Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2-methylbutanol (“active amyl alcohol”), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was elaborated by the addition of a chiral α-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps (Scheme 6).