Item – Theses Canada

​
OCLC number
502629568
Link(s) to full text
LAC copy
LAC copy
Author
Côté, Jamie Blake.
Title
Alcohol dehydrogenase catalyzed Diels-Alder reactions and synthetic studies toward putative intermediates in the post-PKS transformations of dihydromonacolin L.
Degree
Ph. D. -- University of Alberta, 2007
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2008]
Description
3 microfiches
Notes
Includes bibliographical references.
Abstract
The ability of three different alcohol dehydrogenase enzymes (yeast alcohol dehydrogenase, horse liver alcohol dehydrogenase and hydroxysteroid dehydrogenase) to activate a dienophile by oxidation and catalyze an intramolecular Diels-Alder reaction was explored. To this end four different substrates ((2'E ',7'E')-deca-2,7,9-decatrien-1-ol (28), (2'E',7'E',9'E')-undeca-2,7,9-trien-1-ol (29), (2'E'8'E',10'E')-dodeca-2,8,10-trien-1-ol (30) and (2'E',9'E',11' E')-trideca-2,9,11-trien-1-ol (31)) were synthesized which featured a dienophile (allylic alcohol) tethered to a diene. All three enzymes were able to activate the dienophile by oxidation to the corresponding aldehyde although the oxidation was very slow (3 to 5 days at room temperature) and low yielding (<5%). However, the Diels-Alder reaction occurred in solution rather than in the active site of the enzyme. During the course of this study, it was discovered that 'o'-iodoxybenzoic acid (IBX) is able to act as both an oxidant and as a Lewis acid for the Diels-Alder reaction. The IBX oxidized undecatrienol 29 and dodecatrienol 30 to the corresponding aldehyde. The Diels-Alder reaction which ensued produced the 'endo' stereoisomers (racemic) with high diastereoselectivity (indene aldehyde and decalin aldehyde). A new lactone precursor, dimethyl ('R')-('tert'-butyldimethylsilyloxy)-2,6-dioxo-6((S)-1-phenylethylamino)hexylphosphonate (70), was synthesized by using a modification of a literature route. This reagent was utilized in a Horner-Emmons-Wadsworth reaction with decalin aldehyde 79 and 6-Me-decalin aldehyde 78. In addition, a labeled version, 13/14C-amide phosphonate 76, was constructed and was unstable. It had a half life of two weeks at -20°C. The synthesis of unlabeled desmethyl DHL ' 77' analog was pursued. However, in the last step of the synthesis to form the lactone, elimination of the C3 hydroxyl group occurred and provided the [alpha],[beta]-unsaturated compound 82. Finally, two short synthetic routes were discovered which provide access to monacolin L (21) and 3[alpha]-3,5-hydroxy-DHL 20. The Hendrickson reagent was used to dehydrate TBDPS epoxides 92([beta]) and 93([alpha]) which provided TBDPSmonL 95. The Lewis acid aluminum isopropoxide was employed to rearrange TBDPS epoxides 92([beta]) and 93([alpha]) and yielded 3[beta]-3,5-hydroxy-DHL 96. While the aluminum isopropoxide reaction was very low yielding and provided the allylic alcohol with the opposite stereochemistry desired, it is possible that the alcohol of 3[beta]-3,5-hydroxy-DHL 96 could be inverted to form 3[alpha]-3,5-hydroxy-DHL 20 after removal of the protecting group.
ISBN
9780494329443
0494329440