Graduate Thesis Or Dissertation
 

The isolation and structure of leptosphaerin : a metabolite of the marine ascomycete, Leptosphaeria oraemaris (Linder) and A synthesis of the marine toxin, 9-isocyanopupukeanane

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  • The ethyl acetate extract of the culture filtrate of the marine Ascomycete, Leptosphaeria oraemaris (Linder) yielded a novel metabolite designated by the common name leptosphaerin. An x-ray crystallographic structure analysis was disproved by the synthesis of 3-acetoxy-S-(1,2-dihydroxyethyl)- 3-pyrrolin-2-one 1, starting with N,N-dibenzylhydroxylamine 47 and D-mannitol 44. Oxidation of 47 followed by acid catalyzed hydrolysis gave N-benzylhydroxylamine 4_9. D-mannitol 44 was converted to a bis acetonide and the resulting vicinal diol was cleaved with lead tetraacetate to afford 2.3-0-isopropylidene-D-glyceraldehyde 46. Condensation of 46 and 49 gave N-benzyl-N-(2,3-0-isopropylideneglyceraldimine)-N-oxide 50 which, upon thermolyeis in the presence of methyl acryiate yielded 2- benzy1-3-(1,2-0-isopropylidene dihydroxyethyl)-S-carbomethoxyisoxazolidine 7S. Catalytic hydrogerolysis followed by oxidation and acetylation produced 3-acetoxy-5-(1,2-0-isopropylidenedihydroxyetnyi)-3-pyrroline-2- one 81. Removal of the acetonide protecting group generated 1, which proved to be ncnidentical with the natural product. The structure of the metabolite was established by spectral analysis and literature comparisons to be 2-acetamido-2,3-dideoxy-erythro-hex-2- enono-1,4-lactone 86. II A formal synthesis of the marine toxin, 9-isocyanopupukeanane 1 is described starting with 4-methylanisole 23. Birch reduction of 23 afforded 1-methoxy-4-methylcyclohexa-1,4-diene 24 which was sequentially cyclopropanated with methylene iodide-zinc-silver couple and ethyldiazoacetate to give 4-carboxyethyl-l-methoxy-5-methyltricyclo[5.1.0.03'5]octane 26. Acid catalyzed hydrolysis and rearrangement of 26 followed by ketalization and elimination of methanol yielded methyl 1,5-dimethy1-4-methoxy-2,4- cyclohexadienyl acetate 30. Conversion of the acetic ester residue of 30 to a vinyl ketone was effected by a conventional sequence of reduction, oxidation, addition of vinyl magnesium bromide and oxidation to produce (1,5-dimethy1-4-methoxy-2,4-cyclohexadieny1)-but-3-en-2-one 36. The generation of the [4.3.1.03'71tricyclodecane skeleton was accomplished by an intramolecular Diels-Alder reaction of 36 which gave 1,5-dimethy1-9-methoxy-5-oxotricyclo[4.3.1.0³,⁷]dec-8-ene 47. Treatment of 47 with isopropenyllithium afforded 1,3-dimethy1-5-isopropeny1-9-methoxytricyclo[4.3.1- 0³,⁷]dec-8-en-5-ol 52. Thermolysis of 52 in dimethyl sulfoxide led to the elimination of the tertiary alcohol and was attended by the hydrolysis of the vinyl ether to yield 1,3-dimethy1-5-isopropeny1-9-oxatricyclo[4.3.- 1.0³,⁷]dec-4-ene 54. Upon catalytic hydrogenation with platinum, diene 54 produced 1,3-dimethy1-5-isopropyl-9-oxotricyclo[4.3.1.0³,⁷]decane 5 which constitutes a formal synthesis of the toxin by virtue of its previous conversion to 9-isocyanopupukeanape.
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