Part I: Vanadium–catalyzed Asymmetric Oxidative Coupling Of Phenols And Hydroxycarbazoles And Its Mechanistic Study Part Ii: Total Synthesis Of Chaetoglobin A Part Iii: Ligand Evolution To Drive Reaction Discovery Part Iv: Oxidative Coupling Of 3-Oxindoles To Construct Quaternary Centers
Date of Award
Doctor of Philosophy (PhD)
Marisa C. Kozlowski
Amos B. Smith, III
Part I: The axially chiral biaryl motif is found in many natural products as well as in ligands for catalysis such as 1,1’-binaphthol. Formation of axially chiral compounds was accomplished by means of the asymmetric oxidative coupling, which has proven to be both an efficient and environmentally benign synthetic method. Interests toward an effective asymmetric oxidative coupling of simple phenols, which are challenging substrates because of relatively high oxidation potential and regioselectivity issues, have arisen due to a lack of corresponding methods. After many efforts to design and modify the catalyst scaffold, we found that a monomeric vanadium(V) catalyst together with LiCl or HOAc as an additive accomplished C-C bond formation to afford the bisphenol moiety in good yield and good enantioselectivity. The carbazole moiety is another good candidate to apply our oxidative coupling method because of its electron-rich nature. Using various 3-substituted-2-hydroxycarbazole derivatives, oxidative coupling afforded products containing diverse functional groups, including ketone, ester, trifluoromethyl, halides, allyl, etc.
Part II: The azaphilone alkaloid, chaetoglobin A, has drawn attention due to its intriguing dimeric structure. The molecule features a 2H-isoquinoline-6,8-dione moiety containing quaternary centers and a chiral axis that connects two identical motifs. Although a variety of monomeric azaphilone alkaloids have been synthesized, a dimeric class of azaphilone has not been synthesized to date. Installing axial chirality by means of the asymmetric oxidative phenol coupling is the key step in making the natural product. Afterwards, bisformylation and oxidative dearomatization were carried out smoothly to afford highly oxygenated bicyclic cores. Thorough optimization of the selective acetyl deprotection and final amination afforded access to the synthetic chaetoglobin A in 12 linear steps.
Part III: These days, the ligand plays an important role in versatile chemical reactions. Understanding the ligand effect provided critical information to tackle challenging issues. Taking advantage of High Throughput Experimentation (HTE) allowed access to a variety of ligands in a rapid and efficient manner. Due to easy synthesis of a series of different alkynylphosphine oxides and azides, our efforts were focused on generating the diverse triazole-based phosphine ligands. The ligand was prepared by [3+2]-cycloaddition with the alkynylphosphine oxide and azide, followed by the corresponding phosphine oxide reduction. Ultimately, a one-pot protocol reinforced the efficient ligand synthesis and accomplished the synthesis of a number of ligands by HTE parallel synthesis. Currently, with the ClickPhos ligands, the ligand effect was explored under the challenging chemical reaction conditions.
Part IV: 2,2-Disubstituted indolin-3-one is not only a core structure for many natural products but also serves as a useful synthetic intermediate. To construct the C-2 quaternary center via the oxidative coupling between 3-oxindole and various aryl substrates, including indoles, pyrroles, and electron-rich aryl compounds, was achieved in the presence of a copper catalyst incorporated with a salan ligand. This milder catalytic protocol efficiently generated the quaternary center with various functional groups tolerance, such as halide, ester, nitrile, etc. In addition, use of a chiral monomeric vanadium catalyst gave promising levels of asymmetric transformation.
Kang, Houng, "Part I: Vanadium–catalyzed Asymmetric Oxidative Coupling Of Phenols And Hydroxycarbazoles And Its Mechanistic Study Part Ii: Total Synthesis Of Chaetoglobin A Part Iii: Ligand Evolution To Drive Reaction Discovery Part Iv: Oxidative Coupling Of 3-Oxindoles To Construct Quaternary Centers" (2018). Publicly Accessible Penn Dissertations. 2859.