Asymmetric electrophilic substitutions at the alpha-position of gamma- anddelta-lactams

Enantioselective electrophilic substitutions with Michael acceptors and alk ylating agents at the a-positions of gamma- and delta -lactams are presente d. The asymmetric Michael addition of lactam is to nitroalkenes 2 was used as the key step for the synthesis, over three steps, of alpha-(beta -aminoa lkyl)-gamma -lactams 5 in good overall yields (37-61%) and with very good d iastereomeric and enantiomeric excesses (de greater than or equal to 96%, e e = 82 to greater than or equal to 96%). Conjugate addition to alkenylsulfo nes 6a and fib afforded Michael adducts 7a and 7b in good yields, but with only moderate diastereoselectivities (de = 38-41%). alpha -Substituted N-di alkylamino lactams 9a-c were obtained by asymmetric alkylation of N-(dialky lamino)lactam 1a with functionalised electrophiles 8a-c in good yields (66- 84%) and with moderate to excellent diastereomeric excesses (66 to greater than or equal to 96%). The auxiliary was removed by reductive N-N bond clea vage to afford the lactam 10 (ee = 83%). A second alkylation of alpha -alky lated d N-(dialkylamino)lactams 11 yielded alpha -disubstituted gamma -buty rolactams (12a, 12b) in good yields and diastereomeric excesses (de = 83-88 %) and alpha -disubstituted delta -valerolactams (12c-e) in good yields but with low to moderate diastereoselectivities (de = 6-52%). The alpha -silyl ated gamma -lactam 15 was obtained in good yield (53% over two steps) and w ith an enantiomeric excess of 83% by alpha -silylation of N-(dialkylamino)l actam 1a and subsequent reductive removal of the auxiliary.