Synthesis of bridged bicyclic ring systems using a novel variation of the Nicholas Reaction in the key cyclisation step

Bashir, Tahmina (1999) Synthesis of bridged bicyclic ring systems using a novel variation of the Nicholas Reaction in the key cyclisation step. (PhD thesis), Kingston University,


This thesis details an investigation into the development of a novel annulation reaction for the synthesis of bridged ring systems. Using the Nicholas reaction, that is, the reaction of a stabilised dicobált hexacarbonyl propargyl cation with an intramolecular nucleophile, cyclisation was achieved to suggest a novel variant of this reaction. In all examples studied, the variant key step involved a double bond isomerisation of the pendant alkenyl nucleophile, that led to the observed novel allylic anion mediated attack onto the cobalt stabilised cation. In addition, the observed incorporation of a halogen atom observed in the cyclised product, further contributed to the novel variance of this reaction. After the initial discussion, a review of the biological importance and past synthetic approaches for the construction of the bridged ring system in taxane, aphidicolane, stemodane and gibanne families is given. This is followed by a general review of the cobalt-alkyne chemistry, that details the structure and properties of the cobalt-alkyne complex and its chemistry in context with the Nicholas reaction. The results of these investigations into this novel methodology is then detailed. These studies commenced with the successful cyclisation of a 1,3-difunctionalised cycloalkane. The reaction between the dicobalt hexacarbonyl complexed propynyl alcohol and the pendant pentenyl group, gave in the presence of titanium (IV) chloride, the chloro-substituted bicyclo[3.3.l ]nonane ring system. When conducting preIiminary studies into the mechanism for the reaction, that initially involved an investigation into the halogen atom incorporation, additional cyclisation was observed. Using the Lewis acids, titanium (IV) bromide and titanium (IV) fluoride, the successful syntheses of the bromo- and fluoro-substituted bicyclo[3.3.l]nonanes were achieved respectively. In addition to this, the consequence of. using other Lewis acids, that included boron trifluoride diethyl etherate, tetrafluoroboric acid, tin (IV) chloride and zinc chloride, is also discussed. The investigations were continued with optimising the reaction conditions for the cyclisation step. An examination into the effect of changing the solvent, temperature, reaction time, and the stoichiometry of the Lewis acid is included. During the course of these studies, a range of decomplexing agents was also examined. In extending these investigations, the generality of this protocol was looked into. The consequence of reducing the pendant alkenyl group in the 1,3-difunctionalised cycloalkane, led to the successful synthesis of other bicyclic systems. This included bicyclo[3.2.1]octane and bicyclo[4.3.1]decane. A subsequent study in which the size of the first ring was changed, led to the synthesis of5,6 and 7,6- bridge ring systems. In the later stages of the research programme, a stereoselective approach for the synthesis of bicyclo[3.3.1 ]nonane, using the precursor derived from (S)-( + )-carvone was studied, in which no significant stereoselective control was achieved. Additional work involving procedures undertaken to obtain a crystalline derivative to determine the absolute stereochemistry for the bicyclo[3.3.1 ]nonane system is also included. In conclusion to these studies, an investigation into the synthesis of the challenging 6,8 membered ring system, present in taxol, is discussed. Preliminary results for this study, show that success may have been achieved.

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