Formation of five-membered lactams by 5-endo-trigonal radical cyclisations of 2-chloro-N-(cycloalk-1-enyl)acetamides: new synthesis of erythrinane skeleton

Abstract

Free-radical cyclisations of a range of 2-chloro-N-(cycloalk-1-enyl)acetamides have been examined. The enamide 5, upon treatment with Bu₃SnH in the presence of azoisobutyronitrile, underwent cyclisation via the carbamoylmethyl radical 6 in a ‘disfavoured’ 5-endo-trig manner to give octahydro-1-methylindol-2-one 8. Similarly, the enamides 10 and 11 gave the corresponding octahydroindol-2-ones 12–15. The N-(3,4-dihydro-2-naphthyl) derivative 16, however, afforded the β-lactam 17 instead of a γ-lactam. The phenyl-substituted congener 24 and the benzocycloheptenyl derivative 29 gave again the five-membered lactams 25 and 30, respectively. The difference in the mode of cyclisations among substrates 5, 16, 24 and 29 has been discussed in terms of the electronic stability and/or the steric congestion of the radical intermediates formed by ring closure of the carbamoylmethyl radical. The carbonyl group incorporated into the five-membered lactams proved to be essential for the 5-endo-trig radical cyclisation, by examination of the reactions of the enamides 33 and 38, in which only the former gave five-membered lactams, viz. compounds 34 and 35. The tandem cyclisation initiated by the carbamoylmethyl radical has also been examined. The method was applied to the synthesis of perhydroerythrinane 58.