1,3-Dipolar Cycloadditions Created by Alexandra Kent and Judy Zhu Edited by Margaret Hilton Honors Organic Chemistry Chem 2321 (Sigman), 2013

1,3-Dipolar Cycloadditions Overview: A 1,3-dipolar cycloaddition is a fascinating and diverse reaction that can be used in stepwise syntheses of large molecules, such as masked aldol reactions, and has potential biological applications. While it is an incredibly useful reactions, is also has a simple mechanism. Mechanism Early Examples Huisgen cycloaddition, 1963 Copper-Free Strain Promoted Bertozzi cycloaddition, 2004 Copper-catalyzed Sharpless cycloaddition, 2002 Wiki Page:1,3-Dipolar Cycloaddition, Huisgen: R. Huisgen, Angewandte Chemie, 1963, 2, 633-696, Sharpless: Rostovtsev et al, Angewandte Chemie, 2002, 114, 2708-2711, Bertozzi: Agard et al, J. Am. Chem. Soc., 2004, 126, 15046-15047

Examples and Applications Jewett and Bertozzi Bertozzi’s group synthesized a cyclooctyne that becomes fluorescent after a reaction with an azide. This cyclootyne-based probe is an important target for real-time imaging of azide-labeled biomolecules. Swarts and Bertozzi A cell can be fluorescently labeled by a strain-promoted cycloaddition. The azide is attached to a cell and upon the addition of a fluorescently labeled cylooctyne, the flurorophore is bound to the cell and can be imaged. References: Jewett et al, Organic Letters, 2011, 13, 5937-5939, Swarts et al, J. Am. Chem. Soc., 2012, 134, 16123-16126

Problems 1. This is a synthesis for a Miyakolide precursor which is an anti-cancer agent. Propose a mechanism for the cycloaddition. 2. This is a synthesis for a Phorbol precursor which is a carcinogen. Propose a mechanism for the cycloaddition. Higa et al, J. Am. Chem. Soc., 1992, 114, 7587-7588 Wender et al, J. Am. Chem. Soc., 1997, 119, 7897-7898

Contributed by: Created by Alexandra Kent and Judy Zhu (Undergraduates) Edited by Margaret Hilton Honors Organic Chemistry University of Utah Chem 2321 (Sigman), 2013