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Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism
Niphakis, Micah James Turunen, Brandon J. Georg, Gunda I.
Niphakis, Micah James
Turunen, Brandon J.
Georg, Gunda I.
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Abstract
Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multi-step process involves deprotection of Boc-aminoynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g. indolizidine, quinolizidine and Stemona alkaloids).
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Date
2010-10-15
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American Chemical Society
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Keywords
Enaminone, Vinylogous amide, Ynone, 6-endo-trig, 6-endo-dig, 6-exo-trig, ®-amino elimination, Retro-Michael, 3-dihydro-4-pyridone, Azepine, Boc-deprotection
Citation
Niphakis, M. J., Turunen, B. J., & Georg, G. I. (2010). Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism. The Journal of Organic Chemistry, 75(20), 6793–6805. http://doi.org/10.1021/jo100907u