Biomimetic Organocatalytic C–C-Bond Formations
69
vert a furan moiety into the corresponding carboxylic acid group (Enders and Vrettou 2006). Thus, starting from 4 and the known imine 50
(Wenzel and Jacobsen 2002) we were able to access the corresponding
Mannich base 51 in 85% yield and with excellent selectivity (>96% de
as judged by
1 H NMR, 92% ee as determined by HPLC). Following optimization of the reaction, (S)-proline was found to be the optimum catalyst at room temperature and trifluoroethanol the most suitable solvent.
The desired syn-configuration of the Mannich base was determined by
NOE experiments.
Diastereoselective reduction of the ketone 51 using l-selectride afforded the desired syn-isomer 52 in 90% yield as a single diastereoisomer as judged by
1 H-NMR and NOE experiments. With the intermediate amino alcohol 52 at hand, the corresponding carboxylic acid 53
was obtained by ozonolysis at –78°C in MeOH. Subsequent deprotection with aqueous trifluoroacetic acid afforded the free (+)-polyoxamic
acid (49) in a good yield of 60% over two steps. Thus, it was possible
to synthesize 49 in four steps from the known imine 50 in 46% overall
yield as a single diastereoisomer, as judged by
1 H-NMR, and with 92%
ee (Scheme 13) (Enders and Vrettou 2006).
2.2
Proline-Catalyzed Asymmetric Synthesis
of Ulosonic Acid Precursors
The forthcoming advent of a post-antibiotic era has driven much research towards developing new tools to fight the emergence of devastating diseases and has prompted much effort to identify the biological functions of carbohydrates in physiological processes (Varki 1993;
Dwek 1996; Sears and Wong 1998). Naturally occurring 2-keto-3-deoxy-nonulosonic acids such as Neu5Ac (54) and KDN (55), generally
known as sialic acids, have been significantly implicated in the pathogenesis of microorganisms and various disease states (Unger 1981;
Schauer 1982; Schauer R 1982; Alexander and Rietschel 1999; Angata and Varki 2002; Kiefel and von Itzstein 2002; Varki 1992; Troy
1992; and references therein). Likewise, pivotal biological roles are
constantly ascribed to widely diffuse higher 3-deoxy-2-ulosonic acids.
For example, 3-deoxy-d-manno-2-octulosonic acid (KDO, 56), present
in the outer membrane lipopolysaccharide (LPS) of Gram-negative bac-
69
vert a furan moiety into the corresponding carboxylic acid group (Enders and Vrettou 2006). Thus, starting from 4 and the known imine 50
(Wenzel and Jacobsen 2002) we were able to access the corresponding
Mannich base 51 in 85% yield and with excellent selectivity (>96% de
as judged by
1 H NMR, 92% ee as determined by HPLC). Following optimization of the reaction, (S)-proline was found to be the optimum catalyst at room temperature and trifluoroethanol the most suitable solvent.
The desired syn-configuration of the Mannich base was determined by
NOE experiments.
Diastereoselective reduction of the ketone 51 using l-selectride afforded the desired syn-isomer 52 in 90% yield as a single diastereoisomer as judged by
1 H-NMR and NOE experiments. With the intermediate amino alcohol 52 at hand, the corresponding carboxylic acid 53
was obtained by ozonolysis at –78°C in MeOH. Subsequent deprotection with aqueous trifluoroacetic acid afforded the free (+)-polyoxamic
acid (49) in a good yield of 60% over two steps. Thus, it was possible
to synthesize 49 in four steps from the known imine 50 in 46% overall
yield as a single diastereoisomer, as judged by
1 H-NMR, and with 92%
ee (Scheme 13) (Enders and Vrettou 2006).
2.2
Proline-Catalyzed Asymmetric Synthesis
of Ulosonic Acid Precursors
The forthcoming advent of a post-antibiotic era has driven much research towards developing new tools to fight the emergence of devastating diseases and has prompted much effort to identify the biological functions of carbohydrates in physiological processes (Varki 1993;
Dwek 1996; Sears and Wong 1998). Naturally occurring 2-keto-3-deoxy-nonulosonic acids such as Neu5Ac (54) and KDN (55), generally
known as sialic acids, have been significantly implicated in the pathogenesis of microorganisms and various disease states (Unger 1981;
Schauer 1982; Schauer R 1982; Alexander and Rietschel 1999; Angata and Varki 2002; Kiefel and von Itzstein 2002; Varki 1992; Troy
1992; and references therein). Likewise, pivotal biological roles are
constantly ascribed to widely diffuse higher 3-deoxy-2-ulosonic acids.
For example, 3-deoxy-d-manno-2-octulosonic acid (KDO, 56), present
in the outer membrane lipopolysaccharide (LPS) of Gram-negative bac-