Total synthesis of ferrugine and synthetic studies towards ferrugine and stemofoline

Ahmed, Shamim (2010). Total synthesis of ferrugine and synthetic studies towards ferrugine and stemofoline. University of Birmingham. Ph.D.

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Abstract

Tropane alkaloids, containing the 8-azabicyclo[3.2.1]octane ring system, are widespread in Nature. This thesis describes the total synthesis of the tropane alkaloid ferrugine, isolated from the arboreal species Darlingiana ferruginea and attempted synthesis of ferruginine, isolated from the arboreal species D. darlingiana. Formation of a bridged 6-azabicyclic-[3.2.2]-ring system was achieved using a transannular photomediated cyclisation of a carbamoyl radical, generated from a carbamoyl diethyldithiocarbamate, onto an unactivated pendant alkene, followed by group transfer of the dithiocarbamate moiety. The carbamoyl radical cyclisation precursor was synthesised from a known seven-membered ring carboxylic acid. The diastereomeric dithiocarbamates converged to a single alkene upon thermal elimination. Addition of phenyllithium to the amide followed by base-mediated skeletal rearrangement resulted in the total synthesis of the natural product ferrugine, and using a similar strategy the core structure of ferruginine was secured. The stemona alkaloid stemofoline is characterised by a complex azatricyclic ring system unique to this class of natural products. Synthetic efforts have been made toward the synthesis of a cyclisation precursor required for the assembly of this azatricyclic framework, via a proposed tandem 7-endo-trig/5-exo-trig carbamoyl radical cyclisation. The synthesis commenced with the commercially available dimethyl 3,3-thiodipropanoate which was further elaborated and coupled with 5-hepten-2-one to provide an advanced intermediate enone. Addition of ammonia gave a pyrroline which was condensed with triphosgene followed by sodium diethyldithiocarbamate to produce a carbamoyl radical precursor. Unfortunately, efforts towards oxidation and elimination of the sulfide to obtain an α,β-unsaturated ketone proved ineffective. Attempted carbamoyl radical cyclisation-dithiocarbamate group transfer onto enones and nitriles are also presented.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):