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UBC Theses and Dissertations

Application of ring-closing metathesis to the synthesis of unsaturated 14-membered lactams and the marine alkaloids motuporamines A-C Goldring, William Peter Donald


The construction of unsaturated 14-membered lactams 77-92 via ring-closing metathesis (RCM) of a series of diene-amides using Grubbs' benzylidene 3 was examined as part of an ongoing study in our laboratory into the chemistry and formation of macrocyclic compounds. Specifically, nine contiguous sites for ring closure were examined to explore the factors governing the yield and the resulting diastereomeric ratio of the newly formed olefin. The position of the olefin within the lactam products was confirmed with 2D NMR experiments, and the configuration was determined with 1 H NMR homonuclear decoupling experiments. The diene-amide substrates were in turn synthesized from simple carboxylic acids, alkenyl amines, and alkenyl halides using amidation or amide alkylation methods. Further exploration of the factors governing these reactions was conducted by studies into the effects of additives, reaction conditions, and structural modifications to the diene-amide. With respect to the latter, selected diene-amides were protected with a BOC group, and in one case a diene was differentially substituted with respect to the double bonds to provide the only observed formation of lactams 91 and 92 via RCM. The observed trend in yield for the series of RCM reactions was rationalized based on relative enthalpies of ring closure, relative product energies, and the formation of unproductive intramolecular catalyst complexes. The latter appeared to be the predominant factor governing cyclization. Cyclization yields increased with the distance between the amide group and the terminal double bonds of the diene-amide. The observed H Z ratios at each site of ring closure from the RCM reactions were rationalized by comparison to calculated HZ ratios based on the energy difference between molecular mechanics calculated global minimum energy conformations for each pair of isomeric lactams. The moderate to high correlation between the observed and calculated ratios suggested that the relative transition state energies were reflected in the relative energies of the (£)- and (2)-lactam products. Olefin isomerization of selected lactams with ruthenium methylidene 4 was attempted, and the isomeric ratios were found to be different from those obtained from the RCM reactions. The knowledge gained from the previous studies was applied to the total synthesis of the cytotoxic marine alkaloids motuporamines A (33), B (34), and C (39) and the respective diacetylated derivatives 36, 37, and 41. The macrocyclic amine units of motuporamines B and C were constructed via RCM, and the spermidine-like unit common to all three natural products was constructed using Michael addition and amidation methods. Lactams 83, 85, and 86 were constructed via RCM and applied in the synthesis of motuporamine B. The structural ambiguity of motuporamine C, with respect to the position of the olefin within the macrocyclic amine unit, prompted the synthesis of the two positional isomers 39 and 40. These compounds were synthesized from the 15-membered lactams 171 and 162 respectively, which were in turn constructed from the corresponding diene-amides via RCM. Comparisons were made between the spectral data of the authentic and synthetic compounds. Minor differences between compounds 37 and 37-TFA, and authentic diacetylmotuporamine B were observed. This indicated that the structure assigned to motuporamine B was incorrect. Compounds 36-TFA and 41-TFA were found to be identical to authentic diacetylmotuporamines A and C, respectively. This indicated that the authentic compounds were isolated as the ammonium trifluoroacetate salts. The position of the olefin within authentic motuporamine C was assigned to the C-14/C-15 bond position, as represented in compound 39.

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