Organocatalyzed Reactions for Breaking Symmetry and Reduced Protecting Group Drug Synthesis

  • The first part of my Ph.D. work focused on an ignored reaction, the enantioselective mono-aldolization of diketones. 4-substituted cyclohexanone based diketones were synthesized and it was convincingly shown that the regio-, diastereo- and enantiocontrol could be imparted at the cyclohexanone ketone carbonyl unit while acyclic methyl, aromatic, or benzyl ketones remained unreacted. The mono-aldol products were then converted into diastereomerically pure keto-1,3-diols or keto-lactones with excellent enantioselectivity ee. These advanced building blocks then allowed a variety of Alzheimer -secretase inhibitor drug targets to formally be accessed. Beyond those fundamental achievements, but within the same project, I was able to show a catalyst based achievement, the first useful access to previously inaccessible diastereomeric aldol products. The last third of my research focused on the use of primary amine catalysts, amino acid based, for the first extensive broadening of the Michael substrate scope since its broader introduction decades ago. Here I was able to show that acidic functional groups, e.g., phenolic OH, amide NH, and carboxylic acid moieties are fully tolerated under catalytic enantioselective conditions. This is important because it shows that protecting groups can be avoided and this lead to the shortest and highest yielding route to (R)-Pristiq, (-)-O-desmethylvenlafaxine, a commercially prescribed antidepressant.

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Meta data
Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Hussein Ali El Damrany Hussein
Referee:Thomas C. Nugent, Nikolai Kuhnert, Muhammad Sharif Akbar
Advisor:Thomas C. Nugent
Persistent Identifier (URN):urn:nbn:de:gbv:579-opus-1007042
Document Type:PhD Thesis
Language:English
Date of Successful Oral Defense:2017/07/04
Date of First Publication:2017/05/12
Academic Department:Life Sciences & Chemistry
PhD Degree:Chemistry
Focus Area:Health
Call No:Thesis 2017/4

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