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Application of ring-closing metathesis to the synthesis of unsaturated 14-membered lactams and the marine alkaloids motuporamines A-C Goldring, William Peter Donald
Abstract
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.
Item Metadata
Title |
Application of ring-closing metathesis to the synthesis of unsaturated 14-membered lactams and the marine alkaloids motuporamines A-C
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2000
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Description |
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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Extent |
19484739 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-07-23
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0061436
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2000-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.