Cycloaddition Routes to Tricyclo1,7.02,9>undecanes: A Direct Total Synthesis of (+)-Longifolene via an Intramolecular Diels-Alder Strategy

Article abstract of DOI:10.1021/jo00060a039

The total synthesis of the sesquiterpene (+)-longifolene (1) by an intramolecular Diels-Alder cycloaddition strategy is described.Addition of methyllithium to the epoxyfulvene 13, derived from cyclopentadiene and 3,4-epoxy-2-butanone, led to an exo-tet cyclization of the resulting cyclopentadienyl anion to generate the spiro<2.4>hepta-4,6-diene alcohol 14.Resolution of this material was effected via its menthyl carbonate derivative 15.Oxidation of the (+)-R-alcohol with active MnO2 afforded the cyclopropyl aldehyde 16 which was condensed with the anion derived from methyl 3-methylcrotonate in the presence of cadmium chloride to gen erate the unsaturated lactone 20 or the unsaturated ester 18.Microwave heating of the silyl triene 19 effected cycloaddition to the adduct 21.Hydrogenolysis of the alcohol 22 afforded the "sinularene" skeleton 25.Cyclopropane ring cleavage of the derived ketones 23, 30, and the thiocarbonate 27 was examined but only in the Li/NH3 reduction of 30 was the longifolene skeleton 33 produced as a significant product which unfortunately could not be separated from its isomer 32.Consequently the successful route utilized regiospecific cleavage of the cyclopropane ring in the cyclopentadiene 20 in methanol catalyzed by BF3*Et2O to afford the substituted cyclopentadiene lactone(s) 34 (83percent).Cyclization proceeded smoothly, in a sealed tube, in toluene, in a microwave oven to afford the single tetracyclic adduct 39 in 97percent yield.Double bond hydrogenation and reduction of the lactone with LiAlH4 afforded the substituted longifolene skeleton, and the resulting primary alcohol was acetylated selectively to give 40.Free-radical-mediated replacement of the secondary oxygen functions was accomplished via the phenoxythiocarbonate derivative to afford the methoxy acetate 43.Alternatively the reaction sequence could b e modified to convert 39 to 41 to 42 and then to 43.Methoxy cleavage (Me3SiI) and a second free-radical reaction gave the acetate 44.Pyrolysis of this acetate (525 deg C) provided (+)-longifolene (1).