This thesis describes synthetic work directed towards the synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A 1.46 and its regioisomer 2.77. The synthetic strategy adopted is based on a double furofuran annulation/oxidative rearrangement strategy that has been successfully used by this research group to prepare a related dimeric pyranonaphthoquinone based on the actinorhodin skeleton. The retrosynthesis that was adopted (see Scheme 1.47, page 59) required the initial preparation of a key bis-naphthoquinone 1.267 which in turn is available from bisnaphthalene 1.268 that bears acetyl groups at C-7 and C-7’. Initial work concentrated on the construction of the biaryl linkage of bis-7- acetylnaphthalene 1.268 using a palladium(0)-mediated Suzuki-Miyaura homocoupling of the key triflate 1.269 (prepared in 10 steps from vanillin 1.271) using bis(pinacolato)diboron 1.179. This coupling method successfully afforded binaphthyls 2.8b and 2.8d which were subjected to attempts to effect either double bromination, double acetylation or double Fries rearrangement to a more functionalised biaryl system. Disappointingly, none of these methods allowed introduction of the key acetyl group at C-7 and C-7’ onto the initial biaryls 2.8b and 2.8d. Attention then turned to the synthesis of the bis-7-acetylnaphthalene 1,268 that was required for the ensuing furofuran annulation reaction starting from triflate 2.7 that already contained an acetyl group at C-7, then effecting formation of the key biaryl linkage. Attempts to prepare 7-acetyltriflate 2.7 via either Fries rearrangement of acetates 2.33a or 2.9a, or via bromination of acetate 2.33a, naphthol 2.56 or benzyl ether 2.6 were unsuccessful. An alternative approach for the preparation of 7-acetyltriflate 2.7 involved the preparation of 2-acetylcarbamate 2.74 from carbamate 2.64 via a directed ortho-metalation, followed by reaction of the derived ortho-lithiated species with N-methoxy-N-methylacetamide 2.71. However, this strategy resulted only in low yields of the desired 2-acetylcarbamate 2.74, although initial model work did provide methodology for the successful conversion of carbamate 2.68 to 2-acetyl-l-naphthol 2.73. The synthetic target of this thesis shifted to the regioisomer of crisamicin A 2.77 when attempts to introduce an acetyl group atC-7 of triflate 2.9 failed. However formation of the 6-acetyltriflate 2.81b was successful from triflate 2.9b. A subsequent one-pot in situ Suzuki-Miyaura homocoupling of triflate 2.81b with boronate 2.89 furnished dimmer 2.76b. Oxidation of dimer 2.76b to bis-naphthoquinone 2.80 was then accomplished using silver(II) oxide and 6 M nitric acid. With the key bis-6-acetylnaphthoquinone 2.80 in hand, an efficient double furofuran annulation reaction was carried out using 2-trimethylsilyloxyfuran 1.88 affording the desired bis-furonaphthofuran adduct 2.79 as an inseparable l:l mixture of diastereomers 2.79a and 2.79b. However, initial experiments to effect the double oxidative rearrangement of bis-furonaphthofuran adducts 2.79 using either silver(Il) oxide and 6 M nitric acid or with ceric ammonium nitrate in aqueous acetonitrile to the bisfuronaphthopyran 2.7 8 were unsuccessful. Attention then turned to the preparation of bis-furonaphthopyran 2.78 from the 6-acetyltriflate 2.81b via initial oxidation of triflate 2.81b to naphthoquinone 3.3 followed by furofuran annulation and then oxidative rearrangement. Attempts to effect the key Suzuki-Miyaura homocoupling of furonaphthofuran 3.2 to bis-furonaphthofuran 2.79, or of furonaphthopyran 3.1 to bis-furonaphthopyran 2.78, using catalyst PdCl2(dppf) and ligand dppf were unsuccessful. The work achieved herein constitutes the synthesis of an advanced intermediate for the synthesis of the crisamicin analogue 2.79. The final synthesis of the regioisomer of crisamicin A 2.77 can be completed by preparing bis-furonaphthopyran bis-lactol 2.78 using more powerful palladium(0) catalysts and ligands for the Suzuki-Miyaura homocoupling of the monomeric furonaphthopyran 3.1. Subsequent reduction af 2.78 using triethylsilane and trifluoroacetic acid will then afford the bis-cyclic ether 3.15, which can undergo deprotection of the methyl ether and epimerisation at C-5 upon treatment with excess boron tribromide to finally furnish the regioisomer of crisamicin A 2.77. An investigation into the double oxidative rearangement of bis-furonaphthofuran 2.79 to the bis-lactol 2.78 could also be carried out by the use of several alternative oxidising agents, such as phenyliodine(III) bis(trifluoroacetate) (PIFA), phenyliodine(III) diacetate (PIDA), polymer-supported (diacetoxyiodo)benzene (PSDIB), Fremy's salt, iron trichloride or CrO3.
| Identifer | oai:union.ndltd.org:ADTP/278294 |
| Date | January 2002 |
| Creators | Lai, Michelle Yu Huay |
| Publisher | ResearchSpace@Auckland |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated., http://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm, Copyright: The author |
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