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dc.contributor.authorNairn, Michael Royce
dc.date.accessioned2011-11-07T03:18:50Z
dc.date.available2011-11-07T03:18:50Z
dc.date.issued1995
dc.identifier.urihttp://hdl.handle.net/10179/2846
dc.description.abstractThis thesis presents the synthesis and attempted functionalization of the unsaturated ring system of the naturally occurring pyranonaphthoquinone antibiotic griseusin A 88. Unsaturated spiroketals 333,334 were constructed via the addition of 2-trimethylsilyloxyfuran 189 to quinone 328. Initial work using acetylenic quinone 321 afforded a pentacyclic product 323, wherein an unanticipated third Michael reaction occurred due to the phenolic hydroxyl group cyclizing onto the α,β-unsaturated ketone moiety. Altering the reaction conditions gave trimethylsilyl analogue 325, where the final Michael reaction abstracted not a proton (323) but a trimethylsilyl cation liberated from 189. Naphthoquinone 328, bearing a 2-alkenyl side chain rather than an acetylene, was synthesized using similar methodology to 321 and subsequently converted to furonaphthofuran adduct 330. Ceric ammonium nitrate oxidative rearrangement of 330 produced diol 332, which was then cyclized to spiroketals 333,334 under a variety of conditions. The isomer ratio 333:334 resulting from these conditions was determined by high field 1H nmr spectroscopy. With the two spiroketals 333,334 in hand, efforts were directed towards the functionalization of the C3'-C4' double bond. Osmium tetraoxide catalytic dihydroxylation of model olefin 345 gave diol 353, where approach of the reagent was from the opposite face to that required for griseusin A 88. Selective acetylation of the less hindered hydroxyl group was however achieved, giving 354. The Woodward-Prevost reaction of olefin 345 formed the iodoacetates 367-369. Attempts to displace the iodine from the major diaxial iodoacetate 368 gave a complex mixture. Iodoacetate 387 was then prepared wherein the iodine and acetate positions were reversed, treatment of which with silver acetate afforded the fragmentation products 401 and 402. The minor diequatorial iodoacetate 367 gave, like its stereoisomer 368, a complex mixture when subjected to displacement conditions. Only iodoacetate 410, formed from 367, produced spiroketal hydroxyacetates as hoped for, however both of these had the opposite stereochemistry at C-4 and C-5 to that desired. One of these two hydroxyacetates (354) had also been isolated from the selective acetylation of diol 353. Several attempts using a variety of reaction conditions were made in an effort to force 333,334 to react with osmium tetraoxide. It was found that the functional groups present in 333, 334, 336, 330 and 323 were incompatible with this reagent. Ketone 327 was the only compound that successfully underwent syn-hydroxylation, affording diols 419 and 420. Use of cetyltrimethylammonium permanganate as an hydroxylation reagent for 333,334 afforded 423 and 421 rather than 343 and 344, where reaction had occurred at the C5a-C11a double bond. The difficulty in introducing the oxygenated substituents onto the O1'-C6' spiroketal ring was proposed to be overcome by synthesizing naphthoquinone 430. The protected hydroxyl groups at C-2' and C-3' in this compound would possess the correct stereochemistry for elaboration to the hydroxyl and acetate groups at C-3' and C-4' respectively in griseusin A 88. Towards this end, the synthesis of the required naphthalene precursor (432) was undertaken via an enantioselective aldol condensation of imide 435 with (R)-aldehyde 437. 435 was formed from (R)-phenylalanine and 2-(benzyloxy)acetyl chloride 439 and reacted with 437 using stannous triflate and tetramethylethylenediamine. The major product 452, possessing the desired 2',3'-anti stereochemistry, was protected and the auxiliary reductively removed to give alcohol 459. Oxidation of 459 using tetra-n-propylammonium perruthenate gave aldehyde 434, ready to be coupled to the Grignard reagent (498) of trimethoxybromide 433. Trials using heptanal and various organometallic reagents found n-butyllithium to be the reagent of choice for generating the anion (in this case the lithiate, 500) of 433. With the optimum time determined, the coupling of 500 with 434 was undertaken but yielded only the debrominated compound 499. The basicity of 500 and the hindrance at the carbonyl group of 434 were cited as possible reasons for this result, and attempts were made to "soften" the anion. Unfortunately both magnesium bromide and cerie chloride failed to produce the desired products 503,504.en_US
dc.language.isoenen_US
dc.publisherMassey Universityen_US
dc.rightsThe Authoren_US
dc.subjectAntibioticsen_US
dc.subjectSynthesisen_US
dc.subjectHydroxylationen_US
dc.subjectNaphthoquinoneen_US
dc.titleSynthetic studies towards Griseusin A : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey Universityen_US
dc.typeThesisen_US
thesis.degree.disciplineChemistry
thesis.degree.grantorMassey University
thesis.degree.levelDoctoral
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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