10
S.C. Pan, B. List
2.3
Enamine Catalysis of Nucleophilic Substitution Reactions
The first example of an asymmetric enamine catalytic nucleophilic substitution was a reaction that may have been considered impossible only
a few years ago. We found that proline and certain derivatives such as
α-methyl proline efficiently catalyze the asymmetric α-alkylation of
aldehydes (Vignola and List 2004). Catalytic α-alkylation reactions of
substrates other than glycine derivatives have been rare and that of aldehydes has been completely unknown before. In our process we could cyclize 6-halo aldehydes to give cyclopentane carbaldehydes in excellent
yields and ees (Scheme 7; Eq. 11). Other important and remarkably useful enamine catalytic nucleophilic substitution reactions have been developed subsequently and include enantioselective α-chlorinations
(Brochu et al. 2004; Halland et al. 2004), α-fluorinations (Enders and
Hüttl 2005; Marigo et al. 2005c; Steiner et al. 2005; Beeson and MacMillan 2005), α-brominations (Bertelsen et al. 2005), α-iodinations, and
α-sulfenylations (Marigo et al. 2005a; Eqs. 12–16).
Once again, most of these reactions have never been realized before
using preformed enamines or any other methodology but lead to highly
valuable products of potential industrial relevance.
2.4
The Proline-Catalyzed Asymmetric Mannich Reactions
The catalytic asymmetric Mannich reaction is arguably the most useful
approach to chiral β-amino carbonyl compounds. In the year 2000, we
discovered a proline-catalyzed version of this powerful reaction (List
2000). Originally, ketones, aldehydes, and an aniline as the amine component were used in a catalytic asymmetric three-component reaction
(Scheme 8; Eq. 17). After our report, proline-catalyzed Mannich reactions with aldehydes as the donor were also developed (Córdova et al.
2002c; Hayashi et al. 2003b; Eqs. 18,19). Despite its frequent use, both
in an academic as well as an industrial context, the main limitation
of the proline-catalyzed Mannich reaction has been the requirement to
use anilines as the amine component. Although optically enriched panisidylamines are of potential utility in asymmetric synthesis, facile
and efficient removal of the N-protecting group to yield the unfunctionalized amine is required. Generally, the removal of the most commonly
S.C. Pan, B. List
2.3
Enamine Catalysis of Nucleophilic Substitution Reactions
The first example of an asymmetric enamine catalytic nucleophilic substitution was a reaction that may have been considered impossible only
a few years ago. We found that proline and certain derivatives such as
α-methyl proline efficiently catalyze the asymmetric α-alkylation of
aldehydes (Vignola and List 2004). Catalytic α-alkylation reactions of
substrates other than glycine derivatives have been rare and that of aldehydes has been completely unknown before. In our process we could cyclize 6-halo aldehydes to give cyclopentane carbaldehydes in excellent
yields and ees (Scheme 7; Eq. 11). Other important and remarkably useful enamine catalytic nucleophilic substitution reactions have been developed subsequently and include enantioselective α-chlorinations
(Brochu et al. 2004; Halland et al. 2004), α-fluorinations (Enders and
Hüttl 2005; Marigo et al. 2005c; Steiner et al. 2005; Beeson and MacMillan 2005), α-brominations (Bertelsen et al. 2005), α-iodinations, and
α-sulfenylations (Marigo et al. 2005a; Eqs. 12–16).
Once again, most of these reactions have never been realized before
using preformed enamines or any other methodology but lead to highly
valuable products of potential industrial relevance.
2.4
The Proline-Catalyzed Asymmetric Mannich Reactions
The catalytic asymmetric Mannich reaction is arguably the most useful
approach to chiral β-amino carbonyl compounds. In the year 2000, we
discovered a proline-catalyzed version of this powerful reaction (List
2000). Originally, ketones, aldehydes, and an aniline as the amine component were used in a catalytic asymmetric three-component reaction
(Scheme 8; Eq. 17). After our report, proline-catalyzed Mannich reactions with aldehydes as the donor were also developed (Córdova et al.
2002c; Hayashi et al. 2003b; Eqs. 18,19). Despite its frequent use, both
in an academic as well as an industrial context, the main limitation
of the proline-catalyzed Mannich reaction has been the requirement to
use anilines as the amine component. Although optically enriched panisidylamines are of potential utility in asymmetric synthesis, facile
and efficient removal of the N-protecting group to yield the unfunctionalized amine is required. Generally, the removal of the most commonly