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Title page for ETD etd-03032016-112954

Type of Document Dissertation
Author Danneman, Michael William
URN etd-03032016-112954
Title Applications of Chiral Amidine Catalysis Towards the Synthesis of Small Molecule Therapeutics and Recent Advances in Vicinal Diamine Synthesis
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Brian O. Bachmann Committee Member
Charles M. Lukehart Committee Member
Gary A. Sulikowski Committee Member
  • doubly intermolecular alkene diamination
  • enantioselective iodolactonization
  • azaindoline
  • amidine-amide catalysis
  • aza-Henry addition
  • bisamidine catalysis
Date of Defense 2016-02-25
Availability unrestricted
Applications of Chiral Amidine Catalysis Towards the Synthesis of Small Molecule Therapeutics and Recent Advances in Vicinal Diamine Synthesis

Michael W. Danneman

Dissertation Under the Direction of Professor Jeffrey N. Johnston

A potent GlyT1 inhibitor, discovered by Lindsley & Williams [U.S. Patent WO 2010/114907 A1], has been synthesized via the use of chiral Pyrrolidine Bis(AMidine) [PBAM] organocatalysis (Chem. Commun. 2012, 48, 5578-5580). A 3-nitroazetidine nucleophile is used in an asymmetric aza-Henry addition reaction, catalyzed by a PBAM-triflic acid salt, to furnish the expected adduct in high yield and enantioselectivity (93% yield, 92% ee). Subsequent denitration of this adduct affords a scalemic scaffold which, through a short sequence, can be converted to the pharmacologically more potent enantiomer.

Additionally, a novel class highly of efficacious Mono(AMidine) [MAM] organocatalysts have been synthesized in order to facilitate the development of Nutlin analogs (J. Org. Chem. 2014, 79, 6913-6938). These catalysts allow for the aza-Henry addition of aryl nitroalkane pronucleophiles to azomethine to furnish nonsymmetric, masked cis-stilbene diamine backbones with high levels of diastereo- and enantioselectivity (up to 200:1 dr and 99% ee). These diamines, via a short synthetic sequence, can then be converted to their respective cis-imidazoline Nutlin analogs and subsequently analyzed for MDM2- and MDMX-p53 inhibition in collaboration with St. Jude Children’s Research Hospital.

Also reported is the use of an oxidant-additive combination to promote the metal-free synthesis of vicinal-diamines. Herein, doubly intermolecular alkene diamination is achieved with electron-rich, terminal alkenes through the use of a hypervalent iodine (PhI(OAc)2) reagent, iodide (KI), and electron-rich amines (Org. Lett. 2015, 17, 2558-2561). Mono- and disubstituted amines combine with electron-rich alkenes, particularly ortho-hydroxystyrenes, to achieve the greatest level of generality. A key novelty of this diamination is that commercially available electron-rich amines can coexist as both a nucleophile and an electrophile without conventional transition metal-based activation. Mechanistically, this reaction is unique in the sense that alkene attack of an activated haloamine may lead to an ortho-quinone methide intermediate, a suitable electrophile for subsequent nucleophilic attack of amine en route to homodiamination.

The same oxidant-additive combination (PhI(OAc)2-KI) is employed to achieve an operationally straightforward, transition metal-free, inter/intramolecular diamination of vinyl aminopyridines (Org. Lett. 2015, 17, 3806-3809). Electron-rich mono- and disubstituted amines combine with these vinyl pyridines to arrive at their corresponding aza-3-aminoindolines, achieving a high degree of generality. Since indoline and azaindoline scaffolds are present in many bioactive alkaloids and pharmaceuticals, this annulative diamination of vinyl pyridines is of high importance as it can serve as a unified approach in order to access all four azaindoline heterocyclic families.

Lastly, chiral proton catalysis is employed in order to promote the enantioselective iodolactonization of internal Z-alkenes. Herein, a stilbene diamine-derived PBAM catalyst (StilbPBAM), in the presence of N-iodosuccinimide, is able to convert an unsaturated Z-alkenyl carboxylic acid to its respective iodolactone with promising levels of enantioselection (up to 65% ee). Once fully optimized, this methodology can be applied towards the enantioselective synthesis of sesbanine.

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