Stereoselective Total Syntheses and Reassignment of Stereochemistry of the Freshwater Cyanobacterial Hepatotoxins Cylindrospermopsin and 7-Epicylindrospermopsin

Abstract

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).

Evaluation of quantitative real-time PCR to characterise spatial and temporal variations in cyanobacteria, Cylindrospermopsis raciborskii (Woloszynska) Seenaya et Subba Raju and cylindrospermopsin concentrations in three subtropical Australian reservoirs

“…At least two CYN's can be produced by Australian strains of C. raciborskii -CYN and deoxycylindrospermopsin (d-CYN) -referred here collectively as cylindrospermopsins (CYNs). The CYN analogue produced by Australian strains of C. raciborskii is actually an epimer of CYN and is called 7-epi-cylindrospermopsin (7-epi-CYN) (Heintzelman et al, 2002). In our study we now refer to the CYN epimer produced by C. raciborskii in Australia as 7-epi-CYN.…”

Cycloadditions with StereoselectiveCNBond Formation in Total Syntheses

“…74 Weinreb and co-workers contributed to showcase the synthetic utility of this reaction with the total syntheses of the freshwater cyanobacterial hepatotoxins cylindrospermopsins, which featured a sulfinyl Diels-Alder reaction/ allylic sulfoxide [2,3]-sigmatropic rearrangement sequence to form the syn,syn-7-hydroxy-8,10-diamino centers of 75 The cyclindrospermopsins are secondary metabolites from the freshwater blue-green algae cyanobacterium Cylindrospermopsis raciborskii, which display severe hepatotoxicity. They were responsible of cases of human poisoning in Palm Island, Australia in 1979 after the contamination of a supplying drinking water reservoir.…”

Occupational and environmental hazard assessments for the isolation, purification and toxicity testing of cyanobacterial toxins

“…anatoxin-a [3-5], cylindrospermopsins [6,7], saxitoxins [8,9], lyngbyatoxin A [10,11], aplysiatoxins [12], and one of the microcystins and some microcystin structural components [13,14]. However, the processes involved in synthesis of cyanotoxins like cylindrospermopsin and microcystins are complex and multiple steps are required, so those particular molecules are unlikely to be synthesised on a commercial scale in the near future.…”