Total Synthesis of Ciguatoxin and 51-HydroxyCTX3C

Abstract

Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers with the 13 ether rings ranging from five- to nine-membered. In this paper, we describe the total synthesis of the two most toxic members of the ciguatoxin family, ciguatoxin 1 and 51-hydroxyCTX3C 2, based on a unified synthetic strategy. The key features in our syntheses were (i) direct construction of the O,S-acetal from the corresponding left and right wing fragments (3, 4, 14); (ii) stereo- and chemoselective radical reaction of the alpha-oxyradical with pentafluorophenyl acrylate to achieve cyclization of the seven-membered G-ring; (iii) ring-closing metathesis reaction to build the nine-membered F-ring; and (iv) an efficient protective group strategy using the oxidatively removable 2-naphthylmethyl groups.

A study on mechanisms of toxic actions of ciguatoxins: existence of functional relationship between CTX3C and charged residues of voltage sensors in Nav1.4 sodium channel

“…. The ciguatoxin congener CTX3C was chemically synthesized as described previously [13,[25][26][27]. The stock solution of CTX3C (1 mM) in dimethylsulfoxide was diluted with the external solution to a final concentration of 1 lM.…”

Total synthesis and related studies of large, strained, and bioactive natural products

“…4) Our synthesis was appreciated as “The Art of Total Synthesis” by Science (2001, 294 , 1842), “A Synthetic Tour de Force” by Chemical & Engineering News (USA) (2001, Dec. 3, p. 9), and “Organic Chemistry Takes on Tropical Seafood Poisoning” by The Lancet (2001, 358 , 1278). Since then, our highly convergent and unified strategic approach featuring chemoselective RCM/radical cyclization reactions as key tactics has been improved, 5,6,8) and enabled the total synthesis of three other important Pacific congeners, 51-hydroxyCTX3C, 7) CTX1B, 7,9) and 54-deoxyCTX1B, 9) as well as F-ring modified analogs. 38,39) The synthesis of these compounds has significantly impacted the biological and pharmacological studies of CTXs.…”

“…The synthetic challenge presented by 4 is heightened by the presence of the acid/base/oxidant-sensitive bisallylic C5-ether. 7,57) Indeed, the C-O bond at C5 was readily cleaved and rearrangement occurred, especially when Lewis acid was used (Scheme 6). 9) Furthermore, the C21–C22 double bond in the E-ring presented unexpected additional complications upon radical cyclization.…”

“…The right wing sulfide 84a 44,45) was chlorinated using freshly recrystallized NCS and the resultant α-chlorosulfide was coupled without purification to the left wing alcohol 74 by the action of AgOTf to provide O , S -acetal 85a . 7) Despite extensive efforts, the yield of 85a could not be improved (∼26%), possibly due to the presence of the A-ring dihydroxybutenyl substituent. Strongly electron-withdrawing pentafluorophenyl acrylate 58) was attached to 86a instead of the methyl ester to improve chemoselective 7-exo radical cyclization.…”

Synthesis of Natural Products Containing Medium‐Size Oxygen Heterocycles by Ring‐Closing Alkene Metathesis

“…Hirama et al also utilized dienyl substrate 204a as a precursor to the F,G-ciguatoxin ring system (Scheme 3.38) [47]. Although the use of 204a enabled a more convergent coupling sequence, it suffered from a competitive free-radical cyclization reaction to generate the pyranyl substrate 205a.…”