Synthesis of palytoxin

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... 

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

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. 

In the course of his synthesis of palytoxin. Ars/i/17 noted that only certain batches of CrCb were effective. Closer investigation showed that an impurity of NiCl is essential if the reaction is to succeed. 

The Nozaki-Hiyama Kishi reaction has been successfully utilized in the total synthesis of palytoxin (355) [170] brefeldin (356) [172], halichondrin B [173], brevetoxin [174], pinnatoxin A [174a] and others. The coupling of alkynyl iodides with aldehydes can be carried out smoothly using CrCl2 and 0.01% of NiCk... 

Enantioselective reduction of an a, -enone. One of the final steps in a synthesis of palytoxin, a toxin of marine soft corals containing 115 carbon atoms and 60 chiral centers, involves, in addition to the usual deprotections, enantioselective reduction of an enone to an allylic alcohol. A mixture (1 1) is obtained with borohydrides, but lithium borohydride combined with EuC13 provides an 8 1 mixture, with the desired isomer being favored. 

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

The two cyclization reactions shown below were used for the synthesis of palytoxin segments28. Since no products stereoisomeric to 2 and 4 are mentioned by the authors28, the transformations of 1 and 3 apparently proceed quite stereoselectively. This is in sharp contrast to the cyclization of the enoate rac-5, which yields a 1 1 mixture of the racemates 629. 

For example, Suzuki cross-coupling was a key step in the synthesis of palytoxin, perhaps the most potent nonpeptide toxin known, which is isolated from coral. Palytoxin possesses over 70 stereogenic centers (which means that the number of stereoisomers possible approaches Avogadro s number ) and has a molecular weight of 2680 Da, making it the heaviest secondary metabolite to be synthesized to date. For a report on the synthesis of palytoxin, see E. M. Suh and Y. Kishi, J. Am. Chem. Soc., 1994,116, 11205. 

Natural products Before the advent of spectroscopic methods (UV, IR, NMR, MS), total synthesis by independent methods was a way to achieve a proof of the proposed structure of a molecule. Today, spectroscopic methods solve most structural problems. Total synthesis by independent routes is still used occasionally as structural proofs, and recent examples are provided by Corey [5] in the synthesis of leukotriene and Kishi [6] in the synthesis of palytoxine. Today, most natural product synthesis is used to prepare sufficient amounts of interesting compounds, e.g. 

The culmination of which came about later with the synthesis of palytoxin in 1989 by Y. Kishi s team at Harvard, a monument to the Promethean ability of chemists. 

P. tuberculosa [62], with a yield of 100%. It is, however, unlikely that chemical synthesis of palytoxin will be of practical use, as the whole procedure involves approximately 65 steps [63],... 

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]. 

However, the chemoselectivity in Pd-catalyzed cross-coupling of alkenylborons would suffer from the strongly basic condition and elevated reaction tanperatures, when substrates with sensitive functional groups are employed. This limitation has been overcome, to some extent, by the use of aqueous solution of TlOH in place of NaOH or KOH as demonstrated by Kishi and co-workers in the synthesis of palytoxin. The dramatic rate enhancement of Suzuki coupling by TlOH allows the reaction to proceed smoothly even at 0 °C. The utility of this method has been demonstrated in other natural product syntheses as (Sect. IIL2.18). 

Scheme 7.1 Protecting group pattern in the final phase of the synthesis of palytoxin carboxyUc acid...

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