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M. Rueping, E. Sugiono
9
Development of the First Brønsted Acid Assisted
Enantioselective Brønsted Acid Catalyzed Direct
Mannich Reaction
Mannich reactions represent one of the most important methods for
the preparation of natural products and biologically active nitrogencontaining compounds, including β-amino acids, aldehydes and ketones
(for reviews: Kobayashi and Ishitani 1999; Kleinmann 1991; Arend
et al. 1998; Arend 1999; Cordova 2004). Consequently, various enantioselective variants of the Mannich reaction have been reported. However, most of the protocols focused on reactions of aldimines with preformed enolate equivalents (Fujieda et al. 1997; Ishitani et al. 1997;
Kobayashi et al. 1998, 2002; Ishitani et al. 2000; Hagiwara et al. 1998;
Fujii et al. 1999; Ferraris et al. 1998a,b, 1999, 2002). Hence, the development of a direct catalytic enantioselective Mannich reaction of
prior unmodified carbonyl donors would be desirable, as it prevents the
necessity of enolate preformation, isolation and purification (Yamasaki
et al. 1999a,b; Matsunaga et al. 2003; Trost and Terrell 2003; Juhl et al.
2001; Bernardi et al. 2003; Hamashima et al. 2005).
Based on our previously developed Brønsted acid catalyzed reactions
(for selected references: see Rueping et al. 2005a,b, 2006a–e, 2007a),
we assumed that a direct reaction of an aromatic ketone 25 and aldimine
26 should lead to the desired β-amino ketone 27 (Fig. 9).
Fig. 9. Catalytic cycle for direct Brønsted acid catalyzed Mannich reaction
M. Rueping, E. Sugiono
9
Development of the First Brønsted Acid Assisted
Enantioselective Brønsted Acid Catalyzed Direct
Mannich Reaction
Mannich reactions represent one of the most important methods for
the preparation of natural products and biologically active nitrogencontaining compounds, including β-amino acids, aldehydes and ketones
(for reviews: Kobayashi and Ishitani 1999; Kleinmann 1991; Arend
et al. 1998; Arend 1999; Cordova 2004). Consequently, various enantioselective variants of the Mannich reaction have been reported. However, most of the protocols focused on reactions of aldimines with preformed enolate equivalents (Fujieda et al. 1997; Ishitani et al. 1997;
Kobayashi et al. 1998, 2002; Ishitani et al. 2000; Hagiwara et al. 1998;
Fujii et al. 1999; Ferraris et al. 1998a,b, 1999, 2002). Hence, the development of a direct catalytic enantioselective Mannich reaction of
prior unmodified carbonyl donors would be desirable, as it prevents the
necessity of enolate preformation, isolation and purification (Yamasaki
et al. 1999a,b; Matsunaga et al. 2003; Trost and Terrell 2003; Juhl et al.
2001; Bernardi et al. 2003; Hamashima et al. 2005).
Based on our previously developed Brønsted acid catalyzed reactions
(for selected references: see Rueping et al. 2005a,b, 2006a–e, 2007a),
we assumed that a direct reaction of an aromatic ketone 25 and aldimine
26 should lead to the desired β-amino ketone 27 (Fig. 9).
Fig. 9. Catalytic cycle for direct Brønsted acid catalyzed Mannich reaction