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Investigations towards the synthesis of vinblastine and vinblastine analogs Pedersen, Ove
Abstract
This dissertation describes research towards a feasible synthesis of vinbiastine 1, by coupling of a suitable catharanthine analog with vindoline 4. In this connection a reinvestigation of the modified Polonovski reaction was undertaken in order to gain a better understanding of the factors affecting the yield of the reaction. The Diels-Alder reaction of the methyl α-chloroacrylate 31 with the dihydropyridine 30 afforded the isomeric Diels Alder adducts 32 and 33. The two adducts were separated and transformed into the indole-amides 40 and 51 as well as the corresponding thioamides. Photochemical cyclization of the amides and the thioamides gave lactam 55 and thiolactam 61. However, with a best overall yield of 7% of lactam 55 the investigated strategy did not lead to a practical synthesis of vinbiastine. The low yields obtained in the coupling of catharanthine derivatives with vindoline 4 necessitated a reinvestigation of the modified Polonovski reaction. In using fractional factorial design as experimental strategy and exocatharanthine 89 as a suitable catharanthine analog, a new intermediate was discovered and the yield of dimeric alkaloid was improved from 35% to 70%. The better understanding obtained of the factors influencing the yield of the modified Polonovski reaction
Item Metadata
Title |
Investigations towards the synthesis of vinblastine and vinblastine analogs
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1992
|
Description |
This dissertation describes research towards a feasible
synthesis of vinbiastine 1, by coupling of a suitable
catharanthine analog with vindoline 4. In this connection a
reinvestigation of the modified Polonovski reaction was
undertaken in order to gain a better understanding of the
factors affecting the yield of the reaction.
The Diels-Alder reaction of the methyl α-chloroacrylate
31 with the dihydropyridine 30 afforded the isomeric Diels
Alder adducts 32 and 33. The two adducts were separated and
transformed into the indole-amides 40 and 51 as well as the
corresponding thioamides. Photochemical cyclization of the
amides and the thioamides gave lactam 55 and thiolactam 61.
However, with a best overall yield of 7% of lactam 55 the
investigated strategy did not lead to a practical synthesis
of vinbiastine.
The low yields obtained in the coupling of
catharanthine derivatives with vindoline 4 necessitated a
reinvestigation of the modified Polonovski reaction. In
using fractional factorial design as experimental strategy
and exocatharanthine 89 as a suitable catharanthine analog,
a new intermediate was discovered and the yield of dimeric
alkaloid was improved from 35% to 70%.
The better understanding obtained of the factors
influencing the yield of the modified Polonovski reaction
|
Extent |
2863485 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-01-05
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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 |
10.14288/1.0061752
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1992-05
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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.