Structure elucidation of natural products from endophytic fungi and higher plants and total synthesis of microcarpalide

• Main Author: Ratnayake, Anokha Sayani
• Other Authors: Hemscheidt, Thomas K
• Published: University of Hawaii at Manoa 2009
• Online Access: http://hdl.handle.net/10125/6907

Part-1: Microcarpalide (1.1), a new alkyl-substituted nonenolide was isolated from fermentation broths of an unidentified fungus. Microcarpalide is weakly cytotoxic to mammalian cells and acts as a microfilament disrupting agent. The gross structure of 1.1 was elucidated by the application of spectroscopic methods, particularly high-resolution NMR spectroscopy. The relative stereochemistry of the C-4/C-5 diol function was determined as syn (threo) based on spectroscopic correlations. The absolute configuration at C-4/C-5 (determined by the exciton chirality method) was related by means of conformational analysis to the C-9 stereochemistry in order to elucidate the absolute configuration at C-9/C-10. The relative stereochemistry of the latter two centers was established as threo by the application of the J-based method of Murata. This is the first successful application of Murata's method for assigning the relative configuration of carbon atoms that are part of a medium size ring (8≤11). On the basis of a cytotoxicity assay, the crude organic extract of the Hawaiian endemic plant Tetraplasandra hawaiiensis was selected as a candidate for bioassay-guided fractionation. The major compound responsible for the in vitro cytotoxicity was isolated and identified by 1H and 13C NMR spectroscopy as the diacetylenic compound (+)-falcarindiol (1.12). The absolute configuration of (+)-falcarindiol (1.12) from T. hawaiiensis was unambiguously determined as 3(R),8(S) by chemical means (olefin cross-metathesis and advanced Mosher method) and by its independent synthesis. Part-2: The proposed structure and stereochemical assignment of microcarpalide (1.1) was verified by total synthesis. A convergent approach was used to assemble the 10-membered lactone carbon skeleton of 1.1, employing ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The stereochemical outcome of the RCM reaction was studied by varying the choice of ruthenium alkylidene catalyst and diene substrate. The ability of the same metathesis catalysts to promote double-bond isomerization via ring opening metathesis (ROM) of the cyclized product was also examined. === xix, 164 leaves