Azaspiracids

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

Volmer, D.A., Brombacher, S., Whitehead, B. (2002). Studies on azaspiracid biotoxins. I. Ultrafast high-resolution liquid chromatography/mass spectrometry separations using monolithic columns. Rapid Commun. Mass Spectrom. 16, 2298-2305. 

The linear-fused tricycle 446 was a key intermediate in the synthesis of the marine toxin azaspiracid (Equation 121) <2004H(63)539, 2004TL351>. 

An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 <06T5338 06JA15114>. 

In Carter s studies toward the total synthesis of azaspiracid, the construction of "fragment B" requires the conversion of the y-lactone 91 into a furan acetal. In this connection, it has been uncovered that the desired furan acetal can indeed be formed in 64% yield under methanolic acidic conditions . 

Microalgae produce many potent natural products in the form of complex polycyclic polyethers, a type of polyketide. The ladder-like polyether brevetoxin B (Fig. 1.8a) (Lin et al. 1981) is representative of a host of such toxins, which include cigua-toxin (Scheuer et al. 1967), yessotoxin (Murata et al. 1987), maitotoxin (Murata et al. 1993), gambieric acids (Murata et al. 1992), and azaspiracid (Satake et al. 1998). Brevetoxin B, one of the causitive agents of red tide poisoning, can be isolated from... 

Satake M, Ofuji K, Naoki H, James KJ, Furey A, Mcmahon T, Silke J, Yasumoto T (1998) Azaspiracid, a new marine toxin having unique spiro ring assemblies, isolated from Irish mussels, Mytilus edulis. J Am Chem Soc 120 9967-9968 Scheuer PJ, Takahashi W, Tsutsumi J, Yoshida T (1967) Ciguatoxin isolation and chemical nature. Science 155 1267-1268... 

Okadaic acid Dinophysistoxins (>6) Domoic acid (3) Azaspiracid (5) Ciguatoxin (>10) Maitotoxin Scaritoxin... 

AZP, the most-recently characterized marine seafood poisoning, is associated with eating shellfish contaminated with azaspiracids. The first human intoxications attributed to AZP occurred in the Netherlands, and the symptoms included those similar to DSP (i.e., nausea, vomiting, severe diarrhea, and stomach cramps). However, although chemical analyses did not identify significant levels of the diarrhetic shellfish poisons, they identified a new class of toxins (James et ah, 2003a). 

The azaspiracids are another class of polyether toxins with unique spiro ring assemblies, a cyclic amine and a carboxylic acid. Five analogs have been described (Ofuji et al., 1999, 2001 Satake et al., 1998). Azaspiracids are produced by species of the dinoflagellate Protoperidinium, a phytoplankton genus historically thought to be benign (James et al., 2003a). 

Little information exists about the mechanism of action of the azaspiracids. The chronic effects observed in mice after oral administration of azaspiracid included interstitial pneumonia, shortened villi in the stomach and small intestine, fatty changes in the liver, and necrosis of lymphocytes in the thymus and spleen (Ito et al., 2002). 

The original cases of AZP were reported in the Netherlands in 1995 and were associated with eating mussels harvested in Ireland (McMahon and Silke, 1996, 1998). AZP in humans has been reported throughout Europe since 1995, and azaspiracids have been found in shellfish harvested in Spain, France, and northern Europe (James et al., 2002 Magdalena et al., 2003a). 

Toxin (primary or class of toxins) Saxitoxin Brevetoxin Okadaic acid, dinophysistoxin Domoic acid, kainic acid Azaspiracid Ciguatoxin... 

Ito, E., et al., Chronic effects in mice caused by oral administration of sublethal doses of azaspiracid, a new marine toxin isolated from mussels, Toxicon, 40, 2, 193, 2002. 

James, K.J., et al.. First evidence of an extensive northern European distribution of azaspiracid poisoning (AZP) toxins in shellfish, Toxicon, 40, 7, 909, 2002. 

James, K.J., et al.. Ubiquitous benign alga emerges as the cause of shellfish contamination responsible for the human toxic syndrome, azaspiracid poisoning, Toxicon, 41, 2, 145, 2003a. 

Magdalena, A.B., et al., The first identification of azaspiracids in shellfish from France and Spain, Toxicon, 42, 1, 105, 2003a. 

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

Ofuji, K., et al.. Two analogs of azaspiracid isolated from mussels, Mytilus edulis, involved in human intoxication in Ireland, Nat. Toxins, 7, 3, 99, 1999. 

Okadaic acid (OA), dinophysistoxins (DTXs), pectenotoxins (PTXs), azaspiracids (AZAs) and spirolides Shellfish 9-2,012 ng/g (mainly OA group toxins) [204]... 

James, K.J., Fidalgo Saez, M.J., Furey, A., and Lehane, M. 2004. Azaspiracid poisoning, the food-borne illness associated with shellfish consumption. Food Additives and Contaminants 21, 879-892. 

YTX appears more water-soluble than the other lipophihc toxins as it predominantly extracts to the aqueous methanolic phase in partitioning with dichloromethane or to the aqueous phase when partitioned with ethyl acetate (T. Yasumoto 2001 and authors observations), which may be explained by the sulphate groups giving YTXs a more polar behavior. This behaviour in partitioning has also posed a problem for the extraction of shellfish samples for determination by MBA where YTX has shown irreproducible recovery in the partitioning with diethyl ether. A revised protocol was proposed by Yasumoto in 2001, allowing for separation of YTXs from other, more lipophilic toxins such as okadaic acid or azaspiracids. 

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).

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