Part I: Synthesis and evaluation of synosutine as an inhibitor of serotonin, norepinephrine, and dopamine transporters Part II: Asymmetric approach to the tetracyclic core of neomangicol A Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/tt44pr01q

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  • Part I: Racemic and asymmetric syntheses of a new substance with prospective antidepressant properties were achieved. In vitro assays with synthetic racemates (±)-25 and (±)-26 suggested that the former is a relatively selective inhibitor of serotonin transporter whereas the latter is a more balanced inhibitor of both serotonin and norepinephrine transporter. An initial approach to enantiomers of 25 and 26 via resolution of carboxylic acids 21 and 22 was unsuccessful but a de novo strategy which introduced asymmetry by means of Charette enantioselective cyclopropanation led to (+)-25, (-)-25, (+)-26 and (-)-26. In vitro assays with (+)-26, now known as synosutine synthesis/OSU), indicate that this substance is a highly effective dual inhibitor of serotonin and norepinephrine transporter. With IC₅₀ and K[subscript i] values in the 1-2 nM range, (+)-26 compares favorably with Eli Lilly's duloxetine (Cymbalta®) as a dual reuptake inhibitor of serotonin and norepinephrine and is thus a potential candidate for development as a drug for treatment of clinical depression. Synosutine was also assayed in vivo for its binding to human monoamine transporters. These studies indicate that synosutine, with a K[subscript i] of 1.2 nM for norepinephrine and 2.1 nM for serotonin, is a more balanced inhibitor than duloxetin. Part II: Synthetic studies towards the tetracyclic core structure of neomangicol A (129) led to advanced intermediate 245 which bears rings A and D of the neomangicol nucleus. This bicylic enone carries the correct stereochemical imprint for tetracycle 129 at C5, C6 and C14 and it contains all of carbon atoms needed to assemble the remaining two rings. Synthesis of bicyclic lactone 170, the precursor for ring A, was accomplished from the monoterpene (S)-(+)-carvone via radical cyclization and a series of Baeyer-Villiger oxidations as the key steps. Alkylation of 170 with alkyl iodide 217, obtained from the monoterpene (S)-(-)-citronellol furnished advanced intermediate 218 which was converted into diene 244. Ring closing metathesis of 244 with Grubbs-Hoveyda second generation catalyst afforded 245. Exploratory functionalization of 245 was carried out for the purpose of assembling rings B and C of the complete neomangicol skeleton.
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