Friday Fun - Maitotoxin Watch

For those keeping tabs on K.C. Nicolaou's potential career capstone, the group has published another fragment (QRSTUVWXYZA') of the ladder polyether maitotoxin. By my count (and thanks to their handy graphic, below), they've now formed 30 of the 32 requisite rings, meaning we'll likely see a completed total synthesis in the next few years.*

Top: Maitotoxin
Bottom: Previously disclosed fragments
Source: Nicolaou et.al. | JACS 2014 ASAP

When Nicolaou's group announced the move to Rice, one of my first thoughts was "who gets to personally chaperone the maitotoxin fragments to their new home?" I'm picturing combination-locked black suitcases handcuffed to postdocs' wrists, but perhaps the samples just went in the back of a U-Haul truck with all the other lab equipment.

Happy Friday,

See Arr Oh

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*Assuming they can work out the ring fusion and selective sulfate chemistry - not trivial tasks by any means!

This Just In - File Under "Huge Marine Polyethers"

K. brevisculata
Source: Te Ara - Encyclopedia of New Zealand
Maggy Wassilieff

There's a new red tide in town: Karenia brevisulcata, a dinoflagellate first discovered in New Zealand in 1998. This ocean denizen was pegged for a wave of fish kills and human illnesses, which cued curious natural products chemists to have a peek at their toxin profile. The scientists noted that several of the cell extracts had molecular masses well above 2000 - large polyether territory - and were lethal to lab mice.


Et voilà! Say hello to brevisulcenal-F, their first solved structure from the algal cells. This toxin, tipping the scales at 2076 amu (M + Na), sets a record in its own right: it has seventeen contiguous 6- and 7-membered rings, A-Q, the most yet identified in a single marine ladder toxin (I can almost hear Mori, Nicolaou, Hirama, and Crimmins sharpening their swords, ready for action!).

Brevisulcenal-F spectrum and structure overlay
Source: JACS and M. Satake, U. of Tokyo

But how big is big? This new natural product certainly contends, but still doesn't approach two of the 850-lb gorillas in the room: palytoxin (PTX) and maitotoxin (MTX). First synthesized from PTX-COOH by Kishi in 1994, palytoxin, a soft-coral isolate from Hawaii, weighs in at 2680 amu. Although not specifically a ladder polyether, it was for decades considered the largest known non-peptide natural product. But PTX pales still in comparison to the largest known non-peptide np, maitotoxin, which totals 3422 amu, with 32 total ether rings. Isolated from Tahitian fish in 1976, maitotoxin eluded full structural characterization until the mid-1990s.

I'm glad my NMRs don't look like maitotoxin.
Source: Murata, JACS 1994

Where are these huge marine toxins coming from, exactly? Nakanishi advanced a polyepoxide cascade theory as early as 1985, which suggested that long, polyunsaturated terpenes (olefin biopolymers) were being somehow oxidized by the microorganisms, then cyclized into long ether "ladders," like a falling stack of dominos. It took another 20 years for experimental confirmation, but new cascade research by Jamison and others has shown that this might indeed be the case.