Collective Synthesis of Aplysiatoxin/Oscillatoxin Analogues by a Bioinspired Strategy

Abstract

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.

Structure Elucidation of Two Intriguing Neo-Debromoaplysiatoxin Derivatives from Marine Cyanobacterium Lyngbya sp. Showing Strong Inhibition of Kv1.5 Potassium Channel and Differential Cytotoxicity

“…The key NOE correlations of 3-OH/H-5a, 3-OH/H-9, H-5a/H 3 -24 and H-5b/H-25/H-26 implicated 3-OH/H-4/H-5a/H 3 -24/H-9 shared syn relationships, while H-5b/H 3 -26/H 3 -25 presented same orientation. The small couplings of H-4 to H-5a and H-5b ( J 5a,4 = 5.8 Hz, J 5b,4 = 2.1 Hz) determined H-4 as the equatorial bond of ring A, which exhibited the opposite configuration with H-4 of Neo-B (( J 5a,4 = 6.8 Hz) [ 23 ]. The NOE cross-peak of H-8/H-10/H 3 -22, H-9/H-11/H 3 -23 defined an anti-relationship between H-8 and H-9, H-9 and H-10 and H-10 and H-11.…”

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

“…3-((1S,4S,5R,6R)-5-Acetoxy-1-methoxy-4,6-dimethyl-7oxoheptyl)phenyl Acetate (5). A stirred solution of alkene 4 (21.4 mg, 0.0590 mmol) in MeOH (7.5 mL) cooled at −78 °C was bubbled with O 3 for 8 min.…”

“…Recently, many new analogs of ATX/OTX possessing various different ring systems have been reported, but the tiny quantities in which they have been isolated from natural sources have precluded a detailed investigation of their biological activity. We have an ongoing interest in the new family members due to their diverse structures and unexplored biological activity and recently reported syntheses of several new analogues including O -methyl derivatives of neo-deBr-ATX-B, OTX-H, OTX-D, neo-deBr-ATX-H, and OTX-I …”

“…Our interest in these two truncated derivatives arose during the course of our collective syntheses of ATX/OTX analogues in our laboratory. , This paper describes asymmetric total syntheses of aplysiaenal and nhatrangin A, confirmation of their configurations, and evaluation of their bioactivity.…”

“…We have an ongoing interest in the new family members due to their diverse structures and unexplored biological activity and recently reported syntheses of several new analogues including O-methyl derivatives of neo-deBr-ATX-B, OTX-H, OTX-D, neo-deBr-ATX-H, and OTX-I. 5 Aplysiaenal (1) was isolated from the marine cyanobacterium Moorea producens collected in Okinawa, Japan, in 2021 by Nagai and classified as a new member of the ATX/OTX family. 6 Structurally, aplysiaenal incorporates an unsaturated aldehyde moiety instead of the hydroxy acid unit present in ATX/OTX.…”