Of swinholide

Swinholide A, isolated from the marine sponge Theonella swinhoei, sequesters actin dimers and induces their formation. One molecule of swinholide A binds to one dimer. In addition, swinholide A can sever F-actin by binding to the neighbouring protomers. Increased depolymerization of F-actin has also been reported. 

Andrianasolo EH, Gross H, Goeger D, Musafija-Girt M, McPhail KP, Leal RM, Mooberry SL, Gerwick WH (2005) Isolation of swinholide A and related glycosylated derivatives from two field collections of marine cyanobacteria. Org Lett 7 1375-1378... 

Todd JS, Alvi KA, Crews P (1992) The isolation of a monomeric carboxylic acid of swinholide A from the Indo-Pacific sponge, Theonella swinhoei. Tetrahedron Lett 33 441 142... 

Tsukamoto S, Ishibashi M, Sasaki T, Kobayashi J (1991) New congeners of swinholides from the Okinawan marine sponge Theonella sp. J Chem Soc Perk Trans 1 3185-3188... 

Scheme 22 Vinylogous aldol reaction used in Paterson s synthesis of swinholide A...

Doi, M. Ishida, T. Kobayashi, M. Kitagawa, I. (1991) Molecular confcnmation of swinholide A, a potent cytotoxic dimo ic macrolide from the Okinawan marine sponge Theonella swinhoei. J. Org. Chem., 56, 3629-32. 

Hayakawa, H. Miyashita, M. An efficient and stereoselective construction of the C(9)-C(17) dihydropyran segment of swinholides A-C via a novel reductive cleavage of an epoxy aldehyde. Tetrahedron Lett. 2000, 41, 707-711. 

An excellent simple and induced selectivity could be obtained by Mulzer and his group [92] in the cycloaddition of 2-trimethylsilyl-oxy-l,3-pentadiene 2-31 and (lR,2S,5R)-8-phenylmenthyl glyoxylate 2-32 [93] in the presence of 0.2 equivalents of anhydrous MgBr2 in THF at 0 °C. After acidic workup the ketone 2-33 was isolated as a single diastereomer (>98%), which was then used for synthesis of the C-26-C-32 tetrahydropyran moiety of swinholide. In contrast,... 

This methodology which bases on Oppolzer s sultams has also been employed in the synthesis of 2,6-N,N-diacetyl-D-purpurosamidine C [475,476]. Hetero Diels-Alder reactions of carbonyl dienophiles are furthermore involved in the preparation of ( )-ketoheptulosic acid [477] and in the already mentioned asymmetric approach to the C-26-C-32 tetrahydropyran subunit of swinholide A [92]. 

Another demanding oxidative cyclisation to a p-methoxybenzylidene acetal taken from a synthesis of Swinholide A by Paterson and co-workers1 2 is shown in Scheme 3.83. Note the preservation of the labile di-fer/-butylsilylene group (see section 3,4). Other applications of the reaction to complex natural product synthesis include Oleandolide,88 Discodermolide153 and the Denticulatins.154... 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Figure 7 Synthetic strategy to solve the 2D structure of swinholide A.

Carmely, S., and Kashman, Y. (1985). Structure of swinholide-A, a new macrolide from the marine sponge Theonella swinhoei. Tetrahedron Lett. 26, 511-514. 

Four new cytotoxic minor congeners, swinholides D-G [72] and the monomeric carboxylic acid of swinholide A, pre-swinholide A (73) [73] were then isolated from the Okinawan marine sponge Theonella sp. The high cytotoxic activity exhibited by swinholide A (68) [74], probably related to the spatial ring conformation [75], has been attributed to its ability to dimerize actin and to disrupt the actin cytoskeleton [76]. 

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