Structural and synthetic investigations of diterpenoid natural products from southern African marine invertebrates

Gray, Christopher Anthony (2002) Structural and synthetic investigations of diterpenoid natural products from southern African marine invertebrates. PhD thesis, Rhodes University.




This thesis is divided into two parts. The first part (Chapter Two) documents a bioassay guided investigation of the ethyl acetate extracts of four marine invertebrates from Mozambique (an Irciniid sponge, a Haliclona sp. sponge, an ascidian tentatively identified as Diplosoma sp., and the soft coral Cladiella kashmani). Eight known compounds [ilimaquinone (2.1), renierone (2.7), N-formyl-1,2-dihydrorenierone (2.8), 1,6-dimethyl-7-methoxy-5,8-dihydroisoquinoline-5,8-dione (2.9), mimosamycin (2.10) 7Z-allylidene-5-hydroxy-7,7a-dihydro-2H-cyclopenta[b]pyran-6-one (2.11), flaccidoxide (2.18) and 11S,12S-epoxycembra-1Z,3E,7E-trien-14S-ol (2.19)] and a new diterpene [13S,14R-diacetoxy-11S,12R-epoxycembra-1Z,3E,7E-triene (2.20)] were isolated and identified using standard spectroscopic techniques. Anomalies in the published spectral data of 2.1 and 2.8 were exposed and corrected, and the absolute stereochemistry of the cembrane diterpenes 2.18 and 2.20 established using the modified Mosher’s method. The comparative activities of the nine natural products against four cancer cell lines (A549, LOX, OVCAR3, SNB19) are reported. The second part of the thesis (Chapter Three – Chapter Six) is concerned with an ecological, structural and synthetic study of diterpenes from the endemic South African pulmonate limpet Trimusculus costatus. Two new labdane diterpenes [6b,7a-diacetoxylabda-8,13E-dien-15-ol (3.10) and 2a,6b,7a-triacetoxylabda-8,13E-dien-15-ol (3.11)] were isolated from T. costatus and evaluated for anti-feeding activity against the common predatory fish Pomadasys commersonnii. A strategy for the semi-synthesis of 3.10 from rhinocerotinoic acid (4.14), a diterpene reportedly present in the ubiquitous South African shrub Elytropappus rhinocerotis, was devised in order to allow further bioactivity tests to be performed and unequivocally assign the unknown absolute stereochemistry of the T. costatus metabolites. Attempts to isolate rhinocerotinoic acid from local specimens of Elytropappus rhinocerotis were unsuccessful, and as the repetition of a published synthesis of 4.14 from (-)-sclareol (4.15) gave rhinocerotinoic acid in unacceptably low yields with poor stereoselectivity, an improved synthesis of 4.14 is presented. Comprehensive studies using hispanone (5.1) as a model compound showed that 6,7-dioxygenated labda-8-enes could be prepared from compounds possessing a 7-oxo-labda-8-ene skeleton with some degree of stereocontrol. In the process, fourteen new hispanone analogues were prepared and most of these were tested for activity in a suite of ten agro-chemical assays. The novel compound 7b-hydroxy-9a-carbonitrile-15,16-epoxylabda-13(16),14-dien-6-one (5.34) exhibited significant activity against the crop fungus Phytophthora infestans and is currently being subjected to further agro-chemical tests. Unfortunately, the results from the oxygenation study performed on the model compound 5.1 could not be directly extrapolated to rhinocerotinoic acid. Attempts to prepare the naturally occurring 3.10 from 4.14 via an alternative route were unsuccessful but yielded an analogue of 3.10 in which the substituents at C-6 and C-7 are in a diequatorial rather than a diaxial configuration.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Ethyl acetoacetate, Diterpenes, Limpets, South Africa, Natural products
Subjects:Q Science > QD Chemistry > QD241 Organic chemistry
Divisions:Faculty > Faculty of Science > Chemistry
ID Code:2235
Deposited By: Ms Chantel Clack
Deposited On:23 Nov 2011 08:28
Last Modified:06 Jan 2012 16:22
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