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Regiochemistry of Nitroso Hetero Diels-Alder Reactions, Catechol Siderophore Analogues for Surface Wet Adhesion, and an Inquiry-Based Synthetic Organic Laboratory Course

  • Author(s): Lewis, Robert Bradley
  • Advisor(s): Butler, Alison
  • Read de Alaniz, Javier
  • et al.
Abstract

Carbon-nitrogen bonds are prevalent in a wide range of natural products and biologically active molecules. The availability of efficient methods for the construction of these bonds and means of controlling their regio- and stereochemistry is therefore of great interest to the synthetic community. The nitroso hetero Diels-Alder reactions offers a way to simultaneously generate carbon-nitrogen and carbon-oxygen bonds with high regio- and stereoselectivity. However, there is little experimental evidence to support computational models for the prediction of regioselectivity in the reaction of 2-substituted dienes with nitrosocarbonyl compounds.

A study of the reactivity of 2-substituted 1,3-butadienes with nitrosocarbonyl compounds in the 4+2 cycloaddition has been carried out showing that the regioselectivity involves a delicate balance of steric and electronic effects. 2-Aryl 1,3-butadienes favor the distal isomer with the magnitude of preference ranging from 4:1 to 15:1 depending on the electronic nature of the aryl substituent and the nitrosocarbonyl group. However, sterics can override the observed electronic preference and form the proximal isomer preferentially. The results obtained, together with previous theoretical calculations and experimental data, provide further data to aid in synthetic planning.

Small molecule and polymeric adhesives offer a wide range of potential applications, especially in the biomedical field. In this and other application areas, the hydration layers that form at surfaces in saline solutions severely limit the ability of adhesives to form strong surface interactions that lead to adhesion. However, marine mussels regularly adhere to surfaces in wet saline conditions with a suite of specialized mussel foot proteins (mfps). These proteins rely on the intramolecular catechol-cation synergy of amino acid residues to evict the hydration layer and bond to the underlying surface. A recent theory speculates that the molecular mechanics of detachment also contribute to the synergy enhanced adhesion.

This work focuses on the use of small molecule siderophore-based mfp-mimics to further probe the observed intramolecular catechol-cation synergy. Systematically varying the spacing between the catechol and cation groups in the adhesive molecules reveals that the synergy between catechol and lysine remains effective in promoting adhesion even when the moieties are separated by one or two glycine amino acids. The results also provide evidence that the detachment sequence of catechol and lysine in mussel-inspired adhesives do not contribute significantly to the observed synergy between these moieties. This research clarifies the understanding of mussel adhesion and provides information that will inform the design of synthetic mussel-inspired adhesives.

Laboratory activities have the potential for a large impact on student learning and the development of skills vital to becoming a competent scientist. Traditional or expository teaching laboratories have received their fair share of criticism for not meeting this potential fully. There is a growing call for the departure from traditional laboratory activities and the adoption of more inquiry based instruction. In this work, a course is described where students are engaged in an inquiry-based quarter-long research project to synthesize a known pharmaceutical target. Students use literature search engines, such as Reaxys and SciFinder, and the primary chemical literature as resources to plan and perform the synthesis of their pharmaceutical target. This course provides students with a simulated research experience in which they develop critical thinking, problem solving, and data analysis skills, along with a greater appreciation of the processes of science.

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