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Title:Catalytic C-H oxidation reactions for the synthesis and diversification of hydroxyamino acid motifs
Author(s):Osberger, Thomas Joseph
Director of Research:White, M. Christina
Doctoral Committee Chair(s):White, M. Christina
Doctoral Committee Member(s):Denmark, Scott E; Katzenellenbogen, John A; van der Donk, WIlfred A
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):C-H Functionalization
C-H Oxidation
Catalysis
Abstract:Hydroxyamino acid motifs are well-represented structures in natural products and pharmaceuticals, and are widely employed as synthetic building blocks in organic synthesis. In nature, such compounds are often synthesized via enzymatic C-H oxidation of simple amino acid precursors. Inspired by such processes, small molecule catalysts have been developed to perform a variety of C-H oxidation reactions, which have increased the efficiency of synthetic routes and allowed for late-stage diversification of complex molecules. This work describes the development and application of two transition metal catalyzed C-H oxidation reactions for the synthesis and diversification of hydroxyamino acids and related molecules. α-Hydroxy-β-amino acids are an important subclass of the hydroxyamino acid family, examples of which are found in pharmaceutical agents including taxol and bestatin. Current synthetic methods for the construction of these molecules often rely on the use of pre-oxidized fragments or harsh reagents. This work reports the merging of Brønsted acid catalysis with Pd(II)/bis-sulfoxide catalyzed allylic C-H oxidation to achieve the synthesis of vinyl-oxazolidinones from simple homoallylic, N-Boc protected amines. It is shown that utilization of dibutylphosphate as a co-catalyst with a Pd(II)/bis-sulfoxide catalyst produces optimal reactivity, affording anti¬-vinyl-oxazolidinones. These products are versatile synthetic intermediates, and their synthetic derivatization into α-hydroxy-β-amino acids as well as intermediates to amino sugars is demonstrated. Furthermore, the high functional group tolerance of the reaction enabled late-stage cyclization on a leucine-β-allylglycine dipeptide substrate to install a vinyl oxazolidinone moiety. Mechanistic investigations into the role of the dibutylphosphate co-catalyst revealed that it may play multiple roles beyond promoting formation of a cationic π-allylPd intermediate, including serving as an anionic ligand to palladium capable of performing allylic C-H cleavage. Natural products of nonribosomal peptide synthetase (NRPS) origin posses complex topologies and diverse functional group arrays that lead to varied and impressive therapeutic potential. The structural diversity achieved among these natural products is due in large part to a biosynthetic strategy that employs pre- and post-assembly oxidative modifications of individual amino acid building blocks and fully assembled peptide chains, exemplified in the biosynthesis of vancomycin. In many cases, diversification is achieved via enzymatic hydroxylation of amino acids to form unnatural amino acids that are incorporated into a larger peptide structure, or are intermediates for further diversification of an amino acid. Here we report a strategy inspired by the elegant approach of NRPS biosynthetic systems, wherein small molecule iron catalysts Fe(PDP) and Fe(CF3PDP) enable the oxidative diversification of amino acids and peptides. In particular, a highly chemoselective hydroxylation at C5 of proline residues produces the versatile 5-hydroxyproline derivative, enabling further transformations to rapidly diversify amino acid and proline-containing peptide structures. In total, four chiral pool amino acids (proline, valine, leucine, and norvaline) are rapidly converted to twenty-one unnatural amino acid residues representing seven distinct functional group classes, and a single proline-containing tripeptide is transformed into eight sequences spanning five distinct functional group classes. Finally, the high efficiency and chemoselectivity of the iron catalyst is demonstrated by the chemoselective, late-stage transformation of a proline residue pentapeptide macrocycle to an unnatural residue.
Issue Date:2016-06-17
Type:Thesis
URI:http://hdl.handle.net/2142/92900
Rights Information:Copyright 2016 Thomas Osberger
Date Available in IDEALS:2016-11-10
Date Deposited:2016-08


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