Neutron Diffraction Structure of Melampodin: Its Role in the Reclassification of the Germacranolides

Abstract

The precise crystal and molecular structure of melampodin, C 21 H 24 O 9 , was determined from three-dimensional neutron diffraction data collected by counter techniques and phases by direct statistical methods. Crystals are orthorhombic, P2 1 2 1 2 1 , a = 8,990(9), b = 14.352(14), c = 16.294(16) Å, V = 2102 Å 3 , d(calc.) = 1.328 g·cm -3 , Z = 4 molecules per unit cell. The structural model was refined by full matrix least-squares of 2303 observed independent reflections, with all 54 atoms treated anisotropically, to R(F) = 5.0%. Hydrogen bonds link melampodin molecules together in the solid state. The conformation of the cyclodeca-1,5-diene ring is such that one intraannular hydrogen atom interacts strongly with one double bond, but there is little or no transannular interaction between double bonds. Strain in the ten-membered ring and in the trans -fused lactone ring is discussed, as are chemical implications of the unsymmetric epoxide in the epoxyangelic acid side chain. The previously suggested reclassification of germacranolide sesquiterpene lactones into four subgroups is supported, and a new convention for configurational representations of the four subgroups is proposed.

The Molecular Structure of Melampodinin-A

“…The structure of the basic skeletal arrangement of melampodinin-A closely resembles that of melampodin-A (1), as determined by x-ray (5) and neutron diffraction (6). As the absolute configuration of melampodin-A is known (5), our determination establishes the absolute configuration of the two asymmetric centers of the substituent at C8.…”

Sesquiterpene Lactones from Staehelina fruticosa

“…Parthenolide (1): white, amorphous solid (18.9 mg); Si gel TLC Rf 0.5 (9:1 CH2Cl2-EtOAc); [R] 25 D -80 (c 0.66, CHCl3); EIMS m/z (rel int %) 248 (5), 230 (8), 190 (10), 105 (12), 91 (14), 81 (13), 58 (25).…”

“…This has resulted in the necessary classification of the germacranolides into four subgroups. 11,12 Figure 1 illustrates the configurations that could exist for 4a. It has been found that the trans-trans isomers are most common in nature, followed by the more strained cis-trans or melampolide isomers.…”

Biogenetic-Type Rearrangements of Terpenes

“…This alternative scheme not only accounts for the usual stereochemistry of normal guaianes (e.g., bu1nesol, 71), but also, through cyclization to transfused perhydroazulenes, provides a stereochemically consistent link-up with the pseudoguaianes (108). The isolation of oxygenated derivatives of cis, trans-and trans, cis-1,5-germacradienes (129) and the estab1ishment of the appropriate stereochemical relationships between guaianolides and pseudoguaianolides (I 30), attaches significance to this proposal. In a similar fashion, the stereochemical variations within the aromadendrane family of sesquiterpenes may be rationalized in terms of cyclization of trans, trans-, cis, trans-, and cis, cis-bicyclo germacrenes (double bond isomers of 70) (108).…”