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

2. 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, , Sharpless: Rostovtsev et al, Angewandte Chemie, 2002, 114, , Bertozzi: Agard et al, J. Am. Chem. Soc., 2004, 126,

3. 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, , Swarts et al, J. Am. Chem. Soc., 2012, 134,

4. 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,
Wender et al, J. Am. Chem. Soc., 1997, 119,

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