The design and synthesis of macrocycles for use as components of ion transporters




Cameron, Lynn Michele

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The thesis describes the development of a new set of macrocycles that could be used as part of an existing modular set of components, that when assembled, probe the structure-activity relationship of ion transporters. A property directed synthesis approach was adopted in which the properties, rather than the specific chemical makeup of the final target, guide the synthetic path. This allows for incorporation of the favorable properties and avoidance of the troublesome aspects of the current set of macrocycles into the synthetic design of the new modular components. As components in a modular set, the macrocycles are required in sufficient yield, so the property directed synthesis must provide an economical and efficient route to the targets. Molecular mechanics was used as a tool to estimate the length and rigidity of the macrocyclic systems. The design was also dictated by the need to incorporate high yielding methods for macrocyclization into the synthesis. All targets are formally meta cyclophanes involving overall axial symmetry to limit regioisomerism. The syntheses of 23, 25, 27, and 28 were based on the macrocyclization of bis-α- halo amides with bis-nucleophiles. Target 22 incorporated the bis-chloroamide of meta-phenylene diamine and a diol 23 derived from 1,3 bisbromomethyl benzene and butane diol. Conditions sufficient to deprotonate 23 apparently resulted in concomitant deprotonation of the amides leading to complex mixtures of products. Based on these observations the secondary amides of 23 were replaced with the homologous N-Me tertiary amides to give target 25. As anticipated, macrocyclization of 23 and the bis-chloramide of N,N’ dimethyl metaphenyiene diamine gave 25a in a yield of 7%. The design requires additional functional groups at the 5 and 5’ positions of the cyclophane. The chemistry leading to combinations of nitro and t-Boc protected amino groups in these positions was explored. Additional side reactions of the alkoxide nucleophile with nitro substituted aromatics precluded the desired macrocyclization reactions, and in all cases complex product mixtures were obtained. Additionally, the diol component 23 was replaced with a diol 26 of similar length in which the ether linkages were replaced by secondary amides. This gave a further target 27. In this series as well the side reaction of alkoxide with the nitro aromatic resulted in destruction of starting materials without production of product macrocycle. A corresponding target incorporating a dithiol in place of the diol 23 was explored in a preliminary fashion, but the physical properties of the dithiol complicated the purification of the precursor. The synthesis of a series of tetraester macrocycles derived from isophthalic acid and diols was explored. Direct condensation of 5-nitro isophthaloyl chloride and 1,8-octanediol gave a series of symetrical 2+2, 3+3, and 4+4 tetraesters in high conversion. A step-wise synthesis from the mono-tetrahydropyranyl derivative of 1.8-octane diol gave the 2+2 macrocycle 67 substituted with nitro and t-Boc protected amino in the 5 and 5’ positions in an overall yield of 16%. The efficiency of the synthesis of 67 is analysed using plan graphs as initially described by Hendrickson for natural products synthesis. The synthesis plan is compared with the actual performance in terms of reagent consumption, total weight manipulated, and the time for the synthesis. These results are compared with the synthesis of a comparable target in the existing series of macrocycles. Although tetraester 67 is somewhat less efficiently prepared than earlier examples, it is better functionalized to lead to candidate ion transporters.



Macrocyclic compounds, Synthesis