Synthetic approaches to the hepatotoxic alkaloid cylindrospermopsin

Approaches to the total synthesis of the hepatotoxic alkaloid cylindrospermopsin (1) are described. The feasibility of the key intramolecular N-sulfinyl dienophile Diels-Alder cycloaddition was tested in a model system. Model diene urea 92 was converted to the corresponding N-sulfinyl compound 98, which underwent stereoselective intramolecular (4+2) -cycloaddition to afford dihydrothiazine oxide adduct 99. Treatment of 99 with PhMgBr, followed by stereospecific (2,3) -sigmatropic rearrangement yielded 112, which has the AB ring system and C-7,8, and 10 configuration of 1.; One strategy involved the Diels-Alder cycloaddition of N-tosylimine 158 with oxygenated diene 208 under either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 207 and 209. Although undesired cis enone 209 was the major product under all reaction conditions, it could be converted to desired trans enone 207 by acid-catalyzed isomerization. Copper-mediated addition of vinylmagnesium bromide to trans enone 207, followed by stereoselective ketone reduction with L-Selectride, produced alcohol 213, whose structure was confirmed by X-ray crystallography. Alcohol 213 was then protected as silyl ether 214, which was hydroborated at the terminal olefin to produce primary alcohol ester 216, having the stereochemistry and functionality needed for cylindrospermopsin.; A more economical and straightforward approach to the piperidine ring was also developed. The acylpyridinium salt of 4-methoxypyridine was treated with Grignard reagent 243 which yielded enone 244 after acidic hydrolysis. Alkylation of the enolate of 244, followed by copper-mediated conjugate addition, yielded ketone 246 as a single isomer. Ketone 246 was reduced with L-Selectride to provide alcohol 251, which possessed the correct relative stereochemistry of the A-ring of 1. Protection of the alcohol, followed by Tamao oxidation, yielded cyclic carbamate 253, which was elaborated into diene 258. Hydrolysis of the oxazolidinone and urea formation provided urea 262, which was treated with thionyl chloride. Unfortunately, none of the desired cycloadduct 264 was obtained under any of the experimental conditions tried.