Efficient synthesis of 1β- O-acyl glucuronides via selective acylation of allyl or benzyl d-glucuronate

• Published in: Tetrahedron Vol. 63; no. 32; pp. 7596 - 7605
• Main Authors: Bowkett, Elizabeth R., Harding, John R., Maggs, James L., Park, B. Kevin, Perrie, Jennifer A., Stachulski, Andrew V.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 06.08.2007; Elsevier
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; IN-VITRO; METABOLITES; TRANSACYLATION REACTIVITY; RATS; BIOACTIVATION; CHEMICAL-SYNTHESIS; ACYL GLUCURONIDE; IDENTIFICATION; ZOMEPIRAC; MYCOPHENOLIC-ACID
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2007.05.050

Acyl glucuronides are key metabolites for many carboxylic acid-containing drugs, notably those of the non-steroidal anti-inflammatory class. In the processes of drug safety assessment and new drug development, it is essential that acyl glucuronides, if formed in vivo, should be made conveniently available for bioevaluation. We recently showed that selective acylation of allyl glucuronate is a promising method for the synthesis of these metabolites in good yield and with excellent β-anomeric selectivity. We now give fuller details of the allyl ester method and further report that benzyl glucuronate performs at least equally well in the acylation step, offering the advantage of very mild deprotection by catalytic transfer (or conventional) hydrogenation. Depending on the compatibility of other functional groups, as discussed below, this will be the method of choice for many acyl glucuronide syntheses. The value of the method is demonstrated in particular by the synthesis of several acyl glucuronides that are known metabolites of important drugs. [Display omitted] A number of acyl glucuronides, including examples from important drugs, have been synthesised by the selective acylation of allyl or benzyl d-glucuronate. Deprotection was effected under mild conditions, using a Pd(0) reagent or hydrogenation.