Asymmetric Electrophilic Substitutions at the α-Position of γ- and δ-Lactams

Abstract

Enantioselective electrophilic substitutions with Michael acceptors and alkylating agents at the α-positions of γ- and δ-lactams are presented. The asymmetric Michael addition of lactam 1a to nitroalkenes 2 was used as the key step for the synthesis, over three steps, of α-(β-aminoalkyl)-γ-lactams 5 in good overall yields (37−61%) and with very good diastereomeric and enantiomeric excesses (de ⩾ 96%, ee = 82 to ⩾ 96%). Conjugate addition to alkenylsulfones 6a and 6b afforded Michael adducts 7a and 7b in good yields, but with only moderate diastereoselectivities (de = 38−41%). α-Substituted N-dialkylamino lactams 9a−c were obtained by asymmetric alkylation of N-(dialkylamino)lactam 1a with functionalised electrophiles 8a−c in good yields (66−84%) and with moderate to excellent diastereomeric excesses (66 to ⩾ 96%). The auxiliary was removed by reductive N−N bond cleavage to afford the lactam 10 (ee = 83%). A second alkylation of α-alkylated d N-(dialkylamino)lactams 11 yielded α-disubstituted γ-butyrolactams (12a, 12b) in good yields and diastereomeric excesses (de = 83−88%) and α-disubstituted δ-valerolactams (12c−e) in good yields but with low to moderate diastereoselectivities (de = 6−52%). The α-silylated γ-lactam 15 was obtained in good yield (53% over two steps) and with an enantiomeric excess of 83% by α-silylation of N-(dialkylamino)lactam 1a and subsequent reductive removal of the auxiliary.