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@PHDTHESIS{Wolberg:33330,
      author       = {Wolberg, Michael},
      title        = {{C}hemoenzymatische {S}ynthese optisch aktiver
                      $\beta,\delta$-{D}ihydroxyester},
      volume       = {3988},
      issn         = {0944-2952},
      school       = {Univ. Oldenburg},
      type         = {Dr. (Univ.)},
      address      = {Jülich},
      publisher    = {Forschungszentrum Jülich GmbH Zenralbibliothek, Verlag},
      reportid     = {PreJuSER-33330, Juel-3988},
      series       = {Berichte des Forschungszentrums Jülich},
      pages        = {138 p.},
      year         = {2002},
      note         = {Record converted from VDB: 12.11.2012; Oldenburg, Univ.,
                      Diss., 2001},
      abstract     = {A new access to optically active $\beta, \delta$-dihydroxy
                      esters and $\delta$-hydroxy-$\beta$-keto esters is
                      presented. These compunds are valuable intermediates for the
                      synthesis of important natural products and pharmaceuticals,
                      e. g. HMG-CoA reductase inhibitors of the mevinic acid type.
                      The synthesis strategy is based on an unprecedented highly
                      regio- and enantioselective biocatalytic reduction of
                      achiral $\beta, \delta$-diketo esters. In a screening, two
                      enantiocomplementary biocatalysts were found to be
                      particularly suitable for this purpose. Thus, the $\beta,
                      \delta$-diketo ester $\textit{tert}$-butyl
                      6-chloro-3,5-dioxohexanoate was reduced by NADP(H)-dependent
                      alcohol dehydrogenase of $\textit{Lactobacillus brevis}$ to
                      afford enantiomerically pure $\delta$-hydroxy-$\beta$-keto
                      ester $\textit{tert}$-butyl
                      (S)-6-chloro-5-hydroxy-3-oxohexanoate in a 72-84 \% isolated
                      yield (>99.5\% ee). The enzyme is readily available in the
                      form of a crude cell extract from a recombinant $\textit{E.
                      coli}$ strain (recLBADH). A scale-up of the one-step
                      substrate synthesis (140 g scale) and of the enzymatic
                      reduction (70 g scale, substrate-coupled NADPH-regeneration)
                      was established. The enantiomeric
                      $\delta$-hydroxy-$\beta$-keto ester $\textit{tert}$-butyl
                      (R)-6-chloro-5-hydroxy-3-oxohexanoate was obtained by
                      reduction of $\textit{tert}$-butyl
                      6-chloro-3,5-dioxohexanoate with baker's yeast
                      ($\textit{Saccharomyces cerevisiae}$). A detailed
                      investigation of the reaction parameters of this whole-cell
                      transformation led to the application of a biphasic system
                      by which the enantiomeric excess could be raised from 48\%
                      ee to 94\% ee (50\% isolated yield). The $\beta$-keto group
                      of both enantiomers thus obtained was reduced by
                      $\textit{syn}$- and $\textit{anti}$-selective borohydride
                      reductions. Combination of the reduction methods afforded
                      all four stereoisomers of the crystalline $\beta,
                      \delta$-dihydroxy ester $\textit{tert}$-butyl
                      6-chloro-3,5-dihydroxyhexanoate (>99\% ee and $\textit{dr}$
                      > 200:1 each, 52-70\% isolated yield). Alternatively, the
                      $\textit{syn}$- (3R,5S)-isomer of this known building block
                      was obtained in one step and with high stereoisomeric purity
                      by reduction of $\textit{tert}$-butyl
                      6-chloro-3,5-dioxohexanoate with whole cells of
                      $\textit{Lactobacillus kefir}$. An iodide and an epoxide
                      suitable for C-C-bond formation at C-6 were derived from
                      $\textit{tert}$-butyl
                      $\textit{syn}$-(3R,5S)-6-chloro-3,5-dihydroxyhexanoate.
                      recLBADH accepts a variety of $\beta, \delta$-diketo esters
                      as was determined in a photometric assay. The $\beta,
                      \delta$-diketo esters $\textit{tert}$-butyl
                      3,5-dioxohexanoate and $\textit{tert}$-butyl
                      3,5-dioxoheptanoate were reduced an a 1-10 mmol scale to
                      afford the corresponding (R)-$\delta$-hydroxy-$beta$-keto
                      esters with 99.4\% ee and 98.1\% ee, respectively (61-77 \%
                      isolated yield). The reduction ofthe branched $\beta,
                      \delta$-diketo ester $\textit{tert}$-butyl
                      $\textit{rac}$-4-methyl-3,5-dioxohexanoate proceeds via a
                      dynamic kinetic resolution which resulted in a 66\% isolated
                      yield of the corresponding
                      $\textit{syn}$-(4S,5R)-$\delta$-hydroxy-$beta$-keto ester
                      (99.2\% ee, dr = 35:1). To underline the applicability of
                      the virtually enantiopure enzymatic products, they were used
                      as starting materials for several new natural product
                      syntheses. Furthermore, a convenient process for the
                      large-scale separation of noncrystallising diastereomeric
                      $\textit{syn}$- and $\textit{anti}$- 1,3-diols was
                      developed. The crucial step of this new method is a
                      diastereomer-differentiating hydrolysis of the respective
                      acetonides.},
      cin          = {IBT-2},
      cid          = {I:(DE-Juel1)VDB56},
      pnm          = {Verfahrenstechnik zur mikrobiellen Gewinnung von
                      Primärmetaboliten},
      pid          = {G:(DE-Juel1)FUEK93},
      typ          = {PUB:(DE-HGF)11 / PUB:(DE-HGF)3},
      url          = {https://juser.fz-juelich.de/record/33330},
}