SYNTHESIS OF UNIQUE CERAMIDES AND CEREBROSIDES OCCURRING IN HUMAN EPIDERMIS

The sphingolipids 1a, b and 2a, b, which play important roles in epidermal barrier function, were by N-acylation of C18-sphingosine 3 and 1-O-glucosylated C18-sphingosine 6, respectively, with omega-acyloxy-substituted fatty acids 4 and 5 (Scheme 1). These fatty acids were obtained from omega-hydroxy-substituted fatty acids 8 and 9 by esterification with linoleic acid (7). The C34-fatty acid 8 was prepared as follows: C25-Compound 18 was obtained by means of a Wittig reaction Of C-13-aldehyde 13 with C-12-phosphonium salt 15 or of C-12-aldehyde 24 with C-13-phosphonium salt 21, respectively, and subsequent hydrogenation and O-deprotection (Scheme 2). Alternatively, 8 was prepared via 30 by copper-catalyzed coupling of C-13-alkyl halide 19 with the Grignard reagent derived from C-12-alkyl bromide 14 (Scheme 2). Oxidation of 18 to aldehyde 39 and Wittig reaction with C-9-phoshonium salt 41 furnished the desired omega-hydroxy-substituted fatty acid 8, after 0-deprotection (Scheme 3). Similarly, Wittig reaction of C-11-phosphonium salt 22 with C-12-aldehyde 24 furnished C23-aldehyde 40, after hydrogenation, O-deprotection, and oxidation; Wittig reaction with compound 41 and subsequent deprotection afforded the desired C32-fatty acid 9 (Scheme 3). An alternative strategy furnished compound 8 by a coupling reaction of alkyne 53 with omega-bromo-substituted fatty acid 52, obtained from compounds 24 and 47 by Wittig reaction, hydrogenation, and introduction of bromide (Scheme 4). Hydrogenation (Lindlar's catalyst) of the resulting C34-alkaline 54 and deprotection furnished 8.