Catalytic Asymmetric Michael Reaction of β-Keto Esters: Effects of the Linker Heteroatom in Linked-BINOL

Keisuke Majima, Ryo Takita, Akihiro Okada, Takashi Ohshima, Masakatsu Shibasaki

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106 Citations (Scopus)


We describe the development of a general catalytic asymmetric Michael reaction of acyclic β-keto esters to cyclic enones, in which asymmetric induction occurs at the β-position of the acceptors. Among the various asymmetric catalyst systems examined, the newly developed La-NR-linked-BINOL complexes (R = H or Me) afforded the best results in terms of reactivity and selectivity. In general, the NMe ligand 2 was suitable for the combination of small enones and small β-keto esters, and the NH ligand 1 was suitable for bulkier substrates (steric tuning of the catalyst). Using the La-NMe-linked-BINOL complex, the Michael reaction of methyl acetoacetate (8a) to 2-cyclohexen-1-one (7b) gave the corresponding Michael adduct 9ba in 82% yield and 92% ee. The linker heteroatom in linked-BINOL is crucial for achieving high reactivity and selectivity in the Michael reaction of β-keto esters. The amine moiety in the NR-linked-BINOL can also tune the Lewis acidity of the central metal (electronic tuning of the catalyst), which was supported by density functional studies and experimental results. Another advantage of the NR-linked-BINOL ligand as compared with O-linked-BINOL is the ease of modifying a substituent on the amine moiety, making it possible to synthesize a variety of NR-linked-BINOL ligands for further improvement or development of new asymmetric catalyses by introducing additional functionality on the linker with the amine moiety. The efficiency of the present asymmetric catalysis was demonstrated by the synthesis of the key intermediate of (-)-tubifolidine and (-)-19,20-dihydroakuammicine in only five steps compared to the nine steps required by the original process from the Michael product of malonate. This strategy is much more atom economical. On the basis of the results of mechanistic studies, we propose that a β-keto ester serves as a ligand as well as a substrate and at least one β-keto ester should be included in the active catalyst complex. Further improvement of the reaction by maintaining an appropriate ratio of the La-NMe-linked-BINOL complex and β-keto esters is also described.

Original languageEnglish
Pages (from-to)15837-15845
Number of pages9
JournalJournal of the American Chemical Society
Issue number51
Publication statusPublished - Dec 24 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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