IMINO DIELS-ALDER-BASED CONSTRUCTION OF A PIPERIDINE A-RING UNIT FOR TOTAL SYNTHESIS OF THE MARINE HEPATOTOXIN CYLINDROSPERMOPSIN

The synthesis of a piperidine A-ring precursor to the alkaloid cylindr ospermopsin (1) is described. The initial approach to the A-ring precu rsor focused on the imino Diels-Alder reaction of diene 8 with ethyl ( N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereo isomer. However, all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative strategy involved the Die ls-Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 unde r either thermal or Lewis acid-catalyzed conditions to produce a mixtu re of cis and trans enones 20 and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions, it could be c onverted to the desired trans enone 21 by acid-catalyzed isomerization . Copper-mediated conjugate addition of vinylmagnesium bromide to cis- enone 20 followed by stereoselective ketone reduction with L-Selectrid e produced alcohol 23, whose structure was confirmed by X-ray crystall ography. Similarly, trans-enone 21 was converted to alcohol 25 whose s tructure and stereochemistry were also established by X-ray analysis. Alcohol 25 was then protected as the silyl ether 26, which was hydrobo rated at the terminal olefin to produce primary alcohol ester 28 havin g the stereochemistry and functionality needed for cylindrospermopsin.