Elsevier

Tetrahedron: Asymmetry

Volume 20, Issue 23, 11 December 2009, Pages 2651-2654
Tetrahedron: Asymmetry

Enantioselective Michael reaction of β-keto esters organocatalyzed by recoverable Cinchona-derived dimeric ammonium salts

https://doi.org/10.1016/j.tetasy.2009.11.007Get rights and content

Abstract

Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts in 1–10 mol % for the enantioselective conjugate addition of 2-alkoxycarbonyl-1-indanones to β-unsubstituted Michael acceptors. The corresponding adducts bearing a new all-carbon quaternary center were usually obtained in high yield and with up to 94% ee when using ammonium salts derived from quinidine and its pseudoenantiomer quinine as organocatalysts. These catalysts can be almost recovered quantitatively by precipitation in ether and reused.

Introduction

In spite of the tremendous advances achieved in the field of asymmetric synthesis in recent years, the development of stereoselective approaches for the formation of quaternary stereogenic centers still represents an enormous challenge to synthetic chemists.1 One of the most reliable reactions for their generation is the conjugate addition of acidic carbon nucleophiles to electron-deficient olefins, the so-called Michael reaction.2

Recently, great efforts have been made for the development of efficient enantioselective Michael reactions leading to quaternary stereocenters, mainly performed on readily enolizable compounds such as α-substituted β-keto esters. Thus, enantioselective Michael additions using metal-derived chiral catalysts have been developed,3, 4 although inherent disadvantages associated with the use of metal complexes hamper their use in large scale reactions. Most of them are air and moisture sensitive, requiring careful and strict reaction conditions, which have boosted the development of metal-free procedures.

In the last few years enantioselective organocatalysis has been one of the most active research fields in organic chemistry.5, 6 Studies on organocatalytic enantioselective Michael reactions have been particularly intense,3(a), 7 although the application of these procedures to the enantioselective generation of quaternary stereogenic centers remains less frequent. Noticeably, the first documented efficient enantioselective Michael addition involves the generation of a quaternary stereocenter by reaction of a β-keto ester, such as 2-methoxycarbonyl-1-indanone, and acrolein in the presence of partially resolved (R)-(+)-quinuclidin-2-ylmethanol (57% ee) as an amine base organocatalyst.8 This organocatalytic moiety is present in very popular Cinchona alkaloids, such as cinchonidine and quinine, as well as in their pseudoenantiomers such as cinchonine and quinidine, respectively. Therefore the use of these tertiary amine organocatalyst bases in the Michael reaction of cyclic β-keto esters was immediately explored,9 2-alkoxycarbonyl-1-indanones have frequently been considered as model substrates in these reactions. After this seminal work, several approaches mainly based on changing the substitution pattern of the Cinchona amine base organocatalyst gave excellent results.3(a), 7 Thus, 6′-hydroxy Cinchona alkaloid derivatives have been employed recently in the Michael reaction of 2-tert-butoxycarbonyl-1-indanone, giving excellent enantioselectivity.10

Cinchona alkaloid-derived ammonium salts are nowadays very popular mainly as chiral phase-transfer organocatalysts in enantioselective synthesis,11 and have also been used in different Michael addition reactions.3(a), 7 However, their particular use in the enantioselective Michael reaction of cyclic β-keto esters has been scarce and not very successful; the use of quinine and cinchonidine-derived ammonium salts 1 and 2, respectively, has been reported to afford enantioselections in the range of 4–28%.9(b), 12 The best results using chiral ammonium salts have been obtained using unnatural and less-directly prepared binaphthyl-derived quats.13

Although some of the above-mentioned organocatalytic procedures are quite effective, a serious problem which always arises when scaling-up a synthetic procedure is the recovery of the catalyst. Our research group has been working in recent years on the use of unsupported14, 15 and supported16 recoverable Cinchona alkaloid-derived ammonium salts in organocatalyzed enantioselective reactions. Among them are a series of dimeric anthracenyldimethyl-derived ammonium salts from Cinchona alkaloids, such as the cinchonidine-derivative 3a, which have been used as recoverable chiral phase-transfer catalysts in the asymmetric alkylation14, 16 and Michael addition15 reactions of glycinate Schiff bases for the enantioselective synthesis of α-amino acids, as well as in enantioselective cyanoformylation reactions.17 Herein, we report the use of these types of dimeric ammonium salts as recoverable organocatalysts in the conjugate addition of cyclic β-keto esters to Michael acceptors for the enantioselective generation of quaternary centers.

