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Title:Late-stage C(sp3)–H hydroxylation, amination, and methylation in nitrogen-containing molecules
Author(s):Feng, Kaibo
Director of Research:White, M. Christina
Doctoral Committee Chair(s):White, M. Christina
Doctoral Committee Member(s):Hergenrother, Paul J.; Sarlah, David; Fout, Alison R.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):late-stage functionalization
C–H activation
Abstract:Direct installation of oxygen, nitrogen, and methyl functionalities into C(sp3)–H bonds is a topic of significant synthetic and medicinal interest. These modifications have the potential to drastically change a molecule’s physical and biological properties, which could lead to the discovery of new medications. Among FDA-approved small-molecule drugs, 84% contain at least one nitrogen atom. Functionalization of these molecules via transition metal catalysis faced substantial challenges, as the strongly Lewis basic nitrogen is prone to bind to the Lewis acidic metal center, thereby either shutting down the catalysis or limiting functionalization to sites proximal to itself as a directing group. Consequently, functionalizations at sites remote from nitrogen and mediated by ligated transition metal catalysts were elusive. On the other hand, functionalizations alpha to nitrogen via hydroxylation have been demonstrated, but the hydroxylated intermediates are by nature more hyperconjugatively activated than the substrates and promote overoxidation, thus requiring reduction before further derivatization. In this dissertation, I describe new methods that address these issues and selectively functionalize these nitrogen-containing molecules both at sites remote from nitrogen and alpha to nitrogen to install hydroxyl, amino, and methyl groups at late stages. The first chapter of this dissertation focuses on the development of a remote oxidation strategy using small-molecule iron catalysts Fe(PDP) and Fe(CF3PDP). These catalysts have shown excellent regioselectivity in oxidizing complex molecules based on the electronic, steric, and stereoelectronic environments of their aliphatic C–H bonds, but were previously unreactive toward amines and pyridines due to nitrogen-metal binding. Key to the success of this new strategy was the use of a strong Brønsted acid (HBF4) or azaphilic Lewis acid (BF3), which irreversibly protonates or binds with the basic nitrogen, thus stripping its ability to bind with the iron center. This protection simultaneously renders the nitrogen motif a strong electron-withdrawing group, inductively deactivating its proximal sites and promoting remote oxidation. For tertiary amines and pyridines, the HBF4 protection rendered optimal yields of remotely oxidized products. For sterically unhindered secondary and primary amines, complexation with BF3 is preferred, as it produced stable complexes that can be readily oxidized in good yields and purified via silica chromatography. A site-selective late-stage hydroxylation was demonstrated on an analogue of prostate cancer drug abiraterone. A previously reported computational model was expanded to include nitrogen-containing substrates, and accurately predicted the site of oxidation among fifteen possible sites. In the second chapter, I describe the expansion of the nitrogen protecting strategy to enable late-stage benzylic amination in amines, pyridines, imide, and benzimidazole. Although preparative benzylic amination is achievable with rhodium catalysis, its functionalization of basic amines either only occur alpha to nitrogen and on nitrogen, or does not occur at all when the nitrogen is acid-protected, likely because of the labile ligand. Using a highly acid-stable and easily obtainable catalyst, [MnIII(ClPc)], and an inert polar solvent, 1,2-dichloroethane, remote amination was achieved on a series of basic-nitrogen-containing molecules with high chemoselectivity and site-selectivity. In general, HBF4 protection gave higher yields, but BF3 is preferable when the HBF4 protonation results in low solubility. Imide nitrogens are already deactivated by its carbonyls and need no acid protection. Late-stage amination was demonstrated in six derivatives of drugs and natural products containing competing sites, where only the most electron-rich and sterically accessible secondary benzylic site was aminated. The sulfonamide products can be easily deprotected using zinc-copper couple to produce the free amines. In the final chapter, I discuss the development of a late-stage methylation strategy. Frequently referred to as the “magic methyl” effect, installation of methyl groups adjacent to heteroatoms is especially desirable for medicinal chemists, as this modification often leads to significant potency boost. Traditional alkylation methods rely on metalation followed by treatment with alkyl electrophiles. This process is unselective and has very a limited heterocycle scope. This work describes a different approach via oxidized hemiaminal intermediates, which significantly expanded the substrate scope. Key challenges addressed include chemoselectivity, overoxidation, elimination, and functional group tolerance. A small-molecule manganese catalyst, Mn(CF3PDP), was previously introduced for selective methylene oxidation and tolerates electron-poor arenes. By significantly lowering its catalyst loading to a 200:1 substrate to catalyst ratio, deleterious aromatic oxidation and overoxidation to imides were suppressed and unprecedented tolerance for electron-rich and electron-neutral arenes was established. The use of the commercial mild nucleophile, trimethylaluminum, along with one of three mild hemiaminal activation methods (BF3, DAST, TFAA/TMSOTf), enabled late-stage methylation on nine derivatives of drugs and natural products without eroding electrophilic functional groups or causing elimination. Additionally, methylation of a secondary aniline and remote methylation of the same abiraterone analogue can be achieved by altering the reaction conditions to include a stronger nucleophile or activation method. Collectively, these methods now provide rapid access to metabolites and drug derivatives while reducing synthetic effort, time, and cost, and I expect their wide applications in the discovery research for novel therapeutics.
Issue Date:2020-07-07
Rights Information:Copyright 2020 Kaibo Feng
Date Available in IDEALS:2020-10-07
Date Deposited:2020-08

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