Polycyclic ether toxins

The first total synthesis of the marine polycyclic ether toxin (-)-gambierol was accomplished in the laboratory of M. Sasaki. The introduction of the a,(3-unsaturation into the seven-membered H ring of the FGH tricyclic subunit proved to be problematic, because both the conventional selenium-based method and the Nicolaou oxidation with IBX failed. However, when the seven-membered ketone was treated with LiHMDS in the presence of TMSCI and EtsN, the corresponding silyl enol ether was formed, which was oxidized under Saegusa conditions to give the desired cyclic enone in high yield. Because of the small scale of the reaction, a large excess of Pd(OAc)2 was used in acetonitrile so the presence of a co-oxidant was not necessary. 

The stereoselectivity seen in the reduction of the seven-membered ketone above has proved to be general. This particular result, rationalized by the propensity for pseudoaxial hydride addition under Luche conditions, proved useful in the convergent total synthesis of Gymnocin-A, a polycyclic ether toxin isolated from the red tide dinoflagellate—Karenia mikimotoi.u The Luche reduction was used for the production of allylic alcohol 9 from ketone 8 in 84% yield. Luche conditions were similarly applied to the synthesis of the related polycyclic ether toxin gambierol.12... 

In the total synthesis of (-)-gambierol, a marine polycyclic ether toxin, by two groups [28,29], the sensitive terminal (Z, Z)-triene side chain in 53 was constructed as a crucial step by stereoselective coupling of (Z)-alkenyl iodide 51 with (Z)-l,4-pentadienylstannane 52 in DMSO to afford 53 in 72% yield without isomerization of the triene system. Pd2(dba)3 and Cul as catalysts and TFP (1-3) as a ligand were used [29]. Similar coupling using the less reactive alkenyl bromide provided 53 in 43 % yield [28]. 

Synthetic study on marine polycyclic ethers and total synthesis of hemibreve-toxin B 98YGK940. 

This lithiated epoxysulfone cyclisation strategy has been iteratively applied in the total synthesis of hemibrevitoxin B, a polycyclic ether marine toxin from the red tide organism Gymnodinium breve (Scheme 5.41) [64]. 

The main structural features of yessotoxin (YTX, 1) (Figure 13.1) consist of a ladder-shaped polycyclic ether skeleton, an unsaturated terminal side chain of nine carbons, and two sulfate groups. It was first isolated from scallops, Patinopecten yessoensis, that were implicated in a DSP episode in Japan. The planar structure of YTX was elucidated by means of 2D nuclear magnetic resonance (NMR) techniques, and confirmed by fast atom bombardment mass spectrometry/mass spectrometry (FAB MS/MS) experiments " the stereochemical details were successively determined by assigning the relative and then the absolute stereochemistry. YTX has subsequently been isolated from shellfish collected along the coasts of several different countries such as Norway, Chile, New Zealand, Italy, suggesting the spread of this toxin worldwide. 

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