Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)




The isolation and structure elucidation of two 4,5-dihydrogermacranolides, 9-acetoxymelnerin A (32a) and B (33a), from Melampodium leucanthum Torr. and Gray are reported. Sodium borohydride reduction of 32a proceeds with, besides saturation of the lactonic exocyclic methylene, loss of the C-9 acetoxy group via migration of the 1(10) double bond to the 9,10 position. Pyridinium chlorochromate oxidation of the C-15 primary alcohol function provides the expected aldehyde as the minor product with the major product being a ketone formed by a C-4 to C-15 shift of C-5 of the ten-membered ring, resulting in an eleven-membered ring skeleton. The nucleophilic reactions of nine germacranolides representative of the cis, cis-germacranolide, melampolide, and leucantholide structural classes, commonly found in the genus Melampodium, are described. The cis, cis-germacranolide melcanthin A reacts with two equivalents of sodium ethoxide to form a 13-ethoxydilactone via allylic substitution of the C-9 acetoxy group, saponification of the C-8 sidechain and subsequent 14,8-lactonization. The leucantholide cinerenin forms the identical product via Michael addition of ethanol to the lactonic exocyclic methylene. Substitution of the C-1 acetate function of the leucantholide melampodin B occurs more readily than Michael addition to the lactonic exocyclic methylene. In the case of cinerenin Michael addition proceeds more rapidly than substitution of the C-1 ethoxy group. The results are consistent with an S(,N)2' reaction mechanism for the reaction of cis, cis-germacranolides with alkoxides and either an S(,N)1 or, more likely, a double S(,N)2' mechanism for the corresponding reaction of leucantholides. The in vitro conversion of cis, cis-germacranolides into leucantholide-13-alkoxide adducts provides experimental evidence for the proposed biogenetic relationship between the two structural types. Melampolides are considerably more resistant to S(,N)2' reaction with alkoxide nucleophiles than cis, cis-germacranolides. Tetrahelin B reacts with sodium methoxide to give a 10:1 ratio of saponification product 87 to diactone 88. This difference in reactivity is interpreted as the inherent structural preference for a 1,5 or 1,6-cis, trans arrangement of double bonds in the cyclodecadienolide skeleton over a 1,5-cis, cis or 1,6-trans, trans-arrangement. The structure elucidation of melrosin A, a new cis, cis-germacranolide from Melampodium rosei Robins., is reported. The reactions of melrosin A and the previously reported melcanthin B with sodium methoxide produce the same dilactone-13-alkoxide adduct suggesting that the two compounds differ by the sidechains at the C-8 and C-9 positions. Catalytic reduction of melrosin A proceeds with the unexpected hydrogenolysis of the C-15 hydroxyl group besides reduction of the lactonic exocyclic methylene and conversion of the acrylate sidechains to isobutyrates. The CD data of over fifty sesquiterpene lactones including germacranolides isolated from the genus Melampodium, their derivatives, and related compounds are listed according to the structural variations presented. Each naturally occurring skeletal type exhibits a characteristic CD pattern providing the basis for empirical correlations. The major bands observed for melampolides are attributed to the (alpha),(beta)-unsaturated carbomethoxy chromophore. In the case of the other structural types the results are less clear.