Gymnocin

AU marine polyether ladders thus far characterized (e.g., maito-toxin 16 (Fig. 4a), the brevetoxins 12 and 13 and hemibreve-toxin B, the yessotoxins 14 (and the truncated adriatoxin), the Pacific and Caribbean ciguatoxins, the gambieric acids 15 and gamberiol (the gymnocins and brevenal) can be grouped into 14 backbone structures (3). 

Figure 36 Gymnocin-B 80 and the lowest-energy conformation of its 10,37-bis(TPP-cinnamate) derivative 81 obtained by Monte Carlo/MMFF94s with Spartan 02. Experimental CD (in MeOFI, c —3.0 x 10 6) 419nm (Ae+11), 414 nm (Ae-15) Boltzmann weighted (at 298 K) average CD calculated by De Voe s method 420 nm (Ae +25), 414 nm (Ae -25). Redrawn from K. Tanaka Y. Itagaki M. Satake H. Naoki T. Yasumoto K. Nakanishi N. Berova, J. Am. Chem. Soc. 2005, 127, 9561-9570.

V). The absolute stereochemistry of gymnocin A was clarified by combining the analysis of NOE data and the modified Mosher method. The total syntheses of gymnocins A (167) and B (168) have been accomplished by Sasaki and coworkers. ... 

The stereoselectivity seen in the reduction of the seven-membered ketone above has proved to be general. This particular result, rationalized by the propensity for pseudoaxial hydride addition under Luche conditions, proved useful in the convergent total synthesis of Gymnocin-A, a polycyclic ether toxin isolated from the red tide dinoflagellate—Karenia mikimotoi.u The Luche reduction was used for the production of allylic alcohol 9 from ketone 8 in 84% yield. Luche conditions were similarly applied to the synthesis of the related polycyclic ether toxin gambierol.12... 

Satake, M., Shoji, M., Oshima, Y, Naoki, H., Fujita, T., and Yasumoto, T. Gymnocin-A, a cytotoxic polyether from the notorious red tide dinoflagellate, Gymnodinium mikimotoi, Tet. Lett, 43, 5829-5832, 2002. 

Total synthesis and structure-activity relationship of a cytotoxic polycyclic ether Gymnocin-A 06Y808. 

Gymnocin-A and gymnocin-B showed cytotoxicity against mouse lymphoid P388 cells at 1.3 xg/ml and 1.7 xg/ml, respectively. 

Scheme 14 Total synthesis of gymnocin-A by the Sasaki group (continued)...

Although no natural product synthesis has yet to be completed by a cascade in water under neutral conditions, the Jamison group has used the protocol to prepare the impressively complex tetfa-tetfahydropyran core of the ladder toxin gymnocin (188 Scheme 4.43) [78]. Triepoxide 189 was heated to 80°C in water for 9 days to yield 188 in 35% yield. The reaction rate was slower than previously observed rates because the final cyclization step was sluggish. The authors... 

SCHEME 4.43 Jamison s approach to the gymnocin tetrahydropyran core. 

Sasaki, M Tsukano, C., and Tachibana, K. (2002) Studies toward the total synthesis of gymnocin A, a cytotoxic polyether A highly convergent entry to the F-N ring fragment Org. Lett., 4, 1747-1750. 

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