Palytoxin

According to an ancient legend from Hawaii, on the Island of Maui there was a village of fishermen near the harbour of Hana which was haunted by a curse. One day, when the fishermen returned from the sea, one of the fishermen were missing. On the next day, another loss of fisherman caused the other fishermen assaulted a hunchbacked hermit deemed culprit of the village's misery. While ripping off the hermit's cloak, the villagers were shocked because they found rows a sharp and triangular teeth within a huge jaw. They had caught a shark god. It was clearly that the missing men was eaten by the shark god and the men mercilessly tore the shark god into pieces, burned him, and threw the ashes into a tide pool. Then, a thick brown moss started to grow one the pool's wall which caused an instant death to the victims hit by spear smeared by that moss. Thus, this moss was known  as limu-make-o-hana which means seaweed of death from Hana. From this legend, it turns out that limu-make-o-hana is scientifically known as Palythoa toxica with palytoxin as the active toxic ingredient.

Palytoxin (left) and soft marine corals from genus Palythoa (right)

Palytoxin is intense vasoconstrictor and known to be one of the most toxic non-peptide substances known, second only to maitotoxin. This toxin is commonly found from marine soft corals of genus Palythoa. In 1981, two separate groups, Hirata's and Moore's group, elucidated the gross structure of palytoxin and from this elucidation, it was very clear to organic chemist that this molecule is distinct with the previous organic compounds in term of molecular weight and structure complexity. It was only in 1989 that palytoxin carboxylic acid was totally synthesised and palytoxin itself in 1995 by Kishi's group. In general, the synthesis of palytoxin can be divided into three general steps:

1. synthesis of fully-protected palytoxin carboxylic acid (PTC),
2. synthesis of palytoxin carboxylic acid (PTC),
3. synthesis of palytoxin (PTX).

Synthesis of first fragment 10 of fully protected PTC

In the synthesis of fully protected palytoxin carboxylic acid (PTC), a unique strategy was employed to form the C-C single bond via Wittig reaction followed by hydrogenation for the coupling of C22-C23 and C37-C38. In this Wittig-hydrogenation reaction scheme, aldehylde 3 was prepared under Swern oxidation condition. Another unique strategy for C-C formation also employed to form C7-C8 bond via NiCl₂/CrCl₂ coupling reaction with aldehyde end of 8 was used in this coupling scheme. The first fragment of 10 with aldehyde end would be used to couple with the second fragment to synthesis the fully protected PTC.

Synthesis of second fragment 17 of fully-protected PTC

The second fragment of 17, followed the same route as the first fragment 10 with Wittig olefination with E-configuration of 13 as the product. Another Ni(II)/Cr(II) coupling reaction preceeded by oxidative hydrolysis of thioacetal to yield allylic alcohols. This allylic alcohol is oxidised by pyridinium dichromate (PDC) to give α,β-unsaturated ketone which then underwent Wittig olefination to form a diene. The final piece of 17 is stitched with Pd(0) Suzuki coupling followed by the formation of dimethyl phosphate ester which will be used as Wittig reagent to form the protected PTC.

Final stage of synthesis of fully-protected PTC, synthesis of PTC and PTX

Both fragments of 10 and 17 were joined together via Wittig olefination reaction followed by Luche reduction and reprotection to produce the fully protected PTC. It is noteworthy that several protecting group were employed by Kishi's group in the synthesis of PTC. In this scheme, there are 8 different and 42 protecting groups were used such as p-methoxybenzyl (PMB) for its stability under various reaction conditions of the formation C37-C38  and t-butyldimethylsilyl (TBS). The deprotections were done in 5 steps:

1. deprotection of PMB using DDQ,
2. acid treatment to hydrolyse the acetonide group,
3. base treatment to hydrolyse the acetate and benzoate groups ,
4. fluoride treatment to remove TBS and the urethane groups,
5. aqueous acid to hydrolyse the hemiketal group.

Then, the final piece of jigsaw of palytoxin synthesis was put in place in 1995 via phenylselenide route which consists of coupling and elimination reaction. However, these steps exclusively produce E-isomer which means isomerisation process is required. In this case, the isomerisation process was done using photochemical reaction and it is noteworthy that this reaction is solvent dependent.

Key reaction of the total synthesis of palytoxin

The toxicity of palytoxin is due to its binding to sodium pump where it interacts with the natural binding site of ouabain with high binding affinity and because this sodium protein pump is transmembranal protein, this explain how palytoxin affects all cell. Palytoxin is the first compound found to cause a formation of a channel. One, palytoxin is bound, it flips constantly open and close but when it is open, which is very likely (>90% chance), a million of ions diffuse through the pump per second, whereas only one hundred ions are normally transported with this channel. Thus, an ion gradient of the cell is destroyed.

Ouabain (left) and sodium-potassium ions pump

The most common implication of palytoxin poisoning is rhabdomyolysis whinch involves skeletal muscle breakdown and leakage of intracellular contents into the blood plasma. The other common symptoms related to palytoxin poisoning in human are characterised by a bitter/metallic taste, abdominal cramps, nausea, vomitting, diarrhea, mild acute to lethargy, paresthesia, bradycardia, renal failure, impairment of sensation, muscle spasms, tremor mylagia, cyanosis and respiratory distress. Furthermore, from animal studies, vasodilators such as papaverine and isosorbide dinitrate can be used as antidote but this only shows benefits when injected directly to the heart. Treatment in human is symptomatic and supportive.

References

1. R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. W. McWhorter, M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J. Uenishi, J. B. White, and M. Yonaga, J. Am. Chem. Soc., 1989, 111, 7525.
2. R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. W. McWhorter, M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J. Uenishi, J. B. White, and M. Yonaga, J. Am. Chem. Soc., 1989, 111, 7530. 
3. E. M. Suh, Y. Kishi, J. Am. Chem. Soc., 1994, 116, 11205.