Synthesis of Cylindricines

The family of tricylic compounds despite being known to possess no significant biological activity have been a target of many previous syntheses because of it's challenging structure. The paper in discussion today is the synthesis of Cylindricine C synthesised in the Chemistry Research Laboratory at Oxford University which elaborates the use of the recently published methodology by the Donohoe group.

Most of the previously reported synthesis (Snider, Heathcock, Molander, Trost and Kibayashi) have relied upon the late-stage construction of the six-membered B ring but Donohoe's synthesis was planned to begin with the ring B in place. It began with the commercially available picolinic acid which was converted to the disubstituted N-protected pyridine. Then Donohoe and co-workers extended the scope of their own methodology (previously shown N-methyl and N-allyl pyrdinium salts) by showing more examples of Grignard addition to N-DMB protected pyridinium salts. 

The key intermediate was prepared in a stereo and regio-selective manner with that methodology. After the ring closure and  the subsequent nucleophilic addition of the alkyl Gringard (HexMgBr) gave the desired diastereomer as the major product (X-ray structure). Further maniuplation of the ester side-chain through a series of well-known chemistry yielded them an intermediate aldehyde which could (using Snider's method) lead to cylindricine A, thus completing a formal synthesis of it. Also the same intermediate aldehyde was then converted to give cylidricine C as well.

Donohoe, T., Brian, P., Hargaden, G., & O’Riordan, T. (2010). Synthesis of cylindricine C and a formal synthesis of cylindricine A Tetrahedron, 66 (33), 6411-6420 DOI: 10.1016/j.tet.2010.05.044