Characterization of a Reductively-Activated Elimination Pathway Relevant to the Biological Chemistry of the Kinamycins and Lomaiviticins

The lomaiviticins (1 and 2) and kinamycins (3–5) are bacterial metabolites with potent antimicrobial and antiproliferative activities. Herein we establish that 1–5 are capable of generating electrophilic acylfulvene intermediates (6) under mildly reducing conditions. These acylfulvenes 6 are formed by a multistep process comprising two-electron reduction and loss of dinitrogen to form an ortho-quinone methide, followed by elimination. Based on these studies, the structure of the product formed from 1 in DNA-cleavage assays is proposed (26). We also show that the bis(hydroxynaphthoquinone) substructures of the lomaiviticins activate the metabolites toward reduction. Finally, based on COMPARE and time-dependent cell response profiling analyses, we show that kinamycin C (4) and the monomeric lomaiviticin aglycon (24) operate by a mechanism of action that is distinct from simple diazofluorenes, such as 23

Wittig Reaction

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License: http://creativecommons.org/licenses/by-nc-sa/3.0/A simple preparation of a conjugated diene via the olefination reaction between cinnamaldehyde and triphenylphosphonium chloride under basic conditions. Students are reintroduced to dry glassware techniques, recrystallization, and stereochemical determination by NMR. Modifications of this procedure include use of a Horner-Wadsworth-Emmons reagent or inclusion in a multi-step synthesis (ie. Diels-Alder reaction)

Suzuki Cross Coupling

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License: http://creativecommons.org/licenses/by-nc-sa/3.0/An easy preparation of differentially-substituted biaryls is reported by palladium-catalyzed cross coupling. The Suzuki cross coupling reaction is both fast and substituent-independent. Column chromatography is performed to isolate pure biaryl product, which is analyzed by NMR

Synthesis and cyclometalation of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c]fluorene-1,3-dione scaffold

The synthesis of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c]fluorene-1,3-dione scaffold is disclosed, which was synthesized using a Suzuki cross-coupling reaction and an intramolecular Heck cyclization as the key steps. This heterocyclic system can serve as a bidentate ligand as demonstrated by the formation and structural analysis of a derived ruthenium complex. The new scaffold constitutes an interesting candidate for the development of organometallic protein kinase inhibitors

Grignard Reaction - Synthesis of Substituted Benzoic Acids

A convenient preparation of substituted benzoic acids from Grignard additions to solid carbon dioxide. Students create a library of carboxylic acids by using differentially substituted, commercially available aryl bromides, which can be used as the starting materials for a multistep synthesis. This is a modification and improvement of a very popular undergraduate organic chemistry experiment

Fisher Esterification: Synthesis of Volatile Esters

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License: http://creativecommons.org/licenses/by-nc-sa/3.0/A microwave-accelerated synthesis of volatile aromatic esters is described in this convenient Fisher esterification reaction. Students perform a liquid-liquid extraction to isolate crude product which they purify by distillation. Analysis by GC/MS and NMR allows students to identify an unknown

Claisen-Schmidt (Aldol) reaction

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License: http://creativecommons.org/licenses/by-nc-sa/3.0/A short aldol condensation reaction that produces differentially-substituted dibenzylideneketones whose UV-Vis spectra can be determined. This experiment allows students to construct structure-activity relationships in the context of the synthesis of a new sunscreen

Reductive Amination Reaction

A simple, solventless procedure for reductive amination that results in an impressive color change. Reaction proceeds in three stages: imine formation, reduction, and acetylation and purification is done by crystallization

Kinetic Analysis of Ester Hydrolysis

A two-week multi-step experiment that introduces students to mechanistic organic chemistry and substituent effects. A simple preparation of differentially substituted para-nitrophenyl benzoates is followed by ester hydrolysis with monitoring by UV-Vis spectroscopy to provide rate data for the reaction

Forensic analysis of analgesics by TLC

An introductory laboratory on the identification of analgesics in an unknown sample. Ideal for the first week of an organic chemistry sequence to get students familiar with their surroundings. Students extract, isolate, and perform thin layer chromatography on aspirin, acetominophen, or ibuprofen