Studies directed toward the synthesis of methyllycaconitine

dc.contributor.advisor George A. Kraus
dc.contributor.author Dneprovskaia, Elena
dc.contributor.department Chemistry
dc.date 2018-08-23T16:41:09.000
dc.date.accessioned 2020-06-30T07:22:53Z
dc.date.available 2020-06-30T07:22:53Z
dc.date.copyright Sat Jan 01 00:00:00 UTC 2000
dc.date.issued 2000-01-01
dc.description.abstract <p>Larkspur is a serious toxic plant problem on western U.S. ranges, as larkspur poisoning sporadically kills 5--15% of the cattle on North American mountain lands. Toxic alkaloids comprise about 20--50% of the total alkaloid concentration in tall larkspur. Larkspur (Delphinium species) contain numerous diterpenoid alkaloids of two structural types: lycoctonine and 7,8-methylenedioxylycoctonine (deltaline). Among the lycoctonine type norditerpenoid alkaloids are three N-(methylsiccinimido)anthranoyl alkaloids which appear to be the most toxic: methyllycaconitine (MLA), 14-deacetyl nudicauline and nadicauline;Methyllycaconitine has been reported in at least thirty different Delphinium species and also in Consolida ambigua and Inula royaleana and it is the principle toxic alkaloid in these species. When employed in pharmacological studies, methyllycaconitine was found to be a novel and very potent probe for mammalian and insect nicotinic acetylcholine receptors, displaying remarkable selectivity toward neuronal [125I]-alpha-bungartoxin binding sites that correspond to a7-type nAChR in mammalian brain;Several structurally less complex analogues of MLA have been synthesized over the past decade, but most of the synthetic efforts have been focused on the preparation of small bicyclic analogues and on establishing a structure-activity relationship to assess the structural requirements necessary for potency and selectivity;Although emphasized as a synthetic approach to methyllycaconitine, this dissertation can also be regarded as an attempt to develop a general method for the construction of the skeleton of aconitine alkaloids. Systematic retrosynthetic analysis and the concurrent use of independent strategies to guide problem solving have been used to overcome difficult synthetic problems so common in the synthesis of natural products. An effort has been made to present in the dissertation the essentials of the synthesis in a concise form with emphasis on the logic of synthetic design and specific results. A tricyclic intermediate of methyllycaconitine, possessing the ABE-carbocycle skeleton and 2-methylsuccinimido-benzoate ester important for biological activity, has been synthesized utilizing tandem Michael addition-Mannich reaction sequence. A convenient alternative for the introduction of the 2-methylsuccinimidobenzoate ester side chain onto small molecule analogues of methyllycaconitine has been developed. It was demonstrated that double Michael addition of cyclohexadienones to functionalized dienones allows to obtain ABC-tricyclic fragments and may offer a convenient route to the tetracyclic analogue of methyllycaconitine by the tandem Mannich reaction-Michael addition sequence. An advanced tricyclic intermediate, possessing the ABC-carbocycle skeleton and all necessary functionality for further development of a total synthesis has been obtained. A direct approach, and perhaps the shortest pathway possible, to the synthesis of methyllycaconitine has been developed.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/rtd/12679/
dc.identifier.articleid 13678
dc.identifier.contextkey 6820698
dc.identifier.doi https://doi.org/10.31274/rtd-180813-13943
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath rtd/12679
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/66073
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/rtd/12679/r_9977318.pdf|||Fri Jan 14 19:27:15 UTC 2022
dc.subject.disciplines Organic Chemistry
dc.subject.keywords Chemistry
dc.subject.keywords Organic chemistry
dc.title Studies directed toward the synthesis of methyllycaconitine
dc.type article
dc.type.genre dissertation
dspace.entity.type Publication
relation.isOrgUnitOfPublication 42864f6e-7a3d-4be3-8b5a-0ae3c3830a11
thesis.degree.level dissertation
thesis.degree.name Doctor of Philosophy
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