Asymmetric Organic Synthesis. Radical Cyclizations of Chiral Enamides

• Published in: Journal of organic chemistry Vol. 60; no. 24; pp. 8044 - 8050
• Main Authors: Schultz, Arthur G, Guzzo, Peter R, Nowak, Deanne M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.12.1995; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; 5-ENDO-TRIG; ACID; BOND; ALKYLATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo00129a052

Stereoselective radical cyclizations to the enamide double bond have excellent potential for utilization in alkaloid and related nitrogen heterocycle synthesis. Complete facial selectivity has been found for radical cyclizations of chiral substrates 1a --> 2, 7 --> 8, 11 --> 12 + 13, 15 --> 16 + 17, and 19 --> 20. The stereoselectivity for reduction of the intermediate tertiary radicals with Bu(3)SnH correlates with product stability. For example, 7 gives cis-dihydro 8 with no trace of the trans-dihydro isomer 9, 3.6 kcal/mol less stable than 8. Radical cyclization of 11 gave a 1:1 mixture of the six-membered ring lactam 12 and the spirocyclic lactam 13. Diastereomers 12 and 14 have near equivalent stabilities, but radical reduction from the beta-face is blocked by the presence of the adjacent benzyloxycarbonyl substituent. The formation of 20 from 19, by way of a disfavored 5-endo-trig cyclization pathway may have value as a model for synthesis of kopsinine-type alkaloids. The conversion of 8 to the functionalized hexahydrojulolidine 23 also is described.