D-glucopyranoside (1), in both a- and ßanomeric form, starting from penta-O-acetyl-a(ß)-D-glucopyranoside (2) and 4hydroxyphenylacetate (3) was developed. The BF3·Et2O-catalysed glycosylation reaction of 2 with 3 proceeds with complete retention of anomeric configuration.
Keywords: Arbutin, glycosides, transesterification, Lewis acids, natural products
Introduction
ß-Arbutin is a naturally occuring glycoside found in several common medical plants.1-5 Among them, the bearberry leaves (Arctostaphylos uvae ursi) is a widely used source of this important pharmaceutical active substance.6 The arbutin-containing plant-drugs have been used for the treatment of urinary infections and as depigmenting agent.7-9 The first synthesis of arbutin starting from tetra-O-acetyl-a-bromo-D-glucopyranoside and hydroquinone was described in early 20th centaury.10 However, the first practical synthesis of arbutin from penta-O-acetyl-ß-Dglucopyranoside and hydroquinone monobenzylether is based on the POCl3-mediated glycosylation.11 More recently developed syntheses of ß-arbutin by Lewis acid-catalysed glycosylation of 2,3,4,6-tetra-O-acetyl-1-O-trifluoroacetyl-a-D-glucopyranose with hydroquinone,12 or by employing tributyltin phenoxides13 suffer from several disadvantages: the use of expensive 1-trifluroacetyl-sugars, very toxic organotin reagents, or partial isomerisation at the anomeric position takes place.
Finally an alternative synthesis of ß-arbutin based on enzymatic glycosylation (a-amylase from Bacillus macerance) of hydroquinone with glucose was reported.14 The synthesis was conducted in an aqueous buffered media furnishing both anomeric arbutins in reasonable yields but with tedious work-up. Nowadays, an efficient, inexpensive and scalable route to pure arbutin is still a great challenging area for both academic and industrial chemists.
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