Palytoxin carboxylic acid

Palytoxin carboxylic acid, C,23H2i3N053 (Figure 1, R -R = H), derived from palytoxin, C,29H223N3054, contains 41 hydroxyl groups, one amino group, one ketal, one hemiketal, and one carboxylic acid, in addition to some double bonds and ether linkages. 

Figure 1. Palytoxin carboxylic acid. (Structure kindly provided by Professor Yoshito Kishi.)...

The C. 100-C. 101 diol group, protected as an acetonide, was stable to the Wit-tig reaction used to form the cis double bond at C.98-C.99, and to all the conditions used in the buildup of segment C.99-C. 115 to fully protected palytoxin carboxylic acid (Figure 1,1). 

Thus the 42 functional groups in palytoxin carboxylic acid (39 hydroxyl groups, one diol, one amino group, and one carboxylic acid) were protected by eight different groups ... 

And so the skillful selection, introduction, and removal of a total of 12 different protective groups has played a major role in the successful total synthesis of palytoxin carboxylic acid (Figure 1,2). 

The next major obstacle is the successful deprotection of the fully protected palytoxin carboxylic acid. With 42 protected functional groups and eight different protecting devices, this task is by no means trivial. After much experimentation, the following sequence and conditions proved successful in liberating palytoxin carboxylic acid 32 from its progenitor 31 (see Scheme 10) (a) treatment with excess 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in ie/t-butanol/methylene chloride/phosphate buffer pH 7.0 (1 8 1) under sonication conditions, followed by peracetylation (for convenience of isolation) (b) exposure to perchloric acid in aqueous tetrahydrofuran for eight days (c) reaction with dilute lithium hydroxide in H20-MeOH-THF (1 2 8) (d) treatment with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran first, and then in THF-DMF and (e) exposure to dilute acetic acid in water (1 350) at 22 °C. The overall yield for the deprotection sequence (31 —>32) is ca. 35 %. 

Scheme 9. Coupling of key intermediates 24 and 30 and synthesis of fully protected palytoxin carboxylic acid 31.

Scheme 10. Deprotection of 31 and synthesis of palytoxin carboxylic acid 32.

Palytoxin carboxylic acid, 5-8 Pentaaminecobalt(III) complex, to protect carboxyl groups, 269-270 Pentachlorobenzenesulfenamides, to protect amines, 377-378... 

Suh, E.M., and Kishi, Y. 1994. Synthesis of palytoxin from palytoxin carboxylic acid. Journal of the American Chemical Society 116(24) 11205-11206. 

In 1989, despite the hnge number of possible stereoisomers, a research group led by Professor Kishi managed to achieve the total chemical synthesis of a fully protected palytoxin carboxylic acid [7]. This was subsequently converted to palytoxin carboxylic acid and palytoxin amide without the use of protecting groups [60]. By comparison of biological activity, chromatographic behavior, and... 

In 1980, using plasma desorption mass spectrometry with californium ( Cf), the exact molecular weight of PTX (1) was established as 2680 for the first time [13]. The planar stracture of 1 was eventually clarified in 1981 [14-16], and its complete stereostructure was elucidated in 1982 [17-20]. Finally, the true stereostructure of 1 was established by an overall degradation reaction and chemical synthesis in 1982. Kishi and his coworkers completed the total synthesis of palytoxin carboxylic acid (3) in 1989 [21, 22], and of PTX itself in 1994 (Figure 30.2) [23,24]. 

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