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Asymmetric Electrophilic Substitutions at the α‐Position of γ‐ and δ‐Lactams
Author(s) -
Enders Dieter,
Teschner Pascal,
Raabe Gerhard,
Runsink Jan
Publication year - 2001
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200112)2001:23<4463::aid-ejoc4463>3.0.co;2-1
Subject(s) - chemistry , diastereomer , enantioselective synthesis , lactam , electrophile , alkylation , enantiomer , michael reaction , stereochemistry , chiral auxiliary , adduct , medicinal chemistry , organic chemistry , catalysis
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.