Structure azaspiracid

Ofuji, K., et ah. Structures of azaspiracid analogs, azaspiracid-4 and azaspiracid-5, causative toxins of azaspiracid poisoning in Europe, Biosci. Biotechnol. 

In 1995, a report of human illness with diarrhetic shellfish poisoning (DSP)-like symptoms in the Netherlands was eventually found to result from the consumption of poisoned mussels (Mytilus edulis) harvested from Killary Harbour, Ireland (McMahon 1996). Yasumoto, Satake, and co-workers eventually isolated and proposed a stracture for the causative agent of this condition azaspiracid-1 (la. Fig. 16.1). The unique polyether stracture of azaspiracid-1 (la) is characterized by several spiro-cyclic systems, including an azaspiro ring fused to a 2,9-dioxabicyclo[3.3.1]nonane system and a terminal carboxylic acid. In total, there are nine rings and twenty stereogenic centers within the structure proposed by Yasumoto and co-workers in 1998 (Satake 1998). This stracture was based primarily on NMR spectroscopic data and did not include absolute stereochemistry, nor did it specify relative stereochemistry between the ABCDE and FGHI domains. 

Figure 16.1. Originally proposed structure of azaspiradd-1 (1a, relative stereochemistry between ABCDE and FGHI domains and absolute stereochemistry unknown) and the corrected structure of azaspiracid-1 (1).

Scheme 16.5. Construction of the originally proposed ABCD core structure of azaspiracid-1 through exploitation of intramolecular hydrogen bonding (Nicolaou 2001 b).

Scheme 16.8. Strategies toward the originally proposed structures of azaspiracid-1 (la) and FGHI-epi-azaspiracid-(55) (Nicolaou 2003a, 2003b).

Unsure of how to proceed along the lines of total synthesis, we resorted to new tactics in order to discover the true structure of azaspiracid-1 (Nicolaou 2004a, 2004b). It was requested that the Satake group attempt a chemical degradation of natural azaspiracid-1, a task that was admirably carried out as shown in Scheme 16.9, to produce 56-61. The Satake group then obtained H NMR spectra of these compounds (58, 59, 57, and 61) and we set out to synthesize them in order to confirm their structures. 

Scheme 16.11 shows the completion of the total synthesis of azaspiracid-1, which followed with slight modifications, the synthesis of the originally proposed structure of azaspiracid-1 (la). This chemistry was also carried out with the corresponding ABCD enantiomer in similar yields. Thns, lithiation of dithiane 51 (n-BuLi n-BnjMg) followed by addition into pentafluorophenol ester 68 resulted in CJ-C27 ketone 69 (50% yield). Ketone 69 was then elaborated into diacetate 70, this time as the TBS ether at C-25, as this protecting group was easier to remove than the acetate used in the earlier work directed toward the original stractnre (see Scheme 16.8). Stille coupling of this allylic acetate (70) then proceeded smoothly, as before, affording the complete Cj-C q backbone 71, which was successfully elaborated to the correct structure of azaspiracid-1 (1), identical in all measured physical properties ( H NMR, C NMR, Rf, [aj ) to the natural material.

The isolation of azaspiracid-1 from poisonous mussels (Mytilus edulis) by Yasumoto and Satake was an admirable and Herculian accomplishment. Its originally proposed structure by these investigators stimulated considerable efforts to synthesize it in the laboratoiy. The efforts in om laboratory led first to the demise of the originally proposed structures and subsequently to the proposal and total synthesis of the correct structure of this fascinating natural product. 

Nicolaou, K.C., Koftis, T.Y, Vyskocil, S., Petrovic, G., Ling, T.T., Yamada, Y.M.A., Tang, W.J., and Frederick, M.O. 2004a. Structural revision and total synthesis of azaspiracid-1, part 2 definition of the ABCD domain and total synthesis. Angew Chem 7nf rf43(33) 4318 324. 

Ofuji, K., Satake, M., McMahon, T, James, K.J., Naoki, H., Oshima, Y., and Yasumoto, T. 2001. Structures of azaspiracid analogs, azaspiracid-4 and azaspiracid-5, causative toxins of azaspiracid poisoning in Europe. Biosci Biotechnol Biochem 65(3) 740-742. 

Vilarino, N. Nicolaou, K.C., Frederick, M.O., Cagide, E., Ares, I.R., Louzao, M.C., Vieytes, M.R., and Botana, L.M. 2006. Cell growth inhibition and actin cytoskeleton disorganisation induced by azaspiracid-A. Structure-activities studies. Chem. Res. Toxicol 19, 1459-1466. 

S. Brombacher, S. Edmonds, D.A. Vohner, Studies on azaspiracid biotoxins. II. Mass spectral behavior and structural elucidation of azaspiracid analogs. Rapid Commun. Mass Spectrom., 16 (2002)2306. 

Compared with the previous coupling types, much less has been reported with these relatively more difficnlt conplings. Exceptionally, conplings with allyl electrophiles, usually allyl acetates or halides, have been often nsed in the synthesis of complex natural products.A noteworthy example is the synthesis of the azaspiracids 1-3 (115a-c), neurotoxins isolated from mussels, whose structure was determined by total synthesis by Nicolaon and coworkers.This synthesis features a notable Stille... 

VUarino, N. et al.. Cell growth inhibition and actin cytoskeleton disorganization induced by azaspiracid-1 structure-activity studies, Chem Res Toxicol 19, 1459, 2006. 

Vale, C. et al.. Effects of azaspiracid-1, a potent cytotoxic agent, on primary neuronal cultures. A structure-activity relationship study, J Med Chem 50, 356, 2007. 

It has been recently shown that YTX did not induce any effect in E-cadherin system in vivo [32]. These results confirm the loss of morphological changes the toxin induced in any internal organ after several days of oral treatment, which has been described earlier. Before these last results and from E-cadherin data, YTX was proposed to facilitate tumor spreading and metastasis formation [30] however, now affirmation of this hypothesis should be reviewed. In addition, an effect over E-cadherin levels was recently reported after azaspiracids exposition, suggesting that both toxins share their mechanism of action [33]. However, while human azaspiracids intoxications had been reported, YTX intoxications have never been described, and the data available about azaspiracid effect show a very different effect over cAMP, cytosolic calcium, intracellular pH, and cytoskeleton structure [34-39]. 

FIGURE 35.1 Structures of azaspiracids (see Table 35.1 for the identity of the substituents R... 

Azaspiracid Structures (See Figure 35.1) and Precursor and Product Ion Masses in Positive Mode... 

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