Synthetic studies of heterocyclic natural products

The methods that were developed for the synthesis of the heterocyclic natural products luotonin A, ophiuroidine, cephalandole B, and the indol-3-yl-benzoxazinones of cephalandole A are described in this thesis. The reoccurrence of the 4(3H)-quinazolinone structure is a common theme throughout these studies, and an overview of some quinazoline chemistry is introduced in the first chapter.

The second chapter describes the progression of a series of 9-oxo-pyrroloquinazolinone compounds which led to a new synthetic method of the natural product luotonin A, isolated from Peganum nigellasterum, and some analogues thereof (Paper I). This synthetic strategy proved to be an efficient route, and the new analogues of luotonin A that were created predominantly had substitutions at the 14th position.

The third chapter details the synthesis of cephalandoles A and B, isolated from the orchid Cephalanceropsis gracilis, as well as a revision to the structure of cephalandole A (Paper II). The proposed structures for cephalandole A was reported as 2-(1H-indol-2-ylcarbonyl)-4H(3,1)benzoxazinone, and cephalandole B as methyl 2-(1H-indole-3-carboxamido)benzoate; both compounds had never previously been synthesized. Upon preparation of the target molecule, inconsistencies between the data of the synthesized compound and that of the reported structure prompted further investigations. The revised structure was found to be 3-(1H-indol-3-yl)-2H(1,4)-benzoxazinone, a compound previously synthesized by Moffett in 1966. From the 2-(1H-indol-2-yl-carbonyl)-4H(3,1)-benzoxazinone, the corresponding 4(3H)-quinazolinone was prepared. It was also found that cephalandole B could be prepared from 2-(1H-indol-2-yl-carbonyl)-4H(3,1)benzoxazinone, suggesting cephalandole B may be an artifact of the original extraction process.

The fourth chapter features the development of synthetic strategies towards preparation of the marine natural product ophiuroidine (Paper III), isolated from the brittle star Ophiocoma resii. The 4,8,9-trihydroxytryptanthrin was prepared starting from 5,6-dimethoxyisatin and 8-methoxyisatoic anhydride, and the corresponding 4,8,9-trimethoxytryptanthrin was demethylated using pyridinium hydrochloride in Nmethylpyrrolidone, with the use of microwave heating. A section discussing isatins and their preparation is included in this chapter. A new method for the preparation of several methoxyisatins is described, starting from m-methoxyanilines, which was an improvement over Sandmeyer s isonitrosoacetanilide protocol. The isatins generated from this work led to the preparation of several other methoxytryptanthrins.

As an extension of the ophiuroidine project, investigations of the demethylation of aryl ethers with pyridinium hydrochloride was undertaken with the use of microwave heating and the inclusion of the solvent N-methylpyrrolidone (Paper IV). This modification to the previously known procedure is described, as well as the limitations of the reaction. A dozen compounds containing aryl methyl ethers were assessed using this modification, including two substituted 2-styryl-4(3H)-quinazolinones, which were found not only to undergo demethylation but also dehalogenation under the described reaction conditions.

List of scientific papers

I. Mason JJ, Bergman J (2007). Total synthesis of luotonin A and 14-substituted analogues. Org Biomol Chem. 5(15): 2486-90.
https://pubmed.ncbi.nlm.nih.gov/17637970

II. Mason JJ, Bergman J, Janosik T (2008). Synthetic studies of cephalandole alkaloids and the revised structure of cephalandole A. J Nat Prod. 71(8): 1447-50.
https://pubmed.ncbi.nlm.nih.gov/18651770

III. Mason JJ, Janosik T, Bergman J (2009). Synthesis of ophiuroidine and other hydroxytryptanthrins. Synthesis. 2009(21): 3642-3648.
https://doi.org/10.1055/s-0029-1217004

IV. Mason JJ, Janosik T, Bergman J (2009). Investigation of the microwave assisted deprotection of aryl ethers with Pyridinium Hydrochloride in NMP. [Manuscript]