First Efficient Syntheses of 1-, 4-, and 5-Caffeoylquinic Acid

Efficient synthesis of 1-, 4-, and 5-caffeoylquinic acid was achieved in three or four steps with suitably protected quinic acid precursors, in overall yields of 41%, 36%, and 60% [from quinic acid (1)]. 1-Caffeoylquinic acid was prepared by esterification of acetone quinide 7 with caffeoyl chloride 6, followed by a two-step hydrolysis of all protecting groups. Caffeoylquinic acids 4 and 5 were prepared from known quinic acid derivatives, 13 and 25, by selective esterification of the secondary hydroxy groups and hydrolysis with 1 M HCl. However, initial attempts to prepare fully protected quinic acid derivatives with a free hydroxy group only at either C-4 or C-5, for the synthesis of 4 and 5, were not successful. Kinetic acetalization of pentasilylated quinic acid 15 using bis(dimethoxy acetals) afforded several crystalline reaction products which were identified by X-ray diffraction. Diacetal 20, derived from a vicinal cis-diol, was unambiguously identified for the first time. Unexpectedly, it has two trans-diaxially oriented methoxy groups, forcing the quinide ring into a twist-boat conformation.