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The synthesis and conformational analysis of 13- and 14-membered macrocyclic ethers

University of British Columbia

As part of an ongoing study of the chemistry of macrocyclic compounds in our laboratory, the 14-membered macrocyclic ethers 90, 92, 103, 104, 116, 119, 137, and 154, and the 13-membered macrocyclic ethers 168, 171, 179, 180, 190, and 193 with substituents both close to and remote from the oxygen atom were synthesized. strategy for the preparation of these macrocyclic ethers involved either the Baeyer- Villiger ring expansion of a cyclic ketone, or the macrolactonization of a long chain hydroxy acid to give a lactone. Ultimately, the ether oxygen of the lactone would become the oxygen of the macrocyclic ether. The lactone was often used to introduce substituents in the vicinity of the ether oxygen. Once this purpose was served, the carbonyl of the lactone was removed either via a conversion to an intermediate thionolactone obtained by reaction with Lawesson's reagent, or reduced directly via boron trifluoride etherate mediated sodium borohydride reaction. The diastereomeric 14-membered ethers 103 and 104, and the 13-membered ethers 179 and 180 were prepared under both radical reduction and hydrogenation conditions, and the stereoselectivities of these methods were compared. In general, the stereoselectivities were low (<18% d. e.). The relative configurations of 103, 104, 179, and 180 were determined through chiral GC analysis. The unsaturated 14-membered ethers 157, 158, 163, and 164 were prepared via the ruthenium catalyzed metathesis of an acyclic diene ether. The configuration of the double bond in these unsaturated ethers was determined with 1H homonuclear decoupling NMR experiments. The isomerization of the carbon-carbon double bond using phenyl disulfide under photolysis conditions was studied. The product ratios of the metathesis cyclization and the isomerization reactions were compared to values obtained from molecular mechanics calculations. The conformation of the 13- and 14-membered ethers was analyzed using both NMR spectroscopy and molecular mechanics calculations. The diamond lattic conformations were good starting points in the analysis of the 14-membered rings were not suited to the 13-membered rings. The [13333] conformation was found to a good model for the analysis of the odd-sized 13-membered rings. Additional 1H-DNMR experiments were performed at low temperatures where the conformational interconversion rates of the macrocyclic ethers were slowed. The DNMR spectra were interpreted using predicted A8 values from both anisotropy and van der Waals steric compression effects. The results from the analysis of the DNMR spectra and the molecular mechanics calculations were compared. The calculations often gave one or two preferred low energy conformations with a regular geometry. The alkyl substituents were found to complicate the conformations of some of the macrocyclic ethers studied. The transition state energies of the individual macrocyclic ethers were determined from the DNMR spectra to be approximately 8-10 kcal/mol in the case the 14-membered ethers and 6-8 kcal/mol in the case of the 13-membered ethers. 14-membered ether values were compared to computer calculated values obtained using a dihedral drive method. The calculated values were in general higher and in range of 10-15 kcal/mol.

Thesis/Dissertation

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2009-05-28

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http://hdl.handle.net/2429/8412

Chemistry

University of British Columbia

UBCV

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