Tandem α-Cyano Enamine/Enolate Alkylations on Bicyclic Lactams:  Asymmetric Carbocycle and Heterocycle Synthesis

The alkylation of cyano enamines 1 and 7 with α,ω-dihalides (or dihalide equivalents), followed by hydrolysis to reveal the lactam carbonyl, provided lactams 8 and 10 containing a tethered electrophile. Intramolecular cyclization of the pendant halide onto the lactam enolate provided tricyclic lactams 9 and 13, which were subjected to a second enolate alkylation to form a quaternary stereocenter. In the case of nor-ephedrine tricyclic lactam 13, the intermolecular was highly endo selective, and the resultant lactams 14 were subjected to partial reduction and hydrolytic auxiliary cleavage to provide enantiopure octalones 16 and 17. From this chemistry came the synthesis of the “Woodward ketone” 19, an intermediate in the total synthesis of a number of steroids. Finally, the methoxymethyl bicyclic (or tricyclic) lactams 33 were shown to undergo nonreductive cleavage of the chiral auxiliary to provide 3,4-dihydropyridones containing a quaternary center.