Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin

Abstract

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).

Diastereoselective synthesis of the C29–C41 fragment of karlotoxin 2

“…Compound 13 was then treated with K 2 OsO 4 Á2H 2 O and N-methylmorpholine-N-oxide (NMO) at room temperature in acetone to obtain compound 14 as a major diastereomer (95:5) with 80% yield. 11 The resulting diol was protected as its methoxymethyl ethers with methoxy methyl chloride (MOMCl) and N,N-diisopropylethylamine (DIPEA) in CH 2 Cl 2 at 0°C to afford compound 15 in 90% yield.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…77,78 The oxidation of a complex substrate bearing a primary alcohol has been described by Hirama and co-workers (Scheme 5). ROMPM, 114,115,118,183 ROBn, 80,90,104,106,110,124,191,192 ROTr, 180 ROMe, 94,101,107,113,192 RONPhth, 88 RON=CMe 2 , 88 ArOAllyl, 193 ArOMe, 108,130,131,192,194,195 ArOBn, 127,131 ArOTBS, 174 R 2 NBoc, 174,[194][195][196][197] 208 This IBX analogue generates only water during the oxidation, while DMP releases acetic acid. When DMP was applied the required keto ester was obtained in only 60%, with 40% of the starting lactone recovered (Scheme 6).…”

“…Another example was reported during studies toward maitotoxin by Nicolaou. 104,110 Furthermore, the oxidation system TEMPO/DIB was employed in the oxidative cyclization of a pair of diol epimers to the corresponding lactones in the synthesis of (─)-cyclopamine (Scheme 28). 272 …”

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…However, the stereochemical uniformity inferred from the polyene to polyepoxide to ladder polyether pathway has served as the basis for structural reassignment of brevenal [135,136] and the speculative structural reassignment of the largest known natural product, maitotoxin [120,137,138].…”