Palytoxins

In the total synthesis of the naturally occurring big molecule of palytoxin, which has numerous labile functional groups, this coupling is the most useful for the creation of E, Z-conjugated diene part 653. In this case, thallium hydroxide as a base accelerates the reaction 1000 times more than KOH[523]. Even TECOj can be used instead of a strong base in other cases[524]. 

Covalent synthesis of complex molecules involves the reactive assembly of many atoms into subunits with aid of reagents and estabUshed as well as innovative reaction pathways. These subunits are then subjected to various reactions that will assemble the target molecule. These reaction schemes involve the protection of certain sensitive parts of the molecule while other parts are being reacted. Very complex molecules can be synthesized in this manner. A prime example of the success of this approach is the total synthesis of palytoxin, a poisonous substance found in marine soft corals (35). Other complex molecules synthesized by sequential addition of atoms and blocks of atoms include vitamin potentially anticancer KH-1 adenocarcinoma antigen,... 

Total Synthesis of Palytoxin Carboxylic Ad An Example of the Selection, Introduction, and Removal of Protective Groups... 

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 ... 

SYNTHESIS OF COMPLEX SUBSTANCES TWO EXAMPLES (AS USED IN THE SYNTHESIS OF HIMASTATIN AND PALYTOXIN) OF THE SELECTION, INTRODUCTION, AND REMOVAL OF PROTECTIVE 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). 

Since the syntheses of urea and acetic acid in 1828 and 1845, respectively, synthetic chemists have come a long way in terms of the complexity of the target molecules they can reach. Progress was at first steady, but became rather dramatic in the second half of the 20th century. Vitamin Bi2, ginkgolide B, calicheamicin yi1, taxol, palytoxin, and brevetoxin B (Figure 3) are arguably six of the most impressive molecules to be synthesized to date. 

The execution of this brilliant strategy, culminating in the total synthesis of palytoxin (1) is described below. 

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.

Scheme 11. Construction of the A/-acyl vinylogous urea and synthesis of natural palytoxin (1).

Photochemical equilibration of the 3 2 stereoisomeric mixture of N-acyl vinylogous ureas in DMF by irradiation at 300 nm in a Ray-onet reactor equipped with a stannous chloride filter solution at 37 °C for 4 h leads to a 6 1 mixture of trans-Aa b and c .v-Aa b paly-toxins. The total synthesis of palytoxin (1) is now complete. 

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

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