Synthesis of Breitfussin B by Late-Stage Bromination

The breitfussins are halogenated natural products whose structures were determined with the assistance of atomic-force microscopy. The site selectivity of <i>N</i>-bromosuccinimide-mediated bromination of a model breitfussin core was found to be strongly dependent on solvent selection; use of acetone led to oxazole bromination, and use of a pyridine-containing mixture led to pyrrole bromination. This tunable site-selective bromination was used in a protecting-group-free synthesis of breitfussin B that proceeded in 9.2% yield over 12 reactions and five chromatographic separations. A bromooxazole analogue of breitfussin A was also prepared by late-stage bromination but isomerized on silica gel to form breitfussin B. This isomerization appeared to proceed through a unimolecular pathway

Hormonal, chemical, and transcriptional regulations of Wnt/{221}-catenin signaling in mammary carcinogensis

published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph

Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkyl­zinc reagents is reported. Excellent regio­control is achieved utilizing an 8-amino­quinoline directing group that can be readily cleaved to unmask net β,γ-dicarbo­functionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C­(sp³)–C­(sp³) reductive elimination step

Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkyl­zinc reagents is reported. Excellent regio­control is achieved utilizing an 8-amino­quinoline directing group that can be readily cleaved to unmask net β,γ-dicarbo­functionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C­(sp³)–C­(sp³) reductive elimination step

Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkyl­zinc reagents is reported. Excellent regio­control is achieved utilizing an 8-amino­quinoline directing group that can be readily cleaved to unmask net β,γ-dicarbo­functionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C­(sp³)–C­(sp³) reductive elimination step

Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkyl­zinc reagents is reported. Excellent regio­control is achieved utilizing an 8-amino­quinoline directing group that can be readily cleaved to unmask net β,γ-dicarbo­functionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C­(sp³)–C­(sp³) reductive elimination step

Catalytic, Enantioselective Synthesis of Allenyl Boronates

A method to achieve enantioselective 1,4-hydroboration of terminal and internal enynes to access allenyl boronates under CuH catalysis is described. The reaction typically proceeds in a highly stereoselective manner and tolerates an array of synthetically useful functional groups. The utility of the enantioenriched allenyl boronate products is demonstrated through several representative downstream derivatizations

Kinetically Guided Radical-Based Synthesis of C(sp3)-C(sp3) Linkages on DNA

<div><div><div><p>DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in pharmaceutical industry, mainly due to its powerful diversity and incredible number of molecules. In the past two decades since its disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL-setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C–C bonds on DNA was studied, which represents the first radical-based synthesis in DEL.</p></div></div></div

Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations

From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a <i>p</i>-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy