Palytoxin synthesis

Silver salts are also common activators in numerous Suzuki coupling reactions. The earliest example could probably be found in the Kishi s palytoxin synthesis. Silver oxide as well as thallium hydroxide provided dramatic rate enhancements in the couplings of vinylboronic acids (Scheme 10.41).69 Both thallium and silver ions are most probably abstracting halide in palladium intermediates, but silver is clearly the most efficient. Moreover, with the right counterion, the silver salt also acts as a mild base and activator. 

An example of chain elongation developed in palytoxin synthesis is given below. As shown in Scheme 11.53, compound 239 was reacted with the chiral phosphorane 240 to furnish the Z isomer... 

Uenishi, J.-I. Beau, J.-M. Armstrong, R. W. Kishi, Y. 1987. Dramatic rate enhancement of Suzuki Diene synthesis Its application to palytoxin synthesis. J. Am. Chem. Soc. 109 4756-4758. 

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... 

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). 

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

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. 

To ensure that the inhibition of EGF binding by palytoxin was not a consequence of cell toxicity, the effect of palytoxin on DNA synthesis in Swiss 3T3 cells was monitored. When cells were incubated in the presence of palytoxin, 10% fetal calf serum, and H-thymidine for 19.5 hr, no depression in the extent of H-thymidine incorporation into DNA was detected up to 3.7 pM palytoxin (Table I). Although 11 pM palytoxin was toxic when present for a prolonged period, under the conditions of the assays described above no toxicity was detected (Table I). When cells were incubated in the presence of palytoxin, 0.1% fetal calf serum, and H-thymidine, palytoxin did not stimulate significant incorporation of H-thymidine into DNA. Thus, although it can modulate the EGF receptor system under these conditions, palytoxin alone does not appear to be mitogenic for Swiss 3T3 cells. 

Table I. Effect of Palytoxin on DNA Synthesis in Swiss 3T3 Cells...

Y. Kishi, Natural products synthesis Palytoxin, Pure Appl. Chem., 61 (1989) 313-324. 

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