Synthetic study of ciguatoxin. Absolute configuration of the C2 hydroxy group

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

“…4–6,8,10–12) The synthetic CTX3C was determined to be identical to the naturally occurring form in every respect, including mouse acute toxicity, which unambiguously confirmed the absolute stereochemistry of ciguatoxins. 28,32,33) Thus, the power of our unified convergent [X + 2 + Y] coupling strategy 12,40) for constructing this large and complex ladder-like polyether system was clearly demonstrated. In addition, it should be noted that the synthetic fragments and penultimate intermediate, tris-benzyl ether 46 , did not exhibit detectable toxicity (see Fig.…”

“…Early on, we developed enantioselective routes to the medium (7-, 8-, and 9-membered) ring ethers of ciguatoxins 27–31) and the circular dichroism (CD) studies of synthetic AB ring fragments implicated the absolute configuration of CTXs. 28,32,33) Then, we quickly realized that convergent assembly of the structural fragments was the key for successful construction of the huge ladder-like polycyclic ether system. 12,34) …”

Total Synthesis of (−)‐Brevenal: A Streamlined Strategy for Practical Synthesis of Polycyclic Ethers

“…To test this idea, the bicyclic ether 9 was elaborated to the alcohol 26 in two steps involving debenzylation and selective silylation of the resulting primary hydroxy group (Scheme b). We examined several leaving groups for regioselective elimination of the C15 secondary hydroxy group and found that the corresponding mesylate29 and monochloromesylate30 were not sufficiently reactive toward base‐mediated elimination, whereas the triflate 27 was very unstable and readily decomposed during attempted isolation. Eventually, a one‐pot triflation/elimination protocol (Tf 2 O, 2,6‐lutidine, CH 2 Cl 2 , −78 °C; then DBU, room temperature) was devised to address this problem, cleanly giving the olefin 28 in 80 % yield.…”

Total synthesis of ciguatoxin CTX3C: a venture into the problems of ciguatera seafood poisoning

“…After considerable effort, in 1997, the absolute configuration of 5 as well as the stereochemistry of C3′ of 4 were determined in collaboration with the Yasumoto group, as shown in Figure 1, mainly by comparing the CD spectra of the synthetic fragments and the derivatives of minute amounts of natural products 3,24,25. We found that the configuration‐defined synthetic p ‐bromobenzoate ( 7 ) of the AB ring fragment of 5 exhibited an intense positive split Cotton effect, which was caused by interaction between the 1,3‐diene and p ‐bromobenzoate (MeOH, λ ext 242 nm, Δε +25; λ ext 225 nm, Δε −14).…”

“…In the early studies on the synthesis, we developed enantioselective routes to the medium ring ethers of the ciguatoxins 22,24. In this context, a Pd‐catalyzed stereospecific cyclization reaction of hydroxy epoxides23 and then an extensive ring‐expansion strategy to the 7‐, 8‐, and 9‐membered cyclic ether rings were devised 26.…”