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Title:Development of palladium catalyzed intramolecular allylic C―H amination and oxidation towards pharmacological motifs
Author(s):Rice, Grant
Director of Research:White, Maria C.
Doctoral Committee Chair(s):White, Maria C.
Doctoral Committee Member(s):Denmark, Scott E.; Katzenellenbogen, John A.; Nuzzo, Ralph G.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):C-H Activation
Palladium
Bis-Sulfoxide
Allylic Amination
Allylic Oxidation
Abstract:It is often said that with enough time, money and resources organic chemists can synthesize any complex organic small molecule. While those sentiments are rooted in fact, the reality is that chemists are often met with limited time, money and resources. As a result, great demand exists for chemical methods that mitigate these factors, thus achieving the goals of unconstrained organic synthesis. In this vein, research in the White group has been focused on the utility of C―H activation methodologies allowing for the streamlining of total synthesis. Using Pd(II)/sulfoxide catalysis, the White group has made significant developments in the area of allylic C―H oxidation and functionalization reactions. Using these methodologies, a variety of pharmacologically relevant small molecules have been synthesized in highly efficient sequences that minimized overall step counts as well as increasing the total synthetic yield. Classical synthetic methods necessitate the use of pre-oxidized starting materials en route to the formation of the desired targets. As a result, many steps within these synthetic sequences are not related to the formation of the primary molecular framework. Instead, many synthetic routes require secondary manipulations such as oxidation/reductions, protecting group manipulations and functional group interconversions. Alternatively, the robust, latent functionality of the terminal olefin obviates the need for many of these wasteful steps via C―H activation processes. Herein, the development of methodologies for the synthesis of syn-1,3 amino alcohol motifs, syn- and anti- vicinal diamine motifs and chroman heterocycle motifs is described. A highly selective and general Pd(II)/bis-sulfoxide-catalyzed allylic C—H amination reaction en route to syn-1,3-amino alcohol motifs is first demonstrated. This reactivity is achieved under mild conditions through the use of electron-deficient N-nosyl carbamate nucleophiles. These nucleophiles are thought to promote functionalization by furnishing higher concentrations of anionic species in situ. The reaction is shown to be orthogonal to classical C—C bond forming/reduction sequences as well as nitrene-based C—H amination methods. Advances made within this research are then used to enhance the reaction profile of the previously published C―H amination system towards syn-1,2 amino alcohol motifs. Next, intramolecular allylic C—H amination reactions are applied towards rapidly diversifying structures containing a sensitive β-lactam core similar to that found in the monobactam antibiotic Aztreonam. Pharmacologically interesting oxazolidinone and oxazinanone motifs are rapidly installed with predictable and high diastereoselectivities. Additionally, it is demonstrated for the first time that intramolecular C—H amination processes may be accelerated using catalytic amounts of a Lewis acid co-catalyst. The stereodivergent synthesis of syn- or anti-1,2-diamine precursors is then discussed. From a common terminal olefin, the synthesis of these motifs has been accomplished using a combination of Pd(II) catalysis with azaphilic Lewis acid co-catalysis. A Pd(II)/bis-sulfoxide/silver triflate co-catalyst system is demonstrated for the first time to lead to syn-1,2-diamine precursors in good to excellent yields and diastereoselectivities. It is then shown that simple removal of the bis-sulfoxide ligand from this reaction results in a complete reversal in the stereo outcome affording anti- products in good yields and excellent diastereoselectivities. Mechanistic studies suggest the divergent diastereoselectivities arise from a switch in mechanism from allylic C—H cleavage/functionalization to olefin isomerization/oxidative amination. Lastly, the synthesis of biologically active chroman motifs has been accomplished using a combination of Pd(II) catalysis and Lewis acid co-catalysis. High yields are achieved by tuning the bis-sulfoxide ligand to retard direct nucleophile-catalyst interaction of non-acidic nucleophiles. High substrate generality is shown, allowing this method to synthesize chroman motifs found in a variety of biologically active pharmacophores. Mechanistic insights suggest that allylic oxidation is proceeding through standard allylic C―H oxidation, similar to previously published mechanisms for carboxylic acid and N-nosyl carbamate nucleophile functionalization.
Issue Date:2013-02-03
URI:http://hdl.handle.net/2142/42435
Rights Information:Copyright 2012 Grant Rice
Date Available in IDEALS:2013-02-03
2015-02-03
Date Deposited:2012-12


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