3 Synthetic Study of (-)-Grayanotoxin

Grayanotoxins (1-4), toxic principles isolated from leaves of various plants of family Ericaceae, have been shown to increase specifically membrane permeability to sodium cation in sodium-dependent excitable membranes. These diterpenes are characterized by the A-nor-B-homo-kaurane skeleton, unique tetracyclic carbon framework, and by the dense arrangement of hydroxyl groups. Effective synthetic routes to the CD-, A-, and B-rings of grayanotoxins has been successfully developed. Construction of CD-Ring. A reliable synthetic scheme to produce the CD-ring, a diol-γ-lactone 17, in an optically active form was explored. Stereoselective formation of the C-ring was performed through enantioselective Diels-Alder reaction of an α, β-unsaturated ester 10, prepared from L-ethyl lactate, stereocontrolled alkylation of a β-ketoester 13, and regio- and stereoselective reduction of a keto-γ-lactone 14. The D-ring was constructed via radical cyclization of a hydroxy-γ-lactone 9 and stereoselective iodohydrin formation of an olefine-γ-lactone 16. Construction of A-Ring. Connection of the CD- and A-rings was examined. It turned out that cross Aldol reaction of the acyclic precursor of the A-ring, aldehyde 7 and the CD-ring, methylketone 8 took place cleanly, giving an α, β-unsaturated ketone 18. Thus, elaboration of the A-ring was studied using model compounds. Stereocontrolled cyclization of the A-ring meditated by samarium(II) iodide was achieved by employing an allylsulfide 19 as a starting material to afford an alcohol 20. Construction of B-Ring. The tertiary hydroxyl group of the B-ring was introduced by stereocontrolled epoxidation of a homoallylalcohol 24, synthesized from grayanotoxin II (2), followed by reduction, giving rise to a diol 25. Ring closure reaction that lead directly to the vicinal cis-diol moiety of the B-ring was also investigated. Samarium(II) iodide induced pinacol coupling reaction of ketoaldehyde 5, prepared from grayanotoxin III (3), was found to occur in a stereoselective manner to afford a triol 26.