Remarkable asymmetric induction from remote stereocenters in conjugate addition chemistry for the synthesis of alkyl-branched α,ω-diaminoazelates

Conjugate addition of aryl Grignard reagents to (2S, 5E, 8S)-di-tertbutyl 4-oxo-2,8-bis-[N-(PhF)aminolnon-5-enedioate (6, PhF = 9-(9-phenylfluorenyl)) in THF proceeded with complete chemoselectivity and >9:1 stereoselectivity to provide predominantly (2S,6S,8S)-6-aryl 4-oxo-2,8-diaminoazelates 7. In the presence of magnesium dibromide, diastereoselectivity in the addition of PhMgBr to enone 6 was improved to 15:1 in favor of the 6S-isomer. Although lower chemoselectivity and stereoselectivity were obtained from the analogous reaction of 6 with isopropyl magnesium bromide in the absence of MgBr2, both were improved significantly when the addition reaction was performed in the presence of MgBr2. In contrast, the corresponding higher-order cyanocuprates reacted with low diastereoselectivity on 6 by a 1,4-addition pathway. In an attempt to identify the source of the high selectivity in the conjugate addition chemistry with 6 and Grignard reagents, the syntheses of enones 12 and 13 provided model systems in which one of the two amino carboxylate moieties of 6 was replaced by a branched alkyl substituent. Conjugate addition reactions on 12 and 13 demonstrated that chemoselectivity with Grignard reagents in the 1,4-addition reaction was contingent on the presence of an amino carboxylate moiety near the ketone of the enone system. Furthermore, because diastereoselectivity with Grignard reagents was significantly lower in additions to amino enones 12 and 13 relative to diamino enone 6, the presence of both amino carboxylate moieties has been highlighted as an important factor for remarkable asymmetric induction in the conjugate addition of Grignard reagents.