Bufadienolides. Introduction and Base-Catalyzed Condensation of Methyl Ketones with Glyoxylic Acid

Introduction to a series of contributions pertaining to syntheses of isocardenolides, cardenolides, isobufadienolides, and bufadienolides is presented. A comprehensive study of an aldol condensation between glyoxylic acid and various methyl ketones is described. At high hydroxyl ion concentration, methyl β-naphthyl ketone gives bis(β-naphthacyl)acetic acid (11a), but by careful control of pH the condensation can be directed to yield the γ-ketoacrylic acid 16a and/or a mixture of α-hydroxy-β-oxobutyric acid (ISa) and α-methoxy-γ-oxobutyric acid (17a). The reaction is applied to methyl cyclopentyl ketone, 2,5-dimethoxyacetophenone, 2,4-dimethylacetophenone, pinonic acid (18), and the steroidal ketones, 3β-hydroxy-20-oxo-5α-pregnene (7a) and 3β-hydroxy-20-oxo-5α-pregnane (24a).