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-Ī±-
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,Nā dimethyl metaphenyiene diamine gave 25a in a
yield of 7%.
The design requires additional functional groups at the 5 and 5ā 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 5ā 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. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/9806 |
| Date | 01 August 2018 |
| Creators | Cameron, Lynn Michele |
| Contributors | Fyles, Thomas M. |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
Page generated in 0.0057 seconds