Asymmetric synthesis of long chain β-hydroxy fatty acid methyl esters as new elastase inhibitors

Herein, β-hydroxy methyl esters with an even carbon chain length of 12–20 1b–5b were synthesized by three different asymmetric reduction methods I, II III from their corresponding β-keto methyl esters 1a–5a with the aim of determining their elastase activities. In method I, chiral catalyst A was prepared from chiral ligand (R)-binaphthol 1, while in method II, chiral catalyst B was synthesized from (2R,3R)-diisopropyl tartrate 2. Chiral catalyst B has not previously been used in asymmetric borane reductions or in the asymmetric synthesis of chiral β-hydroxy methyl esters. In method III, an asymmetric reduction was catalysed by (R)-Me-CBS oxazaborolidine 3. Hydride transfer was carried out in all of these methods by BH3·SMe2. Chiral hydroxy methyl esters with an (S)-configuration were synthesized by method I and with an (R)-configuration via methods II and III. The chiral hydroxy methyl esters obtained were analysed by chiral HPLC for their ee % values. Methods I, II and III were applied to long chain β-keto methyl esters for the first time. The reduction methods I, II and III were examined in terms of reaction yield and enantiomeric excess according to carbon chain length and the variable ratio of chiral catalysts to β-keto methyl ester. The highest enantiomeric excess of 90% ee was found in method III for 12 and 14 carbon numbers.

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3-Hydroxy dodecanoic acid methylesterC13H26O3Ee 90%[α]D25=-15.7 (c 1, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

3-Hydroxy tetradecanoic acid methylesterC15H30O3Ee 90%[α]D25=-16.0 (c 1, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

3-Hydroxy hexadecanoic acid methylesterC17H34O3Ee 85%[α]D25=-15.2 (c 1, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

3-Hydroxy octadecanoic acid methylesterC19H38O3Ee 75%[α]D25=-12.9 (c 1, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

3-Hydroxy eicosanoic acid methylesterC21H42O3Ee 75%[α]D25=-12.8 (c 1, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)