Crane, Sheldon N. (1999) Geminal acylation of ketones and acetals : use of methyl-substituted analogues of 1,2-bis[trimethylsilyl(oxy)]cyclobutene and application of this methodology in model studies aimed toward an enantioselective synthesis of the antitumor antibiotic fredericamycin A. Doctoral (PhD) thesis, Memorial University of Newfoundland.
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The BF₃.Et₂O-catalyzed geminal acylation of ketones and acetals with 3-methyl-1,2-bis(trimethylsilyloxy)cyclobutene (3) provided methylcyclopentanediones in yields that ranged from 40 to 94%. The best substrates were unhindered cyclohexanones. With acetals, stereochemical preferences in the initial Mukaiyama-like aldol step giving cyclobutanones translated into the stereochemistry of the ultimate cyclopentanedione products. With ketones, equilibration of the initial cyclobutanone compounds resulted in cyclopentanedione products with a different stereochemical preference. The gem-dimethyl cyclobutene reagent 4 reacted with ketones to give gem-dimethylcyclopentanediones in modest yield. The process was much more stereochemically efficient than the reaction with 3. Rearrangement from the initial cyclobutanone compound was partially diverted towards air-sensitive 3-furanone compounds and ring-opened 1,2-diones. Use of BCI₃ as the Lewis acid in reactions of ketones with 4 inhibited cyclobutanone equilibration by formation of five-membered borate-containing compounds. Conversion to the corresponding diol cyclobutanones with hydrofluoric acid and thence to dimethylcyclopentanediones with trifluoroacetic acid provided dimethylcyclopentanediones in synthetically acceptable yields. -- Treatment of aromatic ketones with 1,2-bis(trimethylsilyloxy)cyclobutene 1 or its methylated analogues 3 and 4 in the presence of BF₃.Et₂O smoothly led to products of geminal acylation, i.e., 2,2-disubstituted 1,3-cyclopentanedione derivatives. Yields ranged from 42 to 76%. Minor products (up to 27%) were lactones that are proposed to have arisen by an alternate rearrangement pathway from a common cyclobutanone intermediate. -- Since its discovery in 1981, the antitumor antibiotic fredericamycin A (91) has been the subject of extensive synthetic efforts focused mainly on construction of its spiro-1,3-cyclopentanedione subunit. Six total syntheses of 91 in racemic form have been reported. An asymmetric synthesis of fredericamycin A was accomplished only very recently. We have devised a potentially enantioselective route to fredericamycin A relying on precedents set in our laboratory for the construction of spiro-1,3-cyclopentanediones and their reduction in an enantioselective manner by Baker's yeast. The naphthoquinone portion of 91 was to be constructed by a silicon-tethered photochemical [2+2] cycloaddition or alternatively an intermolecular Diels-Alder reaction. The isoquinoline fragment was to be introduced using a Beckmann rearrangement strategy. A review of the literature dealing with 91 and the results of our own preliminary studies directed toward an enantioselective synthesis of this interesting molecule are presented.
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Bibliography: leaves 170-177.|
|Department(s):||Science, Faculty of > Chemistry|
|Library of Congress Subject Heading:||Acylation; Ketones; Antineoplastic antibiotics|
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