Highly Regio- and Enantioselective Reduction of 3,5-Dioxocarboxylates
Michael Wolberg Dipl.-Chem.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorWerner Hummel Dr.
Institut für Enzymtechnologie Heinrich-Heine-Universität Düsseldorf 40225 Düsseldorf (Germany)
Search for more papers by this authorChristian Wandrey Prof. Dr.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorMichael Müller Dr.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorMichael Wolberg Dipl.-Chem.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorWerner Hummel Dr.
Institut für Enzymtechnologie Heinrich-Heine-Universität Düsseldorf 40225 Düsseldorf (Germany)
Search for more papers by this authorChristian Wandrey Prof. Dr.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorMichael Müller Dr.
Institut für Biotechnologie 2 Forschungszentrum Jülich GmbH 52425 Jülich (Germany) Fax (+49) 2461-61-3870
Search for more papers by this authorThis work was supported by the Deutsche Forschungsgemeinschaft in the scope of SFB 380. We thank Silke Bode for skillful technical support.
Abstract
Alkoholdehydrogenase aus Lactobacillus brevis (LBADH) katalysiert hochselektiv die Reduktion von 3,5-Dioxocarboxylaten in Position C-5 (siehe Schema). In Anlehnung an die natürlichen Transformationen des Polyketidstoffwechsels wurde ein chemoenzymatischer Zugang zu nahezu enantiomerenreinen 3,5-Dihydroxycarboxylaten entwickelt. Der entscheidende enzymatische Schritt kann in einem präparativ attraktiven Maßstab durchgeführt werden.
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- 12 DAICEL Chiracel OB (plus guard column), isohexane/2-propanol (80/20 v/v), 1.0 mL min−1, 25 °C, 215 nm (UV-DAD). Retention times: (S)-3: 17.6, (R)-3: 23.8, (R)-6: 20.9, (S)-6: 24.3 min. In the case of the (S)-lactone derived from the enzymatic product 5, none of the R enantiomer could be detected.
- 13 Prepared by acylation of the lithium bis-enolate of tert-butyl acetoacetate with methyl chloroacetate (THF, −60 °C, 70 % yield of isolated product after column chromatography).
- 14
Prepared according to ref. [7g], starting from commercially available ethyl (S)-4-chloro-3-hydroxybutyrate (Aldrich, 97 % ee). [α]
=−23.0 (c=1.5, CHCl3), 97 % ee; enzymatic product 5: [α]
=−24.9 (c=1.4, CHCl3), >99.5 % ee; 1H NMR (300 MHz, CDCl3, 20 °C, only signals of the keto form are given): δ=4.31 (m, 1 H; CHOH), 3.62 (dd, J=11.2, 5.1 Hz, 1 H; H-6), 3.57 (dd, J=11.2, 5.0 Hz, 1 H; H-6), 3.41 (s, 2 H; H-2), 3.10 (br s, 1 H; OH), 2.90 (dd, J=17.5, 5.0 Hz, 1 H; H-4), 2.83 (dd, J=17.5, 7.3 Hz, 1 H; H-4), 1.47 (s, 9 H, C(CH3)3); 13C NMR (75.5 MHz, CDCl3, 20 °C, only signals of the keto form are given): δ=28.1 (C(CH3)3), 46.6, 48.4, 51.3 (C-2, C-4, C-6), 67.6 (C-5), 82.7 (C(CH3)3), 166.2 (C-1), 202.9 (C-3).
- 15 The diastereomeric excess was determined by GC after formation of the corresponding acetonides (2,2-dimethoxypropane, cat. camphorsulfonic acid).
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