Section snippets

Results and discussion

To test the suitability of our previously employed cinchonidine-derived ammonium salt 3a14, 15 in this process, we performed a reaction between 2-tert-butoxycarbonyl-1-indanone 4a18 and methyl vinyl ketone (3 equiv) as the typical model reaction (Table 1). We used diisopropylethylamine as the base (30 mol %) and dichloromethane as the solvent, at room temperature. Under these conditions using cinchonidine-derived salt 3a,14, 15 the corresponding Michael adduct 5aa was obtained as the (S

Conclusion

In conclusion, quaternary stereocenters have been generated enantioselectively by the Michael reaction of cyclic β-keto esters, such as 2-alkoxycarbonyl-1-indanones, and electron-deficient olefins organocatalyzed by new chiral dimeric Cinchona-derived ammonium salts. The corresponding dimeric quinine-derived salt gave a higher enantioselection than its 6′-demethoxylated analogue from cinchonidine, whereas the dimeric quinidine-derived ammonium salt gave a better and opposite enantioselection

Acknowledgments

We thank the financial support from the Spanish Ministerio de Educación y Ciencia (Projects CTQ2007-62771/BQU and Consolider Ingenio 2010, CSD2007-00006), the Generalitat Valenciana (Prometeo/2009/039), and the University of Alicante. S. T. thanks the Generalitat Valenciana for a pre-doctoral fellowship.

References (24)

  • A. Berkessel et al.

    Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

    (2005)
  • R. Chinchilla et al.

    Tetrahedron: Asymmetry

    (2002)
    R. Chinchilla et al.

    Tetrahedron: Asymmetry

    (2004)
  • T.A. Moss et al.

    J. Am. Chem. Soc.

    (2008)
  • P.G. Cozzi et al.

    Eur. J. Org. Chem.

    (2007)
  • P. Perlmutter

    Conjugate Addition in Organic Synthesis

    (1992)
  • S.C. Jha et al.

    Arkivoc

    (2002)
    J. Christoffers et al.

    Angew. Chem., Int. Ed.

    (2003)
  • M. Nakajima et al.

    Tetrahedron

    (2003)
    G. Kumaraswamy et al.

    Adv. Synth. Catal.

    (2005)
    Y. Hamashima et al.

    Adv. Synth. Catal.

    (2005)
    C. Ogawa et al.

    Chem. Asian J.

    (2006)
  • P.I. Dalko et al.

    Angew. Chem., Int. Ed.

    (2001)
    J. Seayad et al.

    Org. Biomol. Chem.

    (2005)
    P.I. Dalko et al.

    Angew. Chem., Int. Ed.

    (2004)
  • D. Almasi et al.

    Tetrahedron: Asymmetry

    (2007)
    J.L. Vicario et al.

    Synthesis

    (2007)
    S.B. Tsogoeva

    Eur. J. Org. Chem.

    (2007)
  • B. Långström et al.

    Acta Chem. Scand.

    (1973)
  • H. Wynberg et al.

    Tetrahedron Lett.

    (1975)
    K. Hermann et al.

    J. Org. Chem.

    (1979)
    A. Sera et al.

    J. Org. Chem.

    (1988)
    G. Szöllösi et al.

    Chirality

    (2001)
  • F. Wu et al.

    Angew. Chem., Int. Ed.

    (2006)
    F. Wu et al.

    Angew. Chem., Int. Ed.

    (2006)
    C.L. Rigby et al.

    Chem. Commun.

    (2008)
  • Cited by (25)

    • Asymmetric Michael addition of malonates to unsaturated ketones catalyzed by rare earth metal complexes bearing phenoxy functionalized chiral diphenylprolinolate ligands

      2016, Tetrahedron Asymmetry
      Citation Excerpt :

      Hence, more attention was paid to develop new and high efficient chiral rare earth metal catalysts continuously. Our group previously developed a set of heterobimetallic rare earth metal–lithium complexes bearing a chiral phenoxy-functionalized diphenylprolinolate ligand and successfully introduced them in the asymmetric epoxidation of α,β-unsaturated ketones.14 Recently, we addressed the further issue of asymmetric epoxidation of α,β-unsaturated ketones catalyzed by rare-earth amides [(Me3Si)2N]3RE(μ-Cl)Li(THF)3 with a series of phenoxy-functionalized chiral prolinols.15

    • Asymmetric Organocatalysis for the Construction of Quaternary Carbon Stereogenic Centers

      2013, New and Future Developments in Catalysis: Catalysis for Remediation and Environmental Concerns
    • Recent applications of Cinchona alkaloids and their derivatives as catalysts in metal-free asymmetric synthesis

      2011, Tetrahedron
      Citation Excerpt :

      The most effective catalysts for the reaction were silyl-substituted dihydrocinchonines 107a or 107b giving yields of 40–63% with ees of 40–56% (Scheme 40). Although the enantioselectivities of the reactions were only moderate, the products 109–111 have proved to be difficult to access by other methods.71 An enantioselective synthesis of α,α-disubstituted cyanosulfones has been developed by Ruano and co-workers.72

    View all citing articles on Scopus
    View full text