The Asymmetric Total Synthesis and Configuration Confirmation of Aplysiaenal and Nhatrangin A, Truncated Derivatives of Aplysiatoxin and Oscillatoxin.

Asymmetric total syntheses of aplysiaenal (1) and nhatrangin A (2), truncated derivatives of the aplysiatoxin/oscillatoxin family of marine natural products, from configurationally defined intermediates are described. NMR spectra of our synthesized nhatrangin A did not match with either those obtained from authentic samples of the natural product or material obtained via two other total syntheses, but were similar to that obtained from a sample obtained in a third total synthesis. By independently synthesizing the fragments used in its total syntheses, we were able to confirm the configuration of nhatrangin A and clarified that the discrepancy in the spectroscopic data is due to salt formation of the carboxylic acid moiety.

Collective Synthesis of Aplysiatoxin/Oscillatoxin Analogues by a Bioinspired Strategy.

Interest in the marine cyanobacteria natural products aplysiatoxin (ATX) and oscillatoxin (OTX) has been renewed recently due to the discovery of many new analogues, some exhibiting intriguing biological activities. We sought to develop a collective synthesis of these natural products, hypothesizing that ATX could serve as a common biosynthetic precursor. Herein, we reveal that the core structure of ATX has unique multiple reactivities giving access to the distinct ring structures of five of the analogues, depending upon the specific conditions used. Based on these findings, syntheses of the O-Me derivative of five analogues neo-deBr-ATX-B, OTX-H, OTX-D, neo-deBr-ATX-H, and OTX-I were achieved from the main fragment of ATX as a common intermediate in a few steps. These synthetic studies also led us to revise the relative configuration in the elucidated structures of neo-deBr-ATX-B and OTX-H, and obtain unnatural 8- and 12-membered lactones from the same intermediate